Parallel randomized controlled feasibility trials of the "Active Brains" digital intervention to protect cognitive health in adults aged 60-85.
Multidomain interventions to address modifiable risk factors for dementia are promising, but require more cost-effective, scalable delivery. This study investigated the feasibility of the "Active Brains" digital behavior change intervention and its trial procedures. Active Brains aims to reduce cognitive decline by promoting physical activity, healthy eating, and online cognitive training. We conducted 12-month parallel-design randomized controlled feasibility trials of "Active Brains" amongst "lower cognitive scoring" (n = 180) and "higher cognitive scoring" (n = 180) adults aged 60-85. We collected 67.2 and 76.1% of our 12-month primary outcome (Baddeley verbal reasoning task) data for the "lower cognitive score" and "higher cognitive score" groups, respectively. Usage of "Active Brains" indicated overall feasibility and satisfactory engagement with the physical activity intervention content (which did not require sustained online engagement), but engagement with online cognitive training was limited. Uptake of the additional brief telephone support appeared to be higher in the "lower cognitive score" trial. Preliminary descriptive trends in the primary outcome data might indicate a protective effect of Active Brains against cognitive decline, but further investigation in fully-powered trials is required to answer this definitively. Whilst initial uptake and engagement with the online intervention was modest, it was in line with typical usage of other digital behavior change interventions, and early indications from the descriptive analysis of the primary outcome and behavioral data suggest that further exploration of the potential protective benefits of Active Brains are warranted. The study also identified minor modifications to procedures, particularly to improve online primary-outcome completion. Further investigation of Active Brains will now seek to determine its efficacy in protecting cognitive performance amongst adults aged 60-85 with varied levels of existing cognitive performance.


Differential expression of arginase and iNOS in the lung in sepsis.
The primary metabolic fates of L-arginine are conversion to L-citrulline by nitric oxide synthase (NOS) and to L-ornithine by arginase. In the lung, arginine utilization is increased after the inducible form of NOS (iNOS) is expressed during inflammation. The expression of arginase in normal lung and after sepsis, and its potential relationships with iNOS, however, are not known. Since arginase and iNOS share the substrate L-arginine, we tested the hypothesis that lung arginase would be co-induced with iNOS in sepsis and its cellular distribution would be related to that of iNOS in the lung. Lungs from cecal ligation and puncture (CLP) and sham-operated (S) rats were harvested 6 or 16 hours after the procedures. Lung wet-to-dry weight ratio, myeloperoxidase content, and lipid peroxidation products were measured as indices of lung injury. Western blot analyses were performed with polyclonal antibodies against two isoforms of rat arginase (I and II) and iNOS. Additional lungs from CLP and S animals were inflation-fixed for immunohistochemistry using the same antibodies. We found by Western blot that arginase II at 39 kDa was the main isoform present in normal rat lung. The enzyme was distributed diffusely in alveolar and bronchial epithelial cells, endothelial cells, and alveolar macrophages. After CLP, arginase II was almost undetectable in rat lungs at 16 hours. In contrast, in normal lung, the iNOS was not detectable by Western blot or immunohistochemistry. After CLP, strong expression of iNOS was found in similar cell types to arginase II. These data demonstrate loss of constitutive expression of arginase II in rat lung as iNOS is upregulated by the response to sepsis.


The tolkin gene is a tolloid/BMP-1 homologue that is essential for Drosophila development.
The Drosophila decapentaplegic (dpp) gene, a member of the transforming growth factor beta superfamily of growth factors, is critical for specification of the embryonic dorsal-ventral axis, for proper formation of the midgut, and for formation of Drosophila adult structures. The Drosophila tolloid gene has been shown to genetically interact with dpp. The genetic interactions between tolloid and dpp suggests a model in which the tolloid protein participates in a complex containing the DPP ligand, its protease serving to activate DPP, either directly or indirectly. We report here the identification and cloning of another Drosophila member of the tolloid/bone morphogenic protein (BMP) 1 family, tolkin, which is located 700 bp 5' to tolloid. Its overall structure is like tolloid, with an N-terminal metalloprotease domain, five complement subcomponents C1r/C1s, Uegf, and Bmp1 (CUB) repeats and two epidermal growth factor (EGF) repeats. Its expression pattern overlaps that of tolloid and dpp in early embryos and diverges in later stages. In larval tissues, both tolloid and tolkin are expressed uniformly in the imaginal disks. In the brain, both tolloid and tolkin are expressed in the outer proliferation center, whereas tolkin has another stripe of expression near the outer proliferation center. Analysis of lethal mutations in tolkin indicate it is vital during larval and pupal stages. Analysis of its mutant phenotypes and expression patterns suggests that its functions may be mostly independent of tolloid and dpp.


Preservation of primordial follicles from lions by slow freezing and xenotransplantation of ovarian cortex into an immunodeficient mouse.
Assisted reproductive technology (ART) is considered an important tool in the conservation of endangered species, but often the most limiting factor of ART is the availability of mature oocytes. The aim of the present study was to investigate the feasibility of preserving female germ cells from ovaries of female lions (Panthera leo). Good quality cumulus-oocyte complexes (COCs) were isolated and subjected to in vitro maturation (IVM). In addition, ovarian cortex was obtained and cut into pieces for culture and cryopreservation by slow freezing. The survival of ovarian follicles was assessed by histology. Frozen-thawed samples of ovarian cortex samples were xenotransplanted under the skin of ovariectomized immunodeficient mouse for 28 days. Overall, 178 intact COCs were obtained from 13 lions, but only 28.1% were matured in vitro indicating insufficient IVM conditions. In contrast, almost all follicles within the ovarian cortex survived culture when the original sample was from a young healthy lion collected immediately after euthanasia. Within the xenotransplants, the number of primordial follicles decreased after 28 days by 20%, but the relation between primordial and growing follicles changed in favour of follicular growth. Female gamete rescue from valuable felids may be performed by slow freeze cryopreservation of ovarian cortex. Although the IVM protocol for lions is not yet optimized, mature oocytes may be obtained after long-term xenotransplantation and IVM and could potentially represent one way of salvage of endangered felid species in the future.


GWA analysis for milk production traits in dairy sheep and genetic support for a QTN influencing milk protein percentage in the LALBA gene.
In this study, we used the Illumina OvineSNP50 BeadChip to conduct a genome-wide association (GWA) analysis for milk production traits in dairy sheep by analyzing a commercial population of Spanish Churra sheep. The studied population consisted of a total of 1,681 Churra ewes belonging to 16 half-sib families with available records for milk yield (MY), milk protein and fat yields (PY and FY) and milk protein and fat contents (PP and FP). The most significant association identified reached experiment-wise significance for PP and FP and was located on chromosome 3 (OAR3). These results confirm the population-level segregation of a previously reported QTL affecting PP and suggest that this QTL has a significant pleiotropic effect on FP. Further associations were detected at the chromosome-wise significance level on 14 other chromosomal regions. The marker on OAR3 showing the highest significant association was located at the third intron of the alpha-lactalbumin (LALBA) gene, which is a functional and positional candidate underlying this association. Sequencing this gene in the 16 Churra rams of the studied resource population identified additional polymorphisms. One out of the 31 polymorphisms identified was located within the coding gene sequence (LALBA_g.242T>C) and was predicted to cause an amino acid change in the protein (Val27Ala). Different approaches, including GWA analysis, a combined linkage and linkage disequilibrium study and a concordance test with the QTL segregating status of the sires, were utilized to assess the role of this mutation as a putative QTN for the genetic effects detected on OAR3. Our results strongly support the polymorphism LALBA_g.242T>C as the most likely causal mutation of the studied OAR3 QTL affecting PP and FP, although we cannot rule out the possibility that this SNP is in perfect linkage disequilibrium with the true causal polymorphism.


CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.
Cellular immune responses are likely to play a key role in determining the clinical outcome in acute infection with hepatitis C virus (HCV), but the dynamics of such responses and their relationship to viral clearance are poorly understood. In a previous study we have shown highly activated, multispecific cytotoxic T lymphocyte responses arising early and persisting in an individual who subsequently cleared the virus. In this study the HCV-specific CD8+ lymphocytes response has been similarly analyzed, using peptide-HLA class I tetramers, in a further nine individuals with documented acute HCV infection, six of whom failed to clear the virus. Significant populations of virus-specific CD8+ lymphocytes were detected at the peak of acute hepatic illness (maximally 3.5% of CD8+ lymphocytes). Frequencies were commonly lower than those seen previously and were generally not sustained. Early HCV-specific CD8+ lymphocytes showed an activated phenotype in all patients (CD38+ and HLA class II+), but this activation was short-lived. Failure to sustain sufficient numbers of activated virus-specific CD8+ lymphocytes may contribute to persistence of HCV.


The Dorsal Attention Network Reflects Both Encoding Load and Top-down Control during Working Memory.
The dorsal attention network is consistently involved in verbal and visual working memory (WM) tasks and has been associated with task-related, top-down control of attention. At the same time, WM capacity has been shown to depend on the amount of information that can be encoded in the focus of attention independently of top-down strategic control. We examined the role of the dorsal attention network in encoding load and top-down memory control during WM by manipulating encoding load and memory control requirements during a short-term probe recognition task for sequences of auditory (digits, letters) or visual (lines, unfamiliar faces) stimuli. Encoding load was manipulated by presenting sequences with small or large sets of memoranda while maintaining the amount of sensory stimuli constant. Top-down control was manipulated by instructing participants to passively maintain all stimuli or to selectively maintain stimuli from a predefined category. By using ROI and searchlight multivariate analysis strategies, we observed that the dorsal attention network encoded information for both load and control conditions in verbal and visuospatial modalities. Decoding of load conditions was in addition observed in modality-specific sensory cortices. These results highlight the complexity of the role of the dorsal attention network in WM by showing that this network supports both quantitative and qualitative aspects of attention during WM encoding, and this is in a partially modality-specific manner.


Phagocytic killing of encapsulated and microencapsulated Staphylococcus aureus by human polymorphonuclear leukocytes.
Phagocytosis by human polymorphonuclear leukocytes (PMNs) is an important host defense against infections caused by Staphylococcus aureus. Using an in vitro assay, we compared the opsonic requirements for phagocytic killing of prototype strains of encapsulated (type 1) and microencapsulated (type 5 and type 8) S. aureus by human PMNs. More than 85% of broth-grown, logarithmic-phase type 5 and 8 S. aureus organisms were killed by PMNs incubated with fresh normal human, rabbit, or guinea pig serum with complement activity. Under similar conditions, the highly encapsulated type 1 strain was not killed. Both encapsulated and microencapsulated strains were opsonized for phagocytosis by heat-inactivated serum raised in rabbits to killed bacteria. Opsonization by homologous serum was required for phagocytosis of the type 1 strain. In contrast, microencapsulated type 5 and 8 S. aureus organisms were killed by heat-inactivated rabbit serum raised to type 5, type 8, or nonencapsulated isolates; this result suggested that antibodies to the capsule or to cell wall components other than the capsule could opsonize these organisms for phagocytosis. The specificity of the assay was confirmed with capsule type 5-specific monoclonal antibodies, which were opsonic only for the type 5 S. aureus isolate. These studies indicate that, unlike the highly encapsulated type 1 strain, broth-grown microencapsulated S. aureus strains do not resist opsonophagocytic killing in vitro by normal serum.


Dihydropyridine binding and Ca(2+)-channel characterization in clonal calcitonin-secreting cells.
1,4-Dihydropyridine-sensitive voltage-dependent Ca2+ channels play a crucial role in the extracellular Ca(2+)-sensing of calcitonin-secreting parafollicular cells of the thyroid (C-cells). To characterize the Ca2+ channels in C-cells, we studied 1,4-dihydropyridine binding and performed electrophysiological experiments with Ca(2+)-sensitive C-cells (rat C-cell line rMTC 44-2) in comparison with 'defective' Ca(2+)-insensitive C-cells (human C-cell line TT). In membranes of rMTC cells, we detected a high-affinity, stereoselective and Ca(2+)-dependent binding site for the Ca(2+)-channel-blocking 1,4-dihydropyridine, (+)-[3H]PN 200-110. Radioligand binding was saturable (Bmax. = 18 +/- 2 fmol/mg of protein), reversible [Ki for (+)-PN 200-110 = 37 +/- 1 pM) and allosterically modulated by the phenylalkylamine (-)-desmethoxyverapamil [(-)-D888] as well as the bis-benzylisoquinoline alkaloid (+)-tetrandrine. Thus the 1,4-dihydropyridine binding in rMTC cells featured all characteristics of binding to the alpha 1-subunit of L-type Ca2+ channels. In contrast, in membranes of TT cells, which are known to lack Ca(2+)-sensitivity, no Ca(2+)-channel-specific (+)-[3H]PN 200-110 binding was detected. In voltage-clamp experiments, rMTC cells exhibited slowly inactivating Ca2+ currents which proved sensitive to (+)-PN 200-110, (-)-D888 and (+)-tetrandrine. These L-type Ca(2+)-channel blockers did not affect the Ca2+ currents in TT cells. The numbers of 1,4-dihydropyridine-sensitive Ca2+ channels in rMTC cells as calculated from both the binding studies and the whole-cell/single-channel recordings were 2000 and 7000/cell respectively. Thus qualitative and quantitative detection of 1,4-dihydropyridine-sensitive Ca2+ channels by radioligand-binding in Ca(2+)-sensitive rMTC cells, but not in Ca(2+)-insensitive TT cells, reflects the electrophysiological detection of functional Ca2+ channel in rMTC cells, but not in TT cells.


Global Human-Kinase Screening Identifies Therapeutic Host Targets against Influenza.
During viral infection of human cells, host kinases mediate signaling activities that are used by all viruses for replication; therefore, targeting of host kinases is of broad therapeutic interest. Here, host kinases were globally screened during human influenza virus (H1N1) infection to determine the time-dependent effects of virus infection and replication on kinase function. Desthiobiotin-labeled analogs of adenosine triphosphate and adenosine diphosphate were used to probe and covalently label host kinases in infected cell lysates, and probe affinity was determined. Using infected human A549 cells, we screened for time-dependent signal changes and identified host kinases whose probe affinities differed significantly when compared to uninfected cells. Our screen identified 10 novel host kinases that have not been previously shown to be involved with influenza virus replication, and we validated the functional importance of these novel kinases during infection using targeted small interfering RNAs (siRNAs). The effects of kinase-targeted siRNA knockdowns on replicating virus levels were measured by quantitative reverse-transcription PCR and cytoprotection assays. We identified several novel host kinases that, when knocked down, enhanced or reduced the viral load in cell culture. This preliminary work represents the first screen of the changing host kinome in influenza virus-infected human cells.


Beverage Intake among Children: Associations with Parent and Home-Related Factors.
Beverage intake can influence child diet quality in a positive or negative manner depending on the beverage type and amounts consumed. Parenting practices such as role modeling and control of home beverage availability have been associated with child beverage intake, whereas examination of the influence of parental beverage nutrition knowledge has been more limited. The purpose of this study was to examine the relationships between sugar-sweetened and dairy beverage intake among children (9-12 years) and home and parental factors. A questionnaire was administered among a convenience sample of parents (n = 194) to assess beverage nutrition knowledge, beverage intake and home availability of beverages. Children completed a questionnaire to estimate usual beverage intake. Daily sugar-sweetened beverage intake by children ranged from 0.4 to 48 oz. Logistic regression analysis was used to examine relationships. Parents were mostly female, white, well educated, and employed. Home availability of sugar-sweetened and dairy beverages was positively associated with child sugar-sweetened (OR = 1.48, p = 0.03) and dairy beverage intake (OR = 1.34, p = 0.03), respectively. Parent dairy beverage intake was associated with child dairy beverage intake (OR = 1.06, p = 0.01). Parent knowledge about sugar in beverages was related to child dairy beverage intake (OR = 1.46, p = 0.02), whereas calcium/dairy knowledge and general beverage nutrition knowledge were not related to child beverage intake. Parenting practices and knowledge may play a role in determining child beverage intake.


The sigmaR regulon of Streptomyces coelicolor A32 reveals a key role in protein quality control during disulphide stress.
Diamide is an artificial disulphide-generating electrophile that mimics an oxidative shift in the cellular thiol-disulphide redox state (disulphide stress). The Gram-positive bacterium Streptomyces coelicolor senses and responds to disulphide stress through the sigma(R)-RsrA system, which comprises an extracytoplasmic function (ECF) sigma factor and a redox-active anti-sigma factor. Known targets that aid in the protection and recovery from disulphide stress include the thioredoxin system and genes involved in producing the major thiol buffer mycothiol. Here we determine the global response to diamide in wild-type and sigR mutant backgrounds to understand the role of sigma(R) in this response and to reveal additional regulatory pathways that allow cells to cope with disulphide stress. In addition to thiol oxidation, diamide was found to cause protein misfolding and aggregation, which elicited the induction of the HspR heat-shock regulon. Although this response is sigma(R)-independent, sigma(R) does directly control Clp and Lon ATP-dependent AAA(+) proteases, which may partly explain the reduced ability of a sigR mutant to resolubilize protein aggregates. sigma(R) also controls msrA and msrB methionine sulphoxide reductase genes, implying that sigma(R)-RsrA is responsible for the maintenance of both cysteine and methionine residues during oxidative stress. This work shows that the sigma(R)-RsrA system plays a more significant role in protein quality control than previously realized, and emphasizes the importance of controlling the cellular thiol-disulphide redox balance.


It's not just who you are but where you live: an exploration of community influences on individual HIV status in rural Malawi.
Approximately 1 million people are infected with Human Immunodeficiency Virus (HIV) in Malawi. Despite efforts aimed at changing individual risk behaviors, HIV prevalence continues to rise among rural populations. Both previous research and the Political Economy of Health framework suggest that community-based socio-economic factors and accessibility may influence HIV transmission; however, these community factors have received little empirical investigation. To fill this gap, this research uses data from a nationally representative probability sample of rural Malawians combined with small area estimates of community socio-economic and accessibility data in logistic regression models to: 1) reveal relationships between community factors and individual HIV status; 2) determine whether these relationships operate through individual HIV risk behaviors; and 3) explore whether these associations vary by gender. Community socio-economic factors include relative and absolute poverty; community accessibility factors include distance to roads, cities, and public health facilities. Individual HIV risk behaviors include reported condom use, sexually transmitted infections, multiple partnerships, and paid sex. Results show that higher community income inequality, community proximity to a major road, and community proximity to a public health clinic are associated with increased odds of HIV for women. For men, community proximity to a major road and community proximity to a public health clinic are associated with increased odds of HIV infection. These direct relationships between community factors and individual HIV status are not mediated by individual HIV risk behaviors. The Political Economy of Health frames the discussion. This study provides evidence for expanding HIV prevention efforts beyond individual risk behaviors to consideration of community factors that may drive the HIV epidemic in rural Malawi.


Teaching resident physicians to provide exercise counseling: a needs assessment.
To determine the behaviors, knowledge, and attitudes of resident physicians regarding exercise counseling. In 1997, a self-administered questionnaire was sent to 313 internal medicine resident physicians at six U.S. training programs. Pearson correlation coefficients examined associations between the resident physicians' practices, attitudes, and personal habits. Stepwise multiple linear regression identified predictors of exercise counseling by the resident physicians. A total of 251 resident physicians responded. Only 15.5% reported counseling more than 80% of the clinic patients about exercise. Over 93% understood the benefits of exercise, and almost all (96%) felt that it was a physician's responsibility to counsel patients about exercise. Only 29% felt successful at getting their patients to start exercising, and only 28% felt confident in their skills to prescribe exercise for patients. Ninety-one percent felt that training in exercise counseling would be worthwhile. The significant predictors of physician exercise counseling were perception of exercise counseling as a priority (p <.001), confidence in exercise-counseling skills (p <.001), and postgraduate year of training (p <.05) (R(2) =.18). The significant predictors of physicians' confidence in exercise-counseling skills included physician's gender (i.e., men) (p <.001), perception that exercise is important for a healthy 35-year-old (p <.01), feeling successful at exercise counseling (p <.001), perceiving less interference with counseling by barriers (p <.001), and prior training in exercise counseling (p <.05) (R(2) =.44). Resident physicians' perceptions of exercise counseling as a priority, confidence in counseling skills, and postgraduate year of training are important predictors of their providing exercise counseling. These factors should be addressed in future educational programs.


Sociodemographic risk and early environmental factors that contribute to resilience in executive control: A factor mixture model of 3-year-olds.
Young children at sociodemographic risk generally demonstrate lower executive control (EC), although with substantial heterogeneity across children. Given this marked variability, there may be some at-risk children who display higher EC and may be buffered from or resilient to the effects of sociodemographic risk who can be studied to identify the contributory factors. In this study, factor mixture modelling was used to determine whether subgroups of 3-year-old children existed based on their observed performance on a battery of EC tasks. Results indicated 2 latent groups: One characterized by lower EC and the other by higher EC. Both sociodemographically at-risk and low-risk children were represented in each group, yielding 4 risk-status-by-EC groups, where at-risk higher EC children were termed the resilient group. Proximal household enrichment (e.g., exposure to learning materials, varied enriching experiences, academic and language stimulation, parental responsivity) distinguished the resilient group from lower performing children of similar risk status, whereas distal financial resources and proximal social network resources did not distinguish these two groups. Results suggest potential intervention targets to promote optimal EC development, particularly among children at risk.


Trans-subclavian versus transapical access for transcatheter aortic valve implantation: A multicenter study.
To compare the outcomes of trans-subclavian (TS) and transapical (TA) access for transcatheter aortic valve implantation (TAVI). A considerable proportion of patients undergoing TAVI are not eligible for transfemoral approach. To date, there are few data to guide the choice between alternative vascular access routes. Among 874 consecutive patients who underwent TAVI, 202 procedures were performed through TA (n = 142, 70.3%) or TS (n = 60, 29.7%) access. Medtronic Corevalve (CV, Medtronic, Minneapolis, MN) was implanted in 17.3% of the patients, the Edwards-Sapien (ES, Edwards Lifesciences Inc., Irvine, CA) in 81.2% and other prostheses in 0.1%. In-hospital and long-term outcome were assessed using the Valve Academic Research Consortium (VARC)-2 definitions. Mean age was 82 ± 6 years, STS score 9.3 ± 7.9%. The 2 groups showed a relevant imbalance in baseline characteristics. In hospital mortality was 6.4% (1.7% TS vs. 8.4% TA, P = 0.06), stroke 2.0%, acute myocardial infarction 1.0%, acute kidney injury 39.4%, sepsis 4.0% with no significant differences between groups, while bleeding was more frequent in TA patients (53.5% vs. 11.7% TS, P < 0.001). One- and 2-year survival was 85.2% and 73.2% in TS patients, and 83.9% and 74.9% in TA patients (P = ns for both). Access site was not an independent predictor of mortality at multivariable analysis. Transapical compared with trans-subclavian access for TAVI was associated with a nonsignificant trend to increased periprocedural events. However, 1- and 2-year survival appears similar.


Integrating Ecological and Evolutionary Context in the Study of Maternal Stress.
Maternal stress can prenatally influence offspring phenotypes and there are an increasing number of ecological studies that are bringing to bear biomedical findings to natural systems. This is resulting in a shift from the perspective that maternal stress is unanimously costly, to one in which maternal stress may be beneficial to offspring. However, this adaptive perspective is in its infancy with much progress to still be made in understanding the role of maternal stress in natural systems. Our aim is to emphasize the importance of the ecological and evolutionary context within which adaptive hypotheses of maternal stress can be evaluated. We present five primary research areas where we think future research can make substantial progress: (1) understanding maternal and offspring control mechanisms that modulate exposure between maternal stress and subsequent offspring phenotype response; (2) understanding the dynamic nature of the interaction between mothers and their environment; (3) integrating offspring phenotypic responses and measuring both maternal and offspring fitness outcomes under real-life (either free-living or semi-natural) conditions; (4) empirically testing these fitness outcomes across relevant spatial and temporal environmental contexts (both pre- and post-natal environments); (5) examining the role of maternal stress effects in human-altered environments-i.e., do they limit or enhance fitness. To make progress, it is critical to understand the role of maternal stress in an ecological context and to do that, we must integrate across physiology, behavior, genetics, and evolution.


Nonenzymatic Reactions above Phospholipid Surfaces of Biological Membranes: Reactivity of Phospholipids and Their Oxidation Derivatives.
Phospholipids play multiple and essential roles in cells, as components of biological membranes. Although phospholipid bilayers provide the supporting matrix and surface for many enzymatic reactions, their inherent reactivity and possible catalytic role have not been highlighted. As other biomolecules, phospholipids are frequent targets of nonenzymatic modifications by reactive substances including oxidants and glycating agents which conduct to the formation of advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs). There are some theoretical studies about the mechanisms of reactions related to these processes on phosphatidylethanolamine surfaces, which hypothesize that cell membrane phospholipids surface environment could enhance some reactions through a catalyst effect. On the other hand, the phospholipid bilayers are susceptible to oxidative damage by oxidant agents as reactive oxygen species (ROS). Molecular dynamics simulations performed on phospholipid bilayers models, which include modified phospholipids by these reactions and subsequent reactions that conduct to formation of ALEs and AGEs, have revealed changes in the molecular interactions and biophysical properties of these bilayers as consequence of these reactions. Then, more studies are desirable which could correlate the biophysics of modified phospholipids with metabolism in processes such as aging and diseases such as diabetes, atherosclerosis, and Alzheimer's disease.


Improving transition to adulthood for adolescents with intellectual and developmental disabilities: Proactive developmental and systems perspective.
To demonstrate how family physicians can contribute to a piece of the journey of improving quality-of-life outcomes for people with intellectual and developmental disabilities (IDD) when they undergo the transition from adolescence to adulthood. The "Primary care of adults with intellectual and developmental disabilities. 2018 Canadian consensus guidelines" literature review and interdisciplinary input. Family physicians should be proactive in anticipating and supporting the transition of people with IDD from adolescence to adulthood. Interventions should be guided by a developmental perspective regarding the person with IDD and a life-cycle approach to supporting families. Family physicians also have a role in helping people with IDD and their families to navigate successfully through changing community-based support systems in their province, especially health care and social services systems. Therefore, family physicians should be aware of current services available in their regions. Community and team-based family physicians can optimize the quality of life of people with IDD and their families by adopting a proactive developmental and systems approach to preparing youth with IDD for adulthood. In doing so, they exemplify the 4 principles of family medicine.


CD8 Co-Receptor Enhances T-Cell Activation without Any Effect on Initial Attachment.
The scanning of surrounding tissues by T lymphocytes to detect cognate antigens requires high speed, sensitivity and specificity. T-cell receptor (TCR) co-receptors such as CD8 increase detection performance, but the exact mechanism remains incompletely understood. Here, we used a laminar flow chamber to measure at the single molecule level the kinetics of bond formation and rupture between TCR- transfected CD8+ and CD8- Jurkat cells and surfaces coated with five peptide-exposing major histocompatibility antigens (pMHCs) of varying activating power. We also used interference reflection microscopy to image the spreading of these cells dropped on pMHC-exposing surfaces. CD8 did not influence the TCR-pMHC interaction during the first few seconds following cell surface encounter, but it promoted the subsequent spreading responses, suggesting that CD8 was involved in early activation rather than binding. Further, the rate and extent of spreading, but not the lag between contact and spreading initiation, depended on the pMHC. Elucidating T-lymphocyte detection strategy may help unravel underlying signaling networks.


Therapeutic Implications of Altered Energy Metabolism in Migraine: A State-of-the-Art Review.
Currently, the management strategies aimed at the resolution of migraine are pharmacological. Most of these therapies are known to alter the serotonin balance of the brain. Furthermore, therapies blocking the calcitonin gene-related peptide (CGRP) have also proven to be quite effective in their treatments. However, apart from being expensive, these therapies do not influence premonitory and aura symptoms. This suggests an incomplete approach and an inadequate understanding of the migraine pathophysiology. Recent metabolic studies have indicated that migraine should be considered as an adaptive response to the mismatch between the cerebral energy reserves and expenditure. Therefore, understanding the underlying metabolism helps derive possible novel therapeutic modalities for migraines. In this review, we highlight the underlying metabolic abnormalities found in migraine patients. This will form the basis of our evidence-based discussion on metabolic therapeutic options for migraines.


NiCo2S4 nanosheet-decorated 3D, porous Ni film@Ni wire electrode materials for all solid-state asymmetric supercapacitor applications.
Wire type supercapacitors with high energy and power densities have generated considerable interest in wearable applications. Herein, we report a novel NiCo2S4-decorated 3D, porous Ni film@Ni wire electrode for high performance supercapacitor application. In this work, a facile method is introduced to fabricate a 3D, porous Ni film deposited on a Ni wire as a flexible electrode, followed by decoration with NiCo2S4 as an electroactive material. The fabricated NiCo2S4-decorated 3D, porous Ni film@Ni wire electrode displays a superior performance with an areal and volumetric capacitance of 1.228 F cm-2 and 199.74 F cm-3, respectively, at a current density of 0.2 mA cm-1 with a maximum volumetric energy and power density (EV: 6.935 mW h cm-3; PV: 1.019 W cm-3). Finally, the solid state asymmetric wire type supercapacitor is fabricated using the fabricated NiCo2S4-decorated 3D, porous Ni film@Ni wire as a positive electrode and N-doped reduced graphene oxide (N-rGO) as a negative electrode and this exhibits good areal and volumetric capacitances of CA: 0.12 F cm-2 and CV: 19.57 F cm-2 with a higher rate capability (92%). This asymmetric wire type supercapacitor demonstrates a low leakage current and self-discharge with a maximum volumetric energy (EV: 5.33 mW h cm-3) and power (PV: 855.69 mW cm-3) density.


Communication with the public in the health-care system: a descriptive study of the use of social media in local health authorities and public hospitals in Italy.
In 2010 the Italian Ministry of Health set out recommendations for the use of social technology and Web 2.0, inviting organisations within the Italian national health service (Servizio Sanitario Nazionale, SSN) to equip themselves with instruments. 1. to ascertain how many local health authorities (Aziende Sanitarie Locali, ASL) and public hospitals have a presence on the most widely used social media websites in Italy: Facebook, Twitter and YouTube; 2. to find out how well the Facebook, Twitter and YouTube pages of ASLs and public hospitals are known among the general population; 3. to find out how ASLs and public hospitals engage with the general public on social media sites. The websites of all ASLs and public hospitals across the country were visited to look for the icons of the social media sites under examination. The data considered were publicly available upon access. A total of 245 websites were analysed. 7.34% ASLs and hospitals had social media accounts. 8 organisations had an account on all three of the social media sites considered in the study. The results show a low presence of ASLs and hospitals on social media. Other studies are needed in this field.


Curative Onyx embolization of tentorial dural arteriovenous fistulas.
The authors conducted a study to review their experience with tentorial dural arteriovenous fistulas (DAVFs) treated with transarterial endovascular embolization in which Onyx was used. The authors reviewed prospectively collected data in 9 patients with tentorial DAVFs treated with Onyx embolization between 2008 and 2011. Information reviewed included clinical presentation, angiographic features, treatment, and clinical and radiologically documented outcome. Clinical follow-up was available in every patient. Radiological follow-up studies were available in 8 of 9 patients (mean follow-up 4.6 months). Six of 9 patients had complete angiographic obliteration (in 5 this was confirmed by a follow-up angiogram obtained 3-6 months later), and 2 patients had near-complete obliteration (faint filling of the venous drainage in the late venous phase). One patient had partial obliteration and required surgical disconnection. In all patients with complete obliteration, transarterial embolization was performed through the posterior branch of the middle meningeal artery. There were no procedural complications, and no morbidity or mortality resulted from Onyx embolization. Transarterial Onyx embolization is a valid, effective, and safe alternative to surgical disconnection in many patients with tentorial DAVFs. The presence of an adequate posterior branch of the middle meningeal artery is critical to achieve a microcatheter position distal enough to increase the likelihood of complete obliteration.


Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival.
Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130(CAS)), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing's subset of bone sarcomas at nanomolar concentrations of dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients.


Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand.
Respiratory syncytial virus (RSV) is an important cause of respiratory tract disease worldwide, especially in the pediatric population. For viruses in general, apoptotic death of infected cells is a mechanism for reducing virus replication. Apoptosis can also be an important factor in augmenting antigen presentation and the host immune response. We examined apoptosis in response to RSV infection of primary small airway cells, primary tracheal-bronchial cells, and A549 and HEp-2 cell lines. The primary cells and the A549 cell line gave generally similar responses, indicating their appropriateness as models in contrast to HEp-2 cells. With the use of RNase protection assays with probes representing 33 common apoptosis factors, we found strong transcriptional activation of both pro- and antiapoptotic factors in response to RSV infection, which were further studied at the protein level and by functional assays. In particular, RSV infection strongly up-regulated the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its functional receptors death receptor 4 (DR4) and DR5. Furthermore, RSV-infected cells became highly sensitive to apoptosis induced by exogenous TRAIL. These findings suggest that RSV-infected cells in vivo are susceptible to killing through the TRAIL pathway by immune cells such as natural killer and CD4(+) cells that bear membrane-bound TRAIL. RSV infection also induced several proapoptotic factors of the Bcl-2 family and caspases 3, 6, 7, 8, 9, and 10, representing both the death receptor- and mitochondrion-dependent apoptotic pathways. RSV also mediated the strong induction of antiapoptotic factors of the Bcl-2 family, especially Mcl-1, which might account for the delayed induction of apoptosis in RSV-infected cells in the absence of exogenous induction of the TRAIL pathway.


A simple joint control pattern dominates performance of unconstrained arm movements of daily living tasks.
A trailing joint control pattern, during which a single joint is rotated actively and the mechanical effect of this motion is used to move the other joints, was previously observed during simplified, laboratory-based tasks. We examined whether this simple pattern also underlies control of complex, unconstrained arm movements of daily activities. Six tasks were analyzed. Using kinematic data, we estimated motion of 7 degrees of freedom (DOF) of the shoulder, elbow, and wrist, and the contribution of muscle and passive interaction and gravitational torques to net torque at each joint. Despite task variety, the hand was transported predominantly by shoulder and elbow flexion/extension, although shoulder external/internal rotation also contributed in some tasks. The other DOF were used to orient the hand in space. The trailing pattern represented by production of net torque by passive torques at the shoulder or elbow or both was observed during the biggest portion of each movement. Net torque generation by muscle torque at both joints simultaneously was mainly limited to movement initiation toward the targets and movement termination when returning to the initial position, and associated with needing to overcome gravity. The results support the interpretation of previous studies that prevalence of the trailing pattern is a feature of skillful, coordinated movements. The simplicity of the trailing pattern is promising for quantification of dyscoordination caused by motor disorders and formulation of straightforward instructions to facilitate rehabilitation and motor learning.


Global ethnic and geographic differences in the clinical presentations of anti-neutrophil cytoplasm antibody-associated vasculitis.
There are few data on clinical profiles of ANCA-associated vasculitis (AAV) in different ethnic populations. The aim of this study was to examine the differences in the ANCA type and clinical features of AAV between populations using the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) dataset. The DCVAS is an international, multicentre, observational study recruiting in 133 sites. Eight ethnic categories were analysed: Northern European, Caucasian American, Southern European, Middle Eastern/Turkish, Chinese, Japanese, Indian subcontinent and other. ANCA type was categorized as myeloperoxidase (MPO), PR3 and ANCA negative. Organ system involvement was recorded using a standard dataset. Differences were analysed by chi-squared tests using a Bonferroni correction and logistic regression (adjusting for age and sex). Northern European was the reference population. Data from 1217 patients with AAV were available and the 967 (79.5%) patients recruited by rheumatology departments were analysed to reduce confounding by recruitment specialty. There were differences in ANCA type between ethnic categories (P < 0.001): MPO-ANCA was more common than PR3-ANCA in Japanese, Chinese and Southern Europeans; PR3-ANCA was more common in the other groups. Compared with Northern Europeans, Japanese had a nearly 60-fold increased chance of having MPO-ANCA (vs PR3-ANCA) [odds ratio (OR) 59.2 (95% CI 8.0, 440.7), P < 0.001] and Chinese had a nearly 7-times increased chance [OR 6.8 (95% CI 2.6, 17.8), P < 0.001]. Ophthalmologic and otorhinolaryngologic involvement were less common in Japanese and Chinese populations than Northern Europeans; otherwise, there were few differences in organ involvement between ethnic groups. This study confirms the previously observed differential occurrence of MPO-AAV and PR3-AAV between different ethnic groups.


Case for diagnosis: vesicular pemphigoid?
A 47-year-old man was diagnosed as having dermatitis herpetiformis (DH) in 1957. His failure to respond to therapy and the advent of immunofluorescent techniques led to a subsequent tentative diagnosis of vesicular pemphigoid (VP). High-titered, antibasal zone antibodies were present. However, unlike previously reported cases, direct immunofluorescence microscopy initially showed a DH-like and, later, an atypical granular band instead of a tubular (linear) band but with bullous pemphigoid (BP)-like immunoglobulin composition. No IgA was present. The patient's serum antibasal zone antibodies reacted with his perilesional skin despite granular deposits present at the same site, suggesting concomitant BP- and DH-like immunologic phenomena. The non-IgA-containing atypical granular band might be an immunologic marker for a subset of VP or another distinct disease entity demonstrating an immunologic overlap between BP and DH.


Assessing attitudes toward laxative preparation in colorectal cancer screening and effects on future testing: potential receptivity to computed tomographic colonography.
To investigate whether removal of the laxative preparation would improve colorectal cancer (CRC) screening rates. RESPONDENTS AND METHODS: Data are from a mixed-mode mail and telephone survey of 1636 noninstitutionalized Minnesota residents who were 18 years or older that was conducted from July 15 through October 25, 2005. The overall response rate was 49%. Analysis focused on the 759 respondents who were 50 years or older. One third (32%) of the respondents identified the laxative preparation as the most troublesome part of CRC screening. Overall, the self-reported likelihood and anticipated timing of examination increase when the laxative preparation is removed. Both univariate and multivariate analysis showed that the odds of being "much more likely" to undergo screening in the future with a test that does not include a laxative preparation are greatest among those who have been tested previously, regard the laxative preparation as a big problem, or both. In this prospective survey, laxative preparation appeared to be a major disincentive to CRC screening. Emerging data suggest that performance of laxative-free computed tomographic colonography may represent an attractive option that removes this relatively common disincentive to CRC screening participation.


Use of smoking-cessation treatments in the United States.
Health promotion efforts encourage smokers to quit and to use effective cessation treatments. Randomized controlled trials demonstrate that medications and behavioral treatments improve cessation rates, but retrospective surveys have been inconsistent. This study assessed frequency of quit attempts, use of treatments for cessation, and abstinence rates among treatment users and non-users. Data were analyzed from the 2003 Tobacco Use Special Cessation Supplement to the Current Population Survey. Participants included 29,537 U.S. smokers aged > or =18 years who smoked daily 12 months before the survey. Outcome measures included past-year quit attempts; use of behavioral, pharmacologic, and alternative treatments; receipt of social support; and abstinence for > or =4 weeks at time of survey. Approximately 43.5% of smokers reported a quit attempt in the preceding year: 64.2% of attempters used no cessation treatments; 8.8% used behavioral treatment; 32.2% used medication; and 14.1% used more than one treatment. Social support was reported to have been received by 24.1%. More nicotine-dependent smokers were more likely to use medications (OR=3.58; 95% CI=3.04-4.20). At the time of the survey, 19.3% of attempters were abstinent > or =4 weeks. Smokers who sought treatment were less likely to be abstinent (OR=0.75; 95% CI=0.67-0.84), and those who sought multiple treatments were even less likely to be abstinent. Many U.S. smokers make quit attempts, but most do not use behavioral or pharmacologic treatments. More nicotine-dependent smokers were more likely to seek treatment. Smokers who sought treatment were less likely to report abstinence, probably due to biased self-selection and recall. Retrospective survey data are not well-suited to assess the effectiveness of treatment.


Distinct mechanism for antidepressant activity by blockade of central substance P receptors.
The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.


Contraceptive sales in the setting of the Zika virus epidemic.
Has there been any influence of the Zika virus (ZIKV) outbreak on the sales of contraceptive methods in Brazil? Contraceptive sales in the 24 months of evaluation showed little variation and no significant change has been observed since the ZIKV outbreak. Transmission of ZIKV is primarily by Aedes aegypti mosquitoes; however, sexual transmission has also been described. The association of several birth defects and the ZIKV infection during pregnancy has been established, and it was estimated in Bahia, Brazil that the infection rate could range from 10% to 80%. The World Health Organisation (WHO) declared the cluster of microcephaly cases and other neurological disorders a health emergency on 1 February 2016. The Brazilian government also made recommendations for women who were planning to become pregnant and who reside in ZIKV-affected areas to reconsider or postpone pregnancy. The objective of this study was to assess the sales of contraceptive methods in Brazil, tracking it from before and through the ZIKV outbreak. We obtained information from all pharmaceutical companies based in Brazil and from the manufacturers of long-acting reversible contraceptives (LARCs), including the copper-intrauterine device (IUD), the levonorgestrel-releasing intrauterine system (LNG-IUS) and implants, about contraceptives sales in the public and private sectors between September 2014 and August 2016. We analyzed the data for: (i) oral contraceptives, i.e. combined oral contraceptives (COC) and progestin-only pills (POP), and vaginal and transdermal contraceptives, (ii) injectable contraceptives, i.e. once-a-month and depot-medroxyprogesterone acetate, (iii) LARCs and (iv) emergency contraceptive (EC) pills. Monthly sales of COC, POP, patches and vaginal rings represent the major sales segment of the market, i.e. 12.7-13.8 million cycles/units per month (90%). The second largest group of sales was injectables, representing 0.8-1.5 million ampoules per month (9.5%). Following this, are LARC methods with sales of 37 000-41 000 devices per month (0.5%). It is important to note that although the peak months of sales were different for each group of contraceptives, there were no significant differences overall between the months of observation. The EC pill sales were between 1.0 million and 1.3 million of pills per month. Although the use of contraceptive methods was already high and no change was noted, the ZIKV outbreak may have changed the pregnancy intentions of Brazilian women. Consequently, the number of women planning pregnancy may be lower than that recorded. The contraceptive sales figures did not include condoms. Since condoms might not only prevent pregnancies, but also sexual transmission of ZIKV, this lack of information is a limitation. The results from this assessment showed that the sales of contraceptives presented little variation during the ZIKV outbreak in Brazil. Furthermore, it is possible that access to LARC methods was limited. Although we did not investigate the reason for low LARC uptake, we suspect that it is due to lack of availability of LARC in the public sector, the high cost of the methods and the incomplete insurance coverage on contraception for women. Projections estimate millions of additional cases of ZIKV transmission. Thus, a coordinated response is needed to ensure access to a wide range of contraceptive methods for women during the ZIKV outbreak. In conclusion, this assessment of contraceptive sales in Brazil identifies challenges in contraceptive access, especially for LARC methods, and represents an alternative source of data to help us understand the trends in demand for contraception in ZIKV-affected areas. This study received partial financial support from Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP) award # 2015/20504-9 and from an anonymous donor. The funding sources did not play a role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication. The authors declare no conflict of interest associated with this study. N/A.


Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP.
Vasopressin and its analogue 1-deamino-8-D-arginine vasopressin (DDAVP) are known to raise plasma von Willebrand factor (vWF) levels. DDAVP is used as a hemostatic agent for the treatment of von Willebrand's disease. However, its cellular mechanisms of action have not been elucidated. DDAVP, a specific agonist for the vasopressin V2 receptor (V2R), exerts its antidiuretic effect via a rise in cAMP in kidney collecting ducts. We tested the hypothesis that DDAVP induces vWF secretion by binding to V2R and activating cAMP-mediated signaling in endothelial cells. vWF secretion from human umbilical vein endothelial cells (HUVECs) can be mediated by cAMP, but DDAVP is ineffective, presumably due to the absence of V2R. We report that DDAVP stimulates vWF secretion in a cAMP-dependent manner in HUVECs after transfection of the V2R. In addition, vasopressin and DDAVP induce vWF secretion in human lung microvascular endothelial cells (HMVEC-L). These cells (but not HUVECs) express endogenous V2R, as shown by RT-PCR. Vasopressin-induced vWF secretion is mimicked by DDAVP and inhibited by the selective V2R antagonist SR121463B. It is mediated by cAMP, since it is inhibited by the protein kinase A inhibitor Rp-8CPT-cAMPS. These results indicate that vasopressin induces cAMP-mediated vWF secretion by a direct effect on endothelial cells. They also demonstrate functional expression of V2R in endothelial cells, and provide a cellular mechanism for the hemostatic effects of DDAVP.


The role of dopamine in the pathophysiology and treatment of apathy.
Disorders of diminished motivation, such as apathy, are common and prevalent across a wide range of medical conditions, including Parkinson's disease, Alzheimer's dementia, stroke, depression, and schizophrenia. Such disorders have a significant impact on morbidity and quality of life, yet their management lacks consensus and remains unsatisfactory. Here, we review laboratory and clinical evidence for the use of dopaminergic therapies in the treatment of apathy. Dopamine is a key neurotransmitter that regulates motivated decision making in humans and other species. A large corpus of evidence suggests that it plays an important role in promoting approach behavior by attributing incentive salience to reward stimuli, and facilitating the overcoming of effort costs. Furthermore, dopaminergic neurons innervate several frontostriatal structures that mediate reward-guided behavior. Based on these findings, there are a priori reasons for considering dopamine in the treatment of disorders of diminished motivation. We highlight key studies that have attempted to use dopamine to manage patients with apathy, and that collectively offer cautious evidence in favor of its efficacy. However, many of these studies are small, unblinded, and uncontrolled, and utilize subjective, questionnaire-based measures of apathy. Given the development of novel paradigms which are able to objectively dissect motivational dysfunction, we are now well positioned to quantify the effect of specific classes of dopaminergic medication on reward- and effort-based decision making in apathy. We anticipate that such paradigms will lay the foundation for future studies to evaluate new and existing treatments for disorders of motivation, using sensitive measures of apathy as primary quantifiable end points.


Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis.
The composition of atherosclerotic (AS) plaques is crucial concerning rupture, thrombosis and clinical events. Two plaque types are distinguished: stable and vulnerable plaques. Vulnerable plaques are rich in inflammatory cells, mostly only M1 macrophages, and are highly susceptible to rupture. These plaques represent a high risk particularly with the standard invasive diagnosis by coronary angiography. So far there are no non-invasive low-risk clinical approaches available to detect and distinguish AS plaque types in vivo. The perspective review introduces a whole work-flow for a novel approach for non-invasive detection and classification of AS plaques using the diffusion reflection method with gold nanoparticle loaded macrophages in combination with flow and image cytometric analysis for quality assurance. Classical biophotonic methods for AS diagnosis are summarized. Phenotyping of monocytes and macrophages are discussed for specific subset labelling by nanomaterials, as well as existing studies and first experimental proofs of concept for the novel approach are shown. In vitro and in vivo detection of NP loaded macrophages (MΦ). Different ways of MΦ labelling include (1) in vitro labelling in suspension (whole blood or buffy coat) or (2) labelling of short-term MΦ cultures with re-injection of MΦ-NP into the animal to detect migration of the cells in the plaques and (3) in vivo injection of NP into the organism.


DREB1A promotes root development in deep soil layers and increases water extraction under water stress in groundnut.
Water deficit is a major yield-limiting factor for many crops, and improving the root system has been proposed as a promising breeding strategy, although not in groundnut (Arachis hypogaea L.). The present work was carried out mainly to assess how root traits are influenced under water stress in groundnut, whether transgenics can alter root traits, and whether putative changes lead to water extraction differences. Several transgenic events, transformed with DREB1A driven by the rd29 promoter, along with wild-type JL24, were tested in a lysimeter system that mimics field conditions under both water stress (WS) and well-watered (WW) conditions. The WS treatment increased the maximum rooting depth, although the increase was limited to about 20% in JL24, compared to 50% in RD11. The root dry weight followed a similar trend. Consequently, the root dry weight and length density of transgenics was higher in layers below 100-cm depth (Exp. 1) and below 30 cm (Exp. 2). The root diameter was unchanged under WS treatment, except a slight increase in the 60-90-cm layer. The root diameter increased below 60 cm in both treatments. In the WW treatment, total water extraction of RD33 was higher than in JL24 and other transgenic events, and somewhat lower in RD11 than in JL24. In the WS treatment, water extraction of RD2, RD11 and RD33 was higher than in JL24. These water extraction differences were mostly apparent in the initial 21 days after treatment imposition and were well related to root length density in the 30-60-cm layer (R(2) = 0.68), but not to average root length density. In conclusion, water stress promotes rooting growth more strongly in transgenic events than in the wild type, especially in deep soil layers, and this leads to increased water extraction. This opens an avenue for tapping these characteristics toward the improvement of drought adaptation in deep soil conditions, and toward a better understanding of genes involved in rooting in groundnut.


The analysis of eight transcriptomes from all poriferan classes reveals surprising genetic complexity in sponges.
Sponges (Porifera) are among the earliest evolving metazoans. Their filter-feeding body plan based on choanocyte chambers organized into a complex aquiferous system is so unique among metazoans that it either reflects an early divergence from other animals prior to the evolution of features such as muscles and nerves, or that sponges lost these characters. Analyses of the Amphimedon and Oscarella genomes support this view of uniqueness-many key metazoan genes are absent in these sponges-but whether this is generally true of other sponges remains unknown. We studied the transcriptomes of eight sponge species in four classes (Hexactinellida, Demospongiae, Homoscleromorpha, and Calcarea) specifically seeking genes and pathways considered to be involved in animal complexity. For reference, we also sought these genes in transcriptomes and genomes of three unicellular opisthokonts, two sponges (A. queenslandica and O. carmela), and two bilaterian taxa. Our analyses showed that all sponge classes share an unexpectedly large complement of genes with other metazoans. Interestingly, hexactinellid, calcareous, and homoscleromorph sponges share more genes with bilaterians than with nonbilaterian metazoans. We were surprised to find representatives of most molecules involved in cell-cell communication, signaling, complex epithelia, immune recognition, and germ-lineage/sex, with only a few, but potentially key, absences. A noteworthy finding was that some important genes were absent from all demosponges (transcriptomes and the Amphimedon genome), which might reflect divergence from main-stem lineages including hexactinellids, calcareous sponges, and homoscleromorphs. Our results suggest that genetic complexity arose early in evolution as shown by the presence of these genes in most of the animal lineages, which suggests sponges either possess cryptic physiological and morphological complexity and/or have lost ancestral cell types or physiological processes.


Preweaning nutrient supply alters mammary gland transcriptome expression relating to morphology, lipid accumulation, DNA synthesis, and RNA expression in Holstein heifer calves.
The objective of this study was to analyze the mammary gland transcriptome to determine how preweaning nutrient supply alters the molecular mechanisms that regulate preweaning mammary development. Holstein heifers were fed via milk replacer (MR) either an elevated level of nutrient intake (ELE; on average, 5.9 ± 0.2 Mcal of ME in 8.4 L of MR/d, n = 6) or a restricted amount of nutrients (RES; 2.8 ± 0.2 Mcal of ME in 4 L of MR/d, n = 5) for 54 d after birth, at which point they were slaughtered and samples of mammary parenchyma tissue were obtained. Parenchymal mRNA was analyzed, and the fold change (FC) of 18,111 genes (ELE relative to RES) was uploaded to Ingenuity Pathway Analysis (IPA) software (Qiagen Bioinformatics, Redwood City, CA) for transcriptomic analysis. Using a threshold of P < 0.05, IPA identified that the FC of 1,931 of 18,811 differentially expressed genes (DEG) could be used for the analysis. A total of 18 molecular and cellular functions were relevant to DEG arising from the treatments; the 5 functions most associated with DEG were cell death and survival, cellular movement, cellular development, cellular growth and proliferation, and lipid metabolism. Based on the directional FC of DEG, the mammary gland of ELE heifers was predicted to have increased epithelial-mesenchymal transition (Z = 2.685) and accumulation of lipid (Z = 2.322), whereas the synthesis of DNA (Z = -2.137), transactivation of RNA (Z = -2.254), expression of RNA (Z = -2.405), transcription (Z = -2.482), and transactivation (Z = -2.611) were all predicted to be decreased. Additionally, IPA predicted the activation status of 13 upstream regulators with direct influence on DEG as affected by ELE feeding that were ligand-dependent nuclear receptors (n = 2), enzymes (n = 1), or transcription regulators (n = 10). Of these, 6 were activated (Z > 2) and 7 were inhibited (Z < -2). In summary, feeding ELE preweaning altered the mammary transcriptome of Holstein heifers, affecting cell functions involved in the morphological and physiological development of the mammary gland.


Frequency doubling in periodic nonlinear photonic crystals mediated by random layers.
We study the frequency doubling in a quadratic nonlinear photonic crystal consisting of periodically poled structures mediated by uniform layers with random lengths. These structures can be formed by new local impact methods for ferroelectric crystal structuring. The statistical frequency doubling theory is developed for such structures. The effect of the number of random layers and variation in their thicknesses on the second-harmonic conversion efficiency is clarified. It is demonstrated that a proper choice of the intermediate layer thickness can enhance or suppress the conversion efficiency. A new type of the Maker-fringes-like second-harmonic intensity oscillations is predicted.


Hemocyte responses of the Colorado potato beetle, Leptinotarsa decemlineata, and the greater wax moth, Galleria mellonella, to the entomopathogenic nematodes, Steinernema feltiae and Heterorhabditis bacteriophora.
Hemocyte encapsulation reactions of infective juveniles of two Iranian isolates of the entomopathogenic nematodes, Heterorhabditis bacteriophora Poinar (Rhabditina: Heterorhabditidae) and Steinernema feltiae Filipjev (Tylenchina: Steinernematidae), were compared in the economic pest Colorado potato beetle, Leptinotarsa decemlineata Say (Coleoptera: Chrysomelidae), and the greater wax moth, Galleria mellonella L. (Lepidoptera: Pyralidae). The former was a more responsive host than the latter and the hemocyte responses occurred sooner and more extensively. Complete encapsulation of some of the nematodes occurred by 4 h post injection for H. bacteriophora in both L. decemlineata and G. mellonella, and by 2 h pi for S. feltiae in L. decemlineata. The percentage of encapsulation from 24 h to 72 h pi in L. decemlineata was 86.2% for S. feltiae and 39% for H. bacteriophora. In G. mellonella there were no encapsulation or melanization responses against S. feltiae, whereas when H. bacteriophora was encapsulated and melanized (16.7%) the encapsulation level was lower than in L. decemlineata. This study may contribute to effectively selecting entomopathogenic nematode species active against significant economic pests based on the latter's cellular immune response.


Time integrated detection of femtosecond laser pulses scattered by small droplets.
Scattering of femtosecond laser pulses by small droplets has been measured and compared with predictions, yielding some interesting new applications for time integrated detection of the scattered field. The scattering intensity of integrated detection becomes monotonic with droplet size over large regions of scattering angle and morphology dependent resonances are surpressed, opening the way for particle sizing using the scattered intensity. Furthermore, the ripple structure no longer appears in the rainbow region of scattering, simplifying rainbow refractometry significantly. These scattering proporties of femtosecond laser pulses have been demonstrated in the laboratory using a novel Paul trap for levitating single droplets.


Terminal groups control self-assembly of amphiphilic block copolymers in solution.
The terminal groups of amphiphilic block copolymers are shown to control macromolecular self-assembly in aqueous solutions, in the micellar/lamellar region of the phase diagram. At the same concentration and using the same self-assembly conditions, dramatic differences are observed in polymer hydration and the resulting nano-/microstructure for two series of polymers with identical block chemistry and hydrophilic-lipophilic balance (HLB). This suggests a strong contribution from end groups to the hydration as the initial step of the self-assembly process, and could be conveniently used to guide the particle morphology and size. Additionally, for polymers with those head groups which drive vesicular structures, differences in membrane organization affect their physical properties, such as permeability.


Improving interunit transitions of care between emergency physicians and hospital medicine physicians: a conceptual approach.
Patient care transitions across specialties involve more complexity than those within the same specialty, yet the unique social and technical features remain underexplored. Further, little consensus exists among researchers and practitioners about strategies to improve interspecialty communication. This concept article addresses these gaps by focusing on the hand-off process between emergency and hospital medicine physicians. Sensitivity to cultural and operational differences and a common set of expectations pertaining to hand-off content will more effectively prepare the next provider to act safely and efficiently when caring for the patient. Through a consensus decision-making process of experienced and published authorities in health care transitions, including physicians in both specialties as well as in communication studies, the authors propose content and style principles clinicians may use to improve transition communication. With representation from both community and academic settings, similarities and differences between emergency medicine and internal medicine are highlighted to heighten appreciation of the values, attitudes, and goals of each specialty, particularly pertaining to communication. The authors also examine different communication media, social and cultural behaviors, and tools that practitioners use to share patient care information. Quality measures are proposed within the structure, process, and outcome framework for institutions seeking to evaluate and monitor improvement strategies in hand-off performance. Validation studies to determine if these suggested improvements in transition communication will result in improved patient outcomes will be necessary. By exploring the dynamics of transition communication between specialties and suggesting best practices, the authors hope to strengthen hand-off skills and contribute to improved continuity of care.


Met and unmet needs of homeless individuals at different stages of housing reintegration: A mixed-method investigation.
This study aimed to identify and compare major areas of met and unmet needs reported by 455 homeless or recently housed individuals recruited from emergency shelters, temporary housing, and permanent housing in Quebec (Canada). Mixed methods, guided by the Maslow framework, were used. Basic needs were the strongest needs category identified, followed by health and social services (an emergent category), and safety; very few participants expressed needs in the higher-order categories of love and belonging, self-esteem, and self-actualization. The only significant differences between the three housing groups occurred in basic needs met, which favored permanent housing residents. Safety was the only category where individuals reported more unmet than met needs. The study results suggested that increased overall access to and continuity of care with family physicians, MD or SUD clinicians and community organizations for social integration should be provided to help better these individuals. Case management, stigma prevention, supported employment programs, peer support and day centers should particularly be more widely implemented as interventions that may promote a higher incidence of met needs in specific needs categories.


Trends in self-reported oral health of US adults: National Health and Nutrition Examination Survey 1999-2014.
Single-item self-reported oral health (SROH) is a convenient and reliable measure for the assessment of population-based oral health. However, little is known about trends and its associations among US adults. This study investigated trends in SROH (aged 20+ years) and the associated factors among adults living in the United States. Self-reported oral health data for 41 621 adults aged 20+ years from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2014 were analysed. Survey-weighted descriptive statistics were computed to provide nationally representative estimates. Multivariable logistic regression was performed separately for each survey period with SROH as the primary outcome. Independent variables included were age, gender, race/ethnicity, education level and family poverty income ratio or PIR. Pooled survey-weighted multivariable logistic regression was also performed to consider possible time-changing effects. The survey-weighted proportions of "excellent or very good" in SROH increased from 27% in 1999-2000 (n = 4873) to 38% in 2013-2014 (n = 5765). Separate multivariable logistic analyses for each survey period suggested that females, Whites (vs Mexican and Black Americans) as well as respondents from high family PIR had higher odds of reporting their oral health as "excellent or very good" (P < .05). The pooled multivariable logistic model confirmed results in the separate logistic regression, and respondents in the more recent survey periods had higher probabilities of reporting "excellent or very good" oral health. Respondents aged 50-59 years were found to have relatively lower probabilities of reporting "excellent or very good" oral health, while people aged 20-29 years had higher probabilities than those aged 30-39 years. Compared to respondents with lower education, those with higher education were more likely to report their oral health as excellent or very good. Self-reported oral health improved from 1999 to 2014. In general, respondents who were young, female, White, had higher education or higher income or were surveyed in more recent years reported excellent or very good oral health.


FRET imaging of diatoms expressing a biosilica-localized ribose sensor.
Future materials are envisioned to include bio-assembled, hybrid, three-dimensional nanosystems that incorporate functional proteins. Diatoms are amenable to genetic modification for localization of recombinant proteins in the biosilica cell wall. However, the full range of protein functionalities that can be accommodated by the modified porous biosilica has yet to be described. Our objective was to functionalize diatom biosilica with a reagent-less sensor dependent on ligand-binding and conformational change to drive FRET-based signaling capabilities. A fusion protein designed to confer such properties included a bacterial periplasmic ribose binding protein (R) flanked by CyPet (C) and YPet (Y), cyan and yellow fluorescent proteins that act as a FRET pair. The structure and function of the CRY recombinant chimeric protein was confirmed by expression in E. coli prior to transformation of the diatom Thalassiosira pseudonana. Mass spectrometry of the recombinant CRY showed 97% identity with the deduced amino acid sequence. CRY with and without an N-terminal Sil3 tag for biosilica localization exhibited characteristic ribose-dependent changes in FRET, with similar dissociation constants of 123.3 µM and 142.8 µM, respectively. The addition of the Sil3 tag did not alter the affinity of CRY for the ribose substrate. Subsequent transformation of T. pseudonana with a vector encoding Sil3-CRY resulted in fluorescence localization in the biosilica and changes in FRET in both living cells and isolated frustules in response to ribose. This work demonstrated that the nano-architecture of the genetically modified biosilica cell wall was able to support the functionality of the relatively complex Sil3-CyPet-RBP-YPet fusion protein with its requirement for ligand-binding and conformational change for FRET-signal generation.


The implications of population growth and climate change on sustainable development in Bangladesh.
Bangladesh is characterised by its large population on a small land, rapid and unplanned urbanisation, rising urban inequalities, food and nutritional insecurity and lower level of resilience to climate change. These combined effects are major threats to food security of the country in the near future. This paper examined the implications of population growth and climate change on sustainable development of Bangladesh. This research was based on the analysis of chronological data and synthesis of literature on population growth, greenhouse gases emission, climate change, food security and sustainable development, mainly contextualised on Bangladesh. The analysis found that the population of Bangladesh has almost doubled between 1980 and 2015. The country shared around 2.2% (in 2013) of global population and contributed only 0.19% of global carbon dioxide emission. On the contrary, climate change is the biggest challenge for the country. An increase in temperature could decline rice and wheat production. Moreover, average monsoon rainfall would be increased as a result of increased temperature. The increase in temperature and rainfall may lead to early arrival and late departure of the monsoon season or an increase in mean daily rainfall intensity. Population growth and climate change have multiple implications on development. Therefore, sustainable development may be difficult to attain if climate change continues to jeopardise economic growth, environmental stability as well as the social progress of Bangladesh.


Epidemiology of human brucellosis in Nahavand county, Hamadan Province, western Iran: an 8-year (2010-2017) registry-based analysis.
Brucellosis is an infectious zoonosis, which greatly afflicts human health and animal productivity. To describe the trends and epidemiological characteristics of human brucellosis in Nahavand county, Hamadan Province, western Iran over 8 years (2010-2017). In this registry-based longitudinal study, we analyzed all reported cases of human brucellosis, including 1,130 patients from 2010 to 2017. A checklist including demographic and clinical characteristics of patients with reported cases of brucellosis had been used to gather data. We calculated annual percent changes (APCs) and average annual percent changes (AAPCs) using Joinpoint software to determine the trend of brucellosis using a segmented regression model. Among the patients, 60.9% were male and 87.3% lived in rural areas. The mean age of the patients was 35.9 ± 18.34 years. Compared with male patients, female patients were more affected when they were elderly (15.6% men vs. 24.2% women for those aged ≥55 years) (P = 0.001). Of patients with brucellosis, 65.2% had consumed unpasteurized dairy products and 82.3% had a history of contact with animals. The incidence of human brucellosis in Nahavand county increased between 2010 and 2014, then decreased in 2015, and thereafter remained steady. Per 100,000 population, the AAPC pertaining to the incidence was 17.4 in the male population (95% CI: 4.4, 31.9), 13.8 in the female population (95% CI: 0.2, 29.3), and 16.1 in rural dwellers (95% CI: 2.2, 31.8) indicating an increasing trend from 2010 to 2017 (P < 0.05). The incidence of brucellosis in the western part of Iran is high and remains a challenging health problem. In the present study, age, job, sex, and seasonal changes are important risk factors for human brucellosis.


Student experiences of two small group learning-teaching formats: Seminar and fishbowl.
As teaching strategies, the seminar and fishbowl approaches promote active learning and shift the focus from the teacher to the learner. The aim of this study was to compare the self-reported perceptions of each student-centred teaching technique amongst a group of dental students as well as resultant quiz scores after each teaching technique. During the first semester of 2017, all year-3 (N = 88) Semiology and year-5 (N = 71) Oral Surgery students participated in weekly seminars in which teams of students from both cohorts were given an actual clinical case to study; a diagnosis and treatment plan would be rendered, and an oral case presentation would be presented to the rest of the class. In the second semester, the same students tried to solve similar clinical cases using the fishbowl training format. A course coordinator provided final feedback, and the session culminated with a quiz. Students were invited to provide quantitative and qualitative perceptions whilst quiz scores obtained during seminar and fishbowl teaching formats were compared. A total of 97 (61%) seminar and 92 (58%) fishbowl students provided insights regarding these teaching techniques. Both cohorts believed the fishbowl format allowed them to be actively involved. However, only year-3 students gave the fishbowl format a significantly higher score than the seminar format, considering it an attractive format that allowed them to learn. In contrast, year-5 students believed the seminars met their expectations better than the fishbowl format. Interesting clinical cases as well as the final round of feedback were qualitative themes reported by both cohorts. The mean seminar and fishbowl quiz scores were statistically significant different for year-3 students (P < 0.0001), but not for year-5 students (P = 0.09). These findings suggest that a more structured small-group learning-teaching format can be implemented for younger students whilst at the same time allowing more flexible organisation for senior students.


Developing EMR-based algorithms to Identify hospital adverse events for health system performance evaluation and improvement: Study protocol.
Measurement of care quality and safety mainly relies on abstracted administrative data. However, it is well studied that administrative data-based adverse event (AE) detection methods are suboptimal due to lack of clinical information. Electronic medical records (EMR) have been widely implemented and contain detailed and comprehensive information regarding all aspects of patient care, offering a valuable complement to administrative data. Harnessing the rich clinical data in EMRs offers a unique opportunity to improve detection, identify possible risk factors of AE and enhance surveillance. However, the methodological tools for detection of AEs within EMR need to be developed and validated. The objectives of this study are to develop EMR-based AE algorithms from hospital EMR data and assess AE algorithm's validity in Canadian EMR data. Patient EMR structured and text data from acute care hospitals in Calgary, Alberta, Canada will be linked with discharge abstract data (DAD) between 2010 and 2020 (n~1.5 million). AE algorithms development. First, a comprehensive list of AEs will be generated through a systematic literature review and expert recommendations. Second, these AEs will be mapped to EMR free texts using Natural Language Processing (NLP) technologies. Finally, an expert panel will assess the clinical relevance of the developed NLP algorithms. AE algorithms validation: We will test the newly developed AE algorithms on 10,000 randomly selected EMRs between 2010 to 2020 from Calgary, Alberta. Trained reviewers will review the selected 10,000 EMR charts to identify AEs that had occurred during hospitalization. Performance indicators (e.g., sensitivity, specificity, positive predictive value, negative predictive value, F1 score, etc.) of the developed AE algorithms will be assessed using chart review data as the reference standard. The results of this project can be widely implemented in EMR based healthcare system to accurately and timely detect in-hospital AEs.


Cytotoxic drug-induced lung injury.
Cytotoxic drug-induced pulmonary disease is a major cause of morbidity and mortality in immunocompromised patients. It is estimated that 20% of all patients receiving cytotoxic drugs will develop a symptomatic pulmonary reaction. Therefore, the possibility of a toxic drug reaction must be considered in all patients developing pulmonary disease during or following treatment with these agents. Clinical manifestations of lung toxicity are nonspecific and parallel the signs and symptoms of diffuse lung infection and malignant disease in the chest. For this reason, the diagnosis of cytotoxic drug-induced lung damage is one of exclusion of the various opportunistic infections that afflict this patient population. This typically requires careful microbiologic studies of bronchoalveolar lavage (BAL) samples and lung tissue. The diagnosis of cytotoxic drug-induced lung injury is often vexing. In the future, (BAL) may assume a more prominent diagnostic role and suggest insights into the pathogenesis of this entity.


Concentrations of mercury, lead, chromium, cadmium, arsenic and aluminum in irrigation water wells and wastewaters used for agriculture in Mashhad, northeastern Iran.
Contamination of water by toxic chemicals has become commonly recognized as an environmental concern. Based on our clinical observation in Mashhad, northeastern Iran, many people might be at risk of exposure to high concentrations of toxic heavy metals in water. Because wastewater effluents as well as water wells have been commonly used for irrigation over the past decades, there has been some concern on the toxic metal exposure of crops and vegetables irrigated with the contaminated water. To measure the concentrations of mercury, lead, chromium, cadmium, arsenic and aluminium in irrigation water wells and wastewaters used for agriculture in Mashhad, northeastern Iran. 36 samples were taken from irrigation water wells and a wastewater refinery in North of Mashhad at four times--May 2008, March 2009, and June and July 2010. Atomic absorption spectrometry was used to measure the concentration of toxic metals. Graphite furnace was used for the measurement of lead, chromium, cadmium and aluminum. Mercury and arsenic concentrations were measured by mercury/hydride system. Chromium, cadmium, lead and arsenic concentrations in the samples were within the standard range. The mean±SD concentration of mercury in irrigation wells (1.02±0.40 μg/L) exceeded the FAO maximum permissible levels. The aluminum concentration in irrigation water varied significantly from month to month (p=0.03). All wastewater samples contained high mercury concentrations (6.64±2.53 μg/L). For high mercury and aluminum concentrations, the water sources studied should not be used for agricultural use. Regular monitoring of the level of heavy metals in water and employing the necessary environmental interventions in this area are strongly recommended.


CHD5 is a tumor suppressor at human 1p36.
Cancer gene discovery has relied extensively on analyzing tumors for gains and losses to reveal the location of oncogenes and tumor suppressor genes, respectively. Deletions of 1p36 are extremely common genetic lesions in human cancer, occurring in malignancies of epithelial, neural, and hematopoietic origin. Although this suggests that 1p36 harbors a gene that drives tumorigenesis when inactivated, the identity of this tumor suppressor has remained elusive. Here we use chromosome engineering to generate mouse models with gain and loss of a region corresponding to human 1p36. This approach functionally identifies chromodomain helicase DNA binding domain 5 (Chd5) as a tumor suppressor that controls proliferation, apoptosis, and senescence via the p19(Arf)/p53 pathway. We demonstrate that Chd5 functions as a tumor suppressor in vivo and implicate deletion of CHD5 in human cancer. Identification of this tumor suppressor provides new avenues for exploring innovative clinical interventions for cancer.


Systems biology of embryonic development: Prospects for a complete understanding of the Caenorhabditis elegans embryo.
The convergence of developmental biology and modern genomics tools brings the potential for a comprehensive understanding of developmental systems. This is especially true for the Caenorhabditis elegans embryo because its small size, invariant developmental lineage, and powerful genetic and genomic tools provide the prospect of a cellular resolution understanding of messenger RNA (mRNA) expression and regulation across the organism. We describe here how a systems biology framework might allow large-scale determination of the embryonic regulatory relationships encoded in the C. elegans genome. This framework consists of two broad steps: (a) defining the "parts list"-all genes expressed in all cells at each time during development and (b) iterative steps of computational modeling and refinement of these models by experimental perturbation. Substantial progress has been made towards defining the parts list through imaging methods such as large-scale green fluorescent protein (GFP) reporter analysis. Imaging results are now being augmented by high-resolution transcriptome methods such as single-cell RNA sequencing, and it is likely the complete expression patterns of all genes across the embryo will be known within the next few years. In contrast, the modeling and perturbation experiments performed so far have focused largely on individual cell types or genes, and improved methods will be needed to expand them to the full genome and organism. This emerging comprehensive map of embryonic expression and regulatory function will provide a powerful resource for developmental biologists, and would also allow scientists to ask questions not accessible without a comprehensive picture. This article is categorized under: Invertebrate Organogenesis > Worms Technologies > Analysis of the Transcriptome Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics.


A common region of homozygous deletion in malignant human gliomas lies between the IFN alpha/omega gene cluster and the D9S171 locus.
Deletions of the 9p-localized type-I interferon (IFN) genes and adjacent loci often occur during the development of malignant glioma. We have applied restriction fragment length polymorphism and microsatellite analysis to 12 loci covering this region of 9p and 3 loci on 9q in 74 human glial tumor tissues to define and further localize the smallest region of hemizygous or homozygous deletion common to the tumors. Three regions of homozygous deletion were evident among the panel of tumors; only one of these, however, residing between D9S171 and the IFN alpha/omega gene cluster, was involved in multiple cases (13 glioblastomas). Hemizygous deletion of this same region was observed in an additional 27 tumors. In total these data indicate the frequent inactivation of a novel tumor suppressor gene residing adjacent to and centromeric of the type-I IFN genes in malignant gliomas.


The introduction of functional side groups and the application of the mixed-linker concept in divalent MIL-53(Ni) materials.
Metal-organic framework materials with functional side groups are commonly used for various purposes like post-synthetic modification reactions or the tuning of pore geometries. Additionally, the mixed-linker concept, in which different linkers are statistically distributed over equivalent lattice positions, is a versatile approach to adjust the number of functional groups within the framework. However, neither functional side groups nor the mixed-linker approach have been used in MIL-53 materials with divalent metal ions yet. In the present work, we report on the synthesis of MIL-53(Ni)-Br(100), which contains only 2-bromoterephthalate as a linker molecule, and mixed-linker MIL-53(Ni)-Br(50) containing both terephthalate and 2-bromoterephthalate. These two materials represent the first functionalized and mixed-linker MIL-53 materials in combination with a divalent metal. Consequently, the possibilities to tailor the properties of the still rarely used divalent MIL-53 materials were expanded.


Costs and readmission rates for the resection of primary and metastatic spinal tumors: a comparative analysis of 181 patients.
OBJECTIVE Because the surgical strategies for primary and metastatic spinal tumors are different, the respective associated costs and morbidities associated with those treatments likely vary. This study compares the direct costs and 90-day readmission rates between the resection of extradural metastatic and primary spinal tumors. The factors associated with cost and readmission are identified. METHODS Adults (age 18 years or older) who underwent the resection of spinal tumors between 2008 and 2013 were included in the study. Patients with intradural tumors were excluded. The direct costs of index hospitalization and 90-day readmission hospitalization were evaluated. The direct costs were compared between patients who were treated surgically for primary and metastatic spinal tumors. The independent factors associated with costs and readmissions were identified using multivariate analysis. RESULTS A total of 181 patients with spinal tumors were included (63 primary and 118 metastatic tumors). Overall, the mean index hospital admission cost for the surgical management of spinal tumors was $52,083. There was no significant difference in the cost of hospitalization between primary ($55,801) and metastatic ($50,098) tumors (p = 0.426). The independent factors associated with higher cost were male sex (p = 0.032), preoperative inability to ambulate (p = 0.002), having more than 3 comorbidities (p = 0.037), undergoing corpectomy (p = 0.021), instrumentation greater than 7 levels (p < 0.001), combined anterior-posterior approach (p < 0.001), presence of a perioperative complication (p < 0.001), and longer hospital stay (p < 0.001). The perioperative complication rate was 21.0%. Of this cohort, 11.6% of patients were readmitted within 90 days, and the mean hospitalization cost of that readmission was $20,078. Readmission rates after surgical treatment for primary and metastatic tumors were similar (11.1% vs 11.9%, respectively) (p = 0.880). Prior hospital stay greater than 15 days (OR 6.62, p = 0.016) and diagnosis of lung metastasis (OR 52.99, p = 0.007) were independent predictors of readmission. CONCLUSIONS Primary and metastatic spinal tumors are comparable with regard to the direct costs of the index surgical hospitalization and readmission rate within 90 days. The factors independently associated with costs are related to preoperative health status, type and complexity of surgery, and postoperative course.


Effects of Chinese Herbal Medicines on the Risk of Overall Mortality, Readmission, and Reoperation in Hip Fracture Patients.
Hip fracture is a major public health concern, with high incidence rates in the elderly worldwide. Hip fractures are associated with increased medical costs, patient dependency on families, and higher rates of morbidity and mortality. Chinese herbal medicine (CHM) is typically characterized as cost-effective and suitable for long-term use with few side effects. To better understand the effects of CHM on hip fracture patients, we utilized a population-based database to investigate the demographic characteristics, cumulative incidence of overall mortality, readmission, reoperation, and patterns of CHM prescription. We found that CHM usage was associated with a lower risk of overall mortality [P = 0.0009; adjusted hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.30-0.73], readmission (P = 0.0345; adjusted HR: 0.67, 95% CI: 0.46-0.97), and reoperation (P = 0.0009; adjusted HR: 0.57, 95% CI: 0.40-0.79) after adjustment for age, type of hip fracture, surgical treatment type, and comorbidities. We also identified the herbal formulas, single herbs, and prescription patterns for the treatment of hip fracture by using association rule mining and network analysis. For hip fracture patients, the most common CHM coprescription pattern was Du-Zhong (DZ) → Xu-Duan (XD), followed by Du-Huo-Ji-Sheng-Tang (DHJST) → Shu-Jing-Huo-Xue-Tang (SJHXT), and Gu-Sui-Bu (GSB) → Xu-Duan (XD). Furthermore, XD was the core prescription, and DZ, GSB, SJHXT, and DHJST were important prescriptions located in cluster 1 of the prescription patterns. This study provides evidence for clinical CHM use as an adjunctive therapy that offers benefits to hip fracture patients.