CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations.
Cerebral cavernous malformation is a common human vascular disease that arises due to loss-of-function mutations in genes encoding three intracellular adaptor proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3. CCM1, CCM2, and CCM3 interact biochemically in a pathway required in endothelial cells during cardiovascular development in mice and zebrafish. The downstream effectors by which this signaling pathway regulates endothelial function have not yet been identified. Here we have shown in zebrafish that expression of mutant ccm3 proteins (ccm3Delta) known to cause cerebral cavernous malformation in humans confers cardiovascular phenotypes identical to those associated with loss of ccm1 and ccm2. CCM3Delta proteins interacted with CCM1 and CCM2, but not with other proteins known to bind wild-type CCM3, serine/threonine protein kinase MST4 (MST4), sterile 20-like serine/threonine kinase 24 (STK24), and STK25, all of which have poorly defined biological functions. Cardiovascular phenotypes characteristic of CCM deficiency arose due to stk deficiency and combined low-level deficiency of stks and ccm3 in zebrafish embryos. In cultured human endothelial cells, CCM3 and STK25 regulated barrier function in a manner similar to CCM2, and STKs negatively regulated Rho by directly activating moesin. These studies identify STKs as essential downstream effectors of CCM signaling in development and disease that may regulate both endothelial and epithelial cell junctions.


Temporal and phylogenetic evolution of the sauropod dinosaur body plan.
The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to date, there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here, we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton : body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass (CoM) in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad CoM shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic-Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and CoM position are not strongly correlated with inferred feeding habits. Instead the craniad CoM positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous.


How do microbes evade neutrophil killing?
Many microbial pathogens evolved to circumvent the attack of neutrophils, which are essential effector cells of the innate immune system. Here we review six major strategies that pathogenic bacteria and fungi use to evade neutrophil defences: (i) turning on survival and stress responses, (ii) avoiding contact, (iii) preventing phagocytosis, (iv) surviving intracellularly, (v) inducing cell death and (vi) evading killing by neutrophil extracellular traps. For each category we give examples and further focus on one particular pathogenic microbe in more detail. Pathogens include Candida albicans, Cryptococcus neoformans, Yersinia ssp., Helicobacter pylori, Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae.


Effect of lysophospholipids on signaling in the human Jurkat T cell line.
Lysophospholipids have recently been demonstrated to induce activation and proliferation of fibroblasts and other cell lineages by interacting with high affinity cell surface receptors leading to specific intracellular signaling events. Platelet activation, likely at the site of injury or inflammation, results in increased production of lysophospholipids suggesting a possible source of lysophospholipids. We have recently demonstrated that high concentrations of lysophospholipids are present in ascites and plasma from ovarian cancer patients, suggesting that physiologically produced lysophospholipids could interact with cells present in these fluids, including lymphocytes, and alter their function. We demonstrate herein that lysophosphatidic acid (LPA), lysophosphatidylserine (LPS), and sphingosylphosphorylcholine (SPC) activate the Jurkat T cell line. Each of the lysophospholipids induced a transient increase in cytosolic free calcium ([Ca2+]i) in Jurkat cells. Increases in [Ca2+]i were cross-desensitized by LPA, LPS and SPC, suggesting that the lysophospholipids share the same receptor(s) or that their downstream signaling pathways converge or interact. Lysophosphatidylglycerol (LPG), a competitive inhibitor of the putative LPA receptor, inhibited the calcium releasing activity of LPA, but not that of LPS and SPC, suggesting that these lysophospholipids interact with different receptors and that desensitization is due to interactions in downstream signaling pathways. The ability of the lysophospholipids to induce increases in [Ca2+]i was attenuated, but not completely blocked, by increases in [Ca2+]i induced by activation of the thrombin receptor. In contrast, increases in [Ca2+]i induced by the lysophospholipids and cross-linking the CD3 component of the T cell receptor complex with the UCHT1 antibody did not undergo heterologous desensitization. Strikingly, LPA is sufficient to stimulate proliferation of Jurkat cells in serum-free medium or in synergy with low concentrations of fetal bovine serum. In addition, LPA also increased the production of the T cell growth factor, interleukin 2 (IL-2), by Jurkat cells treated with phorbol esters. LPS, in contrast, inhibited Jurkat proliferation while increasing IL-2 production and SPC inhibited both processes. Thus, although all three lysophospholipids were sufficient to induce a transient increase in [Ca2+]i in Jurkat cells, they induced markedly different physiological consequences.


Covalent interactions are not required to permit or stabilize the non-covalent association of hepatitis C virus glycoproteins E1 and E2.
Hepatitis C virus (HCV) encodes two glycoproteins, E1 and E2, which are thought to locate to the envelope of virus particles. These proteins form two complexes in tissue culture systems, a high molecular mass aggregate that contains intermolecular covalent bonds and a native complex in which E1 and E2 associate by non-covalent interactions. The contribution of either complex to the structures of the proteins on virus particles is not known. Using dithiothreitol to reduce inter- and intramolecular disulphide bonds in situ, we have studied the nature of the interactions within the aggregate and the role of covalent bonds in the early stages of E1-E2 association. Results with two HCV type 1a strains, Glasgow and H77, showed that the aggregate contains not only covalent interactions but also non-covalent associations between E1 and E2. These non-covalent associations are complex since deletion mutant analysis failed to identify any single region which was required for non-covalent interaction. Complex formation by de novo synthesized proteins was not arrested under reducing conditions which prevented the production of inter- and intramolecular disulphide bonds. Moreover, a conformation-specific antibody continued to recognize the E2 protein in reduced complexes, indicating that covalent bonds do not stabilize certain structures of E2 that can interact with E1. These data suggest that disulphide bonds are not required either to allow association between the proteins or to stabilize E1-E2 complexes.


Remodeling a tissue: subtraction adds insight.
Sculpting a body plan requires both patterning of gene expression and translating that pattern into morphogenesis. Developmental biologists have made remarkable strides in understanding gene expression patterning, but despite a long history of fascination with the mechanics of morphogenesis, knowledge of how patterned gene expression drives the emergence of even simple shapes and forms has grown at a slower pace. The successful merging of approaches from cell biology, developmental biology, imaging, engineering, and mathematical and computational sciences is now accelerating progress toward a fuller and better integrated understanding of the forces shaping morphogenesis.


Viral response to specifically targeted antiviral therapy for hepatitis C and the implications for treatment success.
Currently, hepatitis C virus (HCV) antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C) molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.


Calcium-dependent action of osmolality on adenosine 3',5'-monophosphate accumulation in rat renal inner medulla: evidence for a relationship to calcium-responsive arachidonate release and prostaglandin synthesis.
When urea and NaCl are employed as the major solutes of high osmolality buffers, the cyclic AMP (cAMP) content of oxygenated slices of rat renal inner medulla increases three- to fivefold as osmolality is decreased from 1,650 to 305 mosM. Incubation of slices in Ca2+-free media containing 2 mM EGTA largely abolished this action of osmolality on cAMP, whereas exclusion of Mg2+ or 5+ from the incubation media was without effect. Addition of Ca2+ to Ca2+-deprived inner medulla incubated at 750 mosM (175 mM Na+, 380 mM urea) significantly increased tissue cAMP and media prostaglandin (PG)E accumulation. Ca2+ also stimulated the release of 14C-fatty acid from Ca2+-deprived slices prelabeled with [14C]arachidonate, but not from those labeled with [14C]palmitate. The divalent cation ionophore A23187 enhanced the actions of Ca2+ to increase tissue cAMP, media PGE accumulation, and the release of [14C]-arachidonate from prelabeled inner medulla. By contrast, when slices were incubated at 1,650 mosM (365 mM Na+, 900 mM urea) in the presence or absence of A23187, all of these actions of Ca2+ were markedly suppressed or abolished. Addition of exogenous arachidonate increased tissue cAMP and media PGE at both 750 and 1,650 mosM, whereas palmitate and stearate had no effect on cAMP at either osmolality. The actions of Ca2+ and arachidonate to increase cAMP and PGE accumulation were abolished by the cyclo-oxygenase inhibitors, indomethacin and meclofenamate. They were also abolished by exclusion of molecular O2, which serves as cosubstrate with arachidonate in prostaglandin synthesis. At maximally effective concentrations, exogenous PGE2 and arachidonate produced similar increases in inner medullary cAMP. The maximal effects of the two agents on cAMP were not additive, but were expressed in the absence of Ca2+ at both 750 and 1,650 mosM. However, in marked contrast to the O2-dependent action of arachidonate, PGE2 increased cAMP in the presence or absence of O2. Comparison of the separate actions of urea and NaCl indicated that suppression of Ca2+-responsive [14C]arachidonate release, PGE, and cAMP accumulation at 1,650 mosM reflected primarily an effect of urea, whereas hypertonic NaCl, mannitol, and sucrose alone stimulated inner medullary cAMP and PGE accumulation by a pathway which did not require extracellular Ca2+. Analogous to the actions of hypertonic urea, tetracaine and mepacrine inhibited the actions of Ca2+ plus A23187 to stimulate [14C]-arachidonate release, PGE, and cAMP accumulation. Inhibition of PGE and cAMP accumulation by tetracaine and mepacrine was also overcome by arachidonate. The results suggest that high osmolaity media with urea as a major solute reduces inner medullary cAMP content, at least in part, through effects on Ca2+-dependent prostaglandin synthesis. Inhibition of PGE synthesis, in turn, may be the result of osmotic suppression of Ca2+-dependent release of arachidonate, the availability of which is often rate limiting to prostaglandin generation.


Understanding signaling dynamics through synthesis.
Tissue-scale organization emerges from the action of sophisticated multiscale developmental programs. But the design rules for composing elementary signaling and information processing modules into such functional systems and for integrating them into the noisy and convoluted living context remain incompletely addressed. The construction of a synthetic gene circuit encoding contact-dependent signal propagation demonstrates one broadly applicable approach to this problem. The circuit comprises orthogonal signaling through the Delta ligand and the Notch receptor, multicellular positive feedback, and transcriptional signal amplification. Positive feedback and contact signaling proved sufficient for bistability and signal propagation across a population of mammalian cells, but only when combined with signal amplification. Thus, construction and characterization of synthetic gene circuits have made it possible to establish mechanistic sufficiency and the minimal requirements for the phenotype of interest.


Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection.
The prostate gland represents a multifaceted system in which prostate epithelia and stroma have distinct physiological roles. To understand the interaction between stroma and glandular epithelia, it is essential to delineate the gene expression profiles of these two tissue types in prostate cancer. Most studies have compared tumor and normal samples by performing global expression analysis using a mixture of cell populations. This report presents the first study of prostate tumor tissue that examines patterns of differential expression between specific cell types using laser capture microdissection (LCM). LCM was used to isolate distinct cell-type populations and identify their gene expression differences using oligonucleotide microarrays. Ten differentially expressed genes were then analyzed in paired tumor and non-neoplastic prostate tissues by quantitative real-time PCR. Expression patterns of the transcription factors, WT1 and EGR1, were further compared in established prostate cell lines. WT1 protein expression was also examined in prostate tissue microarrays using immunohistochemistry. The two-step method of laser capture and microarray analysis identified nearly 500 genes whose expression levels were significantly different in prostate epithelial versus stromal tissues. Several genes expressed in epithelial cells (WT1, GATA2, and FGFR-3) were more highly expressed in neoplastic than in non-neoplastic tissues; conversely several genes expressed in stromal cells (CCL5, CXCL13, IGF-1, FGF-2, and IGFBP3) were more highly expressed in non-neoplastic than in neoplastic tissues. Notably, EGR1 was also differentially expressed between epithelial and stromal tissues. Expression of WT1 and EGR1 in cell lines was consistent with these patterns of differential expression. Importantly, WT1 protein expression was demonstrated in tumor tissues and was absent in normal and benign tissues. The prostate represents a complex mix of cell types and there is a need to analyze distinct cell populations to better understand their potential interactions. In the present study, LCM and microarray analysis were used to identify novel gene expression patterns in prostate cell populations, including identification of WT1 expression in epithelial cells. The relevance of WT1 expression in prostate cancer was confirmed by analysis of tumor tissue and cell lines, suggesting a potential role for WT1 in prostate tumorigenesis.


Effects of blueberry and cranberry juice consumption on the plasma antioxidant capacity of healthy female volunteers.
To assess whether consumption of 500 ml of blueberry juice or cranberry juice by healthy female subjects increased plasma phenolic content and antioxidant capacity. Latin square arrangement to eliminate ordering effects. After an overnight fast, nine volunteers consumed 500 ml of blueberry juice, cranberry juice or a sucrose solution (control); each volunteer participated on three occasions one week apart, consuming one of the beverages each time. Blood samples were obtained by venipuncture at intervals up to four hours after consumption of the juices. Urine samples were also obtained four hours after consuming the juice. Consumption of cranberry juice resulted in a significant increase in the ability of plasma to reduce potassium nitrosodisulphonate and Fe(III)-2,4, 6-Tri(2-pyridyl)-s-triazine, these measures of antioxidant capacity attaining a maximum after 60-120 min. This corresponded to a 30% increase in vitamin C and a small but significant increase in total phenols in plasma. Consumption of blueberry juice had no such effects. The increase in plasma antioxidant capacity following consumption of cranberry juice could mainly be accounted for by an increase in vitamin C rather than phenolics. This also accounted for the lack of an effect of the phenolic-rich but vitamin C-low blueberry juice. Funded by the Scottish Executive Rural Affairs Department and the Danish Government.


Menstrual knowledge and practices of female adolescents in Vhembe district, Limpopo Province, South Africa.
Although sexual issues are openly discussed in the media, sexuality and reproductive functions are treated as taboo. Menstruation is a normal physiologic process, but carries various meanings within cultures and is rarely discussed amongst families and communities. This study sought to assess the knowledge and practices of secondary school girls towards menstruation in the Thulamela municipality of Limpopo Province, South Africa. A quantitative descriptive study design was used and respondents were selected by means of convenience sampling from a population of secondary school girls. The sample consisted of 273 secondary school girls doing Grades 10-12. A self-administered questionnaire was used to collect data, which was analysed by computing frequencies and percentages using the Statistical Package for Social Sciences (SPSS version 12). The findings revealed that respondents experienced menarche at 13 years and that menstruation is a monthly bleeding (80%) that happens to every female; it is a sign of adulthood (91%). 15% reported that it is the removal of dirt from the stomach and abdomen, 67% indicated the source of menstruation being the uterus, 65% the vagina and 13% from the abdomen. 73% reported having fear and anxiety at the first experience of bleeding and that they could not maintain adequate hygienic practices due to a lack of privacy and sanitary towels. Interventions are needed to increase girls' opportunities to discuss menstruation and access information from adults including mothers, parents and guardians. School-based sexuality education should be comprehensive, begin early and be regularly repeated.


[Language deficits in major forms of dementia and primary progressive aphasias: an update according to new diagnostic criteria].
In this review, we report current data on spoken and written language disorders in the most frequent dementia syndromes, namely Alzheimer' disease, vascular cognitive impairment and dementia with Lewy bodies. Language deficits are also the core features of three variants of primary progressive aphasia, namely the nonfluent/agrammatic, semantic and logopenic variants. This review reveals that, like other cognitive functions, language is highly vulnerable to neurodegenerative diseases. For some, language deficits result from impairment in linguistic processes per se, while for others, they are the direct consequence of impairments affecting working memory and executive functions. Language deficits in Alzheimer's disease and in nonfluent/agrammatic and semantic variants of primary progressive aphasia are well documented. By contrast, those about vascular cognitive impairment and dementia with Lewy bodies remain scarce and limited to large cognitive domains. The identification of logopenic variant of primary progressive aphasia is very recent, and more research is needed to complete the clinical description and identification of the functional origin of the disorders. Finally, knowledge on the impairment of written language in neurodegenerative diseases is less well documented than those on spoken language deficits. Other studies are therefore needed to improve the description of linguistic profiles and to provide additional elements to help in the differential diagnosis.


Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer.
The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, respectively. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumour accumulation have been thoroughly studied to improve the pre-clinical efficiency of PAI and PTT. In this review, we first summarize the development of inorganic and organic nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumours. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, especially regarding their clinical translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.


Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study.
Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.


Identification of Leptosphaeria maculans Pathogenicity Group 4 Causing Blackleg on Winter Canola in Oklahoma.
Winter canola (Brassica napus L.) is a relatively new crop to Oklahoma and other southern U.S. states where it is considered a desirable rotation crop with wheat. In 2009, approximately 15,000 ha of winter canola were harvested in Oklahoma (3); that area is expected to almost double in 2010. Blackleg, a potentially devastating canola disease, was detected in Oklahoma in 2009. Blackleg is caused by Leptosphaeria maculans (Desmaz.) Ces. & de Not (anamorph = Phoma lingam (Tode:Fr.) Desmaz.). In early 2010, leaf samples showing typical symptoms of blackleg were collected from four canola fields near the town of Enid in Garfield County, OK. Small portions of infected tissues were surface disinfested in an aqueous solution of NaOCl (0.5% a.i.) for 1 min, rinsed twice in sterile distilled water, and plated on V8 medium. Seven colonies were isolated and when grown in pure culture, all produced 2 × 4.5 μm guttulate, unicellular, hyaline spores in pycnidia that ranged from 200 to 480 μm in diameter. These morphological characteristics correspond with those of P. lingam (1). To verify the pathogenic nature of the isolates and establish the pathogenicity group (PG) to which they belong, a standard inoculation protocol was followed on a set of three differential cultivars, Quinta, Glacier, and Westar (2). Briefly, for each isolate, tiny puncture wounds were made with sterile needles on the cotyledons of six 10-day-old plants of each differential and a 10-μl aliquot of a pycnidiospore suspension (1 × 107 spores ml-1) was deposited on the wounds. Also, a set of differentials were inoculated with distilled water (mock inoculation). Inoculated plants were incubated overnight in a misting chamber at 21°C in the dark and returned the next day to the greenhouse. Disease severity was recorded 10 days after inoculation using a 0 to 9 scale in which 0 to 2 = resistant, 3 to 6 = intermediate, and 7 to 9 = susceptible. This process was repeated three times. Two of the seven isolates evaluated were highly virulent on all three differentials, an indication they belong to pathogenicity group 4 (2). The other five isolates produced small lesions on Westar (resistant reaction) but failed to develop symptoms on the other two differentials. This phenotypic reaction has been associated with strains of PG-1. Mock-inoculated plants did not develop lesions. To our knowledge, this is the first time blackleg isolates from Oklahoma have been identified to the PG level. While this information will assist breeders in the development of both spring and winter canola lines with resistance to blackleg, additional studies are necessary to determine the relative prevalence and diversity of the various PG in Oklahoma. References: (1) G. H. Boerema. Trans. Br. Mycol. Soc. 67:289, 1976. (2) A. Mengistu et al. Plant Dis. 75:1279, 1991. (3) USDA. National Agricultural Statistics Service. Retrieved from http://www.nass.usda.gov/Statistics_by_State/Ag_Overview/ AgOverview_OK.pdf , September 20, 2010.


Predicted 1,3-dichloropropene air concentrations resulting from tree and vine applications in California.
The preplant soil fumigant 1,3-dichloropropene (1,3-D) is effective for nematode control and is expected to further replace methyl bromide (MeBr) as MeBr use is phased out. Acute human exposure to soil fumigants is managed in part by using buffer zones between treated fields and occupied structures. The required buffer zone for 1,3-D in California is 91.4 m (300 ft) for all uses. However, a 30.5-m (100-ft) buffer setback is desired for 1,3-D to be an important replacement for MeBr in the orchard and vineyard markets. The Industrial Source Complex Short-Term model, Version 3 (ISCST3) was used to simulate township-wide long-term average and short-term air concentration distributions of 1,3-D. The Gaussian plume model ISCST3 can be used to assess dispersion of air pollutants and pollutant concentrations on receptors from a variety of sources and in diverse airsheds. Long-term and daily-average air concentrations can be compared with the California permitted chronic or acute toxicity endpoints, respectively, to assess the potential risk for individuals living within the township at the proposed buffer setback. Modifications to ISCST3 were made for specific nonpoint-source agricultural constraints and management practices. Chronic and acute air concentration distributions of 1,3-D with a 30.5-m buffer constraint around treated fields are similar to currently permitted air concentration distributions in California. Refinement of exposure as a function of buffer distance, application rate, and field size is possible due to the resolution of the simulation and external post-processing capabilities. Simulated examples of 1,3-D acute and chronic exposure cumulative distributions are presented.


Mechanical comparison of barefoot and shod running.
In order to further compare shod versus barefoot running, 35 subjects ran two bouts of 4 minutes at 3.33 m x s(-1) on a treadmill dynamometer. Parameters were measured on about 60 consecutive steps. Barefoot showed mainly lower contact and flight time (p < 0.05), lower passive peak (1.48 versus 1.70 body weight, p < 0.05), higher braking and pushing impulses (p < 0.05), and higher pre-activation of triceps surae muscles (p < 0.05) than shod. It was concluded that when performed on a sufficient number of steps, barefoot running leads to a reduction of impact peak in order to reduce the high mechanical stress occurring during repetitive steps. This neural-mechanical adaptation could also enhance the storage and restitution of elastic energy at ankle extensors level.


The CogBIAS longitudinal study protocol: cognitive and genetic factors influencing psychological functioning in adolescence.
Optimal psychological development is dependent upon a complex interplay between individual and situational factors. Investigating the development of these factors in adolescence will help to improve understanding of emotional vulnerability and resilience. The CogBIAS longitudinal study (CogBIAS-L-S) aims to combine cognitive and genetic approaches to investigate risk and protective factors associated with the development of mood and impulsivity-related outcomes in an adolescent sample. CogBIAS-L-S is a three-wave longitudinal study of typically developing adolescents conducted over 4 years, with data collection at age 12, 14 and 16. At each wave participants will undergo multiple assessments including a range of selective cognitive processing tasks (e.g. attention bias, interpretation bias, memory bias) and psychological self-report measures (e.g. anxiety, depression, resilience). Saliva samples will also be collected at the baseline assessment for genetic analyses. Multilevel statistical analyses will be performed to investigate the developmental trajectory of cognitive biases on psychological functioning, as well as the influence of genetic moderation on these relationships. CogBIAS-L-S represents the first longitudinal study to assess multiple cognitive biases across adolescent development and the largest study of its kind to collect genetic data. It therefore provides a unique opportunity to understand how genes and the environment influence the development and maintenance of cognitive biases and provide insight into risk and protective factors that may be key targets for intervention.


Spontaneous intra-peritoneal bleeding secondary to warfarin, presenting as an acute appendicitis: a case report and review of literature.
Warfarin is a coumarin anti-coagulant, used widely for the therapeutic and prophylactic anticoagulation. Although, it is considered as a life saving medicine, it is associated with the significant adverse effects including intra-abdominal bleeding, which have been very well documented in literature. However, the presentation of warfarin induced intra-peritoneal bleeding as an acute appendicitis has not been reported in English literature. We report this rare, spontaneous intra-peritoneal bleeding secondary to warfarin therapy, mimicking the signs and symptoms of an acute appendicitis for the first time in English literature. A 41 year-old female patient who was on warfarin for prophylaxis following the previous episode of pulmonary embolism, presented to the Casualty with the typical symptoms of an acute appendicitis. During operative intervention, we found it to be the spontaneous intra-peritoneal bleeding secondary to warfarin. The patient recovered well following the operation. We recommend the use of the radiological investigations in all the cases of acute abdomen who are on warfarin even if the INR is within the therapeutic range.


Design Considerations for Smoking Cessation Apps: Feedback From Nicotine Dependence Treatment Providers and Smokers.
Hundreds of smoking cessation apps are commercially available, but most are not theory-based or designed to take advantage of mobile technology in ways that could make them more engaging and possibly more effective. Considering input from both clinical experts (who understand best practice nicotine dependence treatment requirements) to inform appropriate content and from smokers (the end users) to express their preferences is important in designing these programs in the future. To assess and compare the opinions of nicotine dependence treatment providers and smokers regarding the design of future smoking cessation apps. We surveyed providers (n=264) and smokers who own smartphones (n=40) to assess their opinions on the importance of 21 app design features. Features represented 5 domains: cost, reputation, privacy and security, content and user experience, and communication. Domains were chosen to reflect best practice treatment, leverage mobile technology to support smoking cessation, and elicit important user preferences. Data were collected between June and July 2015. Most providers agreed that mHealth apps hold promise for helping people quit smoking (203/264, 76.9%) and would recommend them to their clients/patients (201/264, 76.1%), especially if the app were empirically validated (236/264, 89.4%). Few providers believe effective cessation apps currently exist (112/264, 42.4%). Few smokers (5/40, 13%) had ever downloaded a smoking cessation app; of the ones who had not, most said they would consider doing so (29/35, 83%). Both respondent groups indicated the following features were very to extremely important to include in cessation apps: free or low cost, keeps information private, matches individual needs and interests, adapts as one's needs and interests change, helps to manage nicotine withdrawal symptoms and medication side effects, and allows users to track their progress. Providers and smokers also indicated gaming and social media connectivity were less important than other features. Despite these similarities, the groups had significantly different opinions about the relative importance of various features. In particular, providers rated privacy as the most important feature, whereas smokers rated low cost and the ability to adaptively tailor content as the most important features. Smoking cessation apps hold great promise as intervention tools but only if they engage users and appropriately treat nicotine dependence. Intervention development should take into consideration the perspectives of both treatment experts and smokers. This paper highlights important perspectives from each of these groups to be considered when designing future app-based smoking cessation programs.


Effect of formoterol with or without budesonide in repeated low-dose allergen challenge.
The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 microg Turbuhaler, budesonide 160 microg/formoterol 4.5 microg Turbuhaler and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD(20)), exhaled nitric oxide fraction (F(eNO)), sputum eosinophils and prostaglandin D(2), and diary card recordings of symptoms (on a scale of 0-10), short-acting beta(2)-agonist use and evening forced expiratory volume in one second (FEV(1)). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD(20): 397 (98) microg before versus 168 (82) microg after), F(eNO) (mean+/-sd 46+/-31 ppb before versus 73+/-46 ppb after) and asthma symptom score (mean+/-sd 0.39+/-0.55 before versus 0.68+/-0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV(1). Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.


Intake, growth and carcass traits in male progeny of sires differing in genetic merit for beef production.
Validation of economic indexes under a controlled experimental environment, can aid in their acceptance and use as breeding tools to increase herd profitability. The objective of this study was to compare intake, growth and carcass traits in bull and steer progeny of high and low ranking sires, for genetic merit in an economic index. The Beef Carcass Index (BCI; expressed in euro (€) and based on weaning weight, feed intake, carcass weight, carcass conformation and fat scores) was generated by the Irish Cattle Breeding Federation as a tool to compare animals on genetic merit for the expected profitability of their progeny at slaughter. A total of 107 male suckler herd progeny, from 22 late-maturing 'continental' beef sires of high (n = 11) or low (n = 11) BCI were compared under either a bull or steer production system, and slaughtered at approximately 16 and 24 months of age, respectively. All progeny were purchased after weaning at approximately 6 to 8 months of age. Dry matter (DM) intake and live-weight gain in steer progeny offered grazed grass or grass silage alone, did not differ between the two genetic groups. Similarly, DM intake and feed efficiency did not differ between genetic groups during an ad libitum concentrate-finishing period on either production system. Carcasses of progeny of high BCI sires were 14 kg heavier (P < 0.05) than those of low BCI sires. In a series of regression analyses, increasing sire BCI resulted in increases in carcass weight (P < 0.01) and carcass conformation (P = 0.051) scores, and decreases in carcass fat (P < 0.001) scores, but had no effect on weaning weight or DM intake of the progeny. Each unit increase in sire expected progeny difference led to an increase in progeny weaning weight, DM intake, carcass weight, carcass conformation score and carcass fat score of 1.0 (s.e. = 0.53) kg, 1.1 (s.e. = 0.32) kg, 1.3 (s.e. = 0.31) kg, 0.9 (s.e. = 0.32; scale 1 to 15) and 1.0 (s.e. = 0.25; scale 1 to 15), respectively, none of which differed from the theoretical expectation of unity. The expected difference in profitability at slaughter between progeny of the high and low BCI sires was €42, whereas the observed phenotypic profit differential of the progeny was €53 in favour of the high BCI sires. Results from this study indicate that the BCI is a useful tool in the selection of genetically superior sires, and that actual progeny performance under the conditions of this study is within expectations for both bull and steer beef production systems.


Effect of political decentralization and female leadership on institutional births and child mortality in rural Bihar, India.
In this paper, we investigate the impacts of political decentralization and women reservation in local governance on institutional births and child mortality in the state of Bihar, India. Using the difference-in-differences methodology, we find a significant positive association between political decentralization and institutional births. We also find that the increased participation of women at local governance led to an increased survival rate of children belonging to richer households. We argue that our results are consistent with female leaders having policy preference for women and child well-being.


Nitrogen-doped graphene quantum dots coupled with photosensitizers for one-/two-photon activated photodynamic therapy based on a FRET mechanism.
A novel material with a large two-photon absorption cross-section was conjugated with a typical photosensitizer for inducing a FRET process. The photosensitizer can be excited by a one-/two-photon laser and then induced photo-toxicity in vitro and in vivo. The system presents great potential for improving treatment depth and the precision of traditional photodynamic therapy.


Vibrotactile stimulation promotes embodiment of an alien hand in amputees with phantom sensations.
Tactile feedback is essential to intuitive control and to promote the sense of self-attribution of a prosthetic limb. Recent findings showed that amputees can be tricked to experience this embodiment, when synchronous and modality-matched stimuli are delivered to biological afferent structures and to an alien rubber hand. Hence, it was suggested to exploit this effect by coupling touch sensors in a prosthesis to an array of haptic tactile stimulators in the prosthetic socket. However, this approach is not clinically viable due to physical limits of current haptic devices. To address this issue we have proposed modality-mismatched stimulation and demonstrated that this promotes self-attribution of an alien hand on normally limbed subjects. In this work we investigated whether similar effects could be induced in transradial amputees with referred phantom sensations in a series of experiments fashioned after the Rubber Hand Illusion using vibrotactile stimulators. Results from three independent measures of embodiment demonstrated that vibrotactile sensory substitution elicits body-ownership of a rubber hand in transradial amputees. These results open up promising possibilities in this field; indeed miniature, safe and inexpensive vibrators could be fitted into commercially available prostheses and sockets to induce the illusion every time the prosthesis manipulates an object.


Anti-resorptive therapy for the prevention of postmenopausal osteoporosis : when should treatment begin?
Osteoporosis is a condition associated with decreased bone strength and an increased fracture risk. It may be defined based on bone mineral density (BMD) with a T-score at the hip or spine of less than -2.5 standard deviations in young healthy individuals or from an osteoporotic fracture (i.e. a fracture occurring after low-energy trauma or no apparent trauma). Risk factors predisposing to fractures include: increasing age; female gender; low BMD; a prior fragility fracture; a family history of fragility fractures; low bodyweight; lack of estrogen in women (i.e. post menopause); corticosteroid use; smoking; a number of diseases; deficiency in calcium and vitamin D; an increased risk of falls (i.e. impaired vision); immobilization; and Caucasian race. The more risk factors that are present the higher the risk of fractures over the following 10 years. The need to initiate preventive therapy with anti-osteoporotic treatment increases steeply with the absolute fracture risk. Indications for referral for dual energy x-ray absorptiometry measurement of BMD include: age >65 years; age <65 years in postmenopausal women with any of the risk factors already mentioned; premature menopause (<45 years); prolonged amenorrhea (>1 year) in younger women; fragility fractures; and diseases or conditions known to lead to osteoporosis.Anti-resorptive therapies include calcium plus vitamin D, bisphosphonates (alendronate, etidronate, risedronate, ibandronate), selective estrogen receptor modulators (raloxifene), hormone replacement therapy, and calcitonin. Guidelines from several countries on when to initiate anti-resorptive therapy state that therapy may be started in patients with a prior fragility fracture (some guidelines state that in this situation no BMD measurements are necessary) or in patients with a T-score of less than -2.5 (some guidelines state that additional risk factors need to be present in this situation). Some guidelines state that anti-resorptive therapy may be initiated in patients with a T-score in the osteopenic range (from -1 to -2.5, i.e. not frank osteoporosis) in the presence of other risk factors. The cost effectiveness of anti-resorptive therapy increases with the absolute fracture risk. In some scenarios, treatment with bisphosphonates may be cost effective in a 50-year-old woman with an absolute hip fracture risk of >or=1.1% over the next 10 years.


Activity profiling reveals changes in the diversity and activity of proteins in Arabidopsis roots in response to nematode infection.
Cyst nematodes are obligate, sedentary endoparasites with a highly specialised biology and a huge economic impact in agriculture. Successful parasitism involves morphological and physiological modifications of the host cells which lead to the formation of specialised syncytial feeding structures in roots. The development of the syncytium is aided by a cocktail of nematode effectors that manipulate the host plant activities in a complex network of interactions through post-translational modifications. Traditional transcriptomic and proteomic approaches cannot display this functional proteomic information. Activity-based protein profiling (ABPP) is a powerful technology that can be used to investigate the activity of the proteome through activity-based probes. To better understand the functional proteomics of syncytium, ABPP was conducted on syncytia induced by the beet cyst nematode Heterodera schachtii in Arabidopsis roots. Our results demonstrated that the activity of several enzymes is differentially regulated in the syncytium compared to the control roots. Among those specifically activated in the syncytium are a putative S-formyl-glutathione hydrolase (SFGH), a putative methylesterase (MES) and two unidentified enzymes. In contrast, the activities of vacuolar processing enzymes (VPEs) are specifically suppressed in the syncytium. Competition labelling, quantitative gene expression and T-DNA knock-out mutants were used to further characterise the roles of the differentially regulated enzymes during plant-nematode interaction. In conclusion, our study will open the door to generate a comprehensive and integrated view of the host-pathogen warfare that results in the formation of long-term feeding sites for pathogens.


MicroRNAs of the miR-290-295 Family Maintain Bivalency in Mouse Embryonic Stem Cells.
Numerous developmentally regulated genes in mouse embryonic stem cells (ESCs) are marked by both active (H3K4me3)- and polycomb group (PcG)-mediated repressive (H3K27me3) histone modifications. This bivalent state is thought to be important for transcriptional poising, but the mechanisms that regulate bivalent genes and the bivalent state remain incompletely understood. Examining the contribution of microRNAs (miRNAs) to the regulation of bivalent genes, we found that the miRNA biogenesis enzyme DICER was required for the binding of the PRC2 core components EZH2 and SUZ12, and for the presence of the PRC2-mediated histone modification H3K27me3 at many bivalent genes. Genes that lost bivalency were preferentially upregulated at the mRNA and protein levels. Finally, reconstituting Dicer-deficient ESCs with ESC miRNAs restored bivalent gene repression and PRC2 binding at formerly bivalent genes. Therefore, miRNAs regulate bivalent genes and the bivalent state itself.


2F3 monoclonal antibody recognizes the O26 O-antigen moiety of the lipopolysaccharide of enterohemorrhagic Escherichia coli strain 4276.
Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) organisms are groups of pathogenic strains whose infections are characterized by a typical lesion of enterocyte attachment and effacement. They are involved in enteric diseases both in humans and in animals, and EHEC strains can be responsible for hemolytic uremic syndrome in humans. Previously, it was shown that the 2F3 monoclonal antibody (MAb) is specific for the O26 EHEC and EPEC strains (P. Kerr, H. Ball, B. China, J. Mainil, D. Finlay, D. Pollock, I. Wilson, and D. Mackie, Clin. Diagn. Lab. Immunol. 6:610-614, 1999). As these groups of bacteria play an important role in pathology, the aim of this paper was to characterize the antigen recognized by the 2F3 MAb and its genetic determinant. A genomic locus containing the entire O-antigen gene cluster and half of the colanic acid gene cluster from an O26 EHEC strain was shown to be sufficient for the production of the antigen recognized by the 2F3 MAb in an E. coli DH5alpha strain. By transposon mutagenesis performed on the recombinant plasmid, all 2F3 enzyme-linked immunosorbent assay-negative mutants had their transposons inserted into the O-antigen gene cluster. The O-antigen gene cluster was also cloned from an O26 EHEC strain into the E. coli DH5alpha strain, which then produced a positive result with the 2F3 MAb. Further analysis of the type of lipopolysaccharides (smooth or rough) produced by the clones and mutants and of the O antigen of the 2F3-positive clones confirmed that the epitope recognized by the 2F3 MAb is located on the O antigen in the O26 EHEC and EPEC strains and that its genetic determinant is located inside the O-antigen gene cluster.


Stigma Reduction Training Improves Healthcare Provider Attitudes Toward, and Experiences of, Young Marginalized People in Bangladesh.
Working with health providers to reduce HIV stigma in the healthcare setting is an important strategy to improve service utilization and quality of care, especially for young people who are sexually active before marriage, are sexual minorities, or who sell sex. A stigma reduction training program for health providers in Bangladesh was evaluated. A cohort of 300 healthcare providers were given a self-administered questionnaire, then attended a 2-day HIV and sexual and reproductive health and rights training (including a 90-minute session on stigma issues). Six months later, the cohort repeated the survey and participated in a 1-day supplemental training on stigma, which included reflection on personal values and negative impacts of stigma. A third survey was administered 6 months later. A cross-sectional survey of clients age 15-24 years was implemented before and after the second stigma training to assess client satisfaction with services. Provider agreement that people living with HIV should be ashamed of themselves decreased substantially (35.3%-19.7%-16.3%; p < .001), as did agreement that sexually active young people (50.3%-36.0%-21.7%; p < .001) and men who have sex with men (49.3%-38.0%-24.0%; p < .001) engage in "immoral behavior." Young clients reported improvement in overall satisfaction with services after the stigma trainings (63.5%-97.6%; p < .001). This study indicates that a targeted stigma reduction intervention can rapidly improve provider attitudes and increase service satisfaction among young people. More funding to scale up these interventions is needed.


Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.
OBJECTIVE--To determine the efficacy of short-term administration of a synthetic analogue of alpha-melanotropin, [Nle4D-Phe7] (NDP)-alpha-melanocyte-stimulating hormone (MSH), in darkening (tanning) human skin. DESIGN--Randomized, placebo-controlled, double-blind clinical trial. SETTING--Clinical research unit of a university medical center. SUBJECTS--Twenty-eight healthy white men with a history of either poor tanning (skin type I or II) or good tanning (skin type III or IV) recruited from advertisements and paid to participate in the study. METHODS--Each subject received 10 subcutaneous injections of either a purified NDP preparation or saline over 12 days. They were followed up for 7 weeks after therapy was completed. All subjects used a high-potency sunscreen during the trial. MAIN OUTCOME MEASURE--Skin darkening was quantified by serial chromaticity measurements prior to, during, and after therapy. -A significant parabolic curve of skin darkening activity was noted in subjects with skin type I or II (P less than .001) and with skin type III or IV (P much less than .001) who were given NDP. No darkening occurred in the subjects who were given a placebo. Peak changes were seen 1 to 3 weeks after therapy was completed. CONCLUSION--Human skin darkens as a response to a synthetic melanotropin given by subcutaneous injection. Skin tanning appears possible without potentially harmful exposure to ultraviolet radiation.


Methodology to model the energy and greenhouse gas emissions of electronic software distributions.
A new electronic software distribution (ESD) life cycle analysis (LCA) methodology and model structure were constructed to calculate energy consumption and greenhouse gas (GHG) emissions. In order to counteract the use of high level, top-down modeling efforts, and to increase result accuracy, a focus upon device details and data routes was taken. In order to compare ESD to a relevant physical distribution alternative, physical model boundaries and variables were described. The methodology was compiled from the analysis and operational data of a major online store which provides ESD and physical distribution options. The ESD method included the calculation of power consumption of data center server and networking devices. An in-depth method to calculate server efficiency and utilization was also included to account for virtualization and server efficiency features. Internet transfer power consumption was analyzed taking into account the number of data hops and networking devices used. The power consumed by online browsing and downloading was also factored into the model. The embedded CO(2)e of server and networking devices was proportioned to each ESD process. Three U.K.-based ESD scenarios were analyzed using the model which revealed potential CO(2)e savings of 83% when ESD was used over physical distribution. Results also highlighted the importance of server efficiency and utilization methods.


Estrogen receptor analysis by flow cytometry.
A fluorescently labeled estradiol, N'-fluoresceino-N'-(17 beta-estradiol hemisuccinamide) thiourea (FE) was used for measuring estrogen receptor content per cell in tumor cells. The cellular content of FE was measured quantitatively by flow cytometry. Binding of FE occurs in the nanomolar concentration range, an indication of the high affinity of the labeled estradiol. Competition of FE for binding sites is observed with estrogens, but not with progestins, androgens, or glucocorticosteroids, indicating the specificity of FE binding. In contrast to other estrogen receptor assays, this new technique requires a small sample size (about 5000 cells) and permits the assessment of heterogeneity in estrogen receptor expression among tumor cells.


12-month prevalence of depression among single and married mothers in the 1994 National Population Health Survey.
While a number of studies have documented higher period prevalence rates of depression among single as compared to married mothers, all of the data have been based upon community surveys of mental illness. In Canada, all of the published work comes from Ontario. As a result, we do not know whether these results hold true for other regions of the country. Using a nationally representative sample, we find, consistent with previous work, that single mothers have almost double the 12-month prevalence rates of married mothers (15.4% versus 6.8%). As well, there are no significant differences in rates of depression between single and married mothers by region/province of the country. Our findings are compared with other epidemiologic data on the mental health of single mothers from Ontario.


Optimizing integration of electrosurgical hand controls within a laparoscopic surgical tool.
Abstract In laparoscopic surgery, electrosurgical equipment is operated by means of one or more foot pedals positioned on the floor in front of the surgeon causing poor ergonomic posture and physical discomfort. The focus of this study was to ergonomically explore the integration of electrosurgical hand controls within the previously designed Intuitool™ laparoscopic surgical instrument to optimize functionality. Three different hand control designs (CDs) were implemented within the Intuitool™ and each CD contained the standard cutting and coagulation features, previously operated by foot pedals. This study used 26 right-handed participants, with no previous laparoscopic surgery experience. The participants completed simple tasks using all three CDs within a simulated abdomen. Electromyography (EMG) sensors and force sense resistors (FSRs) were utilized to measure muscle activity and button actuation force, respectively. A questionnaire was also utilized to measure comfort level of each CD. The results indicated that the close proximity of CD 1 generated greater actuation force for all tasks, was rated easier to use (P = 0.003) and was preferred more frequently by the participants (53.8%) compared to CD 2 and 3. As a result, CD 1 was determined to be an optimal ergonomic design for electrosurgical hand controls within the Intuitool™.


Global SARS-CoV-2 seroprevalence from January 2020 to April 2022: A systematic review and meta-analysis of standardized population-based studies.
Our understanding of the global scale of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains incomplete: Routine surveillance data underestimate infection and cannot infer on population immunity; there is a predominance of asymptomatic infections, and uneven access to diagnostics. We meta-analyzed SARS-CoV-2 seroprevalence studies, standardized to those described in the World Health Organization's Unity protocol (WHO Unity) for general population seroepidemiological studies, to estimate the extent of population infection and seropositivity to the virus 2 years into the pandemic. We conducted a systematic review and meta-analysis, searching MEDLINE, Embase, Web of Science, preprints, and grey literature for SARS-CoV-2 seroprevalence published between January 1, 2020 and May 20, 2022. The review protocol is registered with PROSPERO (CRD42020183634). We included general population cross-sectional and cohort studies meeting an assay quality threshold (90% sensitivity, 97% specificity; exceptions for humanitarian settings). We excluded studies with an unclear or closed population sample frame. Eligible studies-those aligned with the WHO Unity protocol-were extracted and critically appraised in duplicate, with risk of bias evaluated using a modified Joanna Briggs Institute checklist. We meta-analyzed seroprevalence by country and month, pooling to estimate regional and global seroprevalence over time; compared seroprevalence from infection to confirmed cases to estimate underascertainment; meta-analyzed differences in seroprevalence between demographic subgroups such as age and sex; and identified national factors associated with seroprevalence using meta-regression. We identified 513 full texts reporting 965 distinct seroprevalence studies (41% low- and middle-income countries [LMICs]) sampling 5,346,069 participants between January 2020 and April 2022, including 459 low/moderate risk of bias studies with national/subnational scope in further analysis. By September 2021, global SARS-CoV-2 seroprevalence from infection or vaccination was 59.2%, 95% CI [56.1% to 62.2%]. Overall seroprevalence rose steeply in 2021 due to infection in some regions (e.g., 26.6% [24.6 to 28.8] to 86.7% [84.6% to 88.5%] in Africa in December 2021) and vaccination and infection in others (e.g., 9.6% [8.3% to 11.0%] in June 2020 to 95.9% [92.6% to 97.8%] in December 2021, in European high-income countries [HICs]). After the emergence of Omicron in March 2022, infection-induced seroprevalence rose to 47.9% [41.0% to 54.9%] in Europe HIC and 33.7% [31.6% to 36.0%] in Americas HIC. In 2021 Quarter Three (July to September), median seroprevalence to cumulative incidence ratios ranged from around 2:1 in the Americas and Europe HICs to over 100:1 in Africa (LMICs). Children 0 to 9 years and adults 60+ were at lower risk of seropositivity than adults 20 to 29 (p < 0.001 and p = 0.005, respectively). In a multivariable model using prevaccination data, stringent public health and social measures were associated with lower seroprevalence (p = 0.02). The main limitations of our methodology include that some estimates were driven by certain countries or populations being overrepresented. In this study, we observed that global seroprevalence has risen considerably over time and with regional variation; however, over one-third of the global population are seronegative to the SARS-CoV-2 virus. Our estimates of infections based on seroprevalence far exceed reported Coronavirus Disease 2019 (COVID-19) cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions.


Low-Energy Shockwave Treatment Promotes Endothelial Progenitor Cell Homing to the Stenotic Pig Kidney.
Endothelial progenitor cells (EPCs) patrols the circulation and contributes to endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave therapy (SW) can induce angiogenesis and restore the STK microcirculation, but the underlying mechanism remains unclear. We tested the hypothesis that SW increases EPC homing to the swine STK, associated with capillary regeneration. Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six sessions of low-energy SW (biweekly for three consecutive weeks) or left untreated. Four weeks after completion of treatment, we assessed EPC (CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor (SDF)-1 in the inferior vena cava and the STK vein and artery, as well as urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β. Subsequently, we assessed STK morphology, capillary count, and expression of the proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide synthase ex vivo. A 3-wk low-energy SW regimen improved STK structure, capillary count, and function in ARAS+SW, and EPC numbers and gradients across the STK decreased. Plasma SDF-1 and renal expression of angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and integrin-1β tended to rise during the SW regimen. In conclusion, SW improves ischemic kidney capillary density, which is associated with, and may be at least in part mediated by, promoting EPCs mobilization and homing to the stenotic kidney.


Evaluating the performance of medicare fee-for-service providers using the health outcomes survey: a comparison of two methods.
Health status measures are now being used for evaluating the performance of health care organizations. Trends in SF-36 component scores have previously been examined for Medicare-managed care plans but not for providers serving Medicare fee-for-service (FFS) beneficiaries. We compared 2 methods for evaluating the performance of Medicare FFS providers, the Research Triangle Institute (RTI) and Health Assessment Laboratory (HAL) methods. Data were collected from 6547 Medicare FFS beneficiaries in 10 cohorts. SF-36 Physical Health (PCS) and Mental Health (MCS) component scores were computed at baseline and after a 2-year follow-up. The RTI approach predicts follow-up scores based on a standard care regression model. The HAL approach determines the percentage of beneficiaries whose status is the "same or better" at follow-up. Both approaches then compare observed to expected scores for each cohort. The HAL method did not detect any statistically significant differences for the PCS; the RTI method detected a small PCS difference for one cohort. The HAL method identified 4 cohorts that had significantly higher MCS scores; the RTI approach identified one cohort with significantly lower scores. The 2 approaches provided consistent assessments of provider performance for the PCS but not for the MCS. The differences in the MCS results may have been affected by differing treatment of deaths during follow-up. The HAL approach disregards deaths for the MCS, whereas the RTI method imputes values for death. Implications of using self-reported health status for monitoring provider performance are discussed.


Molecular organization in the twist-bend nematic phase by resonant X-ray scattering at the Se K-edge and by SAXS, WAXS and GIXRD.
Using a magnetically aligned liquid crystal mixture containing a novel Se-labelled dimer and the difluoroterphenyl dimer DTC5C7, the twist-bend nematic phase (Ntb) was studied by the resonant scattering of hard X-rays and by conventional small and wide-angle X-ray scattering (SAXS, WAXS). Resonant diffraction spots indicated a helix with a 9-12 nm pitch in the Ntb phase and an unprecedentedly high helix orientation. This enabled deconvolution of global and local order parameters. These findings, combined with the simultaneously recorded resonant and non-resonant SAXS and WAXS data, allowed us to construct a locally layered molecular model of the Ntb phase, where the average twisted conformation of each molecule was idealised as a helical segment, matching the local heliconical director field. The dimers were found to be less bent in the Ntb phase than in their minimum energy conformation, and straightening further with increasing temperature. It is proposed that on further heating their low bend angle allows the transition to the normal nematic phase, where the molecules can freely move longitudinally, without the need to perform screw-like motion as in the Ntb phase. At the low-temperature end, the increasing molecular twist becomes unsustainable, leading to a transition to a smectic phase, where no twist is required.


The politics of ideas in welfare state transformation: Christian Democracy and the reform of family policy in Germany.
The expansion of employment-centered family policies of the Grand Coalition in Germany came with some surprise, as Christian Democrats have traditionally been strongly committed to the male breadwinner model and corresponding family policies. This article investigates why Christian Democrats (though with some inconsistencies) promoted "social-democratic" family policies guided by the adult worker rather than by the male breadwinner model. Illuminating the politics of recent family policy reforms, the electoral rationale for this modernization of family policy, the role of political entrepreneurship, and intraparty political conflicts over the new policy paradigm are discussed.


The enantioselective construction of tetracyclic diterpene skeletons with Friedel-Crafts alkylation and palladium-catalyzed cycloalkenylation reactions.
Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.


Photo-oxidative stress down-modulates the activity of nuclear factor-kappaB via involvement of caspase-1, leading to apoptosis of photoreceptor cells.
The mechanisms of photoreceptor cell death via apoptosis, in retinal dystrophies, are largely not understood. In the present report we show that visible light exposure of mouse cultured 661W photoreceptor cells at 4.5 milliwatt/cm2 caused a significant increase in oxidative damage of 661W cells, leading to apoptosis of these cells. These cells show constitutive expression of nuclear factor-kappaB (NF-kappaB), and light exposure of photoreceptor cells results in lowering of NF-kappaB levels in both the nuclear and cytosolic fractions in a time-dependent manner. Immunoblot analysis of IkappaBalpha and p50, and p65 (RelA) subunits of NF-kappaB, suggested that photo-oxidative stress results in their depletion. Immunocytochemical studies using antibody to RelA subunit of NF-kappaB further revealed the presence of this subunit constitutively both in the nucleus and cytoplasm of the 661W cells. Upon exposure to photo-oxidative stress, a depletion of the cytoplasmic and nuclear RelA subunit was observed. The depletion of NF-kappaB appears to be mediated through involvement of caspase-1. Furthermore, transfection of these cells with a dominant negative mutant IkappaBalpha greatly enhanced the kinetics of down modulation of NF-kappaB, resulting in a faster photo-oxidative stress-induced apoptosis. Taken together, these studies show that the presence of NF-kappaB RelA subunit in the nucleus is essential for protection of photoreceptor cells against apoptosis mediated by an oxidative pathway.


The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts.
The present study describes a novel technique for revitalising allogenic intrasynovial tendons by combining cell-based therapy and mechanical stimulation in an ex vivo canine model. Specifically, canine flexor digitorum profundus tendons were used for this study and were divided into the following groups: (1) untreated, unprocessed normal tendon; (2) decellularised tendon; (3) bone marrow stromal cell (BMSC)-seeded tendon; and (4) BMSC-seeded and cyclically stretched tendon. Lateral slits were introduced on the tendon to facilitate cell seeding. Tendons from all four study groups were distracted by a servohydraulic testing machine. Tensile force and displacement data were continuously recorded at a sample rate of 20 Hz until 200 Newton of force was reached. Before testing, the cross-sectional dimensions of each tendon were measured with a digital caliper. Young's modulus was calculated from the slope of the linear region of the stress-strain curve. The BMSCs were labeled for histological and cell viability evaluation on the decellularized tendon scaffold under a confocal microscope. Gene expression levels of selected extracellular matrix tendon growth factor genes were measured. Results were reported as mean ± SD and data was analyzed with one-way ANOVAs followed by Tukey's post hoc multiple-comparison test. We observed no significant difference in cross-sectional area or in Young's modulus among the four study groups. In addition, histological sections showed that the BMSCs were aligned well and viable on the tendon slices after two-week culture in groups three and four. Expression levels of several extracellular matrix tendon growth factors, including collagen type I, collagen type III, and matrix metalloproteinase were significantly higher in group four than in group three (p < 0.05). Lateral slits introduced into de-cellularised tendon is a promising method of delivery of BMSCs without compromising cell viability and tendon mechanical properties. In addition, mechanical stimulation of a cell-seeded tendon can promote cell proliferation and enhance expression of collagen types I and III in vitro.Cite this article: J. H. Wu, A. R. Thoreson, A. Gingery, K. N. An, S. L. Moran, P. C. Amadio, C. Zhao. The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts. Bone Joint Res 2017;6:179-185. DOI: 10.1302/2046-3758.63.BJR-2016-0207.R1.


PGC-1 coactivator activity is required for murine erythropoiesis.
Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) and PGC-1β have been shown to be intimately involved in the transcriptional regulation of cellular energy metabolism as well as other biological processes, but both coactivator proteins are expressed in many other tissues and organs in which their function is, in essence, unexplored. Here, we found that both PGC-1 proteins are abundantly expressed in maturing erythroid cells. PGC-1α and PGC-1β compound null mutant (Pgc-1(c)) animals express less β-like globin mRNAs throughout development; consequently, neonatal Pgc-1(c) mice exhibit growth retardation and profound anemia. Flow cytometry shows that the number of mature erythrocytes is markedly reduced in neonatal Pgc-1(c) pups, indicating that erythropoiesis is severely compromised. Furthermore, hematoxylin and eosin staining revealed necrotic cell death and cell loss in Pgc-1(c) livers and spleen. Chromatin immunoprecipitation studies revealed that both PGC-1α and -1β, as well as two nuclear receptors, TR2 and TR4, coordinately bind to the various globin gene promoters. In addition, PGC-1α and -1β can interact with TR4 to potentiate transcriptional activation. These data provide new insights into our understanding of globin gene regulation and raise the interesting possibility that the PGC-1 coactivators can interact with TR4 to elicit differential stage-specific effects on globin gene transcription.


Indicators on economic risk from global climate change.
Climate change mitigation requires a rapid decrease of global emissions of greenhouse gases (GHGs) from their present value of 8.4 Gt/C/year to, as of current knowledge, approximately 1 GtC/year by the end of the century. The necessary decrease of GHG emissions will have large impacts on existing and new investments with long lifetimes, such coal-fired power plants or buildings. Strategic decision making for major investments can be facilitated by indicators that express the likelihood of costly retrofitting or shut-down of carbon intensive equipment over time. We provide a set of simple indicators that support assessment and decision making in this field. Given a certain emissions target, carbon allowance prices in a cap-and-trade plan will depend on the development of the global economy and the degree to which the target is approached on the global and national levels. The indicators measure the degree to which a given emissions target is approached nationally and assess risks for long-lived investments subject to a range of emissions targets. A comparative case study on existing coal-fired power plants with planned plants and utility-scale photovoltaic power-plants confirms that high risk for coal-fired power plants is emerging. New legislation further confirms this result.


Multimorbidity patterns in primary care: interactions among chronic diseases using factor analysis.
The primary objective of this study was to identify the existence of chronic disease multimorbidity patterns in the primary care population, describing their clinical components and analysing how these patterns change and evolve over time both in women and men. The secondary objective of this study was to generate evidence regarding the pathophysiological processes underlying multimorbidity and to understand the interactions and synergies among the various diseases. This observational, retrospective, multicentre study utilised information from the electronic medical records of 19 primary care centres from 2008. To identify multimorbidity patterns, an exploratory factor analysis was carried out based on the tetra-choric correlations between the diagnostic information of 275,682 patients who were over 14 years of age. The analysis was stratified by age group and sex. Multimorbidity was found in all age groups, and its prevalence ranged from 13% in the 15 to 44 year age group to 67% in those 65 years of age or older. Goodness-of-fit indicators revealed sample values between 0.50 and 0.71. We identified five patterns of multimorbidity: cardio-metabolic, psychiatric-substance abuse, mechanical-obesity-thyroidal, psychogeriatric and depressive. Some of these patterns were found to evolve with age, and there were differences between men and women. Non-random associations between chronic diseases result in clinically consistent multimorbidity patterns affecting a significant proportion of the population. Underlying pathophysiological phenomena were observed upon which action can be taken both from a clinical, individual-level perspective and from a public health or population-level perspective.


α-Amylase@Ferria: Magnetic Nanocomposites with Enhanced Thermal Stability for Starch Hydrolysis.
The present study is devoted to the development of a new class recyclable magnetic catalytic nanocomposites for starch hydrolysis. α-Amylase was entrapped within a magnetite-derived xerogel matrix in a course of a room-temperature sol-gel transition, leading to enzyme immobilization within the pores of a rigid magnetic matrix. For hybrid organo-inorganic composites with enzyme mass fractions less than 10 wt %, no enzyme leaching was observed. At 80 °C, the amylase@ferria composite demonstrates catalytic activity on the level of 10 units/mg and the starch hydrolysis rate comparable to free enzyme, while at 90 °C, the activity of amylase@ferria is at least twice higher than that of free amylase as a result of higher thermal stability of the composite. Entrapped amylase showed excellent stability and lost only 9% of its activity after 21 days of storage in a buffer solution, while free enzyme was totally inactivated after 17 days. The material can be used as either a magnetically separable reusable catalyst or a catalytic ceramic coating with at least 10 cycles of use.


The coordination dynamics of economic decision making: a multilevel approach to social neuroeconomics.
The basic reciprocity between individual parts and collective organization constitutes a key scientific question spanning the biological and social sciences. Such reciprocity is accompanied by the absence of direct linkages between levels of description giving rise to what is often referred to as the aggregation or nonequivalence problem between levels of analysis. This issue is encountered both in neuroscience and economics. So far, in spite of being identified and extensively discussed in various (other) scientific fields, the problem of understanding the nature of the interactions and coordination dynamics between individual (neuron approximately agent) and collective (neural networks approximately population of humans) behaviors has received little, if any attention in the growing field of neuroeconomics. The present contribution focuses on bringing a theoretical perspective to the interpretation of experiments recently published in this field and addressing how the concepts and methods of coordination dynamics may impact future research. First, we very briefly discuss the links between biology and economics. Second, we address the nonequivalence problem between different levels of analysis and the concept of reciprocal causality. Third, neuroeconomics studies that investigate the neural underpinnings of social decision making in the context of two economic games (trust and ultimatum) are reviewed to highlight issues that arise when experimental results exist at multiple scales of observation and description. Finally, in the last two sections, we discuss how coordination dynamics might provide novel routes to studying and modelling the relation between brain activity and decision making.


Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.
Two hundred fifty-three children with newly diagnosed T-cell acute lymphoblastic leukemia (ALL), who were treated uniformly with modified LSA2L2 therapy, were evaluated using univariate and recursive partition analyses to define clinical or biologic features associated with risk of treatment failure. Overall event-free survival (EFS) at 4 years was 43% (SE = 4%). Factors examined included white blood cell (WBC) level, age, gender, race (black v other), presence of a mediastinal mass, hepatomegaly, splenomegaly, marked lymphadenopathy, hemoglobin level, platelet count, blast cell expression of antigens such as the common acute lymphoblastic leukemia antigen (CALLA, CD10), HLA-DR, and T-cell-associated antigens (CD3, CD4, CD8, CD7, CD5, and THY). Univariate analysis showed that age less than or equal to 5 or less than or equal to 7 years, WBC level less than 10, less than 25, less than 50 or less than 100 x 10(3)/microL, and blast cell expression of CD4, CD8, or CALLA were associated with significantly better EFS, while hepatomegaly and splenomegaly were associated with worse EFS. Recursive partitioning analysis showed that the most important single favorable prognostic factor was a WBC level less than 50 x 10(3)/microL and, for patients with WBC counts below this level, the most important predictor of EFS was blast cell expression of the pan-T antigen defined by the monoclonal antibody (MoAb), L17F12 (CD5). For patients with higher WBC levels, the most important predictor of EFS was blast cell expression of THY antigen. The recursive partitioning analysis defined three groups of patients with widely varied prognoses identified as follows: (1) those with a WBC count less than 50 x 10(3)/microL who lacked massive splenomegaly and had blasts expressing CD5 had the best prognosis (66%, SE = 7%, EFS 4 years, n = 84); (2) those with (b1) WBC counts less than 50 x 10(3)/microL with either massive splenomegaly or who had blasts lacking CD5 expression, or (b2) WBC counts greater than 50 x 10(3)/microL with expression of the THY antigen had an intermediate prognosis (39%, SE = 7% EFS at 4 years, n = 94); (3) those with WBC counts greater than 50 x 10(3)/microL and whose blasts lacked expression of THY antigen had the poorest outcome (EFS = 19% at 4 years, SE = 8%, n = 63). A three-way comparison of EFS according to these groupings showed significant differences among the three patient groups (P less than .001). The recursive partitioning was able to classify 241 (95%) of the patients.(ABSTRACT TRUNCATED AT 400 WORDS)


Correction of misleading information in prescription drug television advertising: The roles of advertisement similarity and time delay.
Prescription drug television advertisements containing potentially consequential misinformation sometimes appear in the United States. When that happens, the U.S. Food and Drug Administration can request that companies distribute corrective advertisements to address misinformation and inaccurate claims. Previous research has demonstrated effectiveness in corrective advertising for various products. The present article builds on that work with a randomized experimental study (n = 6454) of corrective advertising investigating the extent to which visual similarity matters between violative and corrective ads and the extent to which time delay matters between violative and corrective advertisement exposure. Our study sample included overweight or obese U.S. adults recruited from an existing online consumer panel representative of the U.S. adult population. We created a brand for a fictitious prescription weight-loss drug and produced corresponding direct-to-consumer (DTC) television ads. All participants viewed the same violative ad, but were randomly assigned to view corrective ads with different levels of visual similarity and exposure time delay using a 4 × 4 between-subjects factorial design. Results suggest corrective ad exposure can influence consumer perceptions of drug efficacy, risks, and benefits previously established by violative ads that overstated drug efficacy, broadened drug indication, and omitted important risk information. Corrective ads also can weaken consumer intentions to consider and investigate a drug. However, ad similarity does not appear to affect consumer perceptions and preferences. Although we found that the effects of violative ad exposure tend to diminish over time, the length of the delay between violative and corrective ad exposure has limited influence. An exception to this was observed with regard to recall of drug benefits and risks, where the impact of corrective ad exposure increases with greater time delay. These results extend previous research to a new health condition and hold implications for regulatory policy.


Massachusetts Child Psychiatry Access Program for Moms: Utilization and Quality Assessment.
To describe the utilization and quality assessment of a population-based program to help health care providers address mental health and substance use disorders among pregnant and postpartum women, the Massachusetts Child Psychiatry Access Program for Moms (MCPAP for Moms). The Massachusetts Child Psychiatry Access Program for Moms builds health care providers' capacity to address perinatal mental health and substance use disorders through 1) trainings and toolkits, 2) telephonic access to perinatal psychiatric consultation, and 3) facilitating referral to community resources. Clinical encounter data were collected during telephone consultations. Focus groups were conducted with health care providers and staff from enrolled practices. In-depth interviews were conducted with patients served by the practices that participated in the focus groups. Transcribed interviews were analyzed by two researchers using an iterative, interpretive process with a grounded theory framework. In the first 3.5 years, MCPAP for Moms enrolled 145 obstetric practices, conducted 145 trainings for 1,174 health care providers, and served 3,699 women. Of telephone consultations provided, 42% were with obstetric care providers-midwives and 16% with psychiatrists. Health care providers perceived that MCPAP for Moms facilitates health care providers detecting and addressing depression and women disclosing symptoms, seeking help, and initiating treatment. Obstetric practices reported that they need additional support to more proactively address and further improve depression care. The high volume of encounters, sustained utilization over 3.5 years, and qualitative themes identified from health care providers and patients demonstrate that MCPAP for Moms is a feasible, acceptable, and sustainable approach to increasing access to evidence-based treatments for perinatal mental health and substance use disorders on a population-based level.


Baicalein increases the expression and reciprocal interplay of RUNX3 and FOXO3a through crosstalk of AMPKα and MEK/ERK1/2 signaling pathways in human non-small cell lung cancer cells.
Baicalein, a natural flavonoid obtained from the Scutellaria baicalensis root, has been reported to inhibit growth of human lung cancer. However, the detailed mechanism underlying this has not been well elucidated. Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Apoptosis was detected by flow cytometry analysis and caspase 3/7 assays. The expression of RUNX3 and FOXO3a mRNA were measured by real time RT-PCR methods. Western blot analysis was performed to measure the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2), runt-related transcription factor 3 (RUNX3) and forkhead box O3a (FOXO3a). Silencing of FOXO3a and RUNX3 were performed by small interfering RNA (siRNA) methods. Exogenous expression of FOXO3a or RUNX3 was carried out by electroporated transfection assays. We showed that baicalein significantly inhibited growth and induced apoptosis of non-small cell lung cancer (NSCLC) cells in a time- and dose-dependent manner. Baicalein induced RUNX3 and FOXO3a protein expression, and increased phosphorylation of AMPKα and ERK1/2. Moreover, the inhibitors of AMPK and MEK/ERK1/2 reversed the effect of baicalein on RUNX3 and FOXO3a protein expression. Interestingly, while compound C had little effect on blockade of baicalein-induced phosphorylation of ERK1/2, PD98059 significantly abrogated baicalein-induced phosphorylation of AMPKα. Intriguingly, while silencing of RUNX3 abolished the effect of baicalein on expression of FOXO3a and apoptosis, silencing of FOXO3a significantly attenuated baicalein-reduced cell proliferation. On the contrary, overexpression of FOXO3a restored the effect of baicalein on cell growth inhibition in cells silencing of endogenous FOXO3a gene and enhanced the effect of baicalein on RUNX3 protein expression. Finally, exogenous expression of RUNX3 increased FOXO3a protein and strengthened baicalein-induced phosphorylation of ERK1/2. Collectively, our results show that baicalein inhibits growth and induces apoptosis of NSCLC cells through AMPKα- and MEK/ERK1/2-mediated increase and interaction of FOXO3a and RUNX3 protein. The crosstalk between AMPKα and MEK/ERK1/2 signaling pathways, and the reciprocal interplay of FOXO3a and RUNX3 converge on the overall response of baicalein. This study reveals a novel mechanism for regulating FOXO3a and RUNX3 signaling axis in response to baicalein and suggests a new strategy for NSCLC associated targeted therapy.


Nutrition assessment and risk prediction in dialysis patients-a new integrative score.
We developed a quantitative nutritional score, based on biochemical measures, taken as part of monthly routine care. The score can be accomplished within a short time after routine laboratory results completion and identify a monthly change in nutritional status. A longitudinal observational cohort study The Institute of Nephrology, Wolfson Medical Center, Holon, Israel. A total of 179 hemodialysis patients were followed up for up to 2.5 years after study baseline. The Integrative Clinical Nutrition Dialysis Score (ICNDS) is based on the biochemical measures of albumin, creatinine, urea, cholesterol, C-reactive protein, dialysis adequacy, and weight change. Each parameter is ranked between 1 and 5, with the higher rank derived from recommended National Kidney Foundation Kidney Disease/Dialysis Outcomes and Quality Initiative values and the lower rank indicating deviation from those values. The final ICNDS is the sum of ranks over 7 parameters. The Pearson correlation coefficient was calculated for association between subjective global assessment and ICNDS in 63 randomly selected patients. In 179 dialysis patients, the baseline ICNDS, the slope of 3 subsequent monthly ICNDS values, were tested for their correlation with odds of all-cause mortality, hospitalization frequency, length of stay, after 31 months. Spline Cox regression was used to select the best cutoff point, associated with severe mortality risk. Score results were significantly correlated with nutrition evaluation by subjective global assessment (r = 0.842, P < .01). For a unit increase in baseline score, death odds were significantly decreased (hazard ratio [HR] = 0.929, 95% confidence interval [CI] 0.88-0.974, P < .002). Each unit increase in slope significantly reduced mortality risk (HR = 0.485, 95% CI 0.278-0.847, P < .011). Hospitalization frequency was significantly increased across worsening baseline score (HR = 0.935, 95% CI 0.906-0.964, P < .0001). A 1-unit increase in slope significantly decreased hospitalization (HR = 0.799, 95% CI 0.726-0.881, P < .0001). Results confirm that ICNDS is a useful prognostic tool that serves to detect nutrition deterioration at its very beginning.


Automated external defibrillators and survival after in-hospital cardiac arrest.
Automated external defibrillators (AEDs) improve survival from out-of-hospital cardiac arrests, but data on their effectiveness in hospitalized patients are limited. To evaluate the association between AED use and survival for in-hospital cardiac arrest. Cohort study of 11,695 hospitalized patients with cardiac arrests between January 1, 2000, and August 26, 2008, at 204 US hospitals following the introduction of AEDs on general hospital wards. Survival to hospital discharge by AED use, using multivariable hierarchical regression analyses to adjust for patient factors and hospital site. Of 11,695 patients, 9616 (82.2%) had nonshockable rhythms (asystole and pulseless electrical activity) and 2079 (17.8%) had shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia). AEDs were used in 4515 patients (38.6%). Overall, 2117 patients (18.1%) survived to hospital discharge. Within the entire study population, AED use was associated with a lower rate of survival after in-hospital cardiac arrest compared with no AED use (16.3% vs 19.3%; adjusted rate ratio [RR], 0.85; 95% confidence interval [CI], 0.78-0.92; P < .001). Among cardiac arrests due to nonshockable rhythms, AED use was associated with lower survival (10.4% vs 15.4%; adjusted RR, 0.74; 95% CI, 0.65-0.83; P < .001). In contrast, for cardiac arrests due to shockable rhythms, AED use was not associated with survival (38.4% vs 39.8%; adjusted RR, 1.00; 95% CI, 0.88-1.13; P = .99). These patterns were consistently observed in both monitored and nonmonitored hospital units where AEDs were used, after matching patients to the individual units in each hospital where the cardiac arrest occurred, and with a propensity score analysis. Among hospitalized patients with cardiac arrest, use of AEDs was not associated with improved survival.


Comparative emissions of random orbital sanding between conventional and self-generated vacuum systems.
Conventional abrasive sanding generates high concentrations of particles. Depending on the substrate being abraded and exposure duration, overexposure to the particles can cause negative health effects ranging from respiratory irritation to cancer. The goal of this study was to understand the differences in particle emissions between a conventional random orbital sanding system and a self-generated vacuum random orbital sanding system with attached particle filtration bag. Particle concentrations were sampled for each system in a controlled test chamber for oak wood, chromate painted (hexavalent chromium) steel panels, and gel-coated (titanium dioxide) fiberglass panels using a Gesamtstaub-Probenahmesystem (GSP) sampler at three different locations adjacent to the sanding. Elevated concentrations were reported for all particles in the samples collected during conventional sanding. The geometric mean concentration ratios for the three substrates ranged from 320 to 4640 times greater for the conventional sanding system than the self-generated vacuum sanding system. The differences in the particle concentration generated by the two sanding systems were statistically significant with the two sample t-test (P < 0.0001) for all three substances. The data suggest that workers using conventional sanding systems could utilize the self-generated vacuum sanding system technology to potentially reduce exposure to particles and mitigate negative health effects.


In situ biosensing with a surface plasmon resonance fiber grating aptasensor.
Surface plasmon resonance (SPR) biosensors prepared using optical fibers can be used as a cost-effective and relatively simple-to-implement alternative to well established biosensor platforms for monitoring biomolecular interactions in situ or possibly in vivo. The fiber biosensor presented in this study utilizes an in-fiber tilted Bragg grating to excite the SPR on the surface of the sensor over a large range of external medium refractive indices, with minimal cross-sensitivity to temperature and without compromising the structural integrity of the fiber. The label-free biorecognition scheme used demonstrates that the sensor relies on the functionalization of the gold-coated fiber with aptamers, synthetic DNA sequences that bind with high specificity to a given target. In addition to monitoring the functionalization of the fiber by the aptamers in real-time, the results also show how the fiber biosensor can detect the presence of the aptamer's target, in various concentrations of thrombin in buffer and serum solutions. The findings also show how the SPR biosensor can be used to evaluate the dissociation constant (K(d)), as the binding constant agrees with values already reported in the literature.