In vivo antimutagenic activity of the medicinal plants Pfaffia glomerata (Brazilian ginseng) and Ginkgo biloba.
Complementary and alternative therapies, including the use of medicinal plants, have become almost standard among the world's population. Pfaffia glomerata (PG), popularly known as Brazilian ginseng, is widely used as a restorer of vital functions, increasing mental balance, and is used for the treatment of diabetes and rheumatism. Ginkgo biloba (GB) is one of the oldest known gymnosperms, whose leaves are widely used for its potentiating action on the nervous system. The biological activities of these plants were determined on bone marrow cells of Wistar rats treated in vivo. For cytotoxic and mutagenic acute analysis, plant extracts were administered by gavage at concentrations of 0.15, 1.5, and 15 mg PG/mL water and 1, 2, and 3 mg GB/mL water. For antimutagenic analysis, plant extracts aqueous solution (PG, 1.5 mg/mL or GB, 2 mg/mL) were administered by gavage before (pretreatment), simultaneous to (simultaneous treatment), or after (post-treatment) the administration of cyclophosphamide (1.5 mg/mL, intraperitoneally). Both plant extracts have no cytotoxic or mutagenic potential, and they significantly reduce the percentage of chromosomal aberrations induced by the cyclophosphamide given simultaneously (PG, 87%; GB, 75%), pretreatment (PG, 98%, GB, 78%) and post-treatment (PG, 99%, GB, 75%). This beneficial antimutagenic property of the medicinal plants P. glomerata and G. biloba presented here, with no cytotoxic or mutagenic activity, can efficiently contribute to improvements in quality of life and recovery for people undergoing chemotherapeutic treatment, or those looking for health and preventive habits.


Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.
Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases.


High-intensity Focused Ultrasound (HIFU) as salvage therapy for radio-recurrent prostate cancer: predictors of disease response.
Some men with localized radio-recurrent prostate cancer may benefit from salvage high-intensity focused ultrasound (HIFU). Herein, we describe oncologic outcomes and predictors of disease response after salvage whole gland HIFU from our prospective cohort. Patients with localized radio-recurrent prostate cancer were prospectively enrolled from January 2005 to December 2014. Participants had to meet both biochemical and histological definitions of recurrence. Exclusion criteria included the receipt of prior salvage therapy, presence of metastatic disease, and administration of ADT in the 6-months prior to enrollment. Participants were treated with a single session of whole-gland HIFU ablation with the AblathermTM device (EDAP, France). The primary endpoint was recurrence-free survival (RFS), defined as a composite endpoint of PSA progression (Phoenix criteria), receipt of any further salvage therapy, receipt of ADT, clinical progression, or death. Kaplan-Meier survival analysis was used to determine the primary end-point and stratifications were used to determine the significance of 6 pre-specified predictors of improved RFS (TRUS biopsy grade, number of study entry TRUS biopsy cores positive, palpable disease at study enrollment, pre-HIFU PSA, an undetectable post-HIFU PSA nadir, and receipt of prior hormone therapy). Survival analysis was performed on participants with a minimum of 1-year follow-up. Twenty-four participants were eligible for study inclusion with a median follow-up of 31.0 months. Median PSA at study entry was 4.02ng/ml. Median time to PSA nadir was 3 months after treatment and median post-HIFU PSA nadir was 0.04ng/ ml. Median 2-year and 5-year RFS was 66.3% and 51.6% respectively. Of our 6 pre-specified predictors, an undetectable PSA nadir was the only significant predictor of improved RFS (HR 0.07, 95% CI 0.02-0.29, log-rank P<0.001). One participant underwent an intervention for a urethral stricture. No participants developed osteitis pubis or rectourethral fistulae. Salvage HIFU allows for disease control in selected patients with localized radio-recurrent prostate cancer. An undetectable PSA nadir serves as an early predictor of disease response.


Current applications of mesenchymal stem cells for tissue replacement in otolaryngology-head and neck surgery.
Cellular therapy utilizing adult mesenchymal stromal/stem cells (MSCs) may very well revolutionize the treatment of a variety of head and neck diseases through the restoration of normal structure and function. Transplanting allogeneic or autologous MSCs into damaged tissues can serve multiple regenerative functions through their self-renewal, differentiation capacity, immune modulation and secretion of bioactive molecules. Further, trophic factors expressed by MSCs have been shown to influence their microenvironment through the promotion of extracellular matrix remodeling, angiogenesis and wound healing needed to regenerate or replace injured tissues. Although clinical applications of MSC based therapies in Otolaryngology-Head and Neck Surgery are still in their infancy, efforts are being made to understand and exploit MSCs for tissue repair as well as engineering strategies. In this review, we highlight pre clinical and clinical investigations employing MSC based therapies for the reconstruction of bone, cartilage, soft tissue and vocal fold defects.


Successful Direct Adsorption of Lipoproteins (DALI) Apheresis During Pregnancy in an Omani Woman with Homozygous Familial Hypercholesterolemia.
We report our experience with Direct Adsorption of Lipoproteins (DALI) apheresis in an Omani pregnant woman affected by homozygous familial hypercholesterolemia. To the best of our knowledge this is the first successful pregnancy treated with DALI apheresis. The patient had a history of coronary artery disease, supra-aortic valvular stenosis and severe carotid artery disease with right carotid artery stenting. She was on a regular biweekly DALI apheresis since 2008. In May 2013, she became pregnant and rosuvastatin and ezetimibe were stopped while she continued on DALI apheresis biweekly. This treatment during pregnancy was successful with no major complications. The average low-density lipoprotein cholesterol reduction during therapy was 50%. She spontaneously delivered a healthy male infant (2,400 g) at 37 weeks. We showed that DALI apheresis therapy was safe during pregnancy with a good outcome for both mother and neonate.


A controlled trial of lambda-cyhalothrin-impregnated bed nets and/or dapsone/pyrimethamine for malaria control in Sierra Leone.
A randomized controlled trial investigated the impact of community-wide use of mosquito nets impregnated with lambda-cyhalothrin alone or with dapsone/pyrimethamine (d/p) prophylaxis on clinical malaria due to perennially transmitted Plasmodium falciparum in children in the Bo district of Sierra Leone. The 17 study communities were pair-matched and randomly allocated to receive treated mosquito nets or no nets and the children (age range = 3 months-6 years) in each community were randomly allocated to receive d/p or placebo individually every two weeks. This resulted in each of the approximately 2,000 children recruited being in one of four study groups (impregnated mosquito nets and d/p prophylaxis, impregnated mosquito nets, d/p prophylaxis, and controls). The intervention phase of the study lasted 12 months. A total of 1,800 children attended more than 25% of the 48 total weekly morbidity surveillance surveys and were included in the analysis. The effects of the exclusive use of either treated mosquito nets or d/p prophylaxis on protection against clinical malaria due to P. falciparum was significantly similar (49% and 42%, respectively), while in combination this protective efficacy was significantly increased to 72% (95% confidence interval = 67-76%). Children in the control group had an average of 1.3 clinical malaria episodes per child annually compared with 0.65 episodes or 0.78 episodes for those using treated mosquito nets and d/p, respectively. Children using both treated mosquito nets and d/p prophylaxis had an average of 0.37 episodes per child. The interventions significantly reduced spleen rates and increased hematocrit values, and reduced the duration of episodes of clinical malaria.


After Action Report: Lessons Learned From Simulating Unified Command In Response to an Active Shooter Incident Using a Command Competency Laboratory.
On October 10, 2019, the Loudoun County Sheriff's Office (LCSO) and Loudoun County Fire and Rescue (LCFR) led one of the largest act of violence (AVI) exercises ever conducted in Loudoun County, Virginia. Over 300 participants and 50 role-players participated across 15 county departments and agencies within Loudoun County. The exercise identified an important recommendation: "future joint unified command trainings are needed throughout the fire and law enforcement command structures." Effective, unified command is an essential NFPA 3000 principle of responding to an AVI. "The success or failure of the response will hinge on the quality of unified command." After-action reports from AVIs across the United States emphasized the importance of unified command. A second exercise recommendation proposed "a joint AVI unified command competency scenario between LCFR and LCSO should be developed and delivered across all levels of supervision... this scenario should demonstrate 'best practices' for establishing and operating unified command between LCFR and LCSO." The authors developed two active shooter command competency simulations that require LCSO and LCFR to form unified command and manage the initial response. The simulations reinforced accepted response practices, such as identification of cold/warm/hot zones, early unified command, rescue task force team deployment, and protected corridor establishment. The simulations were packaged into a unified command competency training and simulation program. Through the facilitated debriefings with participants and facilitator debriefs, three types of lessons learned were identified: 1) high threat incident response lessons, 2) lessons for conducting AVIs in the command competency lab, and 3) active threat operational considerations for command officers.


Dopamine release in the human striatum: motor and cognitive tasks revisited.
Striatal dopamine (DA) release has been shown during behavioural tasks, but the relative contribution of motor, reward, and cognitive components is unclear. Dopamine release was quantified using [(11)C]-raclopride in two studies using a triple-scan approach, comprising active task, motor control, and rest. In the first, bolus radiotracer was delivered during a sequential motor learning paradigm; in the second, a spatial planning task, bolus plus constant infusion was applied. [(11)C]-raclopride binding potentials (BP(ND)s) in striatal functional subdivisions were compared across conditions. [(11)C]-raclopride BP(ND) was significantly reduced in active task compared with rest in both the sensorimotor and associative striatum in both studies, because of differences between rest and motor control conditions. In both regions, the motor control BP(ND) fell between the rest and active task in the planning study, but the difference between motor control and active task conditions was not significant. No such changes were observed in the limbic striatum. Using rigorous methodology, this study validates earlier evidence that striatal DA release occurs during behavioural challenges. Increased DA release during movement was reliably detected in the sensorimotor and associative striatum, supporting use of the functional subdivision model in humans. No additional DA release was observed specific to the cognitive component of either task.


Optimization of microfluidic single cell trapping for long-term on-chip culture.
The poor efficiency of microfluidic single cell trapping is currently restricting the full potential of state-of-the-art single cell analyses. Using fluid dynamics simulations in combination with particle image velocimetry to systematically optimize trap architectures, we present a microfluidic chip with enhanced single cell trapping and on-chip culture performance. Upon optimization of trap geometries, we measured trapping efficiencies of up to 97%. Our device also enables the stable, relatively long-term culture of individual non-adherent mammalian cells in high-throughput without a significant decrease in cell viability. As a first application of this platform we demonstrate the automated separation of the two daughter cells generated upon single cell division. The reliable trapping and re-trapping of mammalian cells should for example provide the fundament for novel types of investigations in stem cell and tumour cell biology, which depend on reliable tracking of genealogical relationships such as in stem cell lineage tracking.


A glucose-utilizing strain, Cupriavidus euthrophus B-10646: growth kinetics, characterization and synthesis of multicomponent PHAs.
This study investigates kinetic and production parameters of a glucose-utilizing bacterial strain, C. eutrophus B-10646, and its ability to synthesize PHA terpolymers. Optimization of a number of parameters of bacterial culture (cell concentration in the inoculum, physiological activity of the inoculum, determined by the initial intracellular polymer content, and glucose concentration in the culture medium during cultivation) provided cell concentrations and PHA yields reaching 110 g/L and 80%, respectively, under two-stage batch culture conditions. Addition of precursor substrates (valerate, hexanoate, propionate, γ-butyrolactone) to the culture medium enabled synthesis of PHA terpolymers, P(3HB/3HV/4HB) and P(3HB/3HV/3HHx), with different composition and different molar fractions of 3HB, 3HV, 4HB, and 3HHx. Different types of PHA terpolymers synthesized by C. eutrophus B-10646 were used to prepare films, whose physicochemical and physical-mechanical properties were investigated. The properties of PHA terpolymers were significantly different from those of the P3HB homopolymer: they had much lower degrees of crystallinity and lower melting points and thermal decomposition temperatures, with the difference between these temperatures remaining practically unchanged. Films prepared from all PHA terpolymers had higher mechanical strength and elasticity than P3HB films. In spite of dissimilar surface structures, all films prepared from PHA terpolymers facilitated attachment and proliferation of mouse fibroblast NIH 3T3 cells more effectively than polystyrene and the highly crystalline P3HB.


Biodegradable electrospun patch containing cell adhesion or antimicrobial compounds for trachea repair in vivo.
Difficulty breathing due to tracheal stenosis (i.e. narrowed airway) diminishes the quality of life and can potentially be life-threatening. Tracheal stenosis can be caused by congenital anomalies, external trauma, infection, intubation-related injury, and tumors. Common treatment methods for tracheal stenosis requiring surgical intervention include end-to-end anastomosis, slide tracheoplasty and/or laryngotracheal reconstruction. Although the current methods have demonstrated promise for treatment of tracheal stenosis, a clear need exists for the development of new biomaterials that can hold the trachea open after the stenosed region has been surgically opened, and that can support healing without the need to harvest autologous tissue from the patient. The current study therefore evaluated the use of electrospun nanofiber scaffolds encapsulating 3D-printed PCL rings to patch induced defects in rabbit tracheas. The nanofibers were a blend of polycaprolactone (PCL) and polylactide-co-caprolactone (PLCL), and encapsulated either the cell adhesion peptide, RGD, or antimicrobial compound, ceragenin-131 (CSA). Blank PCL/PLCL and PCL were employed as control groups. Electrospun patches were evaluated in a rabbit tracheal defect model for 12 weeks, which demonstrated re-epithelialization of the luminal side of the defect. No significant difference in lumen volume was observed for the PCL/PLCL patches compared to the uninjured positive control. Only the RGD group did not lead to a significant decrease in the minimum cross-sectional area compared to the uninjured positive control. CSA reduced bacteria growth in vitro, but did not add clear value in vivo. Adequate tissue in-growth into the patches and minimal tissue overgrowth was observed inside the patch material. Areas of future investigation include tuning the material degradation time to balance cell adhesion and structural integrity.


Desorption electrospray ionization mass spectrometry reveals lipid metabolism of individual oocytes and embryos.
Alteration of maternal lipid metabolism early in development has been shown to trigger obesity, insulin resistance, type 2 diabetes and cardiovascular diseases later in life in humans and animal models. Here, we set out to determine (i) lipid composition dynamics in single oocytes and preimplantation embryos by high mass resolution desorption electrospray ionization mass spectrometry (DESI-MS), using the bovine species as biological model, (ii) the metabolically most relevant lipid compounds by multivariate data analysis and (iii) lipid upstream metabolism by quantitative real-time PCR (qRT-PCR) analysis of several target genes (ACAT1, CPT 1b, FASN, SREBP1 and SCAP). Bovine oocytes and blastocysts were individually analyzed by DESI-MS in both positive and negative ion modes, without lipid extraction and under ambient conditions, and were profiled for free fatty acids (FFA), phospholipids (PL), cholesterol-related molecules, and triacylglycerols (TAG). Principal component analysis (PCA) and linear discriminant analysis (LDA), performed for the first time on DESI-MS fused data, allowed unequivocal discrimination between oocytes and blastocysts based on specific lipid profiles. This analytical approach resulted in broad and detailed lipid annotation of single oocytes and blastocysts. Results of DESI-MS and transcript regulation analysis demonstrate that blastocysts produced in vitro and their in vivo counterparts differed significantly in the homeostasis of cholesterol and FFA metabolism. These results should assist in the production of viable and healthy embryos by elucidating in vivo embryonic lipid metabolism.


Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.
Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.


How equitable is the scaling up of HIV service provision in South Africa?
To assess the extent of inequalities in availability and utilisation of HIV services across South Africa. Cross-sectional descriptive study. Three districts reflecting different socio-economic conditions, but with similar levels of HIV infection, were purposively sampled. Availability and utilisation of HIV services and management and support structures for programmes were assessed through the collection of secondary data supplemented by site visits. There were marked inequalities in service delivery between the three sites. Compared with two poorer sites, clinics at the urban site had greater availability of HIV services, including voluntary counselling and testing (100% v. 52% and 24% respectively), better uptake of this service (59 v. 9 and 5.5 clients per 1000 adults respectively) and greater distribution of condoms (15.6 v. 8.2 condoms per adult male per year). Extra counsellors had also been employed at the urban site in contrast to the other 2 sites. The urban site also had far more intensive management support and monitoring, with 1 manager per 12 health facilities compared with 1 manager per more than 90 health facilities at the other 2 sites. The process of scaling up of HIV services seems to be accentuating inequalities. The urban site in this study was better able to utilise the extra resources. In contrast, the poorer sites have thus far been unable to scale up the response to HIV even with the availability of extra resources. Unless policy makers pay more attention to equity, efficacious interventions may prove to be of limited effectiveness.


Epstein-Barr virus-associated Hodgkin's disease: epidemiologic characteristics in international data.
Hodgkin's disease (HD) has long been suspected to have an infectious precursor, and indirect evidence has implicated Epstein-Barr virus (EBV), a ubiquitous herpesvirus, as a causal agent. Recent molecular studies using EBER in situ hybridization or latency membrane protein-I (LMP-I) immunohistochemistry have identified EBV latent infection in up to 50% of HD tumors. However, the epidemiologic features of these cases have not been examined in detail. To explore the epidemiology of EBV-positive HD so as to understand the role of EBV in HD etiology more clearly, this project accumulated patient data from 14 studies that had applied these EBV assays to HD tumors. With information on age at diagnosis, sex, ethnicity, histologic subtype, country of residence, clinical stage and EBV tumor status from 1,546 HD patients, we examined risk for EBV-positive disease using logistic regression. Forty percent of subjects had EBV-positive tumors, and EBV prevalence varied significantly across groups defined by the study variables. Odds ratios (OR) for EBV-associated HD were significantly elevated for Hispanics vs. whites (OR = 4.1), mixed cellularity vs. nodular sclerosis histologic subtypes (OR = 7.3, 13.4, 4.9 for ages 0-14, 15-49, 50+ years), children from economically less-developed vs. more-developed regions and young adult males vs. females (OR = 2.5). These findings suggest that age, sex, ethnicity and the physiologic effects of poverty may represent biologic modifiers of the EBV association and confirm that this association is strongly but variably linked to histologic subtype. The data augment biologic evidence that EBV is actively involved in HD pathogenesis in some cases but describe epidemiologic complexity in this process.


Socioeconomic correlates of mortality differentials by local government area in rural northern New South Wales, 1981-1995.
Many studies have examined the correlation between socioeconomic status (SES) and mortality in Australia, but little is known about the correlation in rural areas and most studies have not explored the trends in SES differentials in mortality. This ecological study examines this correlation and explores the impact of the national strategies to reduce SES differentials in mortality in a rural area. Mortality data for residents in the New England Health Area, New South Wales (NSW), 1981 to 1995, were analysed. Twenty Local Government Areas (LGAs) in New England were ranked and aggregated into 4 groups according to a composite SES indicator from the 1996 census, and age/sex adjusted mortality rates were calculated for each group and compared. Poisson regression models were used to assess the linear trends in mortality for 1981-95. A strong relationship between working age adult mortality and SES was found for both sexes. The rates for the most disadvantaged LGAs were significantly higher than the least disadvantaged LGAs for both sexes. The mortality rate was consistently higher for the most disadvantaged LGAs than the least disadvantaged LGAs. Although there has been an overall decline in death for all 4 groups of LGAs, the gap between the most disadvantaged and the least disadvantaged groups has widened over the last 15 years. This widening gap in death rates suggests that the strategies implemented as part of the Health for All initiative to reduce inequalities in mortality differentials have not been effective in this rural area.


Insights Into the Mechanism of MCT8 Oligomerization.
Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency, characterized by severe intellectual and motor disability. The MCT8 protein is predicted to have 12 transmembrane domains (TMDs) and is expressed as monomers, homodimers, and homo-oligomers. This study aimed to delineate the mechanism of MCT8 oligomerization. Coimmunoprecipitation studies demonstrated that lithium dodecyl sulfate effectively disrupts MCT8 protein complexes, indicating the involvement of non-covalent interactions. Successive C-terminal truncations of the MCT8 protein altered the oligomerization pattern only if introduced in the N-terminal half of the protein (TMD1-6). The truncation at extracellular loop 1 (E206X) still allowed homodimerization, but completely abrogated homo-oligomerization, whereas both were preserved by the C231X mutant (at TMD2), suggesting that the minimally required oligomerization sites are located proximal of Cys231. However, mutant constructs lacking the intracellular N-terminus or TMD1 and 2 were still capable to form homo-oligomers. Therefore, other domains distal of Cys231 are also likely to be involved in the formation of extensive multidomain interactions. This hypothesis was supported by structural modeling. Despite multiple approaches, MCT8 oligomerization could not be fully abrogated unless a substantial part of the protein was removed, precluding detailed studies into its functional role. Together, our findings suggest that MCT8 oligomerization involves extensive noncovalent interactions between the N-terminal halves of MCT8 proteins. Most mutations identified in patients with MCT8 deficiency have only minor effects on MCT8 oligomerization and, thus, impaired oligomerization does not appear to be an important pathogenic mechanism.


Listeners normalize speech for contextual speech rate even without an explicit recognition task.
Speech can be produced at different rates. Listeners take this rate variation into account by normalizing vowel duration for contextual speech rate: An ambiguous Dutch word /m?t/ is perceived as short /mɑt/ when embedded in a slow context, but long /ma:t/ in a fast context. While some have argued that this rate normalization involves low-level automatic perceptual processing, there is also evidence that it arises at higher-level cognitive processing stages, such as decision making. Prior research on rate-dependent speech perception has only used explicit recognition tasks to investigate the phenomenon, involving both perceptual processing and decision making. This study tested whether speech rate normalization can be observed without explicit decision making, using a cross-modal repetition priming paradigm. Results show that a fast precursor sentence makes an embedded ambiguous prime (/m?t/) sound (implicitly) more /a:/-like, facilitating lexical access to the long target word "maat" in a (explicit) lexical decision task. This result suggests that rate normalization is automatic, taking place even in the absence of an explicit recognition task. Thus, rate normalization is placed within the realm of everyday spoken conversation, where explicit categorization of ambiguous sounds is rare.


Effect of Continuous Positive Airway Pressure on Blood Pressure Variability in Patients With Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) is a common risk factor for cardiovascular disease. Continuous positive airway pressure (CPAP) improves OSA symptoms and blood pressure (BP) control. The effect of CPAP on BP variability (BPV) in patients with and without hypertension treated with autotitrating CPAP (APAP) for 2 weeks was studied. A total of 78 participants (76.9% men, 49% hypertensive, mean body mass index 36.2 [6.9] kg/m2 , age 49.0 [12.9] years) underwent 2 weeks of APAP therapy. Office BP, BPV (standard deviation of three BP measurements), and pulse rate were measured before and after treatment. Systolic BPV (5.3±4.9 vs 4.2±3.4 mm Hg, P=.047) and pulse rate (78.0±14.5 vs 75.5±15.8 beats per minute, P=.032) decreased after treatment, particularly in hypertensive participants. Mask leak was independently associated with reduced changes in systolic BPV (r=-0.237, P=.048). Short-term APAP treatment reduced BPV and pulse rate, particularly in hypertensive patients with OSA.


Gravid females of the mosquito Aedes aegypti avoid oviposition on m-cresol in the presence of the deterrent isomer p-cresol.
p-cresol (4-methylphenol) and its isomer m-cresol (3-methylphenol) have been shown to activate the same sensilla in Aedes aegypti (Linnaeus) mosquitoes. Whereas p-cresol has been suggested to play a role in oviposition site choice, the behavioral significance of m-cresol is unknown. Here, we assayed the oviposition behavior of Aedes aegypti towards p-cresol and m-cresol using cage assay. Specifically we tested different concentrations of p-cresol (10-12-103 ppm) and m-cresol (10-1-103 ppm), the 1:1 mixture of the two compounds at 102 ppm, and the two individual compounds at 102 ppm together in the same cage. We show that (1) p-cresol is a stimulant at a low concentration and deterrent over a broad range of higher concentrations (10-8-103 ppm), while m-cresol was behaviorally ineffective, except for a deterrent effect at the highest concentration (103 ppm) (2) in concentration choice tests (different concentrations tested against each other), both compounds were deterrent only at the highest concentration (3) a 1:1 mixture of both compounds exhibited a deterrent effect on oviposition (4) when presented in separate cups but together in the same cage, p-cresol and m-cresol (102 ppm) both received significantly less eggs than water alone. Our results suggest that p-cresol is a strong oviposition deterrent with a stimulant effect at only a very low concentration, while m-cresol is not a deterrent per se. However, in the presence of p-cresol in the vicinity, m-cresol acts as a deterrent. This finding adds a new twist to the possible interactions of different odors in oviposition site choice: not only the source itself, but nearby odors also influence a mosquito's choice.


Metabolic and respiratory status of stranded juvenile loggerhead sea turtles (Caretta caretta): 66 cases (2008-2009).
To document venous blood gas, acid-base, and plasma biochemical values for stranded juvenile loggerhead turtles at admission to a rehabilitation facility, compare these values among stranding causes, investigate differences in these values for turtles that survived versus those that died, and establish the baseline values for successfully rehabilitated loggerhead turtles (Caretta caretta). Retrospective case series. 66 stranded juvenile loggerhead turtles that were hospitalized between 2008 and 2009. Venous blood gas, acid-base, and plasma biochemical values at the time of admission were compared retrospectively among turtles with different stranding causes. Initial results were compared between turtles that survived and turtles that died. Results for survivors were compared between the time of admission and time of release. Results-57 (86.36%) turtles had various types of acid-base disorders at the time of admission to the rehabilitation facility. Of these, 33 (579%) had mixed acid-base disorders and 24 (42.1%) had primary acid-base disorders. All acid-base disorders were classified as mild to moderate, except 1 case of severe metabolic and respiratory acidosis. Except for the debilitated turtles (in which the mean initial glucose concentration was much lower than that observed for the rest of turtles), there was no difference in initial values when comparing stranding causes. Turtles that died during rehabilitation had significantly higher initial anion gap and osmolality, compared with turtles that survived. Acid-base disorders were present in most stranded juvenile loggerhead turtles. Evaluation of accurately obtained, temperature-corrected venous blood gas, acid-base, and plasma biochemical values can provide important clinical and prognostic information and a valuable basis for the implementation of adequate and rapid treatment for stranded loggerhead turtles admitted to rehabilitation facilities.


Estimating meiotic gene conversion rates from population genetic data.
Gene conversion plays an important part in shaping genetic diversity in populations, yet estimating the rate at which it occurs is difficult because of the short lengths of DNA involved. We have developed a new statistical approach to estimating gene conversion rates from genetic variation, by extending an existing model for haplotype data in the presence of crossover events. We show, by simulation, that when the rate of gene conversion events is at least comparable to the rate of crossover events, the method provides a powerful approach to the detection of gene conversion and estimation of its rate. Application of the method to data from the telomeric X chromosome of Drosophila melanogaster, in which crossover activity is suppressed, indicates that gene conversion occurs approximately 400 times more often than crossover events. We also extend the method to estimating variable crossover and gene conversion rates and estimate the rate of gene conversion to be approximately 1.5 times higher than the crossover rate in a region of human chromosome 1 with known recombination hotspots.


International society of sports nutrition position stand: diets and body composition.
Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3-3.1 g/kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (>3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management.


A rapid review of the rate of attrition from the health workforce.
Attrition or losses from the health workforce exacerbate critical shortages of health workers and can be a barrier to countries reaching their universal health coverage and equity goals. Despite the importance of accurate estimates of the attrition rate (and in particular the voluntary attrition rate) to conduct effective workforce planning, there is a dearth of an agreed definition, information and studies on this topic. We conducted a rapid review of studies published since 2005 on attrition rates of health workers from the workforce in different regions and settings; 1782 studies were identified, of which 51 were included in the study. In addition, we analysed data from the State of the World's Midwifery (SoWMy) 2014 survey and associated regional survey for the Arab states on the annual voluntary attrition rate for sexual, reproductive, maternal and newborn health workers (mainly midwives, doctors and nurses) in the 79 participating countries. There is a diversity of definitions of attrition and barely any studies distinguish between total and voluntary attrition (i.e. choosing to leave the workforce). Attrition rate estimates were provided for different periods of time, ranging from 3 months to 12 years, using different calculations and data collection systems. Overall, the total annual attrition rate varied between 3 and 44% while the voluntary annual attrition rate varied between 0.3 to 28%. In the SoWMy analysis, 49 countries provided some data on voluntary attrition rates of their SRMNH cadres. The average annual voluntary attrition rate was 6.8% across all cadres. Attrition, and particularly voluntary attrition, is under-recorded and understudied. The lack of internationally comparable definitions and guidelines for measuring attrition from the health workforce makes it very difficult for countries to identify the main causes of attrition and to develop and test strategies for reducing it. Standardized definitions and methods of measuring attrition are required.


Controlling sunbathing safety during the summer holidays - The solar UV campaign at Baltic Sea coast in 2015.
Information regarding the intensity of surface UV radiation, provided for the public, is frequently given in terms of a daily maximum UV Index (UVI), based on a prognostic model. The quality of the UV forecast depends on the accuracy of column amount of ozone and cloudiness prediction. Daily variability of UVI is needed to determine the risk of the UV overexposure during outdoor activities. Various methods of estimating the temporary UVI and the maximum duration of UV exposures (received a dose equal to minimal erythemal dose - MED), at the site of sunbathing, were compared. The UV indices were obtained during a field experiment at the Baltic Sea coast in the period from 13th to 24th July 2015. The following UVI calculation models were considered: UVI measurements by simple hand-held biometers (Silver Crest, Oregon Scientific, or more advanced Solarmeter 6.5), our smartphone models based on cloud cover observations at the site and the cloudless-sky UVI forecast (available for any site for all smartphone users) or measured UVI, and the 24h weather predictions by the ensemble set of 10 models (with various cloud parameterizations). The direct UV measurements, even by a simple biometer, provided useful UVI estimates. The smartphone applications yielded a good agreement with the UV measurements. The weather prediction models for cloudless-sky conditions could provide valuable information if almost cloudless-sky conditions (cloudless-sky or slightly scattered clouds) were observed at the sunbathing site.


Directed chloroplast transformation in Chlamydomonas reinhardtii: insertional inactivation of the psaC gene encoding the iron sulfur protein destabilizes photosystem I.
The chloroplast gene psaC encoding the iron sulfur protein of photosystem I (PSI) from the green alga Chlamydomonas reinhardtii has been cloned and characterized. The deduced amino acid sequence is highly related to that of higher plants and cyanobacteria. Using a particle gun, wild type C. reinhardtii cells have been transformed with a plasmid carrying the psaC gene disrupted by an aadA gene cassette designed to express spectinomycin/streptomycin resistance in the chloroplast. Transformants selected on plates containing acetate as a reduced carbon source and spectinomycin are unable to grow on minimal medium lacking acetate and are deficient in PSI activity. Southern blot analysis of total cell DNA of the transformants shows that the wild type psaC gene has been replaced by the interrupted psaC gene through homologous recombination. While authentic transcripts of the psaC gene are no longer detected, aadA gives rise to a few transcripts in the transformants. Biochemical analysis indicates that neither PSI reaction center subunits nor the seven small subunits belonging to PSI accumulate stably in the thylakoid membranes of the transformants. Pulse-chase labeling of cell proteins shows that the PSI reaction center subunits are synthesized normally but turn over rapidly in the transformants. We conclude that the iron sulfur binding protein encoded by the psaC gene is an essential component, both for photochemical activity and for stable assembly of PSI. The present study suggests that any chloroplast gene encoding a component of the photosynthetic apparatus can be disrupted in C. reinhardtii using the strategy described.


Neurotrophic factors in neurodegeneration.
Neurotrophic factors (NTFs) have the unique potential to support neuronal survival and to augment neuronal function in the injured and diseased nervous system. Numerous studies conducted over the last 20 years have provided evidence for the potent therapeutic potential of NTFs in animal models of neurodegenerative diseases. However, major obstacles for the therapeutic use of NTFs are the inability to deliver proteins across the blood-brain-barrier, and dose-limiting adverse effects resulting from the broad exposure of nontargeted structures to NTFs. Two recent developments have allowed NTFs' promise to be truly tested for the first time: first, recent improvements in viral vectors that allow the targeted delivery of NTFs while providing a long-lasting supply and sufficient therapeutic doses of NTFs; and second, improved animal models developed in recent years. In this review, we will discuss some of the potential therapeutic applications of NTFs in neurodegenerative diseases and the potential contribution of disturbed neurotrophic factor signaling to neurodegenerative diseases.


Henneguya sp. in yellowfin goby Acanthogobius flavimanus from the San Francisco Estuary.
Myxozoan spores were observed in yellowfin goby Acanthogobius flavimanus collected from Suisun Marsh, San Francisco Estuary (SFE). Although histopathological changes associated with the parasite were not observed, the spores formed plasmodia that partially blocked the gastric and intestinal mucosa and gut lumen and may affect the perfomance and survival of the yellowfin goby. Morphological features of the spores resembled Henneguya sp. and molecular analysis of the 18S ribosomal DNA (Domain III) confirmed close similarity to H. rhinogobii and H. pseudorhinogobii isolated from the Japanese freshwater goby. The yellowfin goby myxozoan however, is likely an undescribed species based on phylogenetic analysis and morphologic features. Detailed description of vegetative and spore stages are currently lacking for proposal to a new species of Henneguya. A specific PCR test was developed, which confirmed a 100% prevalence of the parasite among randomly collected gobies in group 1 (N = 30) and group 2 (N = 15) at termination of the study at one month in captivity. The myxozoan was also detected from 18 gobies (12%) that died in the first group within two weeks in captivity. Apparently healthy gobies that served as controls did not reveal the presence of the myxozoan by PCR. This study documents the occurrence of a potentially new species of myxozoan in the yellowfin goby and underscores the detection of a parasitic infection in an introduced fish in the SFE. Although the pathogenesis of the myxozoan was not assessed and the prevalence as reported here is restricted to a comparatively small collection site in Suisun slough, the reemergence, identification, and ecological relevance of the parasite on goby populations in the SFE may be investigated in the future using the specific diagnostic tool developed in this study.


Discriminative application of string similarity methods to chemical and non-chemical names for biomedical abbreviation clustering.
Term clustering, by measuring the string similarities between terms, is known within the natural language processing community to be an effective method for improving the quality of texts and dictionaries. However, we have observed that chemical names are difficult to cluster using string similarity measures. In order to clearly demonstrate this difficulty, we compared the string similarities determined using the edit distance, the Monge-Elkan score, SoftTFIDF, and the bigram Dice coefficient for chemical names with those for non-chemical names. Our experimental results revealed the following: (1) The edit distance had the best performance in the matching of full forms, whereas Cohen et al. reported that SoftTFIDF with the Jaro-Winkler distance would yield the best measure for matching pairs of terms for their experiments. (2) For each of the string similarity measures above, the best threshold for term matching differs for chemical names and for non-chemical names; the difference is especially large for the edit distance. (3) Although the matching results obtained for chemical names using the edit distance, Monge-Elkan scores, or the bigram Dice coefficients are better than the result obtained for non-chemical names, the results were contrary when using SoftTFIDF. (4) A suitable weight for chemical names varies substantially from one for non-chemical names. In particular, a weight vector that has been optimized for non-chemical names is not suitable for chemical names. (5) The matching results using the edit distances improve further by dividing a set of full forms into two subsets, according to whether a full form is a chemical name or not. These results show that our hypothesis is acceptable, and that we can significantly improve the performance of abbreviation-full form clustering by computing chemical names and non-chemical names separately. In conclusion, the discriminative application of string similarity methods to chemical and non-chemical names may be a simple yet effective way to improve the performance of term clustering.


Processes of care associated with acute stroke outcomes.
Many processes of care have been proposed as metrics to evaluate stroke care. We sought to identify processes of stroke care that are associated with improved patient outcomes after adjustment for both patient characteristics and other process measures. This retrospective cohort study included patients 18 years or older with an ischemic stroke or transient ischemic attack (TIA) onset no more than 2 days before admission and a neurologic deficit on admission. Patients were excluded if they resided in a skilled nursing facility, were already admitted to the hospital at stroke onset, or were transferred from another acute-care facility. The combined outcome included in-hospital mortality, discharge to hospice, or discharge to a skilled nursing facility. Seven processes of stroke care were evaluated: fever management, hypoxia management, blood pressure management, neurologic evaluation, swallowing evaluation, deep vein thrombosis (DVT) prophylaxis, and early mobilization. Risk adjustment included age, comorbidity (medical history), concomitant medical illness present at admission, preadmission symptom course, prestroke functional status, code status, stroke severity, nonneurologic status, modified APACHE (Acute Physiology and Chronic Health Evaluation) III score, and admission brain imaging findings. Among 1487 patients, the outcome was observed in 239 (16%). Three processes of care were independently associated with an improvement in the outcome after adjustment: swallowing evaluation (adjusted odds ratio [OR], 0.64; 95% confidence interval [CI], 0.43-0.94); DVT prophylaxis (adjusted OR, 0.60; 95% CI, 0.37-0.96); and treating all episodes of hypoxia with supplemental oxygen (adjusted OR, 0.26; 95% CI, 0.09-0.73). Outcomes among patients with ischemic stroke or TIA can be improved by attention to swallowing function, DVT prophylaxis, and treatment of hypoxia.


Injection-related hepatitis C serosorting behaviors among people who inject drugs: An urban/rural comparison.
Although previous research has focused on injection drug use behaviors in both urban and rural settings, few have drawn direct comparisons between adjacent rural and urban areas. Using data from the National HIV Behavioral Surveillance study as well as original data collected in a similar fashion, we compare the risk behaviors of people who inject drugs (PWID) in San Juan, Puerto Rico, with those of PWID in nearby rural areas. Specifically, we examine whether one's own hepatitis C (HCV) infection status can be used to predict whether one asked their most recent co-injection partner about their HCV status. Acquiring such information allows injectors to seek out co-injection partners of concordant status as a way to minimize the risk of viral transmission. Results indicate that urban PWID with a known HCV+ status were more likely to know their last co-injector partner's HCV status than were their peers with a negative or unknown HCV status. However, this relationship was not present in the rural data. These findings suggest that there are different risk norms in rural and urban PWID communities and that interventions successful in one type of community may not be so in others.


Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study.
To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart. Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. Denmark. Pregnant women in Denmark between 1997 and 2009 and their offspring. For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy. The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage. The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.


Acute and sub chronic toxicity study of aqueous extract from the leaves and branches of Campomanesia velutina (Cambess) O. Berg.
Campomanesia velutina leaves and branches infusions are used in Brazilian folk medicine to treat diarrhea and to ameliorate intestinal cramps, respectively. Carry out the acute and sub chronic pre-clinical evaluation and thus assess the safety and toxicological potential of the specie. In vivo toxicity was evaluated by acute and sub chronic toxicity assays conducted according to the guidelines of the Brazilian Agency of National Health Surveillance (Agência Nacional de Vigilância Sanitária - ANVISA). For acute toxicity evaluation, a single dose of aqueous extracts from the leaves (AEL) and branches (AEB) of Campomanesia velutina were orally administered to mice at doses of 300, 600 and 1200mg/kg. Then, the animals were observed for 14 days. In the sub chronic study, the extracts were orally administered to mice for 14 days at doses of 300, 600 and 1200mg/kg. To assess the toxicological effects, animals were closely observed on general behavior, clinical signs of toxicity, body weight, food and water intake. At the end of the experiment, it was performed biochemical and hematological evaluations, as well as histopathological analysis from the following organs: brain, heart, lungs, liver, stomach, small intestine (section) and left kidney. Preliminary phytochemical analysis was performed using thin layer chromatography (TLC) and colorimetric pharmacognostic tests. In oral acute assay, treatment with AEB at the major dose (1200mg/kg) caused diarrhea, abdominal cramps and tremors in females. These effects were reversed at 4th hour. Normochromic normocytic anemia was observed in males treated with AEL 300mg/kg and AEB 600 and 1200mg/kg as well as in females treated with AEB 300 and 1200mg/kg. The kidney of all treated animals showed moderate inflammation and a few hemorrhagic points. In sub chronic assay, treatment with AEL 600mg/kg, AEL 1200mg/kg and AEB 1200mg/kg caused hyper excitability in females that was not reversed. Treatments also had impact on weight gain and the relative weight of males' brain was increased on group treated with AEL 300mg/kg, AEB 300 and AEB 1200mg/kg. Although changes in hematological parameters were not observed, serum creatinine levels were significantly higher in males treated with AEB 300mg/kg. Besides, the heart of all treated animals showed intense hyperemia. Preliminary phytochemical analysis revealed the presence of flavonoids, tannins and phenolic compounds. Toxicity signs were mainly observed after treatment with AEL and AEB at the two highest tested doses (600 and 1200mg/kg), suggesting that the extracts are relatively safe at its effective dose (300mg/kg). However, alterations on hematological and biochemical parameters and on the kidney and heart of the animals were not closely related with the dose, implying caution on its use.


Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking.
As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke-circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers.


Rapid metabolic evolution in human prefrontal cortex.
Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.


Finding and evaluating community structure in networks.
We propose and study a set of algorithms for discovering community structure in networks-natural divisions of network nodes into densely connected subgroups. Our algorithms all share two definitive features: first, they involve iterative removal of edges from the network to split it into communities, the edges removed being identified using any one of a number of possible "betweenness" measures, and second, these measures are, crucially, recalculated after each removal. We also propose a measure for the strength of the community structure found by our algorithms, which gives us an objective metric for choosing the number of communities into which a network should be divided. We demonstrate that our algorithms are highly effective at discovering community structure in both computer-generated and real-world network data, and show how they can be used to shed light on the sometimes dauntingly complex structure of networked systems.


Vaccine-associated paralytic poliomyelitis. United States: 1973 through 1984.
From 1973 through 1984, there were 138 cases of paralytic poliomyelitis reported in the United States; 105 (76%) were vaccine associated. Of the 105 vaccine-associated cases, 35 occurred in recipients of oral polio vaccine (OPV), 50 in contacts to OPV recipients, 14 in immune deficient individuals, and six in individuals who had no history of receiving OPV or contact with recent OPV recipients. Thirty-three (94%) of the recipient cases, 41 (82%) of the contact cases, and five (36%) of the immune deficient cases were associated with the first dose of OPV. The overall frequency of vaccine-associated poliomyelitis was one case per 2.6 million doses distributed. However, the relative frequency of paralysis associated with the first dose in the OPV series was one case per 520,000 doses vs one case per 12.3 million subsequent doses. Vaccine-associated paralytic poliomyelitis is rare and the risks of OPV are small. The greatest likelihood of paralysis occurs in association with the first dose of OPV and that likelihood is reduced in subsequent doses more for recipients than for their contacts.


Bacterial subfamily of LuxR regulators that respond to plant compounds.
Pseudomonas fluorescens are rhizobacteria known for their biocontrol properties. Several antimicrobial functions are crucial for this process, and the experiments described here investigate the modulation of their expression during the plant-bacterium interaction. The role of a LuxR family regulator in interkingdom signaling has been investigated using genome-scale transcriptome analysis, gene promoter studies in vivo and in vitro, biocontrol assays, and response to plant compounds. PsoR, a LuxR solo or orphan regulator of P. fluorescens, was identified. PsoR is solubilized and activates a lux-box-containing promoter only in the presence of macerated plants, suggesting the presence of a plant molecule(s) that most likely binds to PsoR. Gene expression profiles revealed that genes involved in the inhibition of plant pathogens were affected by PsoR, including a chitinase gene, iron metabolism genes, and biosynthetic genes of antifungal compounds. 2,4-Diacetylphloroglucinol production is PsoR dependent both in vitro and in vivo. psoR mutants were significantly reduced for their ability to protect wheat plants from root rot, and damping-off caused by Pythium ultimum infection. PsoR most likely senses a molecule(s) in the plant and modulates expression of genes that have a role in biocontrol. PsoR and related proteins form a subfamily of LuxR family regulators in plant-associated bacteria.


Curvature-dependent adsorption of water inside and outside armchair carbon nanotubes.
The curvature dependence of the physisorption properties of a water molecule inside and outside an armchair carbon nanotube (CNT) is investigated by an incremental density-fitting local coupled cluster treatment with single and double excitations and perturbative triples (DF-LCCSD(T)) study. Our results show that a water molecule outside and inside (n, n) CNTs (n = 4, 5, 6, 7, 8, 10) is stabilized by electron correlation. The adsorption energy of water inside CNTs decreases quickly with the decrease of curvature (increase of radius) and the configuration with the oxygen pointing toward the CNT wall is the most stable one. However, when the water molecule is adsorbed outside the CNT, the adsorption energy varies only slightly with the curvature and the configuration with hydrogens pointing toward the CNT wall is the most stable one. We also use the DF-LCCSD(T) results to parameterize Lennard-Jones (LJ) force fields for the interaction of water both with the inner and outer sides of CNTs and with graphene representing the zero curvature limit. It is not possible to reproduce all DF-LCCSD(T) results for water inside and outside CNTs of different curvature by a single set of LJ parameters, but two sets have to be used instead. Each of the two resulting sets can reproduce three out of four minima of the effective potential curves reasonably well. These LJ models are then used to calculate the water adsorption energies of larger CNTs, approaching the graphene limit, thus bridging the gap between CNTs of increasing radius and flat graphene sheets.


Combination of phage and Gram-positive bacterial display of human antibody repertoires enables isolation of functional high affinity binders.
Surface display couples genotype with a surface exposed phenotype and thereby allows screening of gene-encoded protein libraries for desired characteristics. Of the various display systems available, phage display is by far the most popular, mainly thanks to its ability to harbour large size libraries. Here, we describe the first use of a Gram-positive bacterial host for display of a library of human antibody genes which, when combined with phage display, provides ease of use for screening, sorting and ranking by flow cytometry. We demonstrate the utility of this method by identifying low nanomolar affinity scFv fragments towards human epidermal growth factor receptor 2 (HER2). The ranking and performance of the scFv isolated by flow sorting in surface-immobilised form was retained when expressed as soluble scFv and analysed by biolayer interferometry, as well as after expression as full-length antibodies in mammalian cells. We also demonstrate the possibility of using Gram-positive bacterial display to directly improve the affinity of the identified binders via an affinity maturation step using random mutagenesis and flow sorting. This combined approach has the potential for a more complete scan of the antibody repertoire and for affinity maturation of human antibody formats.


Stereoselective synthesis of E-3-(arylmethylidene)-5-(alkyl/aryl)-2(3H)-furanones by sequential hydroacyloxylation-Mizoroki-Heck reactions of iodoalkynes.
A modular, stereoselective synthesis of E-3-(arylidene)-5-(alkyl/aryl)-2(3H)-furanones was developed. The methodology features regioselective addition of β-aryl acrylic acids to iodoacetylenes to furnish the Z-acyloxy iodoalkenes. A stereoselective 5-exo-trig Mizoroki-Heck reaction of the acyloxy iodoalkenes generates the target E-2(3H)-furanones. The approach was applied in a formal synthesis of the naturally occurring kinase inhibitor BE-23372M.


Parasite-mediated reduction in fecundity of mountain hares.
Mountain hare populations in Scotland exhibit regular 10 year fluctuations in abundance. Simple models of host-parasite population dynamics suggest that parasite-mediated reductions in host fecundity can cause a transition from stable to cyclic host population dynamics. We tested the hypothesis that parasites reduce hare fecundity by experimentally reducing parasite burdens and recording female survival, body condition and fecundity. We captured 41 adult female hares in October 2002; 22 were treated with Ivermectin to remove parasites and 19 were left untreated as controls. The treated and untreated hares were culled in May 2003 together with a second control group of nine unhandled hares. Treatment with Ivermectin significantly reduced the abundance of Trichostrongylus retortaeformis and increased-the fecundity of the hares, but had no measurable effect on body condition or over-winter survival. These results are consistent with the hypothesis that parasites may be a contributory cause of cycles in populations of mountain hares.


Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of [14C]acetate but not [3H] mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by [35S]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.


Domain-general enhancements of metacognitive ability through adaptive training.
The metacognitive ability to introspect about self-performance varies substantially across individuals. Given that effective monitoring of performance is deemed important for effective behavioral control, intervening to improve metacognition may have widespread benefits, for example in educational and clinical settings. However, it is unknown whether and how metacognition can be systematically improved through training independently of task performance, or whether metacognitive improvements generalize across different task domains. Across 8 sessions, here we provided feedback to two groups of participants in a perceptual discrimination task: an experimental group (n = 29) received feedback on their metacognitive judgments, while an active control group (n = 32) received feedback on their decision performance only. Relative to the control group, adaptive training led to increases in metacognitive calibration (as assessed by Brier scores), which generalized both to untrained stimuli and an untrained task (recognition memory). Leveraging signal detection modeling we found that metacognitive improvements were driven both by changes in metacognitive efficiency (meta-d'/d') and confidence level, and that later increases in metacognitive efficiency were positively mediated by earlier shifts in confidence. Our results reveal a striking malleability of introspection and indicate the potential for a domain-general enhancement of metacognitive abilities. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Biodegradable polymeric micelles coencapsulating paclitaxel and honokiol: a strategy for breast cancer therapy in vitro and in vivo.
The combination of chemotherapy drugs attracts more attention in clinical cancer trials. However, the poor water solubility of chemotherapeutic drugs restricts their anticancer application. In order to improve antitumor efficiency and reduce side effects of free drugs, we prepared paclitaxel (PTX) and honokiol (HK) combination methoxy poly(ethylene glycol)-poly(caprolactone) micelles (P-H/M) by solid dispersion method against breast cancer. The particle size of P-H/M was 28.7±2.5 nm, and transmission electron microscope image confirmed that P-H/M were spherical in shape with small particle size. After being encapsulated in micelles, the release of PTX or HK showed a sustained behavior in vitro. In addition, both the cytotoxicity and the cellular uptake of P-H/M were increased in 4T1 cells, and P-H/M induced more apoptosis than PTX-loaded micelles or HK-loaded micelles, as analyzed by flow cytometry assay and Western blot. Furthermore, the antitumor effect of P-H/M was significantly improved compared with PTX-loaded micelles or HK-loaded micelles in vivo. P-H/M were more effective in inhibiting tumor proliferation, inducing tumor apoptosis, and decreasing the density of microvasculature. Moreover, bioimaging analysis showed that drug-loaded polymeric micelles could accumulate more in tumor tissues compared with the free drug. Our results suggested that P-H/M may have potential applications in breast cancer therapy.


Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma.
Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 μmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell-activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3ζ-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3ζ-DAP10. Cancer Immunol Res; 4(7); 574-81. ©2016 AACR.


Changing standard chow diet promotes vascular NOS dysfunction in Dahl S rats.
We hypothesized that vascular nitric oxide synthase (NOS) function and expression is differentially regulated in adult Dahl salt-sensitive rats maintained on Teklad or American Institutes of Nutrition (AIN)-76A standard chow diets from 3 to 16 wk old. At 16 wk old, acetylcholine (ACh)-mediated vasorelaxation and phenylephrine (PE)-mediated vasoconstriction in the presence and absence of NOS inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), was assessed in small-resistance mesenteric arteries and aortas. Rats maintained on either diet throughout the study had similar responses to ACh and PE in the presence or absence of L-NAME in both vascular preparations. We reasoned that changing from one diet to another as adults may induce vascular NOS dysfunction. In the absence of L-NAME, small arteries from Teklad-fed rats switched to AIN-76 diet and vice versa had similar responses to ACh and PE. Small-arterial NOS function was maintained in rats switched to AIN-76A from Teklad diet, whereas NOS function in response to ACh and PE was lost in the small arteries from rats changed to Teklad from AIN-76A diet. This loss of NOS function was echoed by reduced expression of NOS3, as well as phosphorylated NOS3. The change in NOS phenotype in the small arteries was observed without changes in blood pressure. Aortic responses to ACh or PE in the presence or absence of L-NAME were similar in all diet groups. These data indicate that changing standard chow diets leads to small arterial NOS dysfunction and reduced NOS signaling, predisposing Dahl salt-sensitive rats to vascular disease.


Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction.
A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.


Risks to health professionals from hazardous drugs in Japan: a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide.
In Japan, concerns exist regarding the dangers inherent when handling cytotoxic drugs, particularly drugs such as 5-FU, Thiotepa, Cytarabine, Tegaful, and Sizofiran which are contained in ampoules or vials, since nurses and medical doctors have been preparing these cytotoxic drugs in the open spaces of wards in the absence of appropriate garments and personal protective equipment. In addition, the administration tubes for these dangerous drugs have been exchanged at the patients' bedside, typically in rooms shared by several patients. To gain insight into the severity of the occupational hazards posed by these practices, we conducted a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide (CP). At Nagoya University Hospital, Nagoya, Japan, in February 2006, two departments, A and B, were monitored with surface-wipe, and urine samples were analyzed using the Sessink method (exposure control, The Netherlands). Department A had a preparation room with biological safety cabinet (BSC) where the pharmacists prepare cytotoxic drugs. Department B did not have a BSC. Many areas of the treatment rooms were contaminated with CP. CP was detected on tables and telephone stands where cytotoxic drugs were not used as well as tables used to prepare cytotoxic drugs. Significant differences in CP concentrations were detected from the urine of two of the three nurses who cared for the same patients without gloves. The nurses rotated and inherited the patient who had the highest risk of contamination. CP was detected only once from the urine of the medical doctor who prepared CP. He was not wearing any PPE other than gloves. All of the pharmacists wearing PPE were free from contamination of CP. Regardless of the use of BSC, wards were contaminated with CP. The contamination may not occur due to the sealing used in CP containers and administration tubes when discarding them. CP was detected only once in the urine of a medical doctor who prepared CP by warming it. The cause may be inhalation of CP gas from the injector. The contamination of the nurses may be from dermal absorption because absorption continued even after the shift ended and the nurses left the facility. CP was not detected in pharmacists who followed the guidelines for preparation of CP. All of the medical staff should follow the guidelines when they handle CP.


Seated buttocks anatomy and its impact on biomechanical risk.
The objective of this study was to describe the amount, types, and shapes of tissue present in the buttocks during sitting (i.e., seated buttocks soft tissue anatomy), and the impact of seated buttocks soft tissue anatomy on biomechanical risk. The buttocks of 35 people, including 29 full-time wheelchair users with and without a history of pelvic pressure ulcers were scanned sitting upright on 3" of flat HR45 foam in a FONAR Upright MRI. Multi-planar scans were analyzed to calculate bulk tissue thickness, tissue composition, gluteus maximus coverage at the ischium, the contour of the skin, and pelvic tilt. Bulk tissue thickness varied from 5.6 to 32.1 mm, was composed mostly of adipose tissue, and was greatest in the able-bodied cohort. Skin contours varied significantly across status group, with wheelchair users with a history of pressure ulcers having tissue with a peaked contour with a radius of curvature of 65.9 mm that wrapped more closely to the ischium (thickness at the apex = 8.2 mm) as compared to wheelchair users with no pressure ulcer history (radius of curvature = 91.5 mm and apex thickness = 14.5 mm). Finally, the majority of participants presented with little to no gluteus coverage over their ischial tuberosity, regardless of status group. This study provides quantitative evidence that Biomechanical Risk, or the intrinsic characteristic of an individual's soft tissues to deform in response to extrinsic applied forces, is greater in individuals at greater risk for pressure ulcers.


Gold nanoparticle-filled biodegradable photopolymer scaffolds induced muscle remodeling: in vitro and in vivo findings.
Therapeutic stem cell transplantation bears the promise of new directions in organ and tissue replacement, but a number of its difficulties and perils are also well known. Our goal was to develop a method of transplantation by which the transplanted cells remain confined to the transplantation site and induce favorable processes. With the help of mask-projection excimer laser stereolithography, 3D hybrid nanoscaffolds were fabricated from biodegradable, photocurable PPF:DEF resin with incorporated gold nanoparticles (Au NPs). The scaffolds were tested in vitro and in vivo in order to find out about their biocompatibility and fitness for our purposes. In vitro, macrophages and mouse autologous adipose stem cells (ASCs) were seeded over the hybrid scaffolds and non-hybrid (with Au NPs) scaffolds for 4days. The hybrid nanocomposite greater stem cell dispension and stem cell adhesion than PPF scaffolds without Au NPs, but such a difference was not seen in the case of macrophages. In vivo, stem cells, scaffoldings and scaffoldings covered in stem cells were transplanted under the back skin of mice. After 14days, blood samples were taken and the affected skin area was excised. Cytokine and chemokine profiling did not indicate elevated immunomediators in the sera of experimental animals. Interestingly, the autologous-stem-cell-seeded hybrid nanocomposite scaffold induced muscle tissue regeneration after experimental wound generation in vivo. We could not observe such stem cell-induced tissue regeneration when no scaffolding was used. We conclude that PPF:DEF resin nanoscaffolds with incorporated gold nanoparticles offer a safe and efficient alternative for the enhancement of local tissue remodeling. The results also support the idea that adipose derived stem cells are an optimal cell type for the purposes of regenerative musculoskeletal tissue engineering.


Dengue in children and young adults, a cross-sectional study from the western part of Uttar Pradesh.
Dengue has emerged as a major public health problem in India. It presents more aggressively among younger age groups as compared to adults. Therefore, it necessitates the accurate estimation of prevalence in younger age groups. Of all the 1026 clinically suspected cases of dengue up to the age of 18 years were enrolled in this study and grouped into four age groups (Group I - <0 to 1 year, Group II- 1 to 6 years, Group III- 7 to 12 years, and Group IV- 13 to 18 years). Their blood samples were aseptically collected from different clinical departments and were submitted to the Viral Research and Diagnostic Laboratory (VRDL), Department of Microbiology during the outbreak of 2016-17. Serum was separated and processed for dengue Non Structural Protein 1 antigen (NS1 Ag)and Immunoglobuline M antibody (IgM Ab) enzyme-linked immunosorbent assay (ELISA). All the relevant variables like age, sex, and demographic profile were recorded and statistically analyzed. A total 295 of the 1026 cases were detected positive for dengue either by NS1 Ag or IgM Ab ELISA. The results show the susceptibility to dengue being increased in the order of age Group I to IV. We analyzed the outbreak of year 2016 and 2017, of these 159/483 (33%) cases and 136/543 (25%) cases, respectively, were found seropositive during these years. The months of September, October, and November are more prone to dengue infection. Group III and IV were more susceptible to dengue fever (DF). The months of postmonsoon season are more favorable for spread of dengue among different age groups of the population.


Evolutionarily conserved antigens in autoimmune disease: implications for an infective aetiology.
The immune system has evolved to eliminate or inactivate infectious organisms. An inappropriate response against self-components (autoantigens) can result in autoimmune disease. Here we examine the hypothesis that some evolutionarily conserved proteins, present in pathogenic and commensal organisms and their hosts, provide the stimulus that initiates autoimmune disease in susceptible individuals. We focus on seven autoantigens, of which at least four, glutamate decarboxylase, pyruvate dehydrogenase, histidyl-tRNA synthetase and alpha enolase, have orthologs in bacteria. Citrullinated alpha-enolase, a target for autoantibodies in 40% of patients with rheumatoid arthritis, is our main example. The major epitope is highly conserved, with over 90% identity to human in some bacteria. We propose that this reactivity of autoantibodies to shared sequences provides a model of autoimmunity in rheumatoid arthritis, which may well extend to other autoimmune disease in humans.


Magnetism in semiconducting molybdenum dichalcogenides.
Transition metal dichalcogenides (TMDs) are interesting for understanding the fundamental physics of two-dimensional (2D) materials as well as for applications to many emerging technologies, including spin electronics. Here, we report the discovery of long-range magnetic order below T M = 40 and 100 K in bulk semiconducting TMDs 2H-MoTe2 and 2H-MoSe2, respectively, by means of muon spin rotation (μSR), scanning tunneling microscopy (STM), and density functional theory (DFT) calculations. The μSR measurements show the presence of large and homogeneous internal magnetic fields at low temperatures in both compounds indicative of long-range magnetic order. DFT calculations show that this magnetism is promoted by the presence of defects in the crystal. The STM measurements show that the vast majority of defects in these materials are metal vacancies and chalcogen-metal antisites, which are randomly distributed in the lattice at the subpercent level. DFT indicates that the antisite defects are magnetic with a magnetic moment in the range of 0.9 to 2.8 μB. Further, we find that the magnetic order stabilized in 2H-MoTe2 and 2H-MoSe2 is highly sensitive to hydrostatic pressure. These observations establish 2H-MoTe2 and 2H-MoSe2 as a new class of magnetic semiconductors and open a path to studying the interplay of 2D physics and magnetism in these interesting semiconductors.


Examining dynamics in a polymer matrix by single molecule fluorescence probes of different sizes.
Rotational motion of single fluorescence probes with different sizes doped inside films of polyvinylacetate is investigated by defocused single molecule fluorescence microscopy. Discrete vibration modes in the rotational motion of individual probes are clearly exposed in the power spectra of the rotation trajectories, reflecting multiple relaxation dynamics and also the difference in dynamics among separate locations. The power spectra show a strong dependence on the probe size and temperature. By sampling the rotation of a large number of probes, the averaged power spectra show that the activated rotation of the probes falls into the frequency range of the α-relaxation and data analysis shows that activation of the vibration modes with all probes corresponds to the maximum population of rotating probes, and this made the comparison between single molecule data and the ensemble data meaningful (differential scanning calorimetry, as an example). Such an analysis shows a coincidence between the temperature of a significant occurrence of glass transition and the activation of rotational motion of all probes with one specific size, indicating that such a dimension correlates with the size of the cooperative rearrangement region - a volume of approximately 1.0 nm(3).


An endothelial cell line infected by Kaposi's sarcoma-associated herpes virus (KSHV) allows the investigation of Kaposi's sarcoma and the validation of novel viral inhibitors in vitro and in vivo.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a tumor of endothelial origin predominantly affecting immunosuppressed individuals. Up to date, vaccines and targeted therapies are not available. Screening and identification of anti-viral compounds are compromised by the lack of scalable cell culture systems reflecting properties of virus-transformed cells in patients. Further, the strict specificity of the virus for humans limits the development of in vivo models. In this study, we exploited a conditionally immortalized human endothelial cell line for establishment of in vitro 2D and 3D KSHV latency models and the generation of KS-like xenograft tumors in mice. Importantly, the invasive properties and tumor formation could be completely reverted by purging KSHV from the cells, confirming that tumor formation is dependent on the continued presence of KSHV, rather than being a consequence of irreversible transformation of the infected cells. Upon testing a library of 260 natural metabolites, we selected the compounds that induced viral loss or reduced the invasiveness of infected cells in 2D and 3D endothelial cell culture systems. The efficacy of selected compounds against KSHV-induced tumor formation was verified in the xenograft model. Together, this study shows that the combined use of anti-viral and anti-tumor assays based on the same cell line is predictive for tumor reduction in vivo and therefore allows faithful selection of novel drug candidates against Kaposi's sarcoma. KEY MESSAGES: Novel 2D, 3D, and xenograft mouse models mimic the consequences of KSHV infection. KSHV-induced tumorigenesis can be reverted upon purging the cells from the virus. A 3D invasiveness assay is predictive for tumor reduction in vivo. Chondramid B, epothilone B, and pretubulysin D diminish KS-like lesions in vivo.


THE SYNTHESIS, STORAGE, AND EXCRETION OF CREATINE, CREATININE, AND GLYCOCYAMINE IN PROGRESSIVE MUSCULAR DYSTROPHY AND THE EFFECTS OF CERTAIN HORMONES ON THESE PROCESSES.
The diminished excretion of creatinine in progressive muscular dystrophy is a more striking and specific phenomenon than the excess excretion of creatine, marked though this is. While creatinuria is invariably encountered in all cases of long-standing dystrophy, the extent to which the excretion of creatinine is decreased provides a more reliable indication of the severity of the disease since an excess output of creatine may occur physiologically in normal human subjects and in many pathological conditions not known to be associated with muscle disease. In progressive muscular dystrophy the residual muscle mass, as inferred from the excretion of creatinine, provides a useful index of the state of the disease at any given time. Although there is excessive creatinuria in progressive muscular dystrophy, there is no evidence that a deprivation of methyl stores occurs through a loss of urinary creatine. The loss of methyl groups contained in the excess creatine is, under ordinary conditions of diet, almost exactly compensated for by a drop in the excretion of methyl groups in the urinary creatinine. Testosterone propionate, administered over variable periods of time, resulted in the retention of creatine both in normal male children and in male children with progressive muscular dystrophy, as shown in the normal subjects by a diminution in creatine output, and in both by an excess creatinuria for variable periods of time following withdrawal of the hormone. An increase in the excretion of creatine in progressive muscular dystrophy occurred following the administration of methyl testosterone. Neither testosterone propionate nor methyl testosterone appeared to effect any consistent change in the output or urinary creatinine. No effects on the excretion of creatine and creatinine were observed following the prolonged administration of concentrate of gonadotropic and thyrotropic principles of the hypophysis, or from the administration of desoxycorticosterone acetate to patients with progressive muscular dystrophy. Except in one case, in which marked improvement was observed following the administration of testosterone propionate, no effects on the clinical course of the patients with progressive muscular dystrophy were observed as a result of treatment by any of the various hormones employed in this study.


Effect of sex on nadir hematocrit and rates of acute kidney injury in coronary artery bypass.
Findings from a large multicenter experience showed that sex influenced the relationship between low nadir hematocrit and increased risk of acute kidney injury after cardiac surgery. We explored whether sex-related differences persisted among patients undergoing isolated coronary artery bypass grafting. We undertook a prospective, observational study of 17,363 patients without dialysis (13,137 male: 75.7%; 4226 female: 24.3%) undergoing isolated coronary artery bypass grafting between 2011 and 2016 across 41 institutions in the Perfusion Measures and Outcomes registry. Odds ratios between nadir hematocrit and stage 2 or 3 acute kidney injury were calculated, and the interaction of sex with nadir hematocrit was tested. The multivariable, generalized, linear mixed-effect model adjusted for preoperative and intraoperative factors and institution. Median nadir hematocrit was 22% among women and 27% among men (P < .001). Women were administered a greater median net prime volume indexed to body surface area (407 vs 363 mL/m2) and more red blood cell transfusions (55.5% vs 24.3%; both P < .001). Acute kidney injury was higher among women (6.0% vs 4.3%, P < .001). There was no effect of sex on the relationship between nadir hematocrit and acute kidney injury (P = .67). Low nadir hematocrit was inversely associated with acute kidney injury (adjusted odds ratios per 1-unit increase in nadir hematocrit 0.96; 95% confidence interval, 0.93-0.98); this effect was similar across sexes and independent of red blood cell transfusions. We found no sex-related differences in the effect of nadir hematocrit on acute kidney injury after isolated coronary artery bypass grafting. However, the strong inverse relationship between anemia and acute kidney injury across sexes suggests the importance of reducing exposure to low nadir hematocrit.