The Effect of National Family Caregiver Support Program Services on Caregiver Burden.
Extant evidence on the effectiveness of caregiver programs in alleviating caregiver burden is mixed, underscoring the need for further investigations. This study evaluated the effect of the National Family Caregiver Support Program (NFCSP) educational services and respite care on caregiver burden. We used survey data from caregivers assigned to program (n = 491) or comparison (n = 417) group based on their reported use of NFCSP services. Adjusted difference-in-differences (DiD) analysis found an increase in mean burden scores for both groups from baseline to 6 or 12 months. Among program caregivers receiving ≥4 hr of NFCSP respite care per week (n = 307) and matched comparisons (n = 370), burden scores decreased slightly for program caregivers (-0.095 points), but increased for comparison caregivers (+0.145 points). The DiD (0.239 points) was not statistically significant. More research is needed to determine the minimum amount of respite care needed to positively impact caregiver burden.


Physical fitness level affects perception of chronic stress in military trainees.
This study investigated whether physical fitness affects the perception of chronic stress in military trainees while controlling for established factors influencing stress perception. The sample consisted of 273 men (20.23 ± 1.12 years, 73.56 ± 10.52 kg, 1.78 ± 0.06 m). Physical fitness was measured by progressive endurance run (maximum oxygen uptake; VO2 max), standing long jump, seated shot put, trunk muscle strength, and one leg standing test. Perceived stress was measured using the Perceived Stress Questionnaire in Weeks 1 and 11 of basic military training (BMT). VO2 max and four influencing variables (perceived stress in Week 1, neuroticism, transformational leadership style, and education level) explained 44.44% of the variance of the increase in perceived stress during 10 weeks of BMT (R2 = 0.444, F = 23.334, p < .001). The explained variance of VO2 max was 4.14% (R2 = 0.041), with a Cohen's f2 effect size of 0.045 (assigned as a small effect by Cohen, ). The results indicate a moderating influence of good aerobic fitness on the varied level of perceived stress. We conclude that it is advisable to provide conscripts with a specific endurance training program prior to BMT for stress prevention reasons.


Effect of Acute Moderate-Intensity Exercise on the Mirror Neuron System: Role of Cardiovascular Fitness Level.
The aims of this study were to use functional near-infrared spectroscopy (fNIRS) to determine whether cardiovascular fitness levels modulate the activation of the mirror neuron system (MNS) under table-setting tasks in non-exercise situation, to replicate the study that positive effect of acute moderate-intensity exercise on the MNS and investigate whether cardiovascular fitness levels modulates the effect of exercise on the activation of the MNS. Thirty-six healthy college-aged participants completed a maximal graded exercise test (GXT) and were categorized as high, moderate, or low cardiovascular fitness. Participants then performed table-setting tasks including an action execution task (EXEC) and action observation task (OBS) prior to (PRE) and after (POST) either a rest condition (CTRL) or a cycling exercise condition (EXP). The EXP condition consisted of a 5-min warm-up, 15-min moderate-intensity exercise (65% VO2 max), and 5-min cool-down. No significant differences were observed for Oxy-Hb and Deoxy-Hb between different cardiovascular fitness levels in the EXEC or OBS tasks in the non-exercise session. But there were significant improvements of oxygenated hemoglobin (Oxy-Hb) in the inferior frontal gyrus (IFG) and pre-motor area (PMC) regions under the OBS task following the acute moderate exercise. Particularly, the improvements (Post-Pre) of Δ Oxy-Hb were mainly observed in high and low fitness individuals. There was also a significant improvement of deoxygenated hemoglobin (Deoxy-Hb) in the IPL region under the OBS task. The following analysis indicated that exercise improved Δ Deoxy-Hb in high fitness individuals. This study indicated that the activation of MNS was not modulated by the cardiovascular fitness levels in the non-exercise situation. We replicated the previous study that moderate exercise improved activation of MNS; we also provided the first empirical evidence that moderate-intensity exercise positively affects the MNS activation in college students of high and low cardiovascular fitness levels.


Amino triazolo diazepines (Ata) as constrained histidine mimics.
Two synthetic routes for the synthesis of amino-triazolodiazepine (Ata) scaffolds are presented. The scope of both of these proceeding through key intra- and intermolecular Huisgen cycloaddition reactions is discussed. The replacement of the His-Pro dipeptide segment in angiotensin IV by the dipeptide mimetic Ata-Gly and subsequent biological evaluation in two inhibitory enzyme assays validated the use of the Ata moiety as a His mimic given the equipotency of both peptidic analogs.


Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients who could not receive methotrexate: 52-week results from an open-label extension of the HIKARI study.
To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients who could not receive methotrexate (MTX). HIKARI double-blind (DB) patients were entered into an open-label extension (OLE) study. Patients withdrawn at 16 weeks due to lack of efficacy and DB completers without a 24-week American College of Rheumatology (ACR)20 response received CZP 200 mg every 2 weeks (Q2W). DB completers with 24-week ACR20 responses were randomized to CZP 200 mg Q2W or CZP 400 mg every 4 weeks. The ACR20/ACR50/ACR70 response rates of DB completers (n = 98) were 82.7%/56.1%/34.7% at OLE entry, and 83.7%/65.3%/48.0% at 52 weeks, respectively. Other clinical, functional, and radiographic outcomes were sustained during long-term administration of CZP, even without MTX. No new unexpected adverse events were observed during long-term CZP treatment. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Long-term CZP administration is efficacious and safe for RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules. The choice between two maintenace regimens adds flexibility in administration schedules for RA patients and physicians.


The role of propolis against paclitaxel-induced oligospermia, sperm abnormality, oxidative stress and DNA damage in testes of male rats.
Paclitaxel (taxol) is one of the most powerful anticancer drugs but it possesses toxic effects on male reproductive system. Propolis, from folkloric remedy, have antioxidant, anti-inflammatory and anticancer effects. The present study established to examine the protective impact of Propolis against malformation of semen induced by taxol. Twenty-four male rats equally divided into four groups. Group I (normal control); group II, administrated Propolis alone; group III, taxol-treated group received taxol; group IV, co-administered of taxol and Propolis extract. After 4 weeks of treatment, the semen were collected and testis 24 hr after the last treatment. Sperm count, motility, viability and sperm morphology were assayed. Tissue supernatants were isolated for oxidative stress, cell energy parameters and 8-OHdG. DNA damage was evaluated using Comet assay in testes. Our results confirmed that taxol-induced significant reduction in sperm count, motility, viability and recorded marked elevation in sperm abnormalities. Also, taxol caused increased in 8-OHdG and DNA damage versus that recorded in control group. Treatment with Propolis improving semen quality and protected testis from detrimental effects of taxol and minimises its toxicity. In conclusions, Oral administration of Propolis modulates the toxic impact of taxol by amelioration semen quality, diminishing oxidation state, DNA damage and preserving cell energy.


Live virus-free or die: coupling of antivirus immunity and programmed suicide or dormancy in prokaryotes.
The virus-host arms race is a major theater for evolutionary innovation. Archaea and bacteria have evolved diverse, elaborate antivirus defense systems that function on two general principles: i) immune systems that discriminate self DNA from nonself DNA and specifically destroy the foreign, in particular viral, genomes, whereas the host genome is protected, or ii) programmed cell suicide or dormancy induced by infection. Almost all genomic loci encoding immunity systems such as CRISPR-Cas, restriction-modification and DNA phosphorothioation also encompass suicide genes, in particular those encoding known and predicted toxin nucleases, which do not appear to be directly involved in immunity. In contrast, the immunity systems do not appear to encode antitoxins found in typical toxin-antitoxin systems. This raises the possibility that components of the immunity system themselves act as reversible inhibitors of the associated toxin proteins or domains as has been demonstrated for the Escherichia coli anticodon nuclease PrrC that interacts with the PrrI restriction-modification system. We hypothesize that coupling of diverse immunity and suicide/dormancy systems in prokaryotes evolved under selective pressure to provide robustness to the antivirus response. We further propose that the involvement of suicide/dormancy systems in the coupled antivirus response could take two distinct forms:1) induction of a dormancy-like state in the infected cell to 'buy time' for activation of adaptive immunity; 2) suicide or dormancy as the final recourse to prevent viral spread triggered by the failure of immunity. This hypothesis entails many experimentally testable predictions. Specifically, we predict that Cas2 protein present in all cas operons is a mRNA-cleaving nuclease (interferase) that might be activated at an early stage of virus infection to enable incorporation of virus-specific spacers into the CRISPR locus or to trigger cell suicide when the immune function of CRISPR-Cas systems fails. Similarly, toxin-like activity is predicted for components of numerous other defense loci. The hypothesis implies that antivirus response in prokaryotes involves key decision-making steps at which the cell chooses the path to follow by sensing the course of virus infection. This article was reviewed by Arcady Mushegian, Etienne Joly and Nick Grishin. For complete reviews, go to the Reviewers' reports section.


Optical coherence tomography scan circle location and mean retinal nerve fiber layer measurement variability.
To investigate the effect on optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness measurements of varying the standard 3.4-mm-diameter circle location. The optic nerve head (ONH) region of 17 eyes of 17 healthy subjects was imaged with high-speed, ultrahigh-resolution OCT (hsUHR-OCT; 501 x 180 axial scans covering a 6 x 6-mm area; scan time, 3.84 seconds) for a comprehensive sampling. This method allows for systematic simulation of the variable circle placement effect. RNFL thickness was measured on this three-dimensional dataset by using a custom-designed software program. RNFL thickness was resampled along a 3.4-mm-diameter circle centered on the ONH, then along 3.4-mm circles shifted horizontally (x-shift), vertically (y-shift) and diagonally up to +/-500 microm (at 100-microm intervals). Linear mixed-effects models were used to determine RNFL thickness as a function of the scan circle shift. A model for the distance between the two thickest measurements along the RNFL thickness circular profile (peak distance) was also calculated. RNFL thickness tended to decrease with both positive and negative x- and y-shifts. The range of shifts that caused a decrease greater than the variability inherent to the commercial device was greater in both nasal and temporal quadrants than in the superior and inferior ones. The model for peak distance demonstrated that as the scan moves nasally, the RNFL peak distance increases, and as the circle moves temporally, the distance decreases. Vertical shifts had a minimal effect on peak distance. The location of the OCT scan circle affects RNFL thickness measurements. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination (ClinicalTrials.gov number, NCT00286637).


Microbial dysbiosis is associated with human breast cancer.
Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, we investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, we found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, we observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications.


Reliable interfaces for EGaIn multi-layer stretchable circuits and microelectronics.
We tackle two well-known problems in the fabrication of stretchable electronics: interfacing soft circuit wiring with silicon chips and fabrication of multi-layer circuits. We demonstrate techniques that allow integration of embedded flexible printed circuit boards (FPCBs) populated with microelectronics into soft circuits composed of liquid metal (LM) interconnects. These methods utilize vertical interconnect accesses (VIAs) that are produced by filling LM alloy into cavities formed by laser ablation. The introduced technique is versatile, easy to perform, clean-room free, and results in reliable multi-layer stretchable hybrid circuits that can withstand over 80% of strain. We characterize the fabrication parameters of such VIAs and demonstrated several applications, including a stretchable touchpad and pressure detection film, and an all-integrated multi-layer electromyography (EMG) circuit patch with five active layers including acquisition electrodes, on-board processing and Bluetooth communication modules.


Effects of experience in a dynamic environment on postural control.
Surfing is a balance-reliant, open skill performed in a dynamic environment rich in visual, somatosensory and vestibular information. To evaluate adaptations to the postural control system by surfing experience. Postural control was assessed in an upright bipedal stance in 60 male volunteers (21 elite surfers, 20 intermediate level surfers, and 19 controls) using various closed-stance positions. Six tasks were performed with two trials including a cognitive task, in the following order: eyes open, head in a neutral position (EO1); eyes closed, head in a neutral position (EC); eyes closed, head back (ECHB); eyes open, head in a neutral position, cognitive task 1 (EOC1); eyes open head in a neutral position, cognitive task 2 (EOC2); eyes open head in a neutral position (EO2). Dependent variables were area of 95th centile ellipse (AoE) and sway path length (SPL). All participants showed systematic increases in SPL and AoE in EC and ECHB trials. Expert surfers displayed significantly (p<0.05) increased SPL but not AoE when sharing attention with both concurrent mental tasks compared with controls. Controls showed a slight, non-significant change in postural control (reduced SPL and AoE) when attending to concurrent mental tasks. The findings indicate that standard postural sway indices are not able to elucidate whether expertise in surfing facilitates adaptations to the postural control system. However, concurrent mental task findings illustrate that systematic differences in balance abilities between expert surfers and controls may exist.


High-frequency vaccine-induced CD8⁺ T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection.
Relatively few MHC class I epitopes have been identified from Mycobacterium tuberculosis, but during the late stage of infection, CD8(+) T-cell responses to these epitopes are often primed at an extraordinary high frequency. Although clearly available for recognition during infection, their role in resistance to mycobacterial infections still remain unclear. As an alternative to DNA and viral vaccination platforms, we have exploited a novel CD8(+) T-cell-inducing adjuvant, cationic adjuvant formulation 05 (dimethyldioctadecylammonium/trehalose dibehenate/poly (inositic:cytidylic) acid), to prime high-frequency CD8 responses to the immunodominant H2-K(b) -restricted IMYNYPAM epitope contained in the vaccine Ag tuberculosis (TB)10.4/Rv0288/ESX-H (where ESX is mycobacterial type VII secretion system). We report that the amino acid C-terminal to this minimal epitope plays a decisive role in proteasomal cleavage and epitope priming. The primary structure of TB10.4 is suboptimal for proteasomal processing of the epitope and amino acid substitutions in the flanking region markedly increased epitope-specific CD8(+) T-cell responses. One of the optimized sequences was contained in the closely related TB10.3/Rv3019c/ESX-R Ag and when recombinantly expressed and administered in the cationic adjuvant formulation 05 adjuvant, this Ag promoted very high CD8(+) T-cell responses. This abundant T-cell response was functionally active but provided no protection against challenge, suggesting that CD8(+) T cells play a limited role in protection against M. tuberculosis in the mouse model.


Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: a randomized controlled trial.
Sexually transmitted infections (STIs) are common in female sex workers (FSWs) and may enhance susceptibility to infection with human immunodeficiency virus type 1 (HIV-1). To examine regular antibiotic prophylaxis in FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1. Randomized, double-blind, placebo-controlled trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n = 236). Groups were well matched at baseline for sexual risk taking and STI rates. Monthly oral administration of 1 g of azithromycin or identical placebo, as directly observed therapy. All participants were provided with free condoms, risk-reduction counseling, and STI case management. The primary study end point was incidence of HIV-1 infection. Secondary end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi, as well as bacterial vaginosis. Analysis of herpes simplex virus type 2 (HSV-2) infection was performed post hoc. Seventy-three percent of participants (n = 341) were followed up for 2 or more years or until they reached an administrative trial end point. Incidence of HIV-1 did not differ between treatment and placebo groups (4% [19 cases per 473 person-years of follow-up] vs 3.2% [16 cases per 495 person-years of follow-up] rate ratio [RR], 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection was associated with preceding infection with N gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment group of infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI, 1.5-27.1). Despite an association between bacterial STIs and acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis to established HIV-1 risk reduction strategies substantially reduced the incidence of STIs but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have been an important cofactor in acquisition of HIV-1.


Patients and Guns: Florida Physicians Are Not Asking.
The number of deaths from gun violence continues to increase in the United States. Despite multiple studies demonstrating that counseling patients leads to safer gun storage, it is not routinely practiced by physicians. There are multiple barriers to discussing firearms with patients. A barrier in Florida, until recently, was a law preventing physicians from asking patients about firearms. The law was overturned in 2017; however, it is unclear whether physicians are aware of this decision. We undertook a survey to study University of Florida faculty physicians' knowledge, attitudes, and practices related to discussing firearms safety. The survey consisted of 15 questions related to firearms and counseling. Invitations to participate were e-mailed in 2018 to faculty in general internal medicine, emergency medicine, and surgery within our institution. The response rate was 50% (n = 71/142). The majority of faculty surveyed did not own a gun (56%). Ninety-one percent of faculty surveyed agreed that "gun violence is a public health issue" and 93% agreed that gun safety discussion with patients at risk for suicidal or violent behavior is important. More than half of the respondents (62%) believed they could effectively discuss firearms safety with patients; 73% strongly agreed or agreed that they would discuss gun safety with at-risk patients, whereas 27% were either neutral or disagreed. Fewer still (55%) feel comfortable initiating conversations, and only 5% of participants always talk to at-risk patients about gun safety. Twenty-four percent discussed gun safety most of the time, 30% discussed it sometimes, 32% rarely discussed it, and 9% never discussed it; 76% were aware of the 2017 court decision overturning the physician gag law in Florida. The most-often cited barriers to discussions included lack of time (36%), worry about negative reaction from patient (30%), worry about lack of support from administration (13%), and lack of knowledge (20%). Gun owners and nonowners differed significantly on only two survey items: having taken a firearms safety course (gun owners more likely, relative risk 1.63, 95% confidence interval 1.16-2.29, P = 0.001) and agreeing with gun violence being a public health issue (gun owners being less likely, relative risk 1.24, 95% confidence interval 1.03-1.49, P = 0.006). Faculty miss opportunities to prevent gun violence despite acknowledging that it is important to do so. More than 40% of the physicians who were surveyed do not counsel at-risk patients about gun safety, citing a lack of knowledge, a persisting belief that asking patients about guns in Florida is illegal, worry about negative patient reactions, and time limitations. Inaction persists despite increased awareness and activism by physicians regarding gun violence. A wider availability of continuing medical education opportunities to learn about firearms counseling should be considered.


Heterogeneity of vaginal microbial communities within individuals.
Recent culture-independent studies have revealed that a healthy vaginal ecosystem harbors a surprisingly complex assemblage of microorganisms. However, the spatial distribution and composition of vaginal microbial populations have not been investigated using molecular methods. Here, we evaluated site-specific microbial composition within the vaginal ecosystem and examined the influence of sampling technique in detection of the vaginal microbiota. 16S rRNA gene clone libraries were prepared from samples obtained from different locations (cervix, fornix, outer vaginal canal) and by different methods (swabbing, scraping, lavaging) from the vaginal tracts of eight clinically healthy, asymptomatic women. The data reveal that the vaginal microbiota is not homogenous throughout the vaginal tract but differs significantly within an individual with regard to anatomical site and sampling method used. Thus, this study illuminates the complex structure of the vaginal ecosystem and calls for the consideration of microenvironments when sampling vaginal microbiota as a clinical predictor of vaginal health.


5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family.
2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.


Comparative risk assessment for new cow-level Mycobacterium avium ssp. paratuberculosis infections between 3 dairy production types: Organic, conventional, and conventional-grazing systems.
Johne's disease, a granulomatous enteritis of ruminant animals, is a hidden threat on dairy farms, adversely affecting animal welfare as well as herd productivity. Control programs in the United States advocate for specific management practices to temper the spread of the causal organism (Mycobacterium avium ssp. paratuberculosis, MAP), such as improving calving area hygiene and limiting introduction of replacement stock with unknown infection status. A need remains for direct exploration of Johne's disease prevention strategies in the United States with respect to production type. Alongside the growing demand for organic products, the safety of organic dairy practices with respect to MAP control is warranted. Further, conventional herds for which organic practices such as pasture grazing are used should be situated within the risk spectrum. We developed a risk assessment model using the US Voluntary Bovine Johne's Disease Control Program as a framework, with the goal of evaluating the risk of new cow-level MAP infections. A total of 292 organic and conventional farms in 3 states were surveyed on management practices, and an overall analysis was conducted in which each farm was first scored on individual practices using a range of "no risk" to "high risk," according to the literature. The sum of all risk factors was then analyzed to quantify and compare the risk burden for each production type. Organic herds received higher overall risk scores compared with both conventional grazing and nongrazing subtypes. To identify which factors contributed to the overall increased risk for organic herds, the management practices were categorized and evaluated by logistic regression. We determined that the increased risk incurred by organic herds was predominantly due to decisions made in the calving area and preweaned calf group. However, although certain individual risk factors related to calf management are commonly involved in prevention strategies (e.g., cow/calf separation) and were thus included in the overall risk assessment, empirical evidence linking them to the spread of MAP is lacking. Instead, these factors are problematic when executed with other management decisions, leading to a hypothesized synergism of transmission risk. To this end, we developed a set of compound risk factors, which were also evaluated as outcomes in logistic regression models, with production type serving as the predictor of interest. Organic farms in our study were more susceptible to risks associated with the synergism of study variables. Notably, organic producers were most likely to allow calves to spend extended time with the dam, while also lacking a dedicated calving area. Additionally, calves in organic herds were more often permitted to nurse even with poor udder hygiene on farm. A heightened vigilance toward calving area hygiene is therefore indicated for these herds.


Continuous Real-World Gait Monitoring in Idiopathic REM Sleep Behavior Disorder.
Patients with REM sleep behavior disorder (RBD) have a high risk of developing PD, and thus can be used to study prodromal biomarkers. RBD has been associated with changes in gait; quantifying these changes using wearable technology is promising; however, most data are obtained in clinical settings precluding pragmatic application. We aimed to investigate if wearable-based, real-world gait monitoring can detect early gait changes and discriminate individuals with RBD from controls, and explore relationships between real-world gait and clinical characteristics. 63 individuals with RBD (66±10 years) and 34 controls recruited in the Oxford Parkinson's Disease Centre Discovery Study were assessed. Data were collected using a wearable device positioned on the lower back for 7 days. Real-world gait was quantified in terms of its Macrostructure (volume, pattern and variability (S2)) and Microstructure (14 characteristics). The value of Macro and Micro gait in discriminating RBD from controls was explored using ANCOVA and ROC analysis, and correlation analysis was performed between gait and clinical characteristics. Significant differences were found in discrete Micro characteristics in RBD with reduced gait velocity, variability and rhythm (p≤0.023). These characteristics significantly discriminated RBD (AUC≥0.620), with swing time as the single strongest discriminator (AUC=0.652). Longer walking bouts discriminated best between the groups for Macro and Micro outcomes (p≤0.036). Our results suggest that real-world gait monitoring may have utility as "risk" clinical marker in RBD participants. Real-world gait assessment is low-cost and could serve as a pragmatic screening tool to identify gait impairment in RBD.


Nanomodulation of Macrophages in Multiple Sclerosis.
Multiple Sclerosis (MS) is a chronic demyelinating autoimmune disease primarily affecting young adults. Despite an unclear causal factor, symptoms and pathology arise from the infiltration of peripheral immune cells across the blood brain barrier. Accounting for the largest fraction of this infiltrate, macrophages are functionally heterogeneous innate immune cells capable of adopting either a pro or an anti-inflammatory phenotype, a phenomenon dependent upon cytokine milieu in the CNS. This functional plasticity is of key relevance in MS, where the pro-inflammatory state dominates the early stage, instructing demyelination and axonal loss while the later anti-inflammatory state holds a key role in promoting tissue repair and regeneration in later remission. This review highlights a potential therapeutic benefit of modulating macrophage polarisation to harness the anti-inflammatory and reparative state in MS. Here, we outline the role of macrophages in MS and look at the role of current FDA approved therapeutics in macrophage polarisation. Moreover, we explore the potential of particulate carriers as a novel strategy to manipulate polarisation states in macrophages, whilst examining how optimising macrophage uptake via nanoparticle size and functionalisation could offer a novel therapeutic approach for MS.


Asymmetrical late onset motor neuropathy associated with a novel mutation in the small heat shock protein HSPB1 (HSP27).
Distal hereditary motor neuropathy, also known as distal spinal muscular atrophy, is characterised by slowly progressive weakness and wasting of the hands and feet and has a heterogeneous genetic basis. One form of distal hereditary motor neuropathy is associated with mutations in the gene for the small heat shock protein HSPB1 (hsp27). Families have been described in which slowly progressive, symmetrical, lower limb predominant motor weakness is usually evident by middle age. Here we report a novel mutation, G84R, in an elderly patient presenting with strikingly asymmetrical weakness. Expression of this and other known mutations in cell culture demonstrated enhanced aggregation of mutant HSPB1 protein compared with wild-type.


A tris-(manganese(iii))corrole-porphyrin-corrole triad: synthesis, characterization and catalytic epoxidation.
A homotrimetallic manganese(iii) corrole-porphyrin-corrole triad has been synthesized and structurally characterized. Corrole and porphyrin rings in the free base corrole-porphyrin-corrole triad are found to be roughly perpendicular to each other having a dihedral angle of 83° in the solid state. A dihedral angle of nearly 67° was found between Mn(iii)-corroles and Mn(iii)-porphyrin rings in the manganese triad complex, 1-Mn. The absorption spectrum of the manganese triad was observed to be the sum of the absorptions from manganese corrole and manganese porphyrin. The catalytic activity of the manganese triad complex was investigated for the epoxidation of styrene using iodobenzene diacetate as an oxygen source. Preliminary results obtained showed the superior activity of the manganese triad as an oxidation catalyst as compared to the respective monomer catalysts. Moreover, product yield in the oxidation of styrene catalyzed by the manganese triad was found to be higher than that of the combined activity of both monomers taken in same equivalence. The reason behind this higher yield may be attributed to an increased local concentration of the catalytic centers at the reaction site.


Unsupervised Generation of Free-Form and Parameterized Avatars.
We study two problems involving the task of mapping images between different domains. The first problem, transfers an image in one domain to an analog image in another domain. The second problem, extends the previous one by mapping an input image to a tied pair, consisting of a vector of parameters and an image that is created using a graphical engine from this vector of parameters. Similar to the first problem, the mapping's objective is to have the output image as similar as possible to the input image. In both cases, no supervision is given during training in the form of matching inputs and outputs. We compare the two unsupervised learning problems to the problem of unsupervised domain adaptation, define generalization bounds that are based on discrepancy, and employ a GAN to implement network solutions that correspond to these bounds. Experimentally, our methods are shown to solve the problem of automatically creating avatars.


The roles of monkey M1 neuron classes in movement preparation and execution.
The motor cortices exhibit substantial activity while preparing movements, yet the arm remains still during preparation. We investigated whether a subpopulation of presumed inhibitory neurons in primary motor cortex (M1) might be involved in "gating" motor output during preparation, while permitting output during movement. This hypothesis predicts a release of inhibition just before movement onset. In data from M1 of two monkeys, we did not find evidence for this hypothesis: few neurons exhibited a clear pause during movement, and these were at the tail end of a broad distribution. We then identified a subpopulation likely to be enriched for inhibitory interneurons, using their waveform shapes. We found that the firing rates of this subpopulation tended to increase during movement instead of decreasing as predicted by the M1 gating model. No clear subset that might implement an inhibitory gate was observed. Together with previous evidence against upstream inhibitory mechanisms in premotor cortex, this provides evidence against an inhibitory "gate" for motor output in cortex. Instead, it appears that some other mechanism must likely exist.


Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population.
Nonsteroidal antiinflammatory drugs (NSAIDs) are reversible inhibitors of cyclooxygenase (COX)-1 and COX-2. Whether transient and incomplete COX-1 inhibition with NSAIDs other than aspirin will translate into clinical cardioprotection is unclear. Some reports suggest that concurrent aspirin and ibuprofen might be associated with lower cardioprotection than aspirin alone because of a pharmacodynamic interaction. We conducted a cohort study with a nested case-control analysis. Overall, 4975 cases of acute myocardial infarction (MI) and death from coronary heart disease (CHD) were identified (January 1997 to December 2000) in the UK. A total of 20,000 controls were randomly sampled, and frequency was matched to cases by age, sex, and calendar year. The incidence rate was 5.0 per 1000 person-years. The multivariate-adjusted OR for current NSAID use compared with nonuse was 1.07 (95% CI, 0.95 to 1.20). Treatment duration or daily dose did not change the results. The effect was similar among patients free of CHD history (1.04; 95% CI, 0.90 to 1.20) and patients with previous history (1.12; 95% CI, 0.91 to 1.38). Estimates for individual NSAIDs were all comparable, with no major effect on the risk of acute MI. Naproxen was associated with an OR of 0.89 (95% CI, 0.64 to 1.24). The OR of aspirin and concurrent NSAIDs use was 1.10 (95% CI, 0.89 to 1.37) compared with aspirin alone. We observed the same result when analyzing ibuprofen and aspirin taken concomitantly. This study could not demonstrate any detectable risk reduction of NSAIDs on the occurrence of MI. Our results do not support the existence of a clinically meaningful interaction between aspirin and NSAIDs, including ibuprofen.


Activated protein C for the treatment of severe sepsis.
In 2001, the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial demonstrated a 6.1% absolute decrease in mortality in patients with severe sepsis. Recombinant human activated protein C was subsequently licensed for use by both the US Food and Drug Administration and the European Medicines Evaluation Agency. There has been some controversy over aspects of the original study protocol, and subsequent trials have raised concerns about both the efficacy and the side effect profile of recombinant human activated protein C. Significant doubt remains as to the role of recombinant human activated protein C in the management of severe sepsis, and this review aims to summarize the evidence both for and against its use.


Sustainable model building the role of standards and biological semantics.
Systems biology models can be reused within new simulation scenarios, as parts of more complex models or as sources of biochemical knowledge. Reusability does not come by itself but has to be ensured while creating a model. Most important, models should be designed to remain valid in different contexts-for example, for different experimental conditions-and be published in a standardized and well-documented form. Creating reusable models is worthwhile, but it requires some efforts when a model is developed, implemented, documented, and published. Minimum requirements for published systems biology models have been formulated by the MIRIAM initiative. Main criteria are completeness of information and documentation, availability of machine-readable models in standard formats, and semantic annotations connecting the model elements with entries in biological Web resources. In this chapter, we discuss the assumptions behind bottom-up modeling; present important standards like MIRIAM, the Systems Biology Markup Language (SBML), and the Systems Biology Graphical Notation (SBGN); and describe software tools and services for handling semantic annotations. Finally, we show how standards can facilitate the construction of large metabolic network models.


Heat stress does not exacerbate tennis-induced alterations in physical performance.
To assess the time course of changes in physical performance in response to match-play tennis under heat stress. Two matches consisting of 20 min of effective playing time (2×10 min segments) were played in COOL (∼102 min; ∼22°C and 70% relative humidity (RH)) and HOT (∼119 min; ∼36°C and 35% RH) environments. Repeated-sprint ability (3×15 m, 15 s rest), 15 m sprint time with a direction change (180°), vertical jump height (squat and countermovement jumps) and leg stiffness (multirebound jumps) were assessed in 12 competitive male players prematch, midmatch and postmatch, and 24 and 48 h after match completion. During the repeated-sprint ability test, initial (+2.3% and +3.1%) and cumulated sprint (+1.5% and +2.8%) times increased from prematch to midmatch and postmatch, respectively (p<0.001), while the sprint decrement score did not change. Match-play tennis induced a slowing (average of both conditions: +1.1% and +1.3% at midmatch and postmatch time points; p=0.05) of 15 m sprint time with direction change. Compared with prematch, leg stiffness (-6.4% and -6.5%; p<0.001) and squat jump height (-1.5% and -2.4%; p=0.05), but not countermovement jump height (-0.7% and -1.3%; p>0.05), decreased midmatch and postmatch, respectively, regardless of the condition. Complete recovery in all physical performance markers occurred within 24 h. In tennis, match-related fatigue is characterised by impaired repeated-sprint ability, explosive power and leg stiffness at midmatch and postmatch, with values restored to prematch baseline 24 h into recovery. In addition, physical performance responses (match and recovery kinetics) are identical when competing in cool and hot environments.


An algorithm to enumerate all possible protein conformations verifying a set of distance constraints.
The determination of protein structures satisfying distance constraints is an important problem in structural biology. Whereas the most common method currently employed is simulated annealing, there have been other methods previously proposed in the literature. Most of them, however, are designed to find one solution only. In order to explore exhaustively the feasible conformational space, we propose here an interval Branch-and-Prune algorithm (iBP) to solve the Distance Geometry Problem (DGP) associated to protein structure determination. This algorithm is based on a discretization of the problem obtained by recursively constructing a search space having the structure of a tree, and by verifying whether the generated atomic positions are feasible or not by making use of pruning devices. The pruning devices used here are directly related to features of protein conformations. We described the new algorithm iBP to generate protein conformations satisfying distance constraints, that would potentially allows a systematic exploration of the conformational space. The algorithm iBP has been applied on three α-helical peptides.


Genomic epidemiology of SARS-CoV-2 transmission lineages in Ecuador.
Characterisation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic diversity through space and time can reveal trends in virus importation and domestic circulation and permit the exploration of questions regarding the early transmission dynamics. Here, we present a detailed description of SARS-CoV-2 genomic epidemiology in Ecuador, one of the hardest hit countries during the early stages of the coronavirus-19 pandemic. We generated and analysed 160 whole genome sequences sampled from all provinces of Ecuador in 2020. Molecular clock and phylogeographic analysis of these sequences in the context of global SARS-CoV-2 diversity enable us to identify and characterise individual transmission lineages within Ecuador, explore their spatiotemporal distributions, and consider their introduction and domestic circulation. Our results reveal a pattern of multiple international importations across the country, with apparent differences between key provinces. Transmission lineages were mostly introduced before the implementation of non-pharmaceutical interventions, with differential degrees of persistence and national dissemination.


Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans.
Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor' (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (-196 to -174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR = 0.41 [95% CI 0.24-0.68], p = 0.0007) and Africans (II vs. ID&DD, OR = 0.70 [95% CI 0.51-0.95], p = 0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.


Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy.
Increased prevalence of language-based learning disabilities (LDs) has been previously reported in patients with primary progressive aphasia (PPA). This study hypothesized that patients with focal neurodegenerative syndromes outside the language network, such as posterior cortical atrophy (PCA), would have a higher rate of nonlanguage LDs, congruent with their mainly visuospatial presentation. To investigate the prevalence and type of LD (language and/or mathematical and visuospatial) in a large cohort of patients with PCA compared with patients with logopenic variant PPA (lvPPA) and amnestic Alzheimer disease (AD). This case-control study reviewed 279 medical records from a university-based clinic and research center for patients with neurodegenerative diseases for LD history, including patients with PCA (n = 95), patients with lvPPA (n = 84), and a matched cohort with amnestic AD (n = 100). No records were excluded. The study compared cognitive and neuroimaging features of patients with PCA with and without LDs. A review of the records of patients presenting from March 1, 1999, to August 31, 2014, revealed 95 PCA cases and 84 lvPPA cases. Then 100 patients with amnestic AD from this same period were chosen for comparison, matching against the groups for age, sex, and disease severity. Data analysis was performed from September 8, 2013, to November 6, 2017. Prevalence of total LD history and prevalence of language and mathematical or visuospatial LD history across all cohorts. A total of 179 atypical AD cases (95 with PCA and 84 with lvPPA) and 100 disease control cases (amnestic AD) were included in the study. The groups were not statistically different for mean (SD) age at first visit (PCA, 61.9 [7.0] years; lvPPA, 65.1 [8.7] years; amnestic AD, 64.0 [12.6] years; P = .08), mean (SD) age at first symptom (PCA, 57.5 [7.0] years; lvPPA, 61.1 [9.0] years; amnestic AD, 59.6 [13.7] years; P = .06), or sex (PCA, 66.3% female; lvPPA, 56.0% female; amnestic AD, 57.0% female; P = .30) but differed on non-right-hand preference (PCA, 18.3%; lvPPA, 20.2%; amnestic AD, 7.7%; P = .04), race/ethnicity (PCA, 88.3% white; lvPPA, 99.0% white; amnestic AD, 80.0% white; P < .001), and mean (SD) educational level (PCA, 15.7 [3.2] years; lvPPA, 16.2 [3.3] years; amnestic AD, 14.8 [3.5] years; P = .02). A total of 18 of the 95 patients with PCA (18.9%) reported a history of LD, which is greater than the 3 of 100 patients (3.0%) in the amnestic AD cohort (P < .001) and the 10.0% expected rate in the general population (P = .007). In the PCA cohort, 13 of 95 patients (13.7%) had a nonlanguage mathematical and/or visuospatial LD; this rate was greater than that in the amnestic AD (1 of 100 [1.0%]; P < .001) and lvPPA (2 of 84 [2.4%]; P = .006) cohorts and greater than the 6.0% expected general population rate of mathematical LD (P = .003). Compared with the patients with PCA without LDs, the group with LDs had greater preservation of global cognition and a more right-lateralized pattern of atrophy. Nonlanguage mathematical and visuospatial LDs were associated with focal, visuospatial predominant neurodegenerative clinical syndromes. This finding supports the hypothesis that neurodevelopmental differences in specific brain networks are associated with phenotypic manifestation of later-life neurodegenerative disease.


Tool for rapid annotation of microbial SNPs (TRAMS): a simple program for rapid annotation of genomic variation in prokaryotes.
Next generation sequencing (NGS) has been widely used to study genomic variation in a variety of prokaryotes. Single nucleotide polymorphisms (SNPs) resulting from genomic comparisons need to be annotated for their functional impact on the coding sequences. We have developed a program, TRAMS, for functional annotation of genomic SNPs which is available to download as a single file executable for WINDOWS users with limited computational experience and as a Python script for Mac OS and Linux users. TRAMS needs a tab delimited text file containing SNP locations, reference nucleotide and SNPs in variant strains along with a reference genome sequence in GenBank or EMBL format. SNPs are annotated as synonymous, nonsynonymous or nonsense. Nonsynonymous SNPs in start and stop codons are separated as non-start and non-stop SNPs, respectively. SNPs in multiple overlapping features are annotated separately for each feature and multiple nucleotide polymorphisms within a codon are combined before annotation. We have also developed a workflow for Galaxy, a highly used tool for analysing NGS data, to map short reads to a reference genome and extract and annotate the SNPs. TRAMS is a simple program for rapid and accurate annotation of SNPs that will be very useful for microbiologists in analysing genomic diversity in microbial populations.


Identification and testing of control peptides for antigen microarrays.
Peptide microarray slides usually contain positive control spots to gauge for antibody binding. Unlike the good response on earlier prototype microarrays, human immunoglobulin controls do not function consistently on newer generation slides. This may be due to technical problems in high-density printing or degradation. Our objective was to identify and print reliable control peptides that did not suffer from the same problems as proteins. Peptide microarray slides containing 10,000-23,000 synthetic peptides spanning proteins involved in M. tuberculosis or Bordatella pertussis were incubated with secondary antibody in sample dilution buffer. After removal of artefacts due to slide architecture, we identified peptides that gave a high mean response and low co-efficient of variation across all replicates. These control peptides were tested for their performance on newly manufactured slides. We selected three peptides on the TB slides and three peptides on the B. pertussis slides that had a mean response index of at least 5 and a coefficient of variation less than 15%. When used as controls in newly-designed slides, these peptides gave consistently high responses: the median index ranged from 4.5 to 9.5 in the absence of patient serum and was of a somewhat lesser magnitude when incubated with patient serum. We illustrate the use of these control responses to normalize the peptide responses on a set of slides prepared with human serum. Our work shows that it is possible to identify control peptides that can be used when protein controls do not function consistently. This has important consequences for the storage of peptide-microarrays and their use in the field: protein chips need to be kept at +4 degrees C while peptide chips can be kept at room temperature. Although we focused on TB and B. pertussis, our methodology has relevance for any disease or disorder where peptide arrays are used to assess immune response.


Power posing for paranoia: A double-blind randomised controlled experimental test using virtual reality.
Paranoia is theorised to build upon feelings of inferior social rank. Power posing has been shown to increase feelings of power, and hence could reduce paranoia. One hundred participants with current paranoia and 50 individuals without paranoia were recruited. Using a double-blind randomised controlled experimental design, participants twice held powerful or neutral postures before entering neutral virtual reality social environments. In the paranoid sample, those who held a powerful pose did not significantly increase in feelings of power by the end of testing in comparison to controls (group difference = 0.67, C.I. = -1.12; 1.46; p = 0.098), or decrease in paranoia (group difference = -0.23, C.I. = -1.17; 0.72; p = 0.634). In the non-paranoid sample, there was a small significant increase in powerful feelings by the end of testing in the powerful group (group difference = 1.13, C.I. = 0.23; 2.02; p = 0.013), but no significant decrease in paranoia (group difference = -0.71, C.I. = -2.16; 0.74; p = 0.338). Paranoia status was not a modifier on the relationship between condition and feelings of power. We conclude that power posing results in only very small changes in self-reported feelings of power and has no subsequent effect on paranoia.


Information processing in the taste system of primates.
1. Analysis of the activity of single neurones in the gustatory pathways in primates (cynomolgus monkeys) shows that the tuning of neurones to the four prototypical stimuli 1.0 mol l-1 glucose, 1.0 mol l-1 NaCl, 0.001 mol l-1 quinine-HCl and 0.01 mol l-1 HCl becomes sharper as information progresses through the taste system from the first central relay in the brainstem, the nucleus of the solitary tract, via the thalamus to the primary taste cortex in the frontal operculum and insula to reach a secondary cortical taste area in the caudolateral orbitofrontal cortex. 2. Feeding monkeys to satiety with glucose has no effect on the gustatory responses of neurones in the nucleus of the solitary tract, the frontal opercular taste cortex or the insular taste cortex, but decreases the magnitude of the neuronal responses of orbitofrontal cortex taste neurones which respond to glucose to zero. 3. The responses of orbitofrontal cortex taste neurones decrease to foods on which the monkey is fed to satiety, but continue to foods which have not just been eaten, that is, they reflect sensory-specific satiety, the phenomenon in which the pleasantness of the taste of a food and its acceptability, but not those of of other foods, is decreased by eating that food to satiety. 4. It has been found that the orbitofrontal cortex taste area or areas receives inputs from different modalities: single neurones with unimodal responses to taste (47%), olfactory (12%) and visual (10%) stimuli are found in close proximity to each other. Moreover, some single neurones show multimodal convergence, responding, for example, to taste and visual inputs (17%), taste and olfactory inputs (10%), and olfactory and visual inputs (4%). Some of these multimodal single neurones have corresponding sensitivities in the two modalities: they respond best to sweet tastes (e.g. 1 mol l-1 glucose), and respond more in a visual discrimination task to the visual stimulus which signifies sweet fruit juice than to that which signifies saline; or they respond to sweet taste and, in an olfactory discrimination task, to fruit juice odour. These results suggest that multimodal representations are formed in the orbitofrontal cortex secondary and related taste areas.(ABSTRACT TRUNCATED AT 400 WORDS)


Is there a u.s. Productivity crisis?
Long-term data on U.S. productivity growth show its enormous contribution to U.S. living standards but do not confirm fears that the country is losing its manufacturing jobs to other countries. Growth in U.S. manufacturing productivity shows no downward trend; the U.S. share of world manufacturing employment is rising and, although the share of U.S. service sector jobs has increased, that in Japan has risen three times as quickly. The threats to U.S. productivity growth are mostly shorter term, for example, the federal deficit that absorbs savings which would otherwise be used to modernize and expand plant and equipment.


Dynamical density functional theory for molecular and colloidal fluids: a microscopic approach to fluid mechanics.
In recent years, a number of dynamical density functional theories (DDFTs) have been developed for describing the dynamics of the one-body density of both colloidal and atomic fluids. In the colloidal case, the particles are assumed to have stochastic equations of motion and theories exist for both the case when the particle motion is overdamped and also in the regime where inertial effects are relevant. In this paper, we extend the theory and explore the connections between the microscopic DDFT and the equations of motion from continuum fluid mechanics. In particular, starting from the Kramers equation, which governs the dynamics of the phase space probability distribution function for the system, we show that one may obtain an approximate DDFT that is a generalization of the Euler equation. This DDFT is capable of describing the dynamics of the fluid density profile down to the scale of the individual particles. As with previous DDFTs, the dynamical equations require as input the Helmholtz free energy functional from equilibrium density functional theory (DFT). For an equilibrium system, the theory predicts the same fluid one-body density profile as one would obtain from DFT. Making further approximations, we show that the theory may be used to obtain the mode coupling theory that is widely used for describing the transition from a liquid to a glassy state.


Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice.
Glutamate dehydrogenase (GDH) plays an important role in insulin secretion as evidenced in children by gain of function mutations of this enzyme that cause a hyperinsulinism-hyperammonemia syndrome (GDH-HI) and sensitize beta-cells to leucine stimulation. GDH transgenic mice were generated to express the human GDH-HI H454Y mutation and human wild-type GDH in islets driven by the rat insulin promoter. H454Y transgene expression was confirmed by increased GDH enzyme activity in islets and decreased sensitivity to GTP inhibition. The H454Y GDH transgenic mice had hypoglycemia with normal growth rates. H454Y GDH transgenic islets were more sensitive to leucine- and glutamine-stimulated insulin secretion but had decreased response to glucose stimulation. The fluxes via GDH and glutaminase were measured by tracing 15N flux from [2-15N]glutamine. The H454Y transgene in islets had higher insulin secretion in response to glutamine alone and had 2-fold greater GDH flux. High glucose inhibited both glutaminase and GDH flux, and leucine could not override this inhibition. 15NH4Cl tracing studies showed 15N was not incorporated into glutamate in either H454Y transgenic or normal islets. In conclusion, we generated a GDH-HI disease mouse model that has a hypoglycemia phenotype and confirmed that the mutation of H454Y is disease causing. Stimulation of insulin release by the H454Y GDH mutation or by leucine activation is associated with increased oxidative deamination of glutamate via GDH. This study suggests that GDH functions predominantly in the direction of glutamate oxidation rather than glutamate synthesis in mouse islets and that this flux is tightly controlled by glucose.


Analyzing functional status and its correlates in Chinese centenarians: A cross-sectional study.
Factors affecting independence in basic and instrumental activities of daily living have been established in older adults, but not centenarians. The purpose of this study was to examine the state and factors affecting activities of daily living independence in centenarians who resided in Guangxi Province, China. A cross-sectional design was used. Activities of daily living, physical activity, mobility, and physical performance were measured by the Population Study of ChINese Elderly study instruments, and demographics and cognition were assessed. Of the 228 participants, 57% were independent in basic activities of daily living and 5.7% in instrumental activities of daily living. Stepwise regression showed physical activity, cognition, calf circumference, and self-reported health were associated with basic activities of daily living. Physical activity, mobility, cognition, and physical performance were correlated with instrumental activities of daily living. In conclusion, the Chinese centenarians showed impaired instrumental activities of daily living but mostly maintained basic functioning. Physical activity and cognition were associated with activities of daily living independence.


Dynamic modification of the vestibulo-ocular reflex by the nodulus and uvula.
The time constant of the decay of slow-phase eye velocity of postrotatory nystagmus or optokinetic after-nystagmus is reduced during exposure to a stationary visual surround (visual suppression). It is also reduced after tilting the head (tilt suppression). A "dump" mechanism in the vestibulo-ocular reflex has been proposed to rapidly discharge activity from the central vestibular system during both types of suppression. Monkeys lost this mechanism after lesions of the nodulus and uvula. They also lost the ability to habituate the time constant of nystagmus on repeated exposure to optokinetic and vestibular stimuli. Periodic alternating nystagmus, which is believed to represent an instability in the vestibulo-ocular reflex, was observed in two of three monkeys. These data indicate that the nodulus and uvula play an important role in suppressing, habituating, and stabilizing the vestibulo-ocular reflex.


Seizure Onset Detection Using Empirical Mode Decomposition and Common Spatial Pattern.
Automatic seizure onset detection plays an important role in epilepsy diagnosis. In this paper, a novel seizure onset detection method is proposed by combining empirical mode decomposition (EMD) of long-term scalp electroencephalogram (EEG) with common spatial pattern (CSP). First, wavelet transform (WT) and EMD are employed on EEG recordings respectively for filtering pre-processing and time-frequency decomposition. Then CSP is applied to reduce the dimension of multi-channel time-frequency representation, and the variance is extracted as the only feature. Afterwards, a support vector machine (SVM) group consisting of ten SVMs is served as a robust classifier. Finally, the post-processing is adopted to acquire a higher recognition rate and reduce the false detection rate. The results obtained from CHB-MIT database of 977 h scalp EEG recordings reveal that the proposed system can achieve a segment-based sensitivity of 97.34% with a specificity of 97.50% and an event-based sensitivity of 98.47% with a false detection rate of 0.63/h. This proposed detection system was also validated on a clinical scalp EEG database from the Second Hospital of Shandong University, and the system yielded a sensitivity of 93.67% and a specificity of 96.06%. At the event-based level, a sensitivity of 99.39% and a false detection rate of 0.64/h were obtained. Furthermore, this work showed that the CSP spatial filter was helpful to identify EEG channels involved in seizure onsets. These satisfactory results indicate that the proposed system may provide a reference for seizure onset detection in clinical applications.


Reduced glucocorticoid production rate, decreased 5alpha-reductase activity, and adipose tissue insulin sensitization after weight loss.
The epidemics of obesity, insulin resistance, and type 2 diabetes have heightened the need to understand mechanisms that contribute to their pathogenesis. Increased endogenous glucocorticoid production has been implicated based on parallels with Cushing's syndrome. We have assessed the impact of weight loss on glucocorticoid secretion and metabolism (notably 11beta-hydroxysteroid dehydrogenase type 1 and 5alpha-reductase [5alphaR] activity) and insulin sensitivity. Twenty obese volunteers were investigated before and after weight loss. Patients underwent hyperinsulinemic-euglycemic clamps with simultaneous adipose microdialysis and oral cortisone acetate administration. Changes in glucocorticoid secretion and metabolism were assessed using 24-h urine collections. Before weight loss, fat mass correlated with glucocorticoid secretion rate (total fat, r = 0.46, P < 0.05; trunk fat, r = 0.52, P < 0.05); however, glucocorticoid secretion rate was inversely related to insulin sensitivity (r = -0.51, P < 0.05). Hyperinsulinemia failed to suppress adipose tissue interstitial fluid glycerol release (180 +/- 50 micromol [basal] vs. 153 +/- 10 micromol [steady state], NS). After oral cortisone (25 mg), cortisol concentrations within adipose interstitial fluid increased (4.3 +/- 1.1 vs. 14.2 +/- 2.6 nmol/l, P < 0.01), but glycerol concentrations did not change. After weight loss, insulin sensitivity increased. Consistent with insulin sensitization, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinemic conditions (186 +/- 16 vs. 117 +/- 9 micromol, P < 0.05). Glucocorticoid secretion decreased (11,751 +/- 1,520 vs. 7,464 +/- 937 microg/24 h, P < 0.05) as did 5alphaR activity (5alpha-tetrahydrocortisol-to-tetrahydrocortisol ratio 1.41 +/- 0.16 vs. 1.12 +/- 0.17, P < 0.005). Obesity is associated with insulin resistance within adipose tissue and increased cortisol secretion rates; both are reversed with weight loss. Reduced 5alphaR activity after weight loss may decrease hypothalamo-pituitary-adrenal axis activation and reduce glucocorticoid metabolite production.


Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B.
DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.


Distribution of Trace Metals in Street Dusts and Tree Leaves and Their Source Identification in a Mid-Populated Anatolian City.
Sivas is a central Anatolian city in Turkey with mid-population. Due to its geographical structure high air pollution episodes can be observed in the atmosphere of Sivas. A study with city wide sampling campaign can help to identify the possible sources. Therefore, we aimed to investigate the multi-elemental and multi-point analysis of trace metals in street dusts and tree leaves in Sivas. In the street dusts, Ca concentration was > 10%. Fe, Cl, and K contribution was 2.5%, 1.75%, and 1.1%, respectively. The average S and Ti concentrations were between 1 and 10 mg/g, I, Mn, Sr, Cr, V, Ba, Zn, Ni, Zr, and Cu were between 1 and 0.1 mg/g, and W, Pb, Sn, Th, Rb, Sb, Co, Bi, As, U were between 0.1 and 0.01 mg/g, in the ascending order. The same elements were investigated for vegetation. Ca, K, S, and Cl were the elements with highest contribution.


Myasthenia gravis in a woman with congenital AChR deficiency due to epsilon-subunit mutations.
A reduction in the number of acetylcholine receptors (AChR) on the postsynaptic membrane is characteristic of MG. This may be inherited (AChR deficiency syndrome) or acquired (MG). The authors report two sisters with AChR deficiency caused by heteroallelic mutations in the AChR epsilon-subunit gene. The younger sister developed MG at 34 years. This unusual case raises the possibility that genetic defects of the AChR might be a factor in the etiology of autoimmune MG.


Efficient determination of vehicle emission factors by fuel use category using on-road measurements: downward trends on Los Angeles freight corridor I-710.
To evaluate the success of vehicle emissions regulations, trends in both fleet-wide average emissions as well as high-emitter emissions are needed, but it is challenging to capture the full spread of vehicle emission factors (EFs) with chassis dynamometer or tunnel studies, and remote sensing studies cannot evaluate particulate compounds. We developed an alternative method that links real-time on-road pollutant measurements from a mobile platform with real-time traffic data, and allows efficient calculation of both the average and the spread of EFs for light-duty gasoline-powered vehicles (LDG) and heavy-duty diesel-powered vehicles (HDD). This is the first study in California to report EFs under a full range of real-world driving conditions on multiple freeways. Fleet average LDG EFs were in agreement with most recent studies and an order of magnitude lower than observed HDD EFs. HDD EFs reflected the relatively rapid decreases in diesel emissions that have recently occurred in Los Angeles/California, and on I-710, a primary route used for goods movement and a focus of additional truck fleet turnover incentives, HDD EFs were often lower than on other freeways. When freeway emission rates (ER) were quantified as the product of EF and vehicle miles traveled (VMT) per time per mile of freeway, despite a twoto three-fold difference in HDD fractions between freeways, ERs were found to be generally similar in magnitude. Higher LDG VMT on low HDD fraction freeways largely offset the difference. Therefore, the conventional assumption that free ways with the highest HDD fractions are significantly worse sources of total emissions in Los Angeles may no longer be true.


Triple heterozygosity in the integrin alphaIIb subunit in a patient with Glanzmann's thrombasthenia.
We report triple heterozygosity in the integrin alpha(IIb) subunit in a 5-year-old Canadian girl with Glanzmann's thrombasthenia. The patient has a severe bleeding history possibly aggravated by low VWF suggestive of associated type 1 von Willebrand's disease. Platelet aggregation was absent or severely reduced for all physiologic agonists. Flow cytometry showed an approximately 4% residual surface expression of alpha(IIb)beta(3). Western blotting confirmed a low platelet expression of both subunits. PCR-SSCP and direct sequencing showed no abnormalities in the beta(3) gene, but revealed a G-->A transition at a splice site [IVS 19 (+1)] of exon 19 in the alpha(IIb) gene. Of maternal inheritance, the splice site mutation was associated with intermediate levels of alpha(IIb)beta(3) in carriers. Unexpectedly, two G-->A transitions were detected in exon 29 of the alpha(IIb) gene and led to V(951)-->M and A(958)-->T amino acid substitutions. Family studies using restriction enzymes showed that both exon 29 mutations were paternal in origin and cosegregated across three generations. Transient expression in which mutated alpha(IIb) was cotransfected with wild-type beta(3) in COS-7 cells showed that V(951)-->M gave a much reduced surface expression of alpha(IIb)beta(3) and a block in the maturation of pro-alpha(IIb). In contrast, the A(958) substitution appeared to be a novel polymorphism. Our studies highlight an unusual mixture of defects giving rise to severe bleeding in a child and describe the first pathological missense mutation affecting a C-terminal residue of the calf-2 domain of alpha(IIb).


The effect of probiotic and synbiotic supplementation on biomarkers of inflammation and oxidative stress in diabetic patients: A systematic review and meta-analysis of randomized controlled trials.
The role of gut microbiota in the management of diabetes has been shown. Several current trials are investigating the effect of probiotics and prebiotics, which are widely used to modulate intestinal microbiota, on inflammatory factors and biomarkers of oxidative stress in diabetic patients; however, their findings are controversial. The aim of the current meta-analysis was to evaluate the effects of probiotic and synbiotic supplementation on levels of serum high-sensitivity C-reactive protein (hs-CRP) and biomarkers of oxidative stress in diabetic patients. We searched the PubMed, Web of Science, and The Cochrane Library databases from the inception to October 31, 2018. Randomized controlled trials (RCTs) which reported the effect of probiotics or synbiotics on circulating (serum and plasma) inflammatory marker (hs-CRP) and oxidative stress indicators (malondialdehyde [MDA], glutathione [GSH], nitric oxide [NO], and total antioxidant capacity [TAC]) among patients with diabetes were included. Eligible studies were assessed for risk of bias and subjected to qualitative and quantitative synthesis using either fixed- or random-effects models accounting for clinical heterogeneity. Our meta-analysis identified 16 eligible RCTs (n = 1060). The methodological quality varied across these trials. Pooled data from these trials demonstrated that probiotic and synbiotic consumption significantly decreased hs-CRP level (standardized mean difference [SMD]=-0.38; 95% confidence interval [CI]:-0.51,-0.24; P = 0.000) and MDA (SMD=-0.61; 95% CI: -0.89, -0.32; P = 0.000) in diabetic patients compared to those in subjects receiving placebos. In addition, probiotic and symbiotic supplementation was found to increase TAC (SMD = 0.31; 95% CI: 0.09, 0.52; P = 0.006), NO (SMD, 0.62; 95% CI, 0.25 to 0.99; P = 0.001) and GSH (SMD = 0.41; 95% CI: 0.26, 0.55, P = 0.000) levels. The results of this systematic review and meta-analysis suggest that probiotic and synbiotic supplementation may help to improve biomarkers of inflammation and oxidative stress in diabetic patients. Further studies are needed to develop clinical practice guidelines for the management of inflammation and oxidative stress in these patients.


Neural dissociation of number from letter recognition and its relationship to parietal numerical processing.
The visual recognition of letters dissociates from the recognition of numbers at both the behavioral and neural level. In this article, using fMRI, we investigate whether the visual recognition of numbers dissociates from letters, thereby establishing a double dissociation. In Experiment 1, participants viewed strings of consonants and Arabic numerals. We found that letters activated the left midfusiform and inferior temporal gyri more than numbers, replicating previous studies, whereas numbers activated a right lateral occipital area more than letters at the group level. Because the distinction between letters and numbers is culturally defined and relatively arbitrary, this double dissociation provides some of the strongest evidence to date that a neural dissociation can emerge as a result of experience. We then investigated a potential source of the observed neural dissociation. Specifically, we tested the hypothesis that lateralization of visual number recognition depends on lateralization of higher-order numerical processing. In Experiment 2, the same participants performed addition, subtraction, and counting on arrays of nonsymbolic stimuli varying in numerosity, which produced neural activity in and around the intraparietal sulcus, a region associated with higher-order numerical processing. We found that individual differences in the lateralization of number activity in visual cortex could be explained by individual differences in the lateralization of numerical processing in parietal cortex, suggesting a functional relationship between the two regions. Together, these results demonstrate a neural double dissociation between letter and number recognition and suggest that higher-level numerical processing in parietal cortex may influence the neural organization of number processing in visual cortex.


Perspective: Why Whole Grains Should Be Incorporated into Nutrient-Profile Models to Better Capture Nutrient Density.
Healthy eating patterns, as described by dietary guidelines, typically favor whole grains, low-fat dairy, vegetables, fruit, legumes, and nuts and seeds. Nutrient-profiling (NP) models capture nutrient density of individual foods and can inform healthier food choices. Although whole grains are prominently featured in most dietary guidelines, they are not included in most NP models. Healthy foods, as identified by most NP models, are those that contain limited amounts of energy, saturated fat, total or added sugar, and sodium. As global dietary guidance turns to foods and food groups as opposed to individual nutrients, future nutrient-density metrics may need to do the same. Potential methods to incorporate whole grains into the overall concept of nutrient density and into selected NP models are outlined in this review. Incorporating whole grains into the Nutri-Score, Health Star Rating, or the Nutrient Rich Food index will require further analyses of dietary nutrient density in relation to health outcomes across diverse population subgroups. We present the rationale for how the inclusion of whole grains in NP models can assist in the implementation of dietary guidance.


Bullying in children who stutter: speech-language pathologists' perceptions and intervention strategies.
Bullying in school-age children is a global epidemic. School personnel play a critical role in eliminating this problem. The goals of this study were to examine speech-language pathologists' (SLPs) perceptions of bullying, endorsement of potential strategies for dealing with bullying, and associations among SLPs' responses and specific demographic and practice-oriented variables. A survey was developed and mailed to 1000 school-based SLPs. Six vignettes describing episodes of physical, verbal, and relational bullying of hypothetical 10-year students who stutter were developed. Three vignettes described bullying specifically mentioning stuttering behaviors, while three described bullying without mentioning stuttering behavior. The data from 475 SLPs were analyzed. SLPs rated physical bullying as most serious and in need of intervention, followed by verbal bullying. Relational bullying was rated as not serious or in need of intervention. SLPs also responded to the likelihood of using strategies for dealing with bullying. Physical and verbal bullying elicited the use of "talking with the teacher", "working with school personnel", and "reassuring the child of his safety" strategies. Relational bullying elicited "ignore the problem" and "be more assertive" strategies. Correlations among variables are reported. The seriousness of physical and verbal bullying, likelihood of intervention, and the lack of knowledge about relational bullying is discussed. Readers should be able to: (1) summarize the research describing the negative effects of three major types of bullying, (2) summarize the research describing bullying and children with communication disorders, especially stuttering, (3) report results of a survey of speech-language pathologists' (SLPs) perceptions of bullying in school-age children, (4) explain the perceived seriousness of the problem by SLPs and likelihood of intervention, and (5) describe the need for continued prevention and intervention activities for children who stutter.


Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.
The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSC) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK-BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia toward an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T-cell infiltration, activation, and cytotoxicity, and synergizes with anti-programmed cell death protein 1 (anti-PD-1 therapy). In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK-OLFML3-HIF1α-LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for patients with GBM.


Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival.
We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer. Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival. We identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458). Targeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression.


Efficient and gentle delivery of molecules into cells with different elasticity via Progressive Mechanoporation.
Intracellular delivery of cargo molecules such as membrane-impermeable proteins or drugs is crucial for cell treatment in biological and medical applications. Recently, microfluidic mechanoporation techniques have enabled transfection of previously inaccessible cells. These techniques create transient pores in the cell membrane by shear-induced or constriction contact-based rapid cell deformation. However, cells deform and recover differently from a given extent of shear stress or compression and it is unclear how the underlying mechanical properties affect the delivery efficiency of molecules into cells. In this study, we identify cell elasticity as a key mechanical determinant of delivery efficiency leading to the development of "progressive mechanoporation" (PM), a novel mechanoporation method that improves delivery efficiency into cells of different elasticity. PM is based on a multistage cell deformation, through a combination of hydrodynamic forces that pre-deform cells followed by their contact-based compression inside a PDMS-based device controlled by a pressure-based microfluidic controller. PM allows processing of small sample volumes (about 20 μL) with high-throughput (>10 000 cells per s), while controlling both operating pressure and flow rate for a reliable and reproducible cell treatment. We find that uptake of molecules of different sizes is correlated with cell elasticity whereby delivery efficiency of small and big molecules is favoured in more compliant and stiffer cells, respectively. A possible explanation for this opposite trend is a different size, number and lifetime of opened pores. Our data demonstrates that PM reliably and reproducibly delivers impermeable cargo of the size of small molecule inhibitors such as 4 kDa FITC-dextran with >90% efficiency into cells of different mechanical properties without affecting their viability and proliferation rates. Importantly, also much larger cargos such as a >190 kDa Cas9 protein-sgRNA complex are efficiently delivered high-lighting the biological, biomedical and clinical applicability of our findings.


Nutrition transition in Chile: determinants and consequences.
The purpose of this study was to analyse the determinants and consequences of the nutrition transition in Chile and describe the related health promotion policies. This is a descriptive, population-based study including data on demographic, diet, nutrition and biomedical related variables. Data came from the Food and Agriculture Organization (FAO), the National Institute of Statistics (INE), the Ministries of Planning, Health and Education surveillance systems, and national surveys. As malnutrition decreased during the 1980s, obesity increased rapidly in all age groups. In adults, currently about 25% of women are obese (body mass index >30 kg m(-2)); particularly those from low socio-economic levels. Among preschoolers, obesity is now 10% while in 6-year-old children it is 17.5% (weight/height greater than two standard deviations (>2SD) of the World Health Organization reference). Nutritional risk factors are prevalent, diet is changing to a 'Western diet' with an increasing fat consumption, and sedentarianism is constant in all groups. High blood pressure (>140/90) is greater than 10% in adults. Diabetes is increasing in urban areas, including in the indigenous population, and more than 40% of adults have a cholesterol level of more than 200 mg ml(-1). Promotion of healthy lifestyles is the main strategy to cope with this situation, particularly changing behaviour in food habits, physical activity and psychosocial factors. Changes in lifestyles will not only allow the prolonged life expectancy to be of better quality, but also will favour a decrease in the morbidity and mortality from chronic diseases, mainly cardiovascular diseases.


Decrease in the acrylamide content in canned coffee by heat treatment with the addition of cysteine.
Acrylamide (AA) is classified as a Group 2A carcinogen according to the International Agency for Research on Cancer. Although coffee contains a small amount of AA, it is a popular beverage worldwide. Approximately 10 billion canned coffees are consumed each year in Japan. In this study, we investigated how to decrease AA contained in canned coffee by modifying the heat treatment used for sterilization during the manufacturing process. The AA content of both types of canned coffee (black and milk) was decreased by approximately 95% by heat treatment with adding cysteine at 121 °C for 6 min. The content was also decreased by heat treatment with dithiothreitol, although that with cystine had no effect. Therefore, it is shown that thiol groups in cysteine and dithiothreitol might play an important role in decreasing the AA content.


Engineered disulfide bonds in staphylococcal nuclease: effects on the stability and conformation of the folded protein.
Efforts to enhance the stability of proteins by introducing engineered disulfide bonds have resulted in mixed success. Most approaches to the prediction of the energetic consequences of disulfide bond formation in proteins have considered only the destabilizing effects of cross-links on the unfolded state (chain entropy model) [Pace, C. N., Grimsley, G. R., Thomson, J. A., & Barnett, B. J. (1988) J. Biol. Chem. 263, 11820-11825: Doig, A. J., & Williams, D. H. (1991) J. Mol. Biol. 217, 389-398]. It seems clear, however, that disulfide bridges also can influence the stability of the native state. In order to assess the importance of the latter effect, we have studied four variants of staphylococcal nuclease (V8 strain) each containing one potential disulfide bridge created by changing two wild-type residues to cysteines by site-directed mutagenesis. In each case, one of the introduced cysteines was within the type VIa beta turn containing cis Pro117, and the other was located in the adjacent extended loop containing Gly79. In all four cases, the overall loop size was kept nearly constant (the number of residues in the loop between the two cysteines varied from 37 to 42) so as to minimize differences from chain entropy effects. The objective was to create variants in which a change in the reduction state of the disulfide would be coupled to a change in the position of the equilibrium between the cis and trans forms of the Xxx116-Pro117 peptide bond in the folded state of the protein. The position of this equilibrium, which can be detected by NMR spectroscopy, has been shown previously to correlate with the stability of the native protein. Its determination provides a measure of strain in the folded state. The thermal stabilities and free energies for unfolding by elevated temperature and guanidinium chloride were measured for each of the four mutants under conditions in which the introduced cysteines were cross-linked (oxidized) and unlinked (reduced). In addition, reduction potentials were determined for each mutant. Formation of the different disulfide bridges was found to induce varying levels of folded state strain. The stabilization energy of a given disulfide bridge could be predicted from the measured perturbation energy for the peptide bond isomerization, provided that energetic effects on the unfolded state were calculated according to the chain entropy model. Undiagnosed strain in native states of proteins may explain the variability observed in the stabilization provided by engineered disulfide bridges.


Cerebral venous thrombosis: diagnosis and management.
In contrast to arterial stroke, cerebral venous thrombosis (CVT) is an infrequent condition which presents with a wide spectrum of signs and with a highly variable mode of onset. The clinician must therefore consider it systematically in all brain syndromes and perform the appropriate neuroimaging investigations: computed tomography (CT) with computed tomography angiography and/or magnetic resonance imaging with magnetic resonance angiography and, if necessary intra-arterial angiography. Once the diagnosis is established, a wide investigation for should be carried out in search of the cause, and treatment started as soon as possible. Treatment is based on the combination of intravenous heparin (followed by oral anticoagulants for 3-6 months), symptomatic treatment (anticonvulsants, analgesics, treatment of increased intracranial pressure) and treatment of the cause. Local thrombolysis is indicated if there is deterioration due to thrombosis extension despite adequate anticoagulation. Diagnosis and treatment of CVT should be considered as an emergency because of the considerable potential for full recovery in this condition.


Identification of the FRAXE fragile site in two families ascertained for X linked mental retardation.
Chromosome fragility in two families not exhibiting amplification of the CGG trinucleotide associated with the fragile X site has been examined. Fluorescence in situ hybridisation with cosmid DNA from loci immediately flanking FRAXA and other distal loci have confirmed that cytogenetic fragility in these subjects is the result of expression of a new folate sensitive fragile X site, FRAXE.


Changes in endolysosomal organization define a pre-degenerative state in the crumbs mutant Drosophila retina.
Mutations in the epithelial polarity gene crumbs (crb) lead to retinal degeneration in Drosophila and in humans. The overall morphology of the retina and its deterioration in Drosophila crb mutants has been well-characterized, but the cell biological origin of the degeneration is not well understood. Degenerative conditions in the retina and elsewhere in the nervous system often involve defects in degradative intracellular trafficking pathways. So far, however, effects of crb on the endolysosomal system, or on the spatial organization of these compartments in photoreceptor cells have not been described. We therefore asked whether photoreceptors in crb mutants exhibit alterations in endolysosomal compartments under pre-degenerative conditions, where the retina is still morphologically intact. Data presented here show that, already well before the onset of degeneration, Arl8, Rab7, and Atg8-carrying endolysosomal and autophagosomal compartments undergo changes in morphology and positioning with respect to each other in crb mutant retinas. We propose that these changes may be early signs of the degeneration-prone condition in crb retinas.


[Community trajectories of mentally ill and intellectually disabled young people].
In the context of reforms in the field of disability, this study documents the trajectories and mechanisms of support for young people with mental illness or intellectual disability or pervasive developmental disorders, during the teen-adult life transition period; andfactorsfostering or impeding this transition for their maintenance in an everyday environment, particularly in SESSAD (special education and home care service) and the SAMSAH/ SPAC (medico-social support for adults with disabilities/support services in social life). This study was conducted in the French department of Seine-et-Marne. It was supported by a mixed call for tenders, in which 77 respondents (professionals, families and users), and 26 organizations were consulted. The study shows that few young adults in SAMSAH/SPAC programmes are derived from SESSAD, and they encounter major difficulties living in an everyday environment, particularly during the transition period. Clinical or socio-economic factors related to the profiles of users or healthcare service organization facilitate or hinder the inclusion of young people in an everyday environment. Support for users was also often limited to followup over a suboptimal period, and was hampered by insufficient networking within the regional healthcare system. On the other hand, empowerment of users and their optimal inclusion in an everyday environment, as founding principles of the reform, constitute major action priorities for healthcare structures. Strengthening services for young people (16-25 years), including integration strategies, is recommended in order to establish an integrated network of services in the field of disability.