Inorganic arsenic-induced intramitochondrial granules in mouse urothelium.
Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in the drinking water is carcinogenic to the urinary bladder of humans. Recently, models have been developed involving transplacental administration of inorganic arsenic and subsequent administration of another substance that produces a low incidence of urogenital neoplasms. Administration of arsenite or arsenate in the diet or drinking water to five-to eight-week-old mice or rats rapidly induces urothelial cytotoxicity and regenerative hyperplasia. In mice administered arsenite, we observed eosinophilic intracytoplasmic granules present in the urothelial cells. These granules were not present in urothelial cells of untreated mice or in treated or untreated rats. By transmission electron microscopy, the granules were located within the mitochondrial matrix, that is, mitochondrial inclusions. Arsenic, primarily as arsenite, was present in partially purified mitochondria containing these granules. Cells containing the granules were not usually associated with degenerative changes. Lack of these granules in rats suggests that they are not necessary for inorganic arsenic-induced urothelial cytotoxicity or hyperplasia. These granules have also been observed with exposures to other metals in other tissues and other species, suggesting that they represent a protective mechanism against metal-induced toxicity.


Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids.
Antibiotics are widely used in acute exacerbations of COPD (AE-COPD), but their additional benefit to a therapeutic regimen that already includes steroids is uncertain. We evaluated the association between antibiotic therapy and outcomes among a large cohort of patients treated with steroids who were hospitalized with AE-COPD and compared the effectiveness of three commonly used antibiotic regimens. We conducted a retrospective cohort study of patients aged 40 years hospitalized for AE-COPD from January 1, 2006, through December 1, 2007, at 410 acute care hospitals throughout the United States. Of the 53,900 patients who met the inclusion criteria, 85% were treated with antibiotics in the first 2 hospital days; 50% were treated with a quinolone, 22% with macrolides plus cephalosporin, and 9% with macrolide monotherapy. Compared with patients not treated with antibiotics, those who received antibiotics had lower mortality (1% vs 1.8%, P < .0001). In multivariable analysis, receipt of antibiotics was associated with a 40% reduction in the risk of in-hospital mortality (RR, 0.60; 95% CI, 0.50-0.73) and a 13% reduction in the risk of 30-day readmission for COPD (RR, 0.87; 95% CI, 0.79-0.96). The risk of late ventilation and readmission for Clostridium difficile colitis was not significantly different between the two groups. We found little difference in the outcomes associated with three common antibiotic treatment choices. Our results suggest that the addition of antibiotics to a regimen that includes steroids may have a beneficial effect on short-term outcomes for patients hospitalized with AE-COPD.


Functional capacity and treatment data from a community based study of patients with rheumatoid arthritis.
A community based study of rheumatoid arthritis was undertaken to determine patient characteristics and the patterns of treatment. Three hundred and eighty subjects were visited in their homes throughout Tasmania (pop. 430 000) by a research team. The median age of the sample was 60 years (interquartile range (IR) 49-69), with a female predominance of 2.65 to 1. The average onset age was 41 years (IR 30-53). Prescribing data indicated that polypharmacy was not common in the community, and that the use of slow acting antirheumatic drugs (SAARDs) and oral corticosteroids was not widespread. At the time of the study 26% of subjects were assayed fully functional--class I of the American Rheumatism Association's (ARA) functional classifications. The functional capacity data provided evidence that the spectrum of rheumatoid arthritis found in the community differed from that found in specialist rheumatology clinics.


Deviations from Hardy-Weinberg proportions: sampling variances and use in estimation of inbreeding coefficients.
An analysis is made of the distribution of deviations from Hardy-Weinberg proportions with k alleles and of estimates of inbreeding coefficients (f) obtained from these deviations. If f is small, the best estimate of f in large samples is shown to be 2 sigma i(Tii/Ni)/(k - 1), where Tii is an unbiased measure of the excess of the ith homozygote and Ni the number of the ith allele in the sample [frequency = Ni/(2N)]. No extra information is obtained from the Tij, where these are departures of numbers of heterozygotes from expectation. Alternatively, the best estimator can be computed from the Tij, ignoring the Tii. Also (1) the variance of the estimate of f equals 1/(N(k - 1] when all individuals in the sample are unrelated, and the test for f = 0 with 1 d.f. is given by the ratio of the estimate to its standard error; (2) the variance is reduced if some alleles are rare; and (3) if the sample consists of full-sib families of size n, the variance is increased by a proportion (n - 1)/4 but is not increased by a half-sib relationship. If f is not small, the structure of the population is of critical importance. (1) If the inbreeding is due to a proportion of inbred matings in an otherwise random-breeding population, f as determined from homozygote excess is the same for all genes and expressions are given for its sampling variance. (2) If the homozygote excess is due to population admixture, f is not the same for all genes. The above estimator is probably close to the best for all f values.


Quantitative proteomic discovery of dynamic epigenome changes that control human cytomegalovirus (HCMV) infection.
This work represents the first comprehensive quantitative analysis of global histone post-translational modifications (PTMs) from a virus infection, namely human cytomegalovirus (HCMV) infection. We used a nanoLC-MS/MS platform to identify and quantify the dynamic histone H3 and H4 PTMs expressed during HCMV replication in primary fibroblasts. Specifically, we examined the changes in histone PTMs over a 96 h time course to sample the immediate early (IE), early (E), and late (L) stages of viral infection. Several changes in histone H3 and H4 PTMs were observed, including a marked increase in H3K79me2 and H3K27me3K36me2, and a decrease in H4K16ac, highlighting likely epigenetic strategies of transcriptional activation and silencing during HCMV lytic infection. Heavy methyl-SILAC (hm-SILAC) was used to further confirm the histone methylation flux (especially for H3K79) during HCMV infection. We evaluated DOT1L (the H3K79 methyltransferase) mRNA levels in mock and HCMV-infected cells over a 96 h time course, and observed a significant increase in this methyltransferase as early as 24 hpi showing that viral infection up-regulates DOT1L expression, which drives H3K79me2. We then used shRNA to create a DOT1L knockdown cell population, and found that HCMV infection of the knockdown cells resulted in a 10-fold growth defect when compared with infected control cells not subjected to knockdown. This work documents multiple histone PTMs that occur in response to HCMV infection of fibroblasts, and provides a framework for evaluation of the role of epigenetic modifications in the virus-host interaction.


Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males.
Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.).


Gender differences in paediatric patients of the swiss inflammatory bowel disease cohort study.
Gender differences in paediatric patients with inflammatory bowel disease (IBD) are frequently reported as a secondary outcome and the results are divergent. To assess gender differences by analysing data collected within the Swiss IBD cohort study database since 2008, related to children with IBD, using the Montreal classification for a systematic approach. Data on gender, age, anthropometrics, disease location at diagnosis, disease behaviour, and therapy of 196 patients, 105 with Crohn's disease (CD) and 91 with ulcerative or indeterminate colitis (UC/IC) were retrieved and analysed. THE CRUDE GENDER RATIO (MALE : female) of patients with CD diagnosed at <10 years of age was 2.57, the adjusted ratio was 2.42, and in patients with UC/IC it was 0.68 and 0.64 respectively. The non-adjusted gender ratio of patients diagnosed at ≥10 years was 1.58 for CD and 0.88 for UC/IC. Boys with UC/IC diagnosed <10 years of age had a longer diagnostic delay, and in girls diagnosed with UC/IC >10 years a more important use of azathioprine was observed. No other gender difference was found after analysis of age, disease location and behaviour at diagnosis, duration of disease, familial occurrence of IBD, prevalence of extra-intestinal manifestations, complications, and requirement for surgery. CD in children <10 years affects predominantly boys with a sex ratio of 2.57; the impact of sex-hormones on the development of CD in pre-pubertal male patients should be investigated.


Protective effects of electroacupuncture at LR3 on cardiac hypertrophy and apoptosis in hypertensive rats.
To investigate the effect of electroacupuncture (EA) at LR3 on blood pressure (BP) and cardiovascular remodelling and hypertrophy in male spontaneously hypertensive rats (SHRs). Healthy Wistar-Kyoto rats were used as normotensive controls (control group, n=9). SHRs either remained untreated (SHR group, n=9) or received EA treatment at LR3 (SHR+LR3 group, n=9) or a nearby non-acupuncture point (SHR+sham group, n=9) for 3 weeks. BP was measured on day 3 and day 19. Samples of left ventricle were stained with haematoxylin and eosin or subjected to terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labelling (TUNEL) to assess histology and apoptosis, respectively (n=3 per group). Western blotting was used to determine the relative expression of antioxidants and molecular markers of detoxification capacity, cardiac hypertrophy, and apoptosis (n=5 per group). By day 3, the systolic BP, mean BP, and diastolic BP in the untreated SHRs increased from 169.5±14, 131.6±14, and 112.2±15 mm Hg (at baseline) to 179.6±1, 137.6±4, and 118.7±5 mm Hg, respectively (p<0.001 vs control group). BP in the SHR+LR3 rats was approximately 15 mm Hg lower than the SHR and SHR+sham groups (p<0.05). SHRs also exhibited cardiac hypertrophy (evident from histological and Western blot analyses). However, SHR+LR3 rats showed significant reductions in markers of cardiac hypertrophy and apoptosis, as well as elevated expression of antioxidant enzymes including superoxide dismutase-1 (SOD1). EA at LR3 reduced BP and had positive effects on markers of cardiac apoptosis and hypertrophy in a rat model of hypertension. Thus, EA is a potentially promising intervention to treat cardiovascular remodelling secondary to hypertension.


Imaging in gynecological disease (15): clinical and ultrasound characteristics of uterine sarcoma.
To describe the clinical and ultrasound characteristics of uterine sarcomas. This was a retrospective multicenter study. From the databases of 13 ultrasound centers, we identified patients with a histological diagnosis of uterine sarcoma with available ultrasound reports and ultrasound images who had undergone preoperative ultrasound examination between 1996 and 2016. As the first step, each author collected information from the original ultrasound reports from his/her own center on predefined ultrasound features of the tumors and by reviewing the ultrasound images to identify information on variables not described in the original report. As the second step, 16 ultrasound examiners reviewed the images electronically in a consensus meeting and described them using predetermined terminology. We identified 116 patients with leiomyosarcoma, 48 with endometrial stromal sarcoma and 31 with undifferentiated endometrial sarcoma. Median age of the patients was 56 years (range, 26-86 years). Most patients were symptomatic at diagnosis (164/183 (89.6%)), the most frequent presenting symptom being abnormal vaginal bleeding (91/183 (49.7%)). Patients with endometrial stromal sarcoma were younger than those with leiomyosarcoma and undifferentiated endometrial sarcoma (median age, 46 years vs 57 and 60 years, respectively). According to the assessment by the original ultrasound examiners, the median diameter of the largest tumor was 91 mm (range, 7-321 mm). Visible normal myometrium was reported in 149/195 (76.4%) cases, and 80.0% (156/195) of lesions were solitary. Most sarcomas (155/195 (79.5%)) were solid masses (> 80% solid tissue), and most manifested inhomogeneous echogenicity of the solid tissue (151/195 (77.4%)); one sarcoma was multilocular without solid components. Cystic areas were described in 87/195 (44.6%) tumors and most cyst cavities had irregular walls (67/87 (77.0%)). Internal shadowing was observed in 42/192 (21.9%) sarcomas and fan-shaped shadowing in 4/192 (2.1%). Moderate or rich vascularization was found on color-Doppler examination in 127/187 (67.9%) cases. In 153/195 (78.5%) sarcomas, the original ultrasound examiner suspected malignancy. Though there were some differences, the results of the first and second steps of the analysis were broadly similar. Uterine sarcomas typically appear as solid masses with inhomogeneous echogenicity, sometimes with irregular cystic areas but only very occasionally with fan-shaped shadowing. Most are moderately or very well vascularized. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase.
Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis. Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily. With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase. The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.


A novel phase of beryllium fluoride at high pressure.
A previously unknown thermodynamically stable high-pressure phase of BeF2 has been predicted using the evolutionary algorithm USPEX. This phase occurs in the pressure range 18-27 GPa. Its structure has C2/c space group symmetry and contains 18 atoms in the primitive unit cell. Given the analogy between BeF2 and SiO2, silica phases have been investigated as well, but the new phase has not been observed to be thermodynamically stable for this system. However, it is found to be metastable and to have comparable energy to the known metastable phases of SiO2, suggesting a possibility of its synthesis.


Cell membrane penetration and mitochondrial targeting by platinum-decorated ceria nanoparticles.
In this work we investigate the interaction between endothelial cells and nanoparticles emitted by catalytic converters. Although catalyst-derived particles are recognized as growing burden added to environmental pollution, very little is known about their health impact. We use platinum-decorated ceria nanoparticles as model compounds for the actual emitted particles and focus on their fast uptake and association with mitochondria, the cell's powerhouse. Using live-cell imaging and electron microscopy we clearly show that 46 nm platinum-decorated ceria nanoparticles can rapidly penetrate cell membranes and reach the cytosol. Moreover, if suitably targeted, these particles are able to selectively attach to mitochondria. These results are complemented by cytotoxicity assays, thus providing insights into the biological effects of these particles on cells. Interestingly, no permanent membrane disruption or any other significant adverse effects on cells were observed. The unusual uptake behavior observed for 46 nm nanoparticles was not observed for equivalent but larger 143 nm and 285 nm platinum-decorated particles. Our results demonstrate a remarkable particle size effect in which particles smaller than ∼50-100 nm escape the usual endocytic pathway and translocate directly into the cytosol, while particles larger than ∼150 nm are internalized by conventional endocytosis. Since the small particles are able to bypass endocytosis they could be explored as drug and gene delivery vehicles. Platinum-decorated nanoparticles are therefore highly interesting in the fields of nanotoxicology and nanomedicine.


On a Possible Solution to the Tidal Realignment Problem for Hot Jupiters.
Hot stars with hot Jupiters have a wide range of obliquities, while cool stars with hot Jupiters tend to have low obliquities. An enticing explanation for this pattern is tidal realignment of the cool host stars, although this explanation assumes that obliquity damping occurs faster than orbital decay, an assumption that needs further exploration. Here we revisit this tidal realignment problem, building on previous work identifying a low-frequency component of the time-variable tidal potential that affects the obliquity but not the orbital separation. We adopt a recent empirically based model for the stellar tidal quality factor and its sharp increase with forcing frequency. This leads to enhanced dissipation at low frequencies, and efficient obliquity damping. We model the tidal evolution of 46 observed hot Jupiters orbiting cool stars. A key parameter is the stellar age, which we determine in a homogeneous manner for the sample, taking advantage of Gaia DR2 data. We explore a variety of tidal histories and futures for each system, finding in most cases that the stellar obliquity is successfully damped before the planet is destroyed. A testable prediction of our model is that hot Jupiter hosts with orbital periods shorter than 2-3 days should have obliquities much smaller than 1°. With the possible exception of WASP-19b, the predicted future lifetimes of the planets range from 108 yr to more than 1010 yr. Thus, our model implies that these hot Jupiters are probably not in immediate danger of being devoured by their host stars while they are on the main sequence.


Substitutions of two amino acids in the nucleotide-binding site domain of a resistance protein enhance the hypersensitive response and enlarge the PM3F resistance spectrum in wheat.
Proteins with nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domains are major components of the plant immune system. They usually mediate resistance against a subgroup of races of a specific pathogen. For the allelic series of the wheat powdery mildew resistance gene Pm3, alleles with a broad and a narrow resistance spectrum have been described. Here, we show that a broad Pm3 spectrum range correlates with a fast and intense hypersensitive response (HR) in a Nicotiana transient-expression system and this activity can be attributed to two particular amino acids in the ARC2 subdomain of the NBS. The combined substitution of these amino acids in narrow-spectrum PM3 proteins enhances their capacity to induce an HR in Nicotiana benthamiana, and we demonstrate that these substitutions also enlarge the resistance spectrum of the Pm3f allele in wheat. Finally, using Bph14, we show that the region carrying the relevant amino acids also plays a role in the HR regulation of another coiled-coil NBS-LRR resistance protein. These results highlight the importance of an optimized NBS-'molecular switch' for the conversion of initial pathogen perception by the LRR into resistance-protein activation, and we describe a possible approach to extend the effectiveness of resistance genes via minimal targeted modifications in the NBS domain.


De novo mutations in SIK1 cause a spectrum of developmental epilepsies.
Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy.


Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T.
To assess the accuracy of four fat quantification methods at low-flip-angle multiecho gradient-recalled-echo (GRE) magnetic resonance (MR) imaging in nonalcoholic fatty liver disease (NAFLD) by using MR spectroscopy as the reference standard. In this institutional review board-approved, HIPAA-compliant prospective study, 110 subjects (29 with biopsy-confirmed NAFLD, 50 overweight and at risk for NAFLD, and 31 healthy volunteers) (mean age, 32.6 years +/- 15.6 [standard deviation]; range, 8-66 years) gave informed consent and underwent MR spectroscopy and GRE MR imaging of the liver. Spectroscopy involved a long repetition time (to suppress T1 effects) and multiple echo times (to estimate T2 effects); the reference fat fraction (FF) was calculated from T2-corrected fat and water spectral peak areas. Imaging involved a low flip angle (to suppress T1 effects) and multiple echo times (to estimate T2* effects); imaging FF was calculated by using four analysis methods of progressive complexity: dual echo, triple echo, multiecho, and multiinterference. All methods except dual echo corrected for T2* effects. The multiinterference method corrected for multiple spectral interference effects of fat. For each method, the accuracy for diagnosis of fatty liver, as defined with a spectroscopic threshold, was assessed by estimating sensitivity and specificity; fat-grading accuracy was assessed by comparing imaging and spectroscopic FF values by using linear regression. Dual-echo, triple-echo, multiecho, and multiinterference methods had a sensitivity of 0.817, 0.967, 0.950, and 0.983 and a specificity of 1.000, 0.880, 1.000, and 0.880, respectively. On the basis of regression slope and intercept, the multiinterference (slope, 0.98; intercept, 0.91%) method had high fat-grading accuracy without statistically significant error (P > .05). Dual-echo (slope, 0.98; intercept, -2.90%), triple-echo (slope, 0.94; intercept, 1.42%), and multiecho (slope, 0.85; intercept, -0.15%) methods had statistically significant error (P < .05). Relaxation- and interference-corrected fat quantification at low-flip-angle multiecho GRE MR imaging provides high diagnostic and fat-grading accuracy in NAFLD.


Harnessing the genetics of the modern dairy cow to continue improvements in feed efficiency.
Feed efficiency, as defined by the fraction of feed energy or dry matter captured in products, has more than doubled for the US dairy industry in the past 100 yr. This increased feed efficiency was the result of increased milk production per cow achieved through genetic selection, nutrition, and management with the desired goal being greater profitability. With increased milk production per cow, more feed is consumed per cow, but a greater portion of the feed is partitioned toward milk instead of maintenance and body growth. This dilution of maintenance has been the overwhelming driver of enhanced feed efficiency in the past, but its effect diminishes with each successive increment in production relative to body size and therefore will be less important in the future. Instead, we must also focus on new ways to enhance digestive and metabolic efficiency. One way to examine variation in efficiency among animals is residual feed intake (RFI), a measure of efficiency that is independent of the dilution of maintenance. Cows that convert feed gross energy to net energy more efficiently or have lower maintenance requirements than expected based on body weight use less feed than expected and thus have negative RFI. Cows with low RFI likely digest and metabolize nutrients more efficiently and should have overall greater efficiency and profitability if they are also healthy, fertile, and produce at a high multiple of maintenance. Genomic technologies will help to identify these animals for selection programs. Nutrition and management also will continue to play a major role in farm-level feed efficiency. Management practices such as grouping and total mixed ration feeding have improved rumen function and therefore efficiency, but they have also decreased our attention on individual cow needs. Nutritional grouping is key to helping each cow reach its genetic potential. Perhaps new computer-driven technologies, combined with genomics, will enable us to optimize management for each individual cow within a herd, or to optimize animal selection to match management environments. In the future, availability of feed resources may shift as competition for land increases. New approaches combining genetic, nutrition, and other management practices will help optimize feed efficiency, profitability, and environmental sustainability.


What is the present role for general practitioners in dementia care? Experiences of general practitioners, patients and family carers in Portugal.
Governments are being challenged to integrate at least part of dementia care into primary care. However, little is known about the current role of general practitioners (GPs) regarding dementia care, especially in countries that do not have dementia strategies in place. The aim of this study was to explore the experiences of GPs, persons with dementia and their family carers in Portuguese primary care settings, to better understand GPs' contribution to dementia care. A qualitative interview study of participants recruited from six practices in different social contexts within the Lisbon metropolitan area was carried out. Purposive sampling was used to recruit GPs, persons with dementia and carers. Interviews with GPs explored dementia care comprehensiveness, including satisfactory and challenging aspects. Interviews with patients and carers explored the experience of talking to GPs about cognitive impairments and related difficulties and the type of help received. Thematic analysis of interview transcripts was carried out using the framework approach. Five major themes were identified: GPs have a limited contribution to dementia care, the case of advanced dementia, doctor-patient relationships, doctor-carer relationships and management of chronic conditions other than dementia. General practitioners seemed to contribute little to dementia care overall, particularly regarding symptom management. The exception was patients with advanced stages of dementia, given that specialists no longer followed them up. Remarkably, GPs seemed to be alone within primary care teams in providing dementia care. These findings strongly suggest that Portuguese primary care is not yet prepared to comply with policy expectations regarding the management of dementia.


Electrophysiological evidence of alterations to the nucleus accumbens and dorsolateral striatum during chronic cocaine self-administration.
As drug use becomes chronic, aberrant striatal processing contributes to the development of perseverative drug-taking behaviors. Two particular portions of the striatum, the nucleus accumbens (NAc) and the dorsolateral striatum (DLS), are known to undergo neurobiological changes from acute to chronic drug use. However, little is known about the exact progression of changes in functional striatal processing as drug intake persists. We sampled single-unit activity in the NAc and DLS throughout 24 daily sessions of chronic long-access cocaine self-administration, and longitudinally tracked firing rates (FR) specifically during the operant response, an upward vertical head movement. A total of 103 neurons were held longitudinally and immunohistochemically localised to either NAc Medial Shell (n = 29), NAc Core (n = 30), or DLS (n = 54). We modeled changes representative of each category as a whole. Results demonstrated that FRs of DLS Head Movement neurons were significantly increased relative to baseline during all sessions, while FRs of DLS Uncategorised neurons were significantly reduced relative to baseline during all sessions. NAc Shell neurons' FRs were also significantly decreased relative to baseline during all sessions while FRs of NAc Core neurons were reduced relative to baseline only during training days 1-18 but were not significantly reduced on the remaining sessions (19-24). The data suggest that all striatal subregions show changes in FR during the operant response relative to baseline, but longitudinal changes in response firing patterns were observed only in the NAc Core, suggesting that this region is particularly susceptible to plastic changes induced by abused drugs.


Automatic nasal continuous positive airway pressure titration in the laboratory: patient outcomes.
Manual titration of nasal continuous positive airway pressure (NCPAP) treatment for obstructive sleep apnoea (OSA) is time consuming and expensive. There are now "intelligent" NCPAP machines that try to find the ideal pressure for a patient by monitoring a combination of apnoeas, hypopnoeas, inspiratory flow limitation, and snoring. Although these machines usually find similar pressures to skilled technicians, it is not clear if their use in the sleep laboratory influences subsequent acceptance by patients. This study addresses this question. One hundred and twenty two patients undergoing a trial of NCPAP were randomly allocated to either manual or automatic (Horizon, DeVilbiss) titration of pressure during their first night on NCPAP in a hospital sleep laboratory. The primary outcome (available on 112 patients) was the acceptance of NCPAP or otherwise six weeks following the initial titration night. Baseline indicators of severity were compared between the groups, as were the pressures selected and the subsequent improvement in the sleepiness of the patients. The initial severity of OSA was not significantly different in the two groups and the mean (SD) NCPAP pressures were similar (manual 8.7 (2.5) cm H2O, automatic 8.2 (2.1) cm H2O). The percentage of patients successfully established on CPAP at six weeks was 64% and 73% for the manual and automatic groups, respectively; 13% and 2%, respectively, in the manual and automatic groups had given up completely (p < 0.05), and there were about equal numbers (23% versus 25%) in the two groups who were still undecided. The substitution of automatic NCPAP titration for manual titration during the first night of NCPAP in patients with OSA does not reduce the number accepting the treatment at six weeks and may slightly improve it. This has important cost saving potential.


Stump appendicitis after laparoscopic appendectomy: case report.
Stump appendicitis is a rare delayed complication of appendectomy. The delay in diagnosis is usually because of a prior history of appendectomy. We report a case of stump appendicitis diagnosed pre-operatively with a computerized tomography (CT) scan after laparoscopic appendectomy. An 18-year-old male presented with a one-week history of lower abdominal pain, nausea and vomiting. He had a history of laparoscopic appendectomy for acute appendicitis. Physical examination revealed tenderness and guarding in the lower abdomen. CT scan showed free pelvic fluid with a tubular structure of about 2.5 cm in length and 0.78 cm in diameter located posterior to the ileo-cecal junction. Laparoscopic exploration confirmed the findings. A residual appendiceal stump was found and dissected from the adhesion and removed. Histopathology showed a residual appendix with transmural neutrophilic infiltration associated with multifocal hemorrhagic necrosis. The postoperative period was uneventful. The diagnosis of stump appendicitis can be challenging. CT scan has proven to be a useful tool for the diagnosis of this rare condition.


Application of artificial intelligence to the management of urological cancer.
Artificial intelligence techniques, such as artificial neural networks, Bayesian belief networks and neuro-fuzzy modeling systems, are complex mathematical models based on the human neuronal structure and thinking. Such tools are capable of generating data driven models of biological systems without making assumptions based on statistical distributions. A large amount of study has been reported of the use of artificial intelligence in urology. We reviewed the basic concepts behind artificial intelligence techniques and explored the applications of this new dynamic technology in various aspects of urological cancer management. A detailed and systematic review of the literature was performed using the MEDLINE and Inspec databases to discover reports using artificial intelligence in urological cancer. The characteristics of machine learning and their implementation were described and reports of artificial intelligence use in urological cancer were reviewed. While most researchers in this field were found to focus on artificial neural networks to improve the diagnosis, staging and prognostic prediction of urological cancers, some groups are exploring other techniques, such as expert systems and neuro-fuzzy modeling systems. Compared to traditional regression statistics artificial intelligence methods appear to be accurate and more explorative for analyzing large data cohorts. Furthermore, they allow individualized prediction of disease behavior. Each artificial intelligence method has characteristics that make it suitable for different tasks. The lack of transparency of artificial neural networks hinders global scientific community acceptance of this method but this can be overcome by neuro-fuzzy modeling systems.


Field-based Evaluation of a Novel SPME-GC-MS Method for Investigation of Below-ground Interaction between Brassica Roots and Larvae of Cabbage Root Fly, Delia radicum L.
Collection of volatiles from plant roots poses technical challenges due to difficulties accessing the soil environment without damaging the roots. To validate a new non-invasive method for passive sampling of root volatiles in situ, from plants grown under field conditions, using solid phase micro-extraction (SPME). SPME fibres were inserted into perforated polytetrafluoroethene (PTFE) tubes positioned in the soil next to broccoli plants for collection of root volatiles pre- and post-infestation with Delia radicum larvae. After sample analysis by gas chromatography-mass spectrometry (GC-MS), principal component analysis (PCA) was applied to determine differences in the profiles of volatiles between samples. GC-MS analysis revealed that this method can detect temporal changes in root volatiles emitted before and after Delia radicum damage. PCA showed that samples collected pre- and post-infestation were compositionally different due to the presence of root volatiles induced by D. radicum feeding. Sulphur containing compounds, in particular, accounted for the differences observed. Root volatiles emission patterns post-infestation are thought to follow the feeding and developmental progress of larvae. This study shows that volatiles released by broccoli roots can be collected in situ using SPME fibres within perforated PTFE tubes under field conditions. Plants damaged by Delia radicum larvae could be distinguished from plants sampled pre-infestation and soil controls on the basis of larval feeding-induced sulphur-containing volatiles. These results show that this new method is a powerful tool for non-invasive sampling of root volatiles below-ground. Copyright © 2016 John Wiley & Sons, Ltd.


Transport of hyperpolarized samples in dissolution-DNP experiments.
Dissolution dynamic nuclear polarization (D-DNP) experiments rely on the transfer of a sample between two high-field magnets. During this transfer, samples might experience passage through regions where the stray fields of the magnets are very weak, can approach zero, and even change their sign. This can lead to unexpected spectral features in spin systems that undergo transitions from weak- to strong-coupling regimes and vice versa, much like in field cycling nuclear magnetic resonance experiments. We herein demonstrate that the spectral features observed in D-DNP experiments can be rationalized, provided the time-dependence of the spin Hamiltonian upon field cycling is sufficiently adiabatic. Under such conditions, a passage through a weak static field can lead to the emergence of a long-lived state (LLS) based on an imbalance between the populations of singlet and triplet states in pairs of nuclei that are strongly coupled during the passage through low field. The LLS entails the appearance of anti-phase multiplet components upon transfer to a high-field magnet for observation of NMR signals.


Open surgical dislocation versus arthroscopy for femoroacetabular impingement: a comparison of clinical outcomes.
Over the last decade, the surgical treatment of femoroacetabular impingement (FAI) has evolved as surgical techniques through arthroscopy, open surgical dislocation, and combined approaches have been developed. The purpose of this systematic review was to evaluate and compare the clinical results of available surgical approaches for FAI. A review of the literature was performed through the PubMed database and related articles' reference lists. Inclusion criteria were (1) all patients treated for FAI, (2) Level I, II, III, or IV study design, and (3) written in the English language. Case reports and studies involving patients with acetabular dysplasia were excluded. Overall, 1,299 articles fit our keyword search criteria. Of these, 26 articles reported clinical outcomes, using 3 surgical modalities: open surgical dislocation, arthroscopic, and combined approaches. In compiling the data in these articles, we analyzed the outcomes of a total 1,462 hips in 1,409 patients. The most published surgical method was arthroscopy, which included 62% of the patients. Labral repair was performed more frequently in open surgical dislocation (45%) and combined approach (41%) procedures than in arthroscopies (23%). Mean improvement in the modified Harris hip score after surgery was 26.4 for arthroscopy, 20.5 for open surgical dislocation, and 12.3 for the combined approach. A higher rate of return to sport was reported for arthroscopy in professional athletes than for open surgical dislocation. Overall complication rates were 1.7% for the arthroscopic group, 9.2% for the open surgical dislocation group, and 16% in the combined approach group. All 3 surgical approaches led to consistent improvements in patient outcomes. Because a wide variety of subjective hip questionnaires were used, direct comparisons could not be made in many cases, and none of the approaches could be clearly shown to be superior to the others. However, it seems that, overall, the arthroscopic method had the lowest complication and fastest rehabilitation rate.


Role of small proliferative adipocytes: possible beige cell progenitors.
Despite extensive investigation, the mechanisms underlying adipogenesis are not fully understood. We previously identified proliferative cells in adipose tissue expressing adipocyte-specific genes, which were named small proliferative adipocytes (SPA). In this study, we investigated the characteristics and roles of SPA in adipose tissue. Epididymal and inguinal fat was digested by collagenase, and then SPA were separated by centrifugation from stromal vascular cells (SVC) and mature white adipocytes. To clarify the feature of gene expression in SPA, microarray and real-time PCR were performed. The expression of adipocyte-specific genes and several neuronal genes was increased in the order of SVC < SPA < mature white adipocytes. In addition, proliferin was detected only in SPA. SPA differentiated more effectively into lipid-laden cells than SVC. Moreover, differentiated SPA expressed uncoupling protein 1 and mitochondria-related genes more than differentiated SVC. Treatment of SPA with pioglitazone and CL316243, a specific β3-adrenergic receptor agonist, differentiated SPA into beige-like cells. Therefore, SPA are able to differentiate into beige cells. SPA isolated from epididymal fat (epididymal SPA), but not SPA from inguinal fat (inguinal SPA), expressed a marker of visceral adipocyte precursor, WT1. However, no significant differences were detected in the expression levels of adipocyte-specific genes or neuronal genes between epididymal and inguinal SPA. The ability to differentiate into lipid-laden cells in epididymal SPA was a little superior to that in inguinal SPA, whereas the ability to differentiate into beige-like cells was greater in inguinal SPA than epididymal SPA. In conclusion, SPA may be progenitors of beige cells.


Selective underexpression of Kv3.2 and Kv3.4 channels in the cortex of rats exposed to ethanol during early postnatal life.
The expression of voltage-gated potassium channels belonging to the Kv3 family has been studied in the sensori-motor cortex of rats exposed to alcohol inhalation during the first postnatal week (P2-P6). The study was carried out using comparative RT-PCR. At P9, a significant reduction of the expression of Kv3.2 and Kv3.4 subunits occurred in alcohol-treated animals, as compared with controls. The expression of the Kv3.4a splicing variant, which is thought to be critically involved in the high-frequency firing of some cortical interneurons, was also correspondingly reduced. The downregulation of Kv3.2 and Kv3.4a subunits represented a long-lasting effect of alcohol exposure, since it was also observed in P24 animals. The expression of both Kv3.1 and Kv3.3 channels appeared to be not significantly affected by alcohol exposure. An increased susceptibility to apoptotic neuronal death after early postnatal exposure to ethanol was confirmed by the lower bcl-2/bax ratio observed in alcohol-treated animals. Although Kv3.4 subunits are thought to trigger apoptosis, the lack of upregulation in our model argues against their involvement in the mechanism leading to alcohol-induced apoptosis. The possible consequences of the selective downregulation of Kv3 subunits on the cortical function, as well as their relevance for the genesis of fetal alcohol effects, are discussed.


Congenital myasthenic syndrome due to mutation in CHRNE gene with clinical worsening and thymic hyperplasia attributed to association with autoimmune-myasthenia gravis.
We report a patient with congenital myasthenic syndrome (CMS) due to mutation in CHRNE with symptoms since the age of 4; mild to moderate fatigable weakness involved mainly ocular, bulbar and limb muscles; functional impact of the disease in their development and physical activity was modest. By the age of 34, the patient experienced gradual worsening of fatigue with dyspnoea and pronounced limb weakness, requiring significant increase of pyridostigmine. Further, a remarkable and sustained clinical improvement followed thymectomy with hyperplastic thymus. Despite of the absence of detectable antibodies to acetyl-choline receptor (AChR) (including clustered-AChR), muscle-specific kinase and low-density lipoprotein receptor-related protein-4 antibodies in the serum obtained nine years after thymectomy, the clinical, genetic and histological features are in keeping with the extremely rare association of two rare neuromuscular junction disorders - CMS and myasthenia gravis (MG). The inexistence of other conditions that could potentially associate with thymic hyperplasia also supports the diagnosis of MG.


Social anxiety in pre-adolescent children: What do we know about maintenance?
The cognitive theory of social anxiety disorder (SAD) is one of the most widely accepted accounts of the maintenance of the disorder in adults, yet it remains unknown if, or to what extent, the same cognitive and behavioral maintenance mechanisms that occur in adult SAD also apply to SAD among pre-adolescent children. In contrast to the adult literature, current models of SAD in children mostly account for etiology and maintenance processes are given limited attention. Consequently, their clinical utility for the treatment of SAD in children may be limited. This narrative review, first, critically examines the different theoretical conceptualizations of the maintenance of social anxiety in the child and adult literature and illustrates how these have resulted in different treatment approaches and clinical understanding. Second, it reviews the available evidence relating to hypotheses about the maintenance of SAD in children as derived from adult cognitive and etiological models. Third, it highlights the need to attend directly to child specific maintenance mechanisms in SAD, to draw on cognitive theory, and to account for the influence of childhood-specific contextual (e.g. family and school-based interactions) and developmental factors on children's social experiences.


Anion-exchange mechanisms in bacteria.
This article discusses the physiological, biochemical, and molecular properties of bacterial anion-exchange reactions, with a particular focus on a family of phosphate (Pi)-linked antiporters that accept as their primary substrates sugar phosphates such as glucose 6-phosphate (G6P), mannose 6-phosphate, or glycerol 3-phosphate. Pi-linked antiporters may be found in both gram-positive and gram-negative cells. As their name suggests, these exchange proteins accept both inorganic and organic phosphates, but the two classes of substrate interact very differently with the protein. Thus, Pi is always accepted with a relatively low affinity, and when it participates in exchange, it is always taken as the monovalent anion. By contrast, when the high-affinity organic phosphates are used, these same systems fail to discriminate between monovalent and divalent forms. Tests of heterologous exchange (e.g., Pi: G6P) indicate that these proteins have a bifunctional active site that accepts a pair of negative charges, whether as two monovalent anions or as a single divalent anion. For this reason, exchange stoichiometry moves between limits of 2:1 and 2:2, according to the ratio of mono- and divalent substrates at either membrane surface. Since G6P has a pK2 within the physiological range (pK of 6.1), this predicts a novel reaction sequence in vivo because internal pH is more alkaline than external pH. Accordingly, one expects an asymmetric exchange as two monovalent G6P anions from the relatively acidic exterior move against a single divalent G6P from the alkaline interior. In this way an otherwise futile self-exchange of G6P can be biased towards a net inward flux driven (indirectly) by the pH gradient. Despite the biochemical complexity exhibited by Pi-linked antiporters, they resemble all other secondary carriers at a molecular level and show a likely topology in which two sets of six transmembrane alpha-helices are connected by a central hydrophilic loop. Speculations on the derivation of this common form suggest a limited number of structural models to accommodate such proteins. Three such models are presented.


Honey Supplementation and Exercise: A Systematic Review.
Honey is a natural substance formed primarily of carbohydrates (~80%) which also contains a number of other compounds purported to confer health benefits when consumed. Due to its carbohydrate composition (low glycaemic index, mostly fructose and glucose), honey may theoretically exert positive effects when consumed before, during or after exercise. This review therefore appraised research examining the effects of honey consumption in combination with exercise in humans. Online database (PubMed, MEDLINE, SPORTDiscus) searches were performed, yielding 273 results. Following duplicate removal and application of exclusion criteria, nine articles were reviewed. Large methodological differences existed in terms of exercise stimulus, population, and the nutritional interventions examined. All nine studies reported biochemical variables, with four examining the effects of honey on exercise performance, whilst five described perceptual responses. Acute supplementation around a single exercise session appeared to elicit similar performance, perceptual, and immunological responses compared with other carbohydrate sources, although some performance benefit has been observed relative to carbohydrate-free comparators. When consumed over a number of weeks, honey may dampen immunological perturbations arising from exercise and possibly improve markers of bone formation. More well-controlled research is required to better understand the role for honey in a food-first approach to exercise nutrition.


Exploring the genomic diversity of black yeasts and relatives (Chaetothyriales, Ascomycota).
The order Chaetothyriales (Pezizomycotina, Ascomycetes) harbours obligatorily melanised fungi and includes numerous etiologic agents of chromoblastomycosis, phaeohyphomycosis and other diseases of vertebrate hosts. Diseases range from mild cutaneous to fatal cerebral or disseminated infections and affect humans and cold-blooded animals globally. In addition, Chaetothyriales comprise species with aquatic, rock-inhabiting, ant-associated, and mycoparasitic life-styles, as well as species that tolerate toxic compounds, suggesting a high degree of versatile extremotolerance. To understand their biology and divergent niche occupation, we sequenced and annotated a set of 23 genomes of main the human opportunists within the Chaetothyriales as well as related environmental species. Our analyses included fungi with diverse life-styles, namely opportunistic pathogens and closely related saprobes, to identify genomic adaptations related to pathogenesis. Furthermore, ecological preferences of Chaetothyriales were analysed, in conjuncture with the order-level phylogeny based on conserved ribosomal genes. General characteristics, phylogenomic relationships, transposable elements, sex-related genes, protein family evolution, genes related to protein degradation (MEROPS), carbohydrate-active enzymes (CAZymes), melanin synthesis and secondary metabolism were investigated and compared between species. Genome assemblies varied from 25.81 Mb (Capronia coronata) to 43.03 Mb (Cladophialophora immunda). The bantiana-clade contained the highest number of predicted genes (12 817 on average) as well as larger genomes. We found a low content of mobile elements, with DNA transposons from Tc1/Mariner superfamily being the most abundant across analysed species. Additionally, we identified a reduction of carbohydrate degrading enzymes, specifically many of the Glycosyl Hydrolase (GH) class, while most of the Pectin Lyase (PL) genes were lost in etiological agents of chromoblastomycosis and phaeohyphomycosis. An expansion was found in protein degrading peptidase enzyme families S12 (serine-type D-Ala-D-Ala carboxypeptidases) and M38 (isoaspartyl dipeptidases). Based on genomic information, a wide range of abilities of melanin biosynthesis was revealed; genes related to metabolically distinct DHN, DOPA and pyomelanin pathways were identified. The MAT (MAting Type) locus and other sex-related genes were recognized in all 23 black fungi. Members of the asexual genera Fonsecaea and Cladophialophora appear to be heterothallic with a single copy of either MAT-1-1 or MAT-1-2 in each individual. All Capronia species are homothallic as both MAT1-1 and MAT1-2 genes were found in each single genome. The genomic synteny of the MAT-locus flanking genes (SLA2-APN2-COX13) is not conserved in black fungi as is commonly observed in Eurotiomycetes, indicating a unique genomic context for MAT in those species. The heterokaryon (het) genes expansion associated with the low selective pressure at the MAT-locus suggests that a parasexual cycle may play an important role in generating diversity among those fungi.


Posterior interosseous nerve palsy caused by parosteal lipoma: a case report.
An 83-year-old woman presented with weakness in her right-hand and wrist extensors and swelling in the proximal part of the right forearm. Electromyography (EMG) confirmed involvement of posterior interosseous nerve at the level of proximal forearm. MR imaging demonstrated the characteristics of lipoma which extended on the anterolateral aspect of the right forearm and at the level of the radius neck. The lesion was parosteal lipoma causing compression and paralysis of the posterior interosseous nerve without sensory deficit. In this paper, posterior interosseous nerve palsy due to compression of a parosteal lipoma recovered after excision of the lipoma followed by intensive rehabilitation for six month. Surgical excision should be performed to ensure optimal recovery from the nerve paralysis.


Moldable biomimetic nanoscale optoelectronic platforms for simultaneous enhancement in optical absorption and charge transport.
Nano-scale patterns such as those found on the exterior surface of the eyes of certain nocturnal insects have far-reaching implications in terms of optoelectronic device design. The advantage of using these patterns for optoelectronic enhancement in photovoltaic light harvesting has been less explored due to the lack of suitable engineered materials to easily fabricate such nanostructures. Here, an attempt is made to realize these complex patterns using a self-assembly based molding process on hitherto unexplored robust structural epoxies with excellent repeatability and scalability to a larger area. The incorporation of these patterns in the substrate shows nearly a 50% broadband drop in the specular reflectance of the nanostructured substrate. Furthermore, it is demonstrated that by tweaking the bio-inspired patterns on the interior side of a light harvesting device, it is possible to obtain a broadband improvement in the external quantum efficiency in the spectral window between 350 and 650 nm leading to a significant improvement of up to 49% in the photocurrent density in the structured devices. From our experiment and simulations, it is observed that this enhancement stems from a combination of two effects: first, a broadband drop in the specular reflectance exceeding 70%, arising from trapped surface plasmon-polariton modes, and second, an improved charge separation in the structured device arising due to perturbed built-in electric fields. Furthermore, the simulations which take into account the interfacial nano-scale morphology show that for absorbers with low carrier mobilities, a significant improvement in the photocurrent and in the fill factor is simultaneously possible. Overall, this work demonstrates a combination of tweaked bio-mimetic design and the use of unconventional robust structural materials as nanostructured optoelectronic substrates. This effort can bridge the gap between naturally evolved designs and practical optoelectronics to enhance the performance.


Nanosize effect on high-rate Li-ion intercalation in LiCoO2 electrode.
Recently, battery technology has come to require a higher rate capability. The main difficulty in high-rate charge-discharge experiments is kinetic problems due to the slow diffusion of Li-ions in electrodes. Nanosizing is a popular way to achieve a higher surface area and shorter Li-ion diffusion length for fast diffusion. However, while various nanoelectrodes that provide excellent high-rate capability have been synthesized, a size-controlled synthesis and a systematic study of nanocrystalline LiCoO2 have not been carried out because of the difficulty in controlling the size. We have established the size-controlled synthesis of nanocrystalline LiCoO2 through a hydrothermal reaction and, for the first time, clarified the structural and electrochemical properties of this intercalation cathode material. Lattice expansion in nanocrystalline LiCoO2 was found from powder X-ray diffraction measurements and Raman spectroscopy. Electrochemical measurements and theoretical analyses on nanocrystalline LiCoO2 revealed that extreme size reduction below 15 nm was not favorable for most applications. An excellent high-rate capability (65% of the 1 C rate capability at 100 C) was observed in nanocrystalline LiCoO2 with an appropriate particle size of 17 nm.


Characterizing nanoparticles in complex biological media and physiological fluids with depolarized dynamic light scattering.
Light scattering is one of the few techniques available to adequately characterize suspended nanoparticles (NPs) in real time and in situ. However, when it comes to NPs in multicomponent and optically complex aqueous matrices - such as biological media and physiological fluids - light scattering suffers from lack of selectivity, as distinguishing the relevant optical signals from the irrelevant ones is very challenging. We meet this challenge by building on depolarized scattering: Unwanted signals from the matrix are completely suppressed. This approach yields information with an unprecedented signal-to-noise ratio in favour of the NPs and NP-biomolecule corona complexes, which in turn opens the frontier to scattering-based studies addressing the behaviour of NPs in complex physiological/biological fluids.


Impact of regular meditation practice on EEG activity at rest and during evoked negative emotions.
The main objective of the present investigation was to examine how long-term meditation practice is manifested in EEG activity under conditions of non-emotional arousal (eyes-closed and eyes-open periods, viewing emotionally neutral movie clip) and while experiencing experimentally induced negative emotions (viewing aversive movie clip). The 62-channel EEG was recorded in age-matched control individuals (n=25) and Sahaja Yoga meditators (SYM, n=25). Findings from the non-emotional continuum show that at the lowest level of arousal (eyes closed) SYM manifested larger power values in theta-1 (4-6 Hz), theta-2 (6-8 Hz) and alpha-1 (8-10 Hz) frequency bands. Although increasing arousal desynchronized activity in these bands in both groups, the theta-2 and alpha-1 power in the eyes-open period and alpha-1 power while viewing the neutral clip remained still higher in the SYM. During eyes-closed and eyes-open periods the controls were marked by larger right than left hemisphere power, indexing relatively more active left hemisphere parieto-temporal cortex whereas meditators manifested no hemisphere asymmetry. When contrasted with the neutral, the aversive movie clip yielded significant alpha desynchronization in both groups, reflecting arousing nature of emotional induction. In the control group along with alpha desynchronization affective movie clip synchronized gamma power over anterior cortical sites. This was not seen in the SYM. Overall, the presented report emphasizes that the revealed changes in the electrical brain activity associated with regular meditation practice are dynamical by nature and depend on arousal level. The EEG power findings also provide the first empirical proof of a theoretical assumption that meditators have better capabilities to moderate intensity of emotional arousal.


Neutrophil elastase levels in the gingival crevicular fluid following hyaluronan gel application in the treatment of chronic periodontitis: A randomized split-mouth study.
Neutrophils are the predominant leukocytes in the periodontium, which prevent infection from periodontal pathogens and subsequent tissue destruction. A potentially destructive role has been elucidated, especially due to elastase enzyme. Controlling its levels might be crucial in minimizing the tissue destruction. Hyaluronan, known to inhibit the release of this enzyme from neutrophils, might be a viable option to treat chronic periodontitis. The aim of this study is to evaluate and compare the effects of 0.2% hyaluronan gel adjunctive to scaling and root planing on the levels of elastase in gingival crevicular fluid (GCF). This split-mouth study included eighty (forty experimental and forty control) sites from twenty patients representing both sexes. GCF samples were collected from all the eighty sites; simultaneously, clinical periodontal parameters were recorded. Enzyme-linked immunosorbent assay was used to determine the levels of elastase at baseline and 6 weeks after therapy, following mechanical debridement and subsequent subgingival placement of the experimental drug. With the aid of statistical software (SPSS Version 13), Student's t-test and Pearson's correlation test were performed. There was a mean reduction in the elastase levels from baseline to 6 weeks after therapy in the experimental group. However, the difference between the groups was not statistically significant. Adjunctive use of hyaluronan following mechanical debridement resulted in comparable reduction in the elastase levels, suggesting that this substance has an inhibitory effect on elastase, and subsequent tissue destruction. Further long-term studies are mandatory to validate the results of this study.


Exposure-response analyses for platinum salt-exposed workers and sensitization: A retrospective cohort study among newly exposed workers using routinely collected surveillance data.
Chloroplatinate salts are well-known respiratory sensitizing agents leading to work-related sensitization and allergies in the work environment. No quantitative exposure-response relation has been described for chloroplatinate salts. We sought to evaluate the quantitative exposure-response relation between occupational chloroplatinate exposure and sensitization. A retrospective cohort study was conducted using routinely collected health surveillance data and chloroplatinate exposure data. Workers who newly entered work between January 1, 2000, and December 31, 2010, were included, and the relation between measured chloroplatinate exposure and sensitization (as determined by skin prick test responses) was analyzed in more than 1000 refinery workers from 5 refineries for whom a total of more than 1700 personal exposure measurements were available. A clear exposure-response relation was observed, most strongly for more recent platinum salt exposure. Average or cumulative exposure over the follow-up period was less strongly associated with sensitization risk. The exposure-response relation was modified by smoking and atopy. Indications exist that recent exposure explains the risk of platinum salt sensitization most strongly. The precision of the estimate of the exposure-response relation derived from this data set appears superior to previous epidemiologic studies conducted on platinum salt sensitization and as a result, might have possible utility for the development of preventive strategies.


Distribution of immunoglobulin classes and IgG subclasses against a culture filtrate antigen of Burkholderia pseudomallei in melioidosis patients.
The class and subclass distribution of antibody response to the culture filtrate antigen (CFA) of Burkholderia pseudomallei was examined in the sera of 45 septicaemic and 17 localised melioidosis cases and 40 cases clinically suspected of melioidosis and the results were compared with those from high-risk and healthy control groups. The geometric mean titre index (GMTI) values for all classes and subclasses of immunoglobulins examined were higher for sera from the proven and clinically suspected melioidosis cases than for the control groups. However, the highest response in the three patient groups was that of IgG with GMTIs ranging from 219.4 to 291.6 and the lowest was for IgM with GMTIs of 22.5, 24.3 and 28.7. The IgA response was intermediate with GMTIs ranging from 119.2 to 170. The GMTIs were highest for IgG in septicaemic and localised infections and for IgA and IgM in localised infections. As regards IgG subclass distribution, IgG1 and IgG2 were the predominant subclasses produced against the CFA in contrast to IgG3 and IgG4, which were produced in low amounts. None of the sera from the control groups had any significant titres of antibodies.


The psycholinguistics of developing text construction.
This paper outlines functionally motivated quantifiable criteria for characterizing different facets of discourse--global-level principles, categories of referential content, clause-linking complex syntax, local linguistic expression and overall discourse stance--in relation to the variables of development, genre and modality. Concern is with later, school-age language development, in the conviction that the long developmental route of language acquisition can profitably be examined in the context of extended discourse. Findings are reviewed from a cross-linguistic project that elicited narrative and expository texts in both speech and writing at four age groups: (9-10 years, 12-13, 16-17 and adults). Clear developmental patterns emerge from middle childhood to adulthood, with significant shifts in adolescence; global-level text organization is mastered earlier in narratives than in expository essays, but the latter promote more advanced use of local-level lexicon and syntax; and spoken texts are more spread out than their denser written counterparts in clause-linkage, referential content and lexical usage. These and other findings are discussed in terms of the growth and reorganization of knowledge about types of discourse and text-embedded language use.


Air pollution and cause specific mortality in Athens.
The aim was to investigate the reported association between air pollution and cause specific mortality in the city of Athens. Cause specific mortality was contrasted between 199 d with high values of air pollution and 2*199 comparison days with low pollution, matched in a 1:2 ratio on the basis of various confounding factors. Statistical analysis was done, taking matching into account, using analysis of variance for randomised blocks. The study was confined to the city of Athens, using data obtained between 1975 and 1982. Cause of death was assessed in all 25 138 persons dying in the 3*199 d studied. Causes of death were evaluated blindly by two medically qualified investigators on the basis of information in the death certificates. Mortality was generally higher during the high pollution days but the difference was more pronounced and more significant for respiratory conditions, even though the number of deaths in this category was smaller than the corresponding numbers in the other two categories examined (cardiac and "other" deaths). The results show that the short term association between air pollution and overall mortality in Athens is likely to be causal, since it is particularly evident with respect to respiratory conditions, for which a biological air pollution link is more plausible.


Complicated small-bowel diverticulosis: a case report and review of the literature.
While jejunoileal diverticula are rare and often asymptomatic, they may lead to chronic non-specific or acute symptoms. The large majority of complications present with an acute abdomen similar to appendicitis, cholecystitis or colonic diverticulitis but they also may appear with atypical symptoms. As a result, diagnosis of complicated jejunoileal diverticulosis can be quite difficult, and may solely depend on the result of surgical exploration. In the absence of contra-indications, diagnostic laparoscopy has the benefit of thorough examination of the abdominal contents and helps to reach an absolute diagnosis. Surgical resection of the involved small-bowel segment with primary anastomosis is the preferred treatment in patients with symptomatic complicated jejunoileal diverticular disease. An atypical presentation of complicated jejunal diverticulitis in conjunction with sigmoid diverticulitis diagnosed with laparoscopy and treated with surgical resection is presented.


Strategies for the evolution of sex.
We find that the hypothesis made by Jan, Stauffer, and Moseley [Theory Biosci. 119, 166 (2000)] for the evolution of sex, namely, a strategy devised to escape extinction due to too many deleterious mutations, is sufficient but not necessary for the successful evolution of a steady state population of sexual individuals within a finite population. Simply allowing for a finite probability for conversion to sex in each generation also gives rise to a stable sexual population, in the presence of an upper limit on the number of deleterious mutations per individual. For large values of this probability, we find a phase transition to an intermittent, multistable regime. On the other hand, in the limit of extremely slow drive, another transition takes place to a different steady state distribution, with fewer deleterious mutations within the population.


A Qualitative Investigation of Engagement in Mental Health Services Among Black and Hispanic LGB Young Adults.
Little attention has been paid to engagement in mental health services among racially and ethnically diverse youths who identify as a sexual minority, despite research indicating that they face significant mental health disparities. In this study, the authors assessed the service use experiences of black and Hispanic lesbian, gay, and bisexual (LGB) young adults to identify factors that promoted or hindered their engagement. Semistructured interviews with 38 young adults regarding past and present experiences with mental health services were analyzed thematically for perceived challenges to and support for engagement. Participants' service use histories were reviewed for significant interruptions in services reported over the past year. Seventeen participants (45%) reported disengagement despite continuing to need services. Factors that influenced engagement were identified across four domains: personal, social environment, accessibility, and provider characteristics. Stigma related to sexual orientation and cultural attitudes presented engagement barriers, whereas providers who were knowledgeable about sexual-minority issues were important engagement promoters. Additional barriers to engagement were ambivalence about treatment efficacy, lack of family support, and difficulty finding suitable and affordable care. Peers who identified as a sexual minority helped participants locate LGB-affirming services. Rapport with providers and health care autonomy assisted participants to manage barriers to engagement. These findings offer insights about factors that can influence engagement with treatment among black and Hispanic LGB young adults. The findings reveal important provider competencies and can inform interventions to improve engagement and reduce mental health inequities among these youths.


Recent progress in biomedical applications of persistent luminescence nanoparticles.
Persistent luminescence nanoparticles (PLNPs) are an emerging group of promising luminescent materials that can remain luminescent after the excitation ceases. In the past decade, PLNPs with intriguing optical properties have been developed and their applications in biomedicine have been widely studied. Due to the ultra-long decay time of persistent luminescence, autofluorescence interference in biosensing and bioimaging can be efficiently eliminated. Moreover, PLNPs can remain luminescent for hours, making them valuable in bio-tracing. Also, persistent luminescence imaging can guide cancer therapy with a high signal-to-noise ratio (SNR) and superior sensitivity. Briefly, PLNPs are demonstrated to be a newly-emerging class of functional materials with unprecedented advantages in biomedicine. In this review, we summarized recent advances in the preparation of PLNPs and the applications of PLNPs in biosensing, bioimaging and cancer therapy.


DNA Methylation and Expression Profiles of Whole Blood in Parkinson's Disease.
Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.


Mathematical framework for human SLE Nephritis: disease dynamics and urine biomarkers.
Although the prognosis for Lupus Nephritis (LN) has dramatically improved with aggressive immunosuppressive therapies, these drugs carry significant side effects. To improve the effectiveness of these drugs, biomarkers of renal flare cycle could be used to detect the onset, severity, and responsiveness of kidney relapses, and to modify therapy accordingly. However, LN is a complex disease and individual biomarkers have so far not been sufficient to accurately describe disease activity. It has been postulated that biomarkers would be more informative if integrated into a pathogenic-based model of LN. This work is a first attempt to integrate human LN biomarkers data into a model of kidney inflammation. Our approach is based on a system of differential equations that capture, in a simplified way, the complexity of interactions underlying disease activity. Using this model, we have been able to fit clinical urine biomarkers data from individual patients and estimate patient-specific parameters to reproduce disease dynamics, and to better understand disease mechanisms. Furthermore, our simulations suggest that the model can be used to evaluate therapeutic strategies for individual patients, or a group of patients that share similar data patterns. We show that effective combination of clinical data and physiologically based mathematical modeling may provide a basis for more comprehensive modeling and improved clinical care for LN patients.


Reasons for Overcrowding in the Emergency Department: Experiences and Suggestions of an Education and Research Hospital.
In this study, we aimed to determine the causes of overcrowding in the Emergency Department (ED) and make recommendations to help reduce length of stay (LOS) of patients in the ED. We analyzed the medical data of patients admitted to our ER in a one-year period. Demographic characteristics, LOS, revisit frequency, and consultation status of the patients were determined. A total of 163,951 patients were admitted to our ED between January 1, 2013, and December 31, 2013. In this period 1,210 patients revisited the ED within 24 hours. A total of 38,579 patients had their treatment in the observation room (OR) of the ED and mean LOS was found to be 164.1 minutes. Cardiology was the most frequently consulted specialty. Mean arrival time of the consultants in ED was 64 minutes. Similar to EDs in other parts of the world, prolonged length of stay in the ED, delayed laboratory and imaging tests, delay of consultants, and lack of sufficient inpatient beds are the most important causes of overcrowding in the ED. Some drastic measures must be taken to minimize errors and increase satisfaction ratio.


GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling.
We explored the mechanistic involvement of the growth arrest and DNA damage-inducible gene GADD45a in lipopolysaccharide (LPS)- and ventilator-induced inflammatory lung injury (VILI). Multiple biochemical and genomic parameters of inflammatory lung injury indicated that GADD45a(-/-) mice are modestly susceptible to intratracheal LPS-induced lung injury and profoundly susceptible to high tidal volume VILI, with increases in microvascular permeability and bronchoalveolar lavage levels of inflammatory cytokines. Expression profiling of lung tissues from VILI-challenged GADD45a(-/-) mice revealed strong dysregulation in the B-cell receptor signaling pathway compared with wild-type mice and suggested the involvement of PI3 kinase/Akt signaling components. Western blot analyses of lung homogenates confirmed approximately 50% reduction in Akt protein levels in GADD45a(-/-) mice accompanied by marked increases in Akt ubiquitination. Electrical resistance measurements across human lung endothelial cell monolayers with either reduced GADD45a or Akt expression (siRNAs) revealed significant potentiation of LPS-induced human lung endothelial barrier dysfunction, which was attenuated by overexpression of a constitutively active Akt1 transgene. These studies validate GADD45a as a novel candidate gene in inflammatory lung injury and a significant participant in vascular barrier regulation via effects on Akt-mediated endothelial signaling.


Increase of free Mg2+ in the skeletal muscle of chronic fatigue syndrome patients.
In a previous study we evaluated muscle blood flow and muscle metabolism in patients diagnosed with chronic fatigue syndrome (CFS). To better understand muscle metabolism in CFS, we re-evaluated our data to calculate free Magnesium levels in skeletal muscle. Magnesium is an essential cofactor in a number of cell processes. A total of 20 CFS patients and 11 controls were evaluated. Phosphorus magnetic resonance spectroscopy from the medial gastrocnemius muscle was used to calculate free Mg2+ from the concentrations and chemical shifts of Pi, PCr, and beta ATP peaks. CFS patients had higher magnesium levels in their muscles relative to controls (0.47 + 0.07 vs 0.36 + 0.06 mM, P < 0.01), although there was no difference in the rate of phosphocreatine recovery in these subjects, as reported earlier. This finding was not associated with abnormal oxidative metabolism as measured by the rate of recovery of phosphocreatine after exercise. In summary, calculation of free Mg2+ levels from previous data showed CFS patients had higher resting free Mg2+ levels compared to sedentary controls.


Action control in visual neglect.
Patients with unilateral neglect show a variety of impairments when reaching towards objects in contralesional space. The basis of these deficits could be perceptual, motor or at one of the intermediate stages linking these processes. Here, we review studies of visually guided reaching in neglect and integrate these results with findings from normal human and monkey action control. We consider evidence which shows that neglect patients can be slow to initiate or execute reaches particularly to a contralesional target. We discuss the directional and spatial deficits that may interact to contribute to such reaching abnormalities and highlight the importance of effective target selection and on-line guidance, exploring the idea that deficits in these mechanisms underlie increased susceptibility to ipsilesional visual distraction in neglect. We also examine the relationship between optic ataxia and neglect by considering two illustrative cases, one with pure optic ataxia and the other with optic ataxia plus neglect, which reveal differences in the anatomical substrates of the two syndromes. We conclude that many patients with neglect make abnormal visually guided reaches, but the pattern of reaching deficits is highly variable, most likely reflecting heterogeneity of lesion location across subjects. Rather than being specific to the neglect syndrome, abnormalities of reaching in these patients may correspond to the extent of damage to the visuomotor control system which involves critical regions in both the parietal and frontal cortex, the white matter tracts connecting them and subcortical regions. Thus, the action control deficits in neglect may be conceptualised as a range of impairments affecting multiple stages in the visuomotor control process.


A Combined Shotgun and Targeted Mass Spectrometry Strategy for Breast Cancer Biomarker Discovery.
It is of highest importance to find proteins responsible for breast cancer dissemination, for use as biomarkers or treatment targets. We established and performed a combined nontargeted LC-MS/MS and a targeted LC-SRM workflow for discovery and validation of protein biomarkers. Eighty breast tumors, stratified for estrogen receptor status and development of distant recurrence (DR ± ), were collected. After enrichment of N-glycosylated peptides, label-free LC-MS/MS was performed on each individual tumor in triplicate. In total, 1515 glycopeptides from 778 proteins were identified and used to create a map of the breast cancer N-glycosylated proteome. Based on this specific proteome map, we constructed a 92-plex targeted label-free LC-SRM panel. These proteins were quantified across samples by LC-SRM, resulting in 10 proteins consistently differentially regulated between DR+/DR- tumors. Five proteins were further validated in a separate cohort as prognostic biomarkers at the gene expression level. We also compared the LC-SRM results to clinically reported HER2 status, demonstrating its clinical accuracy. In conclusion, we demonstrate a combined mass spectrometry strategy, at large scale on clinical samples, leading to the identification and validation of five proteins as potential biomarkers for breast cancer recurrence. All MS data are available via ProteomeXchange and PASSEL with identifiers PXD001685 and PASS00643.


Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms.
Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 μm) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor β (ERβ): estrogen receptor α (ERα) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.


Evolutionary conservation of biogenesis of beta-barrel membrane proteins.
The outer membranes of mitochondria and chloroplasts are distinguished by the presence of beta-barrel membrane proteins. The outer membrane of Gram-negative bacteria also harbours beta-barrel proteins. In mitochondria these proteins fulfil a variety of functions such as transport of small molecules (porin/VDAC), translocation of proteins (Tom40) and regulation of mitochondrial morphology (Mdm10). These proteins are encoded by the nucleus, synthesized in the cytosol, targeted to mitochondria as chaperone-bound species, recognized by the translocase of the outer membrane, and then inserted into the outer membrane where they assemble into functional oligomers. Whereas some knowledge has been accumulated on the pathways of insertion of proteins that span cellular membranes with alpha-helical segments, very little is known about how beta-barrel proteins are integrated into lipid bilayers and assembled into oligomeric structures. Here we describe a protein complex that is essential for the topogenesis of mitochondrial outer membrane beta-barrel proteins (TOB). We present evidence that important elements of the topogenesis of beta-barrel membrane proteins have been conserved during the evolution of mitochondria from endosymbiotic bacterial ancestors.


High average power 1314 nm Nd:YLF laser, passively Q-switched with V:YAG.
A 1314 nm Nd:YLF laser was designed and operated both CW and passively Q-switched. Maximum CW output of 10.4 W resulted from 45.2 W of incident pump power. Passive Q-switching was obtained by inserting a V:YAG saturable absorber in the cavity. The oscillator delivered a maximum of 825 μJ energy per pulse, with a pulse duration of 135 ns at a pulse repetition frequency of 6.3 kHz, effectively delivering 5.2 W of average power.


Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease.
The transcription factor BMAL1 is a core component of the molecular clock, regulating biological pathways that drive 24 h (circadian) rhythms in behaviour and physiology. The molecular clock has a profound influence on innate immune function, and circadian disruption is linked with increased incidence of multiple sclerosis (MS). However, the mechanisms underlying this association are unknown. Here we show that BMAL1 and time-of-day regulate the accumulation and activation of various immune cells in a CNS autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). In myeloid cells, BMAL1 maintains anti-inflammatory responses and reduces T cell polarization. Loss of myeloid BMAL1 or midday immunizations to induce EAE create an inflammatory environment in the CNS through expansion and infiltration of IL-1β-secreting CD11b+Ly6Chi monocytes, resulting in increased pathogenic IL-17+/IFN-γ+ T cells. These findings demonstrate the importance of the molecular clock in modulating innate and adaptive immune crosstalk under autoimmune conditions.


Local symmetric distortion boosted photon up-conversion and thermometric sensitivity in lanthanum oxide nanospheres.
It is essential to simultaneously boost the luminescence intensity and thermometric sensitivity of up-converted optical thermometers towards potential biomedical sensing applications. Herein, the effects of local site symmetry on the up-conversion (UC) emission and thermal sensing ability in trigonal-phased La2O3:Er3+/Yb3+ nanospheres were qualitatively explored using cubic-phased Lu2O3 and Y2O3 with a similar shape and phonon energy as contrasts. Under 980 nm light excitation, much stronger UC emissions were detected in La2O3 samples than that in cubic Lu2O3 and Y2O3 samples, and the possible mechanisms were elaborately proposed using Eu3+ as a luminescent probe. Thermo-responsive emission intensity from 2H11/2/4S3/2 levels was monitored to evaluate the absolute sensitivity of three samples, which strongly depends on the dopant-induced local site symmetric distortions according to the Judd-Ofelt theory. The potentiality of La2O3:Er3+/Yb3+ for sub-tissue thermometry was also validated by ex vivo experiments. Results open a promising avenue for realizing highly sensitive thermometry with a large signal-to-noise ratio in sub-tissues via finely tailoring the local site symmetry.


Photocatalytic Activity Induced by Metal Nanoparticles Synthesized by Sustainable Approaches: A Comprehensive Review.
Nanotechnology is a fast-expanding area with a wide range of applications in science, engineering, health, pharmacy, and other fields. Among many techniques that are employed toward the production of nanoparticles, synthesis using green technologies is the simplest and environment friendly. Nanoparticles produced from plant extracts have become a very popular subject of study in recent decades due to their diverse advantages such as low-cost synthesis, product stability, and ecofriendly protocols. These merits have prompted the development of nanoparticles from a variety of sources, including bacteria, fungi, algae, proteins, enzymes, etc., allowing for large-scale production with minimal contamination. However, nanoparticles obtained from plant extracts and phytochemicals exhibit greater reduction and stabilization and hence have proven the diversity of properties, like catalyst/photocatalyst, magnetic, antibacterial, cytotoxicity, circulating tumor deoxy ribo nucleic acid (CT-DNA) binding, gas sensing, etc. In the current scenario, nanoparticles can also play a critical role in cleaning wastewater and making it viable for a variety of operations. Nano-sized photocatalysts have a great scope toward the removal of large pollutants like organic dyes, heavy metals, and pesticides in an eco-friendly and sustainable manner from industrial effluents. Thus, in this review article, we discuss the synthesis of several metal nanoparticles using diverse plant extracts, as well as their characterization via techniques like UV-vis (ultraviolet-visible), XRD (X-ray diffraction), SEM (scanning electron microscopy), TEM (transmission electron microscopy), FTIR (Fourier transform infrared spectroscopy), etc., and catalytic activity on various hazardous systems.


Lycopene and cardiovascular diseases: an update.
Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.


Red cell membrane disorders: structure meets function.
The mature red blood cell (RBC) lacks a nucleus and organelles characteristic of most cells, but it is elegantly structured to perform the essential function of delivering oxygen and removing carbon dioxide from all other cells while enduring the shear stress imposed by navigating small vessels and sinusoids. Over the past several decades, the efforts of biochemists, cell and molecular biologists, and hematologists have provided an appreciation of the complexity of RBC membrane structure, while studies of the RBC membrane disorders have offered valuable insights into structure-function relationships. Within the last decade, advances in genetic testing and its increased availability have made it possible to substantially build upon this foundational knowledge. Although disorders of the RBC membrane due to altered structural organization or altered transport function are heterogeneous, they often present with common clinical findings of hemolytic anemia. However, they may require substantially different management depending on the underlying pathophysiology. Accurate diagnosis is essential to avoid emergence of complications or inappropriate interventions. We propose an algorithm for laboratory evaluation of patients presenting with symptoms and signs of hemolytic anemia with a focus on RBC membrane disorders. Here, we review the genotypic and phenotypic variability of the RBC membrane disorders in order to raise the index of suspicion and highlight the need for correct and timely diagnosis.