A Distinct T Follicular Helper Cell Subset Infiltrates the Brain in Murine Neuropsychiatric Lupus.
Neuropsychiatric symptoms in systemic lupus erythematosus (SLE) are not uncommon, yet the mechanisms underlying disease initiation and progression in the brain are incompletely understood. Although the role of T cells in other lupus target organs such as the kidney is well defined, which T cells contribute to the pathogenesis of neuropsychiatric SLE is not known. The present study was aimed at characterizing the CD4 T cell populations that are present in the choroid plexus (CP) of MRL/MpJ-faslpr mice, the primary site of brain infiltration in this classic lupus mouse model which exhibits a prominent neurobehavioral phenotype. T cells infiltrating the CP of MRL/MpJ-faslpr mice were characterized and subset identification was done by multiparameter flow cytometry. We found that the infiltrating CD4 T cells are activated and have an effector phenotype. Importantly, CD4 T cells have a T follicular helper cell (TFH) like phenotype, as evidenced by their surface markers and signature cytokine, IL-21. In addition, CD4 TFH cells also secrete significant levels of IFN-γ and express Bcl-6, thereby conforming to a potentially pathogenic T helper population that can drive the disease progression. Interestingly, the regulatory axis comprising CD4 T regulatory cells is diminished. These results suggest that accumulation of CD4 TFH in the brain of MRL/MpJ-faslpr mice may contribute to the neuropsychiatric manifestations of SLE, and point to this T cell subset as a possible novel therapeutic candidate.


Interaction between Plectranthus barbatus herbal tea components and acetylcholinesterase: binding and activity studies.
Plectranthus barbatus water extracts, have been used as herbal teas, for the treatment of various diseases. In a previous study it was demonstrated that antioxidant and anti-acetylcholinesterase active extract constituents and their metabolites were found in the plasma of rats after P. barbatus tea intraperitoneal administration. Consequently, a decrease in brain acetylcholinesterase activity occurred. The aim of the present research is to elucidate how P. barbatus extract components interact with acetylcholinesterase. The estimated thermodynamic parameters suggest that the main intermolecular interaction is hydrophobic association, although hydrogen bonds between flavonoids and the active gorge of the acetylcholinesterase molecule seem to occur and have a great impact on acetylcholinesterase inhibition. The hydroxyl positions in flavonoids seem to be of utmost importance for enzyme inhibition, as they interact with specific amino acid residues in the active gorge. FTIR analysis showed that the plant extract components do not interfere with the secondary structure of the enzyme, but decreases the rate of hydrogen-deuterium exchange, possibly by decreasing solvent accessibility in the acetylcholinesterase active gorge. The spectroscopic data complements docking studies of acetylcholinesterase inhibition by plant phenolic compounds, clarifying the dominant interactions between enzyme and inhibitor and the most important structural features of the inhibitor molecules.


Frequent loss of chromosome arms 8p and 13q in collecting duct carcinoma (CDC) of the kidney.
Collecting duct carcinoma (CDC) is a malignant renal neoplasm that is believed to arise from the epithelium of the ducts of Bellini in the distal nephron. These tumors are clinically aggressive and more often occur in a younger population than is typical of the more common clear cell renal carcinoma (RCC). Using highly informative polymorphic microsatellite markers on chromosome arms 3p, 5q, 6q, 9p, 9q, 11p, 13q, 17p, and 18q, we analyzed DNA from nonmalignant and tumor tissue in 6 cases of CDC. We found no evidence of 3p loss of heterozygosity (LOH) in these renal tumors by using multiple markers, a finding that distinguishes CDC from RCC in which 3p LOH has frequently been observed. We found LOH of 8p in 50% of the tumors examined; in addition, we observed LOH of 13q in 50% of the tumors studied. Interestingly, 8p LOH may be associated with high stage and poor clinical prognosis. These data suggest that the molecular events responsible for the development of CDC differ from those associated with the origin of RCC, and that tumor suppressor genes on 8p and 13q may be involved in the pathogenesis of CDC.


The emerging role of pharmacology in understanding consumer-prey interactions in marine and freshwater systems.
Within our lakes, streams, estuaries, and oceans, there is an astounding chemodiversity of secondary metabolites produced by microbes, algae, and invertebrates. Nearly 30 years of study have yielded hundreds of examples in which secondary metabolites alter the foraging behavior or fitness of aquatic consumers, or both. However, our understanding of the mechanisms that mediate the fate and consequences of these metabolites in aquatic consumers remains in its infancy. Interactions between metabolites and consumers at the molecular and biochemical level are the purview of modern pharmacology, which is rooted in the long history of human-drug interactions and can be adopted for ecological studies. Here, we argue that a pharmacological approach to consumer-prey interactions will be as productive within aquatic systems as it has been for understanding terrestrial systems. We review the diversity of secondary metabolites in aquatic organisms, their known effects on the feeding behaviors and performance of aquatic consumers, and the few studies that have attempted to describe their biochemical manipulation within consumer tissues, i.e., their absorption, distribution, metabolism (including detoxification), and excretion. We then highlight vexing issues in the ecology and evolution of aquatic consumer-prey interactions that would benefit from a pharmacological approach, including specialist-versus-generalist feeding strategies, dietary mixing, nutrient-toxin interactions, and taste. Finally, we argue that a pharmacological approach could help to predict how consumer-prey interactions are altered by global changes in pH, water temperature and ultraviolet radiation, or by pollution. Arguably, the state of knowledge of aquatic consumer-prey interactions is equivalent to that faced by ecologists studying terrestrial herbivores in the 1970s; the literature documents profound variation among consumers in their feeding tolerances for secondary metabolites without a thorough understanding of the mechanisms that underlie that variation. The subsequent advancement in our understanding of terrestrial herbivores in the intervening decades provides confidence that applying a pharmacological approach to aquatic consumers will prove equally productive.


Suppression of mammary epithelial cell differentiation by the helix-loop-helix protein Id-1.
Cell proliferation and differentiation are precisely coordinated during the development and maturation of the mammary gland, and this balance invariably is disrupted during carcinogenesis. Little is known about the cell-specific transcription factors that regulate these processes in the mammary gland. The mouse mammary epithelial cell line SCp2 grows well under standard culture conditions but arrests growth, forms alveolus-like structures, and expresses beta-casein, a differentiation marker, 4 to 5 days after exposure to basement membrane and lactogenic hormones (differentiation signals). We show that this differentiation entails a marked decline in the expression of Id-1, a helix-loop-helix (HLH) protein that inactivates basic HLH transcription factors in other cell types. SCp2 cells stably transfected with an Id-1 expression vector grew more rapidly than control cells under standard conditions, but in response to differentiation signals, they arrested growth and formed three-dimensional structures similar to those of control cells. Id-1-expressing cells did not, however, express beta-casein. Moreover, 8 to 10 days after receiving differentiation signals, they lost three-dimensional organization, invaded the basement membrane, and then resumed growth. SCp2 cells expressing an Id-1 antisense vector grew more slowly than controls; in response to differentiation signals, they remained stably growth arrested and fully differentiated, as did control cells. We suggest that Id-1 renders cells refractory to differentiation signals and receptive to growth signals by inactivating one or more basic HLH proteins that coordinate growth and differentiation in the mammary epithelium.


The distribution of sleepiness, sleep and work hours during a long distance morning trip: a comparison between night- and non-night workers.
Few studies have examined the extent of driver sleepiness during a long distance morning trip. Sleepiness at this time may be high because of night work, waking early to commence work or travel, sleep disorders and the monotony of driving long distances. The objective of this study was to estimate the prevalence of chronic sleepiness (Epworth sleepiness score ≥10) and sleep restriction (≤5h) in a sample of 649 drivers. Participants driving between 08:00 and 10:00 on three highways in regional Australia participated in a telephone interview. Approximately 18% of drivers reported chronic sleepiness. The proportions of night workers (NW) and non-night workers (NNW) with chronic sleepiness were not significantly different but males reported a significantly greater proportion of chronic sleepiness than females. The NW group had a significantly greater proportion of drivers with ≤5h of sleep in the previous 24 and 48h, fewer nights of full sleep (≤4), acute sleepiness and longer weekly work hours. The NW group reported driving a significantly longer distance at Time 1 (Mean=140.29±72.17km, versus 117.55±89.74km) and an additional longer distance to complete the journey (Mean=89.33±95.23km, versus 64.77±94.07km). The high proportions of sleep restriction and acute sleepiness among the NW group, and the amount of chronic sleepiness in the NW and NNW groups reported during a long distance morning trip may be of concern for driver safety.


NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.
Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.


In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models.
CRISPR-associated protein 9 (Cas9)-mediated genome editing provides a promising cure for HIV-1/AIDS; however, gene delivery efficiency in vivo remains an obstacle to overcome. Here, we demonstrate the feasibility and efficiency of excising the HIV-1 provirus in three different animal models using an all-in-one adeno-associated virus (AAV) vector to deliver multiplex single-guide RNAs (sgRNAs) plus Staphylococcus aureus Cas9 (saCas9). The quadruplex sgRNAs/saCas9 vector outperformed the duplex vector in excising the integrated HIV-1 genome in cultured neural stem/progenitor cells from HIV-1 Tg26 transgenic mice. Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 excised HIV-1 proviral DNA and significantly reduced viral RNA expression in several organs/tissues of Tg26 mice. In EcoHIV acutely infected mice, intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced systemic EcoHIV infection, as determined by live bioluminescence imaging. Additionally, this quadruplex vector induced efficient proviral excision, as determined by PCR genotyping in the liver, lungs, brain, and spleen. Finally, in humanized bone marrow/liver/thymus (BLT) mice with chronic HIV-1 infection, successful proviral excision was detected by PCR genotyping in the spleen, lungs, heart, colon, and brain after a single intravenous injection of quadruplex sgRNAs/saCas9 AAV-DJ/8. In conclusion, in vivo excision of HIV-1 proviral DNA by sgRNAs/saCas9 in solid tissues/organs can be achieved via AAV delivery, a significant step toward human clinical trials.


Critical role of conserved hydrophobic residues within the major homology region in mature retroviral capsid assembly.
During retroviral maturation, the CA protein undergoes dramatic structural changes and establishes unique intermolecular interfaces in the mature capsid shell that are different from those that existed in the immature precursor. The most conserved region of CA, the major homology region (MHR), has been implicated in both immature and mature assembly, although the precise contribution of the MHR residues to each event has been largely undefined. To test the roles of specific MHR residues in mature capsid assembly, an in vitro system was developed that allowed for the first-time formation of Rous sarcoma virus CA into structures resembling authentic capsids. The ability of CA to assemble organized structures was destroyed by substitutions of two conserved hydrophobic MHR residues and restored by second-site suppressors, demonstrating that these MHR residues are required for the proper assembly of mature capsids in addition to any role that these amino acids may play in immature particle assembly. The defect caused by the MHR mutations was identified as an early step in the capsid assembly process. The results provide strong evidence for a model in which the hydrophobic residues of the MHR control a conformational reorganization of CA that is needed to initiate capsid assembly and suggest that the formation of an interdomain interaction occurs early during maturation.


beta-endorphin is a potent analgesic agent.
beta-Endorphin, an opiate-like peptide, has potent antinociceptive properties when it is administered directly into the brain and assayed in the the tail-flick, hot-plate, and writhing tests in mice and in the wet shake test in rats. On a molar basis, beta-endorphin is 18 to 33 times more potent than morphine and its actions are blocked by the specific opiate antagonist, naloxone hydrochloride. The activity of beta-endorphin in vivo is also compared to other peptides that show opiate-like activity in assays in vitro.


IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo.
IP-10 is a member of the -C-X-C-chemokine superfamily of proinflammatory cytokines whose secretion is induced by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS). To date no function has been described for IP-10. We have genetically engineered tumor cells to secrete high levels of murine IP-10 and demonstrate that while IP-10 has no effect on the growth of these tumor cells in culture, it elicits a powerful host-mediated antitumor effect in vivo. The IP-10 antitumor response is T lymphocyte dependent, non-cell autonomous, and appears to be mediated by the recruitment of an inflammatory infiltrate composed of lymphocytes, neutrophils, and monocytes. These results document an important biologic property of IP-10 and raise the possibility that some of the T cell-directed effects of IFN-gamma and LPS may be mediated by this chemokine.


Analysis of changes in implant screws subject to occlusal loading: a preliminary analysis.
Loosening of the abutment screw can present a problem for the stability of the implant-supported crown or prosthesis. The purpose of this study was to understand the parameters of screw loosening, using an in vitro model, including loss of torque, screw head rotation, changes in screw dimension, and distortion of the implant-abutment joint. Implants (4 x 10 mm) were potted in autopolymerizing blocks. Abutments were placed with screws tightened with a 35-Ncm torque and standardized crowns fabricated. There were 3 implant systems used: Nobel Biocare USA, Inc. (Yorba Linda, CA), 3i Implant Innovations, Inc. (Palm Beach Gardens, FL), and Bio-Lok International, Inc. (Deerfield Beach, FL). Seven samples were tested for each system. Samples were loaded with 300-N loads for 50,000 cycles at 1 Hz. Torque turn audits were performed at 10,000, 25,000, and 50,000 cycles. At the conclusion of the loading, counterclockwise rotation of the abutment screw was measured. The screws were retrieved and measurements made compared with the controls. Finally, 1 sample from each group was embedded in resin, sectioned longitudinally, and examined under the standard error of the mean. The Nobel Biocare system showed a 9.4-Ncm loss of torque from the loading protocol. This result was accompanied by a counterclockwise rotation of 7 degrees and a 200-ìm elongation of the screw. Finally, there was compression and distortion of the longitudinally sectioned joint architecture observed with the standard error of the mean. From the 3i and Bio-Lok International groups, no loss of torque, counterclockwise rotation, or lengthening of the screws was observed. Intimate adaptation of the joint without distortion was seen in the longitudinal sections. Screw loosening appears to follow specific parameters that include counterclockwise rotation, lengthening of the screw, and distortion of the screw joint. This process is likely associated with both the physical properties of the screw as well as its configuration.


Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin.
Chronic hepatitis C is a serious global medical problem necessitating effective treatment. Because standard of care with pegylated interferon plus ribavirin therapy is costly, has significant side effects, and fails to cure about half of all infections, many patients seek complementary and alternative medicine to improve their health, such as Silymarin, derived from milk thistle (Silybum marianum). Milk thistle's clinical benefits for chronic hepatitis C are unsettled due to variability in standardization of the herbal product. In the current study, we focused on the anti-inflammatory and antiviral properties of a standardized Silymarin extract (MK-001). MK-001 inhibited expression of tumor necrosis factor-alpha in anti-CD3 stimulated human peripheral blood mononuclear cells and nuclear factor kappa B-dependent transcription in human hepatoma Huh7 cells. Moreover, MK-001 dose dependently inhibited infection of Huh7 and Huh7.5.1 cells by JFH-1 virus. MK-001 displayed both prophylactic and therapeutic effects against HCV infection, and when combined with interferon-alpha, inhibited HCV replication more than interferon-alpha alone. Commercial preparations of Silymarin also displayed antiviral activity, although the effects were not as potent as MK-001. Antiviral effects of the extract were attributable in part to induction of Stat1 phosphorylation, while interferon-independent mechanisms were suggested when the extract was biochemically fractionated by high-performance liquid chromatography. Silybin A, silybin B, and isosilybin A, isosilybin B elicited the strongest anti-NF-kappaB and anti-HCV actions. These effects were independent of MK-001-induced cytotoxicity. The data indicate that Silymarin exerts anti-inflammatory and antiviral effects, and suggest that complementary and alternative medicine-based approaches may assist in the management of patients with chronic hepatitis C.


Perspective on cytoreduction and metastasis-directed therapy in node positive and metastatic urothelial carcinoma of the bladder.
The outcome of node positive or metastatic urothelial carcinoma of the bladder (mUCB) is poor and palliative chemotherapy has long been considered the only treatment option for this patient group. Cytoreduction and metastasis-directed therapy, either by surgery or radiotherapy, has been successfully applied in other metastatic solid tumors in order to increase survival. In this article, we explore the literature supporting cytoreduction and metastasis-directed therapy in node positive and mUCB and try to define a patient cohort that could benefit from these treatments. From these data, it is clear that a selected group of patients survive a long time or could even be cured, however the data are scarce and the level of evidence is low. The criteria of a randomized clinical trial, to deliver the necessary evidence, are proposed.


Structure of bacterial cytoplasmic chemoreceptor arrays and implications for chemotactic signaling.
Most motile bacteria sense and respond to their environment through a transmembrane chemoreceptor array whose structure and function have been well-studied, but many species also contain an additional cluster of chemoreceptors in their cytoplasm. Although the cytoplasmic cluster is essential for normal chemotaxis in some organisms, its structure and function remain unknown. Here we use electron cryotomography to image the cytoplasmic chemoreceptor cluster in Rhodobacter sphaeroides and Vibrio cholerae. We show that just like transmembrane arrays, cytoplasmic clusters contain trimers-of-receptor-dimers organized in 12-nm hexagonal arrays. In contrast to transmembrane arrays, however, cytoplasmic clusters comprise two CheA/CheW baseplates sandwiching two opposed receptor arrays. We further show that cytoplasmic fragments of normally transmembrane E. coli chemoreceptors form similar sandwiched structures in the presence of molecular crowding agents. Together these results suggest that the 12-nm hexagonal architecture is fundamentally important and that sandwiching and crowding can replace the stabilizing effect of the membrane. DOI: http://dx.doi.org/10.7554/eLife.02151.001.


Pseudoautosomal region 1 length polymorphism in the human population.
The human sex chromosomes differ in sequence, except for the pseudoautosomal regions (PAR) at the terminus of the short and the long arms, denoted as PAR1 and PAR2. The boundary between PAR1 and the unique X and Y sequences was established during the divergence of the great apes. During a copy number variation screen, we noted a paternally inherited chromosome X duplication in 15 independent families. Subsequent genomic analysis demonstrated that an insertional translocation of X chromosomal sequence into the Y chromosome generates an extended PAR [corrected].The insertion is generated by non-allelic homologous recombination between a 548 bp LTR6B repeat within the Y chromosome PAR1 and a second LTR6B repeat located 105 kb from the PAR boundary on the X chromosome. The identification of the reciprocal deletion on the X chromosome in one family and the occurrence of the variant in different chromosome Y haplogroups demonstrate this is a recurrent genomic rearrangement in the human population. This finding represents a novel mechanism shaping sex chromosomal evolution.


Association between maternal education and objectively measured physical activity and sedentary time in adolescents.
Investigating socioeconomic variation in physical activity (PA) and sedentary time is important as it may represent a pathway by which socioeconomic position (SEP) leads to ill health. Findings on the association between children's SEP and objectively assessed PA and/or sedentary time are mixed, and few studies have included international samples. Examine the associations between maternal education and adolescent's objectively assessed PA and sedentary time. This is an observational study of 12 770 adolescents (10-18 years) pooled from 10 studies from Europe, Australia, Brazil and the USA. Original PA data were collected between 1997 and 2009. The associations between maternal education and accelerometer variables were examined using robust multivariable regression, adjusted for a priori confounders (ie, body mass index, monitor wear time, season, age and sex) and regression coefficients combined across studies using random effects meta-analyses. Analyses were conducted in March 2014. Adolescents of university educated mothers spent more time sedentary (9.5 min/day, p=0.005) and less time in light activity (10 min/day, p<0.001) compared with adolescents of high school educated mothers. Pooled analysis across two studies from Brazil and Portugal (analysed separately because of the different coding of maternal education) showed that children of higher educated mothers (tertiary vs primary/secondary) spent less time in moderate to vigorous PA (MVPA) (6.6 min/day, p=0.001) and in light PA (39.2 min/day: p<0.001), and more time sedentary (45.9 min/day, p<0.001). Across a number of international samples, adolescents of mothers with lower education may not be at a disadvantage in terms of overall objectively measured PA.


How have we been managing chronic obstructive pulmonary disease in Australia?
Although chronic obstructive pulmonary disease (COPD) is a main cause of disability, hospital admissions and premature deaths in Australia, little is known about the community management of COPD in relation to recently published guidelines. The aim of the article was to report on COPD management in a community based cohort. A random sample of adults aged between 45 and 70 years drawn from the electoral roll participated in the study. They completed a detailed respiratory questionnaire, spirometry, methacholine challenge and measurement of transfer factor. COPD was defined according to the Global initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Current asthma was defined as wheeze during the last 12 months together with bronchial hyperreactivity. Subjects were classified as either COPD-only, asthma-only or both asthma and COPD. Of 1224 subjects completing spirometry, 39 (3.5%) met the GOLD criteria for stage 2 or 3 COPD, asthma-only was found in 99 (8.9%) subjects and 40 (3.6%) subjects had both asthma and COPD. The COPD-only group was significantly older than the other two groups. More than 40% of subjects with COPD did not have a diagnosis of COPD from their doctors. Only 48.7% of subjects with COPD had ever been prescribed medication for their breathing. More than two-thirds of all subjects had seen a doctor for breathing problems, but very few had seen a general practitioner in the last 12 months and even fewer had respiratory function tests. Most subjects with COPD are being undertreated. Diagnosis, monitoring and referral systems should be improved. Preventive activities such as influenza vaccination and smoking cessation should be intensified.


Novel oral detoxification of mercury, cadmium, and lead with thiol-modified nanoporous silica.
We have developed a thiol-modified nanoporous silica material (SH-SAMMS) as an oral therapy for the prevention and treatment of heavy metal poisoning. SH-SAMMS has been reported to be highly efficient at capturing heavy metals in biological fluids and water. Herein, SH-SAMMS was examined for efficacy and safety in both in vitro and in vivo animal models for the oral detoxification of heavy metals. In simulated gastrointestinal fluids, SH-SAMMS had a very high affinity (Kd) for methyl mercury (MeHg(I)), inorganic mercury (Hg(II)), lead (Pb(II)), and cadmium (Cd(II)) and was superior to other SAMMS with carboxylic acid or phosphonic acid ligands or commercially available metal chelating sorbents. SH-SAMMS also effectively removed Hg from biologically digested fish tissue with no effect on most nutritional minerals found in fish. SH-SAMMS could hold Hg(II) and MeHg(I) tightly inside the nanosize pores, thus preventing bacteria from converting them to more absorbable forms. Rats fed a diet containing MeHg(I), Cd(II), and Pb(II) and SH-SAMMS for 2 weeks had blood Hg levels significantly lower than rats fed the metal-rich diet only. Upon cessation of the metal-rich diet, continued administration of SH-SAMMS for 2 weeks facilitated faster and more extensive clearance of Hg than in animals not continued on oral SH-SAMMS. Rats receiving SH-SAMMS also suffered less weight loss as a result of the metal exposure. Retention of Hg and Cd in major organs was lowest in rats fed with SH-SAMMS throughout the entire four weeks. The reduction of blood Pb by SH-SAMMS was significant. SH-SAMMS was safe to intestinal epithelium model (Caco-2) and common intestinal bacteria (Escherichia coli). Altogether, it has great potential as a new oral drug for the treatment of heavy metal poisoning. This new application is enabled by the installation of tailored interfacial chemistry upon nontoxic nanoporous materials.


Glucocorticoid activation of Na+/H+ exchange in renal brush border vesicles: kinetic effects.
Administration of the synthetic glucocorticoid dexamethasone to adrenalectomized rats increased Na+/H+ exchange activity in isolated renal brush border membrane vesicles. Treatment altered the initial rate of Na+ uptake by increasing Vmax (19.90 +/- 2.17 vs. 27.32 +/- 1.50 nmol.mg protein-1.5 s-1) and not the apparent affinity KNa+ (8.33 +/- 1.11 vs. 7.94 +/- 1.60 mM). Dexamethasone treatment resulted in a proportional increase in 1 mM Na+ uptake at every intravesicular pH measured. When these data were analyzed by the Hill equation, it was found that dexamethasone treatment did not change the apparent number of H+ binding sites (1.24 vs. 1.26) or the [H+]0.5 (0.33 vs. 0.32 microM) but increased the apparent Vmax (0.98 vs. 0.55 nmol.mg protein-1.2 s-1). It was also found that dexamethasone injections of 60 micrograms/100 g body wt resulted in maximum stimulation of exchange activity and that a significant increase in amiloride-sensitive Na+ uptake was detected within 12 h after a single dose of dexamethasone.


Hypospadias in sons of women exposed to diethylstilbestrol in utero.
Diethylstilbestrol (DES) is a synthetic estrogen that was widely prescribed to pregnant women before 1971. DES increases the risk of breast cancer in women who took the drug and the risk of reproductive tract abnormalities in their offspring. Dutch investigators have reported a 20-fold increase in risk of hypospadias among sons of women who were exposed to DES in utero. We assessed this relation in data from an ongoing study of DES-exposed persons. Several U.S. cohorts of women with documented exposure in utero to DES have been followed by mailed questionnaires since the 1970s. Comparison subjects are unexposed women of the same ages. In 1997, participants were asked about congenital abnormalities in their children. We calculated prevalence odds ratios for the risk of hypospadias in sons of exposed mothers relative to sons of unexposed mothers using generalized estimating equations to adjust for multiple sons per mother and controlling for maternal age at the son's birth. We obtained data from 3916 exposed and 1746 unexposed women. These women reported a total of 13 liveborn sons with hypospadias (10 exposed, 3 unexposed). The prevalence odds ratio for risk of hypospadias among the exposed was 1.7 (95% confidence interval = 0.4-6.8). Our findings do not support a greatly increased risk of hypospadias among the sons of women exposed to DES in utero, as has been previously reported.


Rethinking the implications of numerical ratio effects for understanding the development of representational precision and numerical processing across formats.
Numerical ratio effects are a hallmark of numerical comparison tasks. Moreover, ratio effects have been used to draw strong conclusions about the nature of numerical representations, how these representations develop, and the degree to which they generalize across stimulus formats. Here, we compute ratio effects for 1,719 children from Grades K-6 for each individual separately by computing not just the average ratio effect for each person, but also the variability and statistical magnitude (effect-size) of their ratio effect. We find that individuals' ratio effect-sizes in fact increase over development, calling into question the view that decreasing ratio effects over development indicate increasing representational precision. Our data also strongly caution against the use of ratio effects in inferring the nature of symbolic number representation. While 75% of children showed a statistically significant ratio effect for nonsymbolic comparisons, only 30% did so for symbolic comparisons. Furthermore, whether a child's nonsymbolic ratio effect was significant did not predict whether the same was true of their symbolic ratio effect. These results undercut the notions (a) that individuals' ratio effects are indicative of representational precision in symbolic numbers, and (b) that a common process generates ratio effects in symbolic and nonsymbolic formats. Finally, for both formats, it was the variability of an individual child's ratio effect (not its slope or even effect-size) that correlated with arithmetic ability. Taken together, these results call into question many of the long-held tenets regarding the interpretation of ratio effects-especially with respect to symbolic numbers.


Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.
To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility.


Left Vertebral Artery to Common Carotid Artery Transposition in a Patient With Bilateral Vertebral Insufficiency: 3-Dimensional Operative Video.
Extracranial vertebral artery (VA) atherosclerosis is responsible for 14% to 32% of posterior circulation infarctions.1 In the posterior circulation, narrowing of the VA > 30% is significantly associated with strokes. Subclavian artery (SCA) atherosclerosis can produce subclavian steal. Retrograde VA flow around an occluded SCA decreases blood flow to the posterior circulation and causes vertebrobasilar insufficiency (VBI). Flow augmentation to the posterior circulation can be achieved by VA endarterectomy, arterial stenting, VA-common carotid artery (CCA) transposition, or bypass using an interposition graft.2,3 This video illustrates microsurgical revascularization of the proximal VA with VA-CCA transposition. A 58-yr-old man with a prior stroke and chronic right VA occlusion presented with dysarthria and gait instability. Angiographic evaluation confirmed complete midcervical right VA occlusion and left SCA occlusion proximal to VA origin, with subclavian steal. After obtaining patient consent and a failed attempt at endovascular recanalization of the left SCA, a left VA-CCA end-to-side transposition was performed. Neck dissection exposed the left CCA. The thyrocervical trunk served as a landmark to identify the SCA, which was traced proximally to the VA origin. After proximal occlusion, the VA was transected and "fish-mouthed" for end-to-side anastomosis to CCA. An intraluminal, continuous suture technique was used to sew the back walls of this anastomosis. Postoperative computed tomography angiography confirmed bypass patency. Collateral circulation through the thyrocervical and costocervical trunks likely supplied the left arm, and no cerebral, or limb, ischemic symptoms were noted on follow-up. VA-CCA transposition is an uncommon technique for safe and effective revascularization of symptomatic, medically refractory VBI caused by VA occlusion or, as in this case, SCA occlusion with secondary subclavian steal. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.


The Mechanism Forming the Cell Surface of Tip-Growing Rooting Cells Is Conserved among Land Plants.
To discover mechanisms that controlled the growth of the rooting system in the earliest land plants, we identified genes that control the development of rhizoids in the liverwort Marchantia polymorpha. 336,000 T-DNA transformed lines were screened for mutants with defects in rhizoid growth, and a de novo genome assembly was generated to identify the mutant genes. We report the identification of 33 genes required for rhizoid growth, of which 6 had not previously been functionally characterized in green plants. We demonstrate that members of the same orthogroup are active in cell wall synthesis, cell wall integrity sensing, and vesicle trafficking during M. polymorpha rhizoid and Arabidopsis thaliana root hair growth. This indicates that the mechanism for constructing the cell surface of tip-growing rooting cells is conserved among land plants and was active in the earliest land plants that existed sometime more than 470 million years ago [1, 2].


A facile route for the fabrication of large-scale gate-all-around nanofluidic field-effect transistors with low leakage current.
Active modulation of ions and molecules via field-effect gating in nanofluidic channels is a crucial technology for various promising applications such as DNA sequencing, drug delivery, desalination, and energy conversion. Developing a rapid and facile fabrication method for ionic field-effect transistors (FET) over a large area may offer exciting opportunities for both fundamental research and innovative applications. Here, we report a rapid, cost-effective route for the fabrication of large-scale nanofluidic field-effect transistors using a simple, lithography-free two-step fabrication process that consists of sputtering and barrier-type anodization. A robust alumina gate dielectric layer, which is formed by anodizing sputtered aluminium, can be rapidly fabricated in the order of minutes. When anodizing aluminium, we employ a hemispherical counter electrode in order to give a uniform electric field that encompasses the whole sputtered aluminium layer which has high surface roughness. In consequence, a well-defined thin layer of alumina with perfect step coverage is formed on a highly rough aluminium surface. A gate-all-around nanofluidic FET with a leak-free gate dielectric exhibits outstanding gating performance despite a large channel size. The thin and robust anodized alumina gate dielectric plays a crucial role in achieving such excellent capacitive coupling. The combination of a gate-all-around structure with a leak-free gate dielectric over a large area could yield breakthroughs in areas ranging from biotechnology to energy and environmental applications.


Computational prediction of human salivary proteins from blood circulation and application to diagnostic biomarker identification.
Proteins can move from blood circulation into salivary glands through active transportation, passive diffusion or ultrafiltration, some of which are then released into saliva and hence can potentially serve as biomarkers for diseases if accurately identified. We present a novel computational method for predicting salivary proteins that come from circulation. The basis for the prediction is a set of physiochemical and sequence features we found to be discerning between human proteins known to be movable from circulation to saliva and proteins deemed to be not in saliva. A classifier was trained based on these features using a support-vector machine to predict protein secretion into saliva. The classifier achieved 88.56% average recall and 90.76% average precision in 10-fold cross-validation on the training data, indicating that the selected features are informative. Considering the possibility that our negative training data may not be highly reliable (i.e., proteins predicted to be not in saliva), we have also trained a ranking method, aiming to rank the known salivary proteins from circulation as the highest among the proteins in the general background, based on the same features. This prediction capability can be used to predict potential biomarker proteins for specific human diseases when coupled with the information of differentially expressed proteins in diseased versus healthy control tissues and a prediction capability for blood-secretory proteins. Using such integrated information, we predicted 31 candidate biomarker proteins in saliva for breast cancer.


Traumatic neuralgia from pressure-point strikes in the martial arts: results from a retrospective online survey.
Many techniques in Asian martial arts hand-to-hand combat systems emphasize hitting or striking specific sites on the body that correlate with exposed portions of peripheral nerves. To evaluate the prevalence and clinical effects of this unique sports-related injury. An anonymous self-administered retrospective 20-question electronic survey was posted on a high-traffic martial arts Web site. Primary outcome measures were demographic and medical history data, including martial arts experience and neuropathic symptoms associated with injury from this form of combat. Risk of symptoms was calculated by dividing the number of individuals with symptoms in each pressure-point area by the number of individuals who were struck in these areas during martial arts training. Of the 651 survey responses received, 605 met inclusion criteria. Neuropathic symptoms were reported by 291 subjects. Most symptoms occurred in individuals aged between 20 and 30 years as well as in individuals with less than 1 year of martial arts training. The majority of respondents with neuropathic symptoms reported a symptom duration of less than 1 year (207 [71%]). Individuals with more than 5 years of combat training experience had a greater risk of chronic symptoms than individuals with less experience. Strikes to pressure points on the back had the greatest risk of inducing neuropathic symptoms. Symptoms of neurapraxia can occur in individuals as a result of practicing martial arts involving strikes on pressure points. Although the majority of symptoms resolve within 1 year, individuals with prolonged exposure to pressure-point strikes may be more likely to have chronic symptoms.


Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014.
To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts. Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations. Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.


Testing antecedents to sales performance in postapartheid era: a field study.
The predictors of objectively measured sales performance were assessed with 245 sales representatives from a large South African life insurance company. Sales representatives completed measures of their locus of control, entrepreneurial attitudes, biographical history, and performance was assessed from company records of sales, net commissions earned, and lapse ratios. The nature of employment contract, job status, and race explained significant differences in performance outcomes. The predictive nature of locus of control and entrepreneurial attitudes for performance outcomes was tested using structural equation modeling procedures, with limited validity. The implications for research and practice are also discussed.


Clonal complexes and diversity of exotoxin gene profiles in methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates from patients in a Spanish hospital.
Molecular epidemiology studies have allowed the identification of the methicillin (meticillin)-resistant (MRSA) and methicillin-susceptible (MSSA) clonal complexes (CCs) and clones of Staphylococcus aureus circulating in a Spanish hospital recently. Of 81 isolates tested, 32.1% were MRSA. Most of them carried staphylococcal cassette chromosome mec (SCCmec) IVc (88.5%) and belonged to CC5 (88.5%; multilocus sequence typing types ST125 [mainly associated with spa type t067], ST5, and ST228). A higher diversity was found among MSSA isolates (67.9%). Eighty percent shared the genetic background of major MRSA lineages (CC5 [38.2%; ST125 and ST5], CC30 [25.5%; ST30], CC45 [14.5%; ST45 and ST47], and CC8 [1.8%; ST8]), but CC12, CC15, CC51, and CC59 were also detected. Many exotoxin genes were present in each of the 81 isolates, independent of whether they were involved in sepsis (11 to 22) or other types of infections (13 to 21), and they appeared in 73 combinations. The relevant data are that (i) all isolates were positive for hemolysin and leukotoxin genes (98.8% for lukED and 25.9% for lukPV); (ii) all contained an enterotoxin gene cluster (egc with or without seu), frequently with one or more genes encoding classical enterotoxins; (iii) about half were positive for tst and 95% were positive for exfoliatin-encoding genes (eta, etb, and/or etd); and (iv) the four agr groups were detected, with agrII (55.6%) and agrIII (23.5%) being the most frequent. Taken together, results of the present study suggest a frequent acquisition and/or loss of exotoxin genes, which may be mediated by efficient intralineage transfer of mobile genetic elements and exotoxin genes therein and by eventual breakage of interlineage barriers.


Effect of expectorants on relaxation behavior of sputum viscoelasticity in vivo.
We studied the effects of expectorants (mucolytic agents) in vivo on the relaxation behavior of sputum viscoelasticity. Seven female and thirty-three male patients (56.8 +/- 19.3 yrs, range: 21 to 82 years old) with a chronic pulmonary disease except bronchial asthma were studied. They were randomly put into the control group or a group which would be given oral treatments with an expectorant for a week after a one week washout period. The groups were as follows: Group I (n = 8), control; Group II (n = 7), Bromhexine hydrochloride 24 mg per day; Group III (n = 10), Ambroxol 90 mg per day; Group IV (n = 9) alpha - Chymotrypsin buccle 100 ch.u. per day; Group V (n = 6), Serratiopeptidase 30 mg per day. In Groups IV & V, frequency dependence of sputum viscoelasticity at the range of omega = 10(-3) to 10(0) rad.sec-1 were clearly changed after the treatments, and the magnitude of the relaxation and its main relaxation time were significantly increased. On the other hand, in Groups I, II & III, no significant changes of the frequency dependences were observed. These findings suggest that proteolytic enzymes administered orally work on the molecular structure of sputum, and break down their linkages between subunits of the structure.


COVID-19 and Organized Crime: Strategies employed by criminal groups to increase their profits and power in the first months of the pandemic.
The COVID-19 pandemic has created new opportunities for organized criminal groups and confronted them with new challenges. Analysis of how these groups have reacted to the pandemic yields better understanding of how they work and enables the devising of more effective counter-strategies. To this end, we identified illustrative cases regarding the provision of illegal governance and infiltration of the legal economy by conducting a systematic content analysis of international media articles and institutional reports published during the first eight months after the outbreak of the pandemic (January to August 2020). These cases were further analyzed in order to cluster the behavior of criminal groups in response to the COVID-19 emergency, and the means by which they tried to exploit the pandemic to strengthen their political and economic power. We found that different governance-type criminal groups proposed themselves as institutions able to mitigate the burdens imposed by the pandemic by providing support to people in need and enforcing social-distancing measures. Further, identified cases did not provide evidence of groups devoted to the provision of illicit services and goods assuming any governance role. In this respect, the available evidence supports previous knowledge about organized crime. Cases of misappropriation of public funds and organized crime infiltration of the legal economy seem less common, at least in the first phase of the pandemic. The wholesale distribution of pharmaceuticals and medicines has been the sector targeted the most.


Inpatient Outcomes for Gastrointestinal Bleeding Associated With Percutaneous Coronary Intervention.
The goal of this study was to evaluate the impact of inpatient outcomes of gastrointestinal bleeding (GIB) related to percutaneous coronary intervention (PCI). With all-cause mortality increasing in patients undergoing PCIs, outcomes for GIB associated with PCI may be adversely impacted. Using the National Inpatient Sample (2007 to 2012), we performed a nested case-control study assessing inpatient outcomes including incidence and mortality for PCI-related GIB hospitalizations. Multivariate logistic regression analyses were performed to determine significant predictors for GIB incidence and mortality. A total of 9332 (1.2%) of PCI hospitalizations were complicated by GIB with the age-adjusted incidence rate increasing 13% from 2007 (11.3 GIB per 1000 PCI) to 2012 (12.8). Patients ≥75 years of age experienced the steepest incline in GIB incidence, which increased 31% during the study period. Compared with non-GIB patients, mean length of stay (9.4 d vs. 3.3 d) and median cost of care ($29,236 vs. $17,913) was significantly higher. Significant demographic risk factors for GIB included older age and comorbid risk factors included gastritis or duodenitis, and Helicobacter pylori infection.In total, 1044 (11%) of GIB patients died during hospitalization with the GIB mortality rate increasing 30% from 2007 (95 deaths per 1000 GIB) to 2012 (123). Older age had the strongest association with inpatient mortality. Inpatient incidence and mortality for PCI-related GIB has been increasing particularly with a large increase in incidence among older patients. A multidisciplinary approach focused on risk-stratifying patients may improve preventable causes of GIB.


Epidemiology of sepsis in Taiwan.
To investigate the epidemiology trend and characteristics of sepsis-related hospitalizations in Taiwan, and to compare the differences among different severity levels of sepsis.This study is a retrospective national claim database analysis. Hospitalized adult patients with sepsis between 2010 and 2014 were identified from the Two-Million-Sample Longitudinal Health and Welfare Database (LHWD) by the International Classification of Diseases 9th Edition Clinical Modification (ICD-9-CM). The patients were divided into 3 severity groups based on their medical records during hospitalization.The study results showed that in Taiwan, there were 643 new cases of sepsis in 100,000 Taiwanese. The mortality of all septic patients in Taiwan was 287 per 100,000 people, and the case fatality was 29.2%. It was found that the mortality and incidence of sepsis in Taiwan have increased year by year, but there has been no significant change over time. In addition, demographic variation exists in the epidemiology of sepsis. In all the rates investigated, the men's were higher than the women's and the elderly's were higher than the youths'. The analysis results also showed that the respiratory system was the most common site of organ failure in septic patients.The incidence and mortality of any severity level of sepsis were 643, and 287 per 100,000 people in Taiwan, respectively, and the average case fatality was 29.2% during the study period (2010-2014). The respiratory system was the major infected site and site of organ dysfunction, especially in the more severe levels.


Optimality and Limitations of Audio-Visual Integration for Cognitive Systems.
Multimodal integration is an important process in perceptual decision-making. In humans, this process has often been shown to be statistically optimal, or near optimal: sensory information is combined in a fashion that minimizes the average error in perceptual representation of stimuli. However, sometimes there are costs that come with the optimization, manifesting as illusory percepts. We review audio-visual facilitations and illusions that are products of multisensory integration, and the computational models that account for these phenomena. In particular, the same optimal computational model can lead to illusory percepts, and we suggest that more studies should be needed to detect and mitigate these illusions, as artifacts in artificial cognitive systems. We provide cautionary considerations when designing artificial cognitive systems with the view of avoiding such artifacts. Finally, we suggest avenues of research toward solutions to potential pitfalls in system design. We conclude that detailed understanding of multisensory integration and the mechanisms behind audio-visual illusions can benefit the design of artificial cognitive systems.


Differences in the daily activity of patients with diabetic foot ulcers compared to controls in their free-living environments.
The aims of our study were to investigate multiple daily activity outcomes in patients with diabetic foot ulcers (DFU) compared to diabetic peripheral neuropathy (DPN) and diabetes (DM) controls in their free-living environments. We examined daily activity outcomes of 30 patients with DFU, 23 DPN and 20 DM. All patients wore a validated multi-sensor device for > 5 days (>22 hours per day) to measure their daily activity outcomes: steps, energy expenditure (kJ), average metabolic equivalent tasks (METs), physical activity (>3·0 METs) duration and energy expenditure, lying duration, sleep duration and sleep quality. We found that DFU patients recorded fewer median (interquartile ranges, IQR) daily steps [2154 (1621-4324)] than DPN [3660 (2742-7705)] and DM [5102 (4011-7408)] controls (P < 0·05). In contrast, DFU patients recorded more mean ± SD daily energy expenditure (kJ) (13 006 ± 3559) than DPN (11 085 ± 1876) and DM (11 491 ± 1559) controls (P < 0·05). We found no other differences in daily activity outcomes (P > 0·1). We conclude that DFU patients typically take fewer steps but expend more energy during their normal daily activity than DPN and DM controls. We hypothesise that the increased energy expenditure for DFU patients may be due to wound healing or an inefficient gait strategy. Further investigations into this energy imbalance in DFU patients may improve healing in future.


Chromosome position effects on gene expression in Escherichia coli K-12.
In eukaryotes, the location of a gene on the chromosome is known to affect its expression, but such position effects are poorly understood in bacteria. Here, using Escherichia coli K-12, we demonstrate that expression of a reporter gene cassette, comprised of the model E. coli lac promoter driving expression of gfp, varies by ∼300-fold depending on its precise position on the chromosome. At some positions, expression was more than 3-fold higher than at the natural lac promoter locus, whereas at several other locations, the reporter cassette was completely silenced: effectively overriding local lac promoter control. These effects were not due to differences in gene copy number, caused by partially replicated genomes. Rather, the differences in gene expression occur predominantly at the level of transcription and are mediated by several different features that are involved in chromosome organization. Taken together, our findings identify a tier of gene regulation above local promoter control and highlight the importance of chromosome position effects on gene expression profiles in bacteria.


Experimental infection of specific-pathogen-free chickens with avian rotaviruses.
One-to-70-day-old specific-pathogen-free chickens were infected with rotaviruses isolated from chickens, turkeys, and pheasants. Chicks infected at 1 or 7 days of age remained largely free of infection: virus could be isolated from a few chicks of these ages, but virus antigen could not be detected in the epithelial cells of the intestinal villi. Treating the virus with trypsin before inoculation did not markedly enhance virus infectivity. The same batches of virus successfully infected chickens at 56 and 70 days of age: virus could be isolated between 1 and 5 days postinfection, and virus antigen was detected in the epithelial cells of the intestinal villi. Rotaviruses isolated from pheasants were infectious for 49-day-old chickens. All infections in the older chickens remained subclinical.


Macrostructure from Microstructure: Generating Whole Systems from Ego Networks.
This paper presents a new simulation method to make global network inference from sampled data. The proposed simulation method takes sampled ego network data and uses Exponential Random Graph Models (ERGM) to reconstruct the features of the true, unknown network. After describing the method, the paper presents two validity checks of the approach: the first uses the 20 largest Add Health networks while the second uses the Sociology Coauthorship network in the 1990's. For each test, I take random ego network samples from the known networks and use my method to make global network inference. I find that my method successfully reproduces the properties of the networks, such as distance and main component size. The results also suggest that simpler, baseline models provide considerably worse estimates for most network properties. I end the paper by discussing the bounds/limitations of ego network sampling. I also discuss possible extensions to the proposed approach.


Emerging formats for next-generation antibody drug conjugates.
Antibody drug conjugates now make up a significant fraction of biopharma's oncology pipeline due to great advances in the understanding of the three key components and how they should be optimised together. With this clinical success comes innovation to produce new enabling technologies that can deliver more effective antibody-drug conjugates (ADCs) with a larger therapeutic index. There are many reviews that discuss the various strategies for ADCs design but the last 5 years or so have witnessed the emergence of a number of different antibody formats compete with the standard whole immunoglobulin. Using published research, patent applications and conference disclosures, the authors review the many antibody and antibody-like formats, discussing innovations in protein engineering and how these new formats impact on the conjugation strategy and ultimately the performance. The alternative chemistries that are now available offer new linkages, stability profiles, drug:antibody ratio, pharmacokinetics and efficacy. The different sizes being considered promise to address issues, such as tumour penetration, circulatory half-life and side-effects. ADCs are at the beginning of the next stage in their evolution and as these newer formats are developed and examined in the clinic, we will discover if the predicted features have a clinical benefit. From the commercial activity, it is envisaged that smaller or fragment-based ADCs will expand oncological applications.


Linking great apes genome evolution across time scales using polymorphism-aware phylogenetic models.
The genomes of related species contain valuable information on the history of the considered taxa. Great apes in particular exhibit variation of evolutionary patterns along their genomes. However, the great ape data also bring new challenges, such as the presence of incomplete lineage sorting and ancestral shared polymorphisms. Previous methods for genome-scale analysis are restricted to very few individuals or cannot disentangle the contribution of mutation rates and fixation biases. This represents a limitation both for the understanding of these forces as well as for the detection of regions affected by selection. Here, we present a new model designed to estimate mutation rates and fixation biases from genetic variation within and between species. We relax the assumption of instantaneous substitutions, modeling substitutions as mutational events followed by a gradual fixation. Hence, we straightforwardly account for shared ancestral polymorphisms and incomplete lineage sorting. We analyze genome-wide synonymous site alignments of human, chimpanzee, and two orangutan species. From each taxon, we include data from several individuals. We estimate mutation rates and GC-biased gene conversion intensity. We find that both mutation rates and biased gene conversion vary with GC content. We also find lineage-specific differences, with weaker fixation biases in orangutan species, suggesting a reduced historical effective population size. Finally, our results are consistent with directional selection acting on coding sequences in relation to exonic splicing enhancers.


Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. To determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.


Hierarchical and symmetric infant image registration by robust longitudinal-example-guided correspondence detection.
To investigate anatomical differences across individual subjects, or longitudinal changes in early brain development, it is important to perform accurate image registration. However, due to fast brain development and dynamic tissue appearance changes, it is very difficult to align infant brain images acquired from birth to 1-yr-old. To solve this challenging problem, a novel image registration method is proposed to align two infant brain images, regardless of age at acquisition. The main idea is to utilize the growth trajectories, or spatial-temporal correspondences, learned from a set of longitudinal training images, for guiding the registration of two different time-point images with different image appearances. Specifically, in the training stage, an intrinsic growth trajectory is first estimated for each training subject using the longitudinal images. To register two new infant images with potentially a large age gap, the corresponding images patches between each new image and its respective training images with similar age are identified. Finally, the registration between the two new images can be assisted by the learned growth trajectories from one time point to another time point that have been established in the training stage. To further improve registration accuracy, the proposed method is combined with a hierarchical and symmetric registration framework that can iteratively add new key points in both images to steer the estimation of the deformation between the two infant brain images under registration. To evaluate image registration accuracy, the proposed method is used to align 24 infant subjects at five different time points (2-week-old, 3-month-old, 6-month-old, 9-month-old, and 12-month-old). Compared to the state-of-the-art methods, the proposed method demonstrated superior registration performance. The proposed method addresses the difficulties in the infant brain registration and produces better results compared to existing state-of-the-art registration methods.


Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.
Chronic constipation affects millions of Americans, consumes significant healthcare resources, and significantly affects quality of life (QOL). Recently, several new treatment options have become available for the treatment of constipation, including intestinal secretagogues such as lubiprotone, and linaclotide, prokinetics such as prucalopride, and bile acid transporter antagonists. Plecanatide is the newest of the secretagogue class of compounds that has been approved by the US Food and Drug Administration for the treatment of adults with chronic idiopathic constipation (CIC) in the USA. It is a guanylate cyclase agonist, and a 16 amino acid synthetic peptide that is a structural analog of human uroguanylin. Two large randomized, double-blind, placebo-controlled studies assessed the efficacy and safety of plecanatide in CIC patients (Rome III). Both doses of plecanatide, 3 mg and 6 mg resulted in a significantly greater percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders (primary endpoint) compared with those who received placebo (plecanatide 3 mg, 21.0%; plecanatide 6 mg, 19.5%; placebo, 10.2%; p < 0.001 for each drug dose versus placebo). Plecanatide treatment also significantly reduced the severity of other CIC symptoms (straining effort, stool consistency, bloating). Also, plecanatide-treated patients reported high levels of satisfaction and improved QOL and desire to continue treatment. The rate of treatment-emergent adverse events with plecanatide was low, including rates of diarrhea (5%). Plecanatide is a luminally acting secretagogue that is efficacious and safe for the treatment of CIC. This article provides an overview of plecanatide in the management of adults with CIC.


Multicenter clinical trial to evaluate the efficacy of correction for photon attenuation and scatter in SPECT myocardial perfusion imaging.
Soft tissue attenuation is a prominent cause of single-photon emission computed tomography (SPECT) imaging artifacts, which may result in reduced diagnostic accuracy of myocardial perfusion imaging. A method incorporating simultaneously acquired transmission data permits nonuniform attenuation correction and when incorporating scatter correction and resolution compensation may substantially reduce interpretive errors. A prospective multicenter trial was performed recruiting patients with angiographically documented coronary disease (n=96) and group of subjects with a low likelihood of disease (n=88). The uncorrected and attenuation/scatter corrected images were read independently, without knowledge of the patient's clinical data. The detection of >/=50% stenosis was similar using uncorrected perfusion data or with attenuation/scatter correction and resolution compensation (visual or visual plus quantitative analysis), 76% versus 75% versus 78%, respectively (P=NS). The normalcy rate, however, was significantly improved with this new methodology, using either the corrected images (86% vs 96%; P=0.011) or with the corrected data and quantitative analysis (86% vs 97%; P=0.007). The receiver operator characteristic curves were also found to be marginally but not significantly higher with attenuation/scatter correction than with tradition SPECT imaging. However, the ability to detect multivessel disease was reduced with attenuation/scatter correction. Regional differences were also noted, with reduced sensitivity but improved specificity for right coronary lesions using attenuation/scatter correction methodology. This multicenter trial demonstrates the initial clinical results of a new SPECT perfusion imaging modality incorporating attenuation and scatter correction in conjunction with 99mTc sestamibi perfusion imaging. Significant improvements in the normalcy rate were noted without a decline in overall sensitivity but with a reduction in detection of extensive coronary disease.


The impact of PM2.5 on the human respiratory system.
Recently, many researchers paid more attentions to the association between air pollution and respiratory system disease. In the past few years, levels of smog have increased throughout China resulting in the deterioration of air quality, raising worldwide concerns. PM2.5 (particles less than 2.5 micrometers in diameter) can penetrate deeply into the lung, irritate and corrode the alveolar wall, and consequently impair lung function. Hence it is important to investigate the impact of PM2.5 on the respiratory system and then to help China combat the current air pollution problems. In this review, we will discuss PM2.5 damage on human respiratory system from epidemiological, experimental and mechanism studies. At last, we recommend to the population to limit exposure to air pollution and call to the authorities to create an index of pollution related to health.


Cancer as Communal: Understanding Communication and Relationships from the Perspectives of Survivors, Family Caregivers, and Health Care Providers.
With cancer increasing in prevalence and high priorities placed on concurrent oncological and palliative care to help meet the familial, spiritual, and individual needs of stakeholders in cancer, research is needed that assesses the factors that facilitate coping across stakeholders in cancer care. We were interested in synthesizing our understanding of communication and relationships among patients, caregivers, and providers based on the reasoning that illness is relational, but often conceptualized and researched from the individual perspectives of various stakeholders. The current study examined the experiences of relational and communication opportunities and challenges during cancer for current and former family caregivers, cancer survivors, and palliative and oncology health care practitioners. The thematic analysis of 30 semi-structured interviews revealed an overarching theme on the benefits of orienting toward cancer as communal, which was, in turn, facilitated or impeded by four additional themes/sets of behaviors: support, presence, perspective-taking, and reframing hope. Results of a cross-case data matrix analysis reveal that stakeholders in different roles experience qualitative differences in their experience of cancer as communal, isolated, or ambivalent. Implications for education, palliative care, and interventions are discussed.


HEALTHeBIKES - Smart E-Bike Prototype for Controlled Exercise in Telerehabilitation Programs.
E-Bikes in telerehabilitation programs could be a new intervention for more sustainable rehabilitation results. The aim is to design and build a prototype of an E-Bike usable for rehabilitation - a HEALTHeBIKE. It should avoid over-exercising, work independently of the environment and it should enable cycling in a group despite different reference exercise intensities. To achieve these goals, requirements for this system architecture have been identified. A system architecture including an Arduino microcontroller, an Android smartphone and a telemonitoring platform was presented. A power output regulated proportional-integral controller to adjust the motor assistance has been implemented. A feasibility study with two subjects cycling in a group was performed. Seven test rides on varying terrain (flat, hilly, mountainous and uphill) with the same and different exercise intensities were completed. The mean power output was close to or below the target power output of the cyclist for all test rides with a maximal error of 6.7% above and 27.6% below the target. Although the exercise intensities of the two subjects were clearly different, cycling in a group was possible without over-exercising.


MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell-Intrinsic and Host-Dependent Mechanisms.
Tumorigenesis is generally caused by genetic changes that activate oncogenes or inactivate tumor suppressor genes. The targeted inactivation of oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell-intrinsic and host-dependent mechanisms.


Intracellular metabolite profiling of platelets: evaluation of extraction processes and chromatographic strategies.
An extraction method for intracellular metabolite profiling should ideally be able to recover the broadest possible range of metabolites present in a sample. However, the development of such methods is hampered by the diversity of the physico-chemical properties of metabolites as well as by the specific characteristics of samples and cells. In this study, we report the optimization of an UPLC-MS method for the metabolite analysis of platelet samples. The optimal analytical protocol was determined by testing seven different extraction methods as well as by employing two different LC-MS methods, in which the metabolites were separated by using hydrophilic interaction liquid chromatography (HILIC) and reversed phase liquid chromatography (RPLC). The optimal conditions were selected using the coverage of the platelets' metabolome, the response of the identified metabolites, the reproducibility of the analytical method, and the time of the analysis as main evaluation criteria. Our results show that methanol-water (7:3) extraction coupled with HILIC-MS method provides the best compromise, allowing identification of 107 metabolites in a platelet cell extract sample, 91% of them with a RSD% lower than 20. A higher number of metabolites could be detected when analyzing the platelet samples with two different LC-MS methods or when using complementary extraction methods in parallel.


Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli.
The cancer-chemopreventive effects of broccoli may be attributed, in part, to isothiocyanates (ITCs), hydrolysis products of glucosinolates. Glucosinolates are hydrolyzed to their respective ITCs by the enzyme myrosinase, which is inactivated by heat. In this study, the metabolic fate of glucosinolates after ingestion of steamed and fresh broccoli was compared in 12 male subjects in a crossover design. During each 48-hour baseline period, no foods containing glucosinolates or ITCs were allowed. The subjects then consumed 200 g of fresh or steamed broccoli; all other dietary sources of ITCs were excluded. Blood and urine samples were collected during the 24-hour period after broccoli consumption. Total ITC equivalents in broccoli and total ITC equivalents in plasma and urine were assayed by high-performance liquid chromatography as the cyclocondensation product of 1,2-benzenedithiol. The content of ITCs in fresh and steamed broccoli after myrosinase treatment was found to be virtually identical (1.1 vs. 1.0 micromol/g wet wt). The average 24-hour urinary excretion of ITC equivalents amounted to 32.3 +/- 12.7% and 10.2 +/- 5.9% of the amounts ingested for fresh and steamed broccoli, respectively. Approximately 40% of total ITC equivalents in urine, 25.8 +/- 13.9 and 6.9 +/- 2.5 micromol for fresh and steamed broccoli, respectively, occurred as the N-acetyl-L-cysteine conjugate of sulforaphane (SFN-NAC). Total ITC metabolites in plasma peaked between 0 and 8 hours, whereas urinary excretion of total ITC equivalents and SFN-NAC occurred primarily between 2 and 12 hours. Results of this study indicate that the bioavailability of ITCs from fresh broccoli is approximately three times greater than that from cooked broccoli, in which myrosinase is inactivated. Considering the cancer-chemopreventive potential of ITCs, cooking broccoli may markedly reduce its beneficial effects on health.


Speckle imaging through turbulent atmosphere based on adaptable pupil segmentation.
We report on the first results to our knowledge obtained with adaptable multiaperture imaging through turbulence on a horizontal atmospheric path. We show that the resolution can be improved by adaptively matching the size of the subaperture to the characteristic size of the turbulence. Further improvement is achieved by the deconvolution of a number of subimages registered simultaneously through multiple subapertures. Different implementations of multiaperture geometry, including pupil multiplication, pupil image sampling, and a plenoptic telescope, are considered. Resolution improvement has been demonstrated on a ∼550 m horizontal turbulent path, using a combination of aperture sampling, speckle image processing, and, optionally, frame selection.


An integrated microfluidic processor for single nucleotide polymorphism-based DNA computing.
An integrated microfluidic processor is developed that performs molecular computations using single nucleotide polymorphisms (SNPs) as binary bits. A complete population of fluorescein-labeled DNA "answers" is synthesized containing three distinct polymorphic bases; the identity of each base (A or T) is used to encode the value of a binary bit (TRUE or FALSE). Computation and readout occur by hybridization to complementary capture DNA oligonucleotides bound to magnetic beads in the microfluidic device. Beads are loaded into sixteen capture chambers in the processor and suspended in place by an external magnetic field. Integrated microfluidic valves and pumps circulate the input DNA population through the bead suspensions. In this example, a program consisting of a series of capture/rinse/release steps is executed and the DNA molecules remaining at the end of the computation provide the solution to a three-variable, four-clause Boolean satisfiability problem. The improved capture kinetics, transfer efficiency, and single-base specificity enabled by microfluidics make our processor well-suited for performing larger-scale DNA computations.


The integration of prosodic speech in high functioning autism: a preliminary FMRI study.
Autism is a neurodevelopmental disorder characterized by a specific triad of symptoms such as abnormalities in social interaction, abnormalities in communication and restricted activities and interests. While verbal autistic subjects may present a correct mastery of the formal aspects of speech, they have difficulties in prosody (music of speech), leading to communication disorders. Few behavioural studies have revealed a prosodic impairment in children with autism, and among the few fMRI studies aiming at assessing the neural network involved in language, none has specifically studied prosodic speech. The aim of the present study was to characterize specific prosodic components such as linguistic prosody (intonation, rhythm and emphasis) and emotional prosody and to correlate them with the neural network underlying them. We used a behavioural test (Profiling Elements of the Prosodic System, PEPS) and fMRI to characterize prosodic deficits and investigate the neural network underlying prosodic processing. Results revealed the existence of a link between perceptive and productive prosodic deficits for some prosodic components (rhythm, emphasis and affect) in HFA and also revealed that the neural network involved in prosodic speech perception exhibits abnormal activation in the left SMG as compared to controls (activation positively correlated with intonation and emphasis) and an absence of deactivation patterns in regions involved in the default mode. These prosodic impairments could not only result from activation patterns abnormalities but also from an inability to adequately use the strategy of the default network inhibition, both mechanisms that have to be considered for decreasing task performance in High Functioning Autism.


Patterns of intimate partner violence in a large, epidemiological sample of divorcing couples.
In many jurisdictions divorcing couples are court-ordered to participate in divorce mediation to resolve parenting plan disputes prior to a court allowing a case to proceed to trial. Historically, a significant number (40-80%) of these divorcing couples enter this highly stressful legal process having experienced violence and abuse within the relationship (Pearson, 1997). Several researchers have developed typologies that describe couple-level patterns of Intimate Partner Violence and Abuse (IPV/A) behaviors; one research team suggested their typology could apply specifically to such divorcing people (Kelly & Johnson, 2008). In this context, identification and accurate classification of IPV/A can lead to better decisions as long-term, difficult to modify custody orders concerning the children are made during divorce mediation. Accurate identification and classification of IPV/A can also assist clinical researchers designing specialized interventions for couples and individuals experiencing IPV/A, mental health practitioners who may treat these families, and custody evaluators who may make recommendations to the courts. The current study includes a large epidemiological sample of divorcing couples and provides a robust statistical solution with five distinct categories of IPV/A. Two of the five categories were similar to those proposed by Johnson (2006c). The current study also provides descriptions and frequencies of each type of IPV/A, and discusses implications for court personnel, researchers and practitioners.


Photofunctional triplet excited states of cyclometalated Ir(III) complexes: beyond electroluminescence.
The development of cyclometalated Ir(III) complexes has enabled important breakthroughs in electroluminescence because such complexes permit the efficient population of triplet excited states that give rise to luminescent transitions. The triplet states of Ir(III) complexes are advantageous over those of other transition metal complexes in that their electronic transitions and charge-transfer characteristics are tunable over wide ranges. These favorable properties suggest that Ir(III) complexes have significant potential in a variety of photofunctions other than electroluminescence. In this critical review, we describe recent photonic applications of novel Ir(III) complexes. Ir(III) complexes have been shown to affect the exciton statistics in the active layers of organic photovoltaic cells, thereby improving the photon-to-current conversion efficiencies. Nonlinear optical applications that take advantage of the strong charge-transfer properties of triplet transitions are also discussed. The tunability of the electrochemical potentials facilitates the development of efficient photocatalysis in the context of water photolysis or organic syntheses. The photoredox reactivities of Ir(III) complexes have been employed in studies of charge migration along DNA chains. The photoinduced cytotoxicity of Ir(III) complexes on live cells suggests that the complexes may be useful in photodynamic therapy. Potential biological applications of the complexes include phosphorescence labeling and sensing. Intriguing platforms based on cyclometalated Ir(III) complexes potentially provide novel protein tagging and ratiometric detection. We envision that future research into the photofunctionality of Ir(III) complexes will provide important breakthroughs in a variety of photonic applications.


Attosecond electron spectroscopy using a novel interferometric pump-probe technique.
We present an interferometric pump-probe technique for the characterization of attosecond electron wave packets (WPs) that uses a free WP as a reference to measure a bound WP. We demonstrate our method by exciting helium atoms using an attosecond pulse (AP) with a bandwidth centered near the ionization threshold, thus creating both a bound and a free WP simultaneously. After a variable delay, the bound WP is ionized by a few-cycle infrared laser precisely synchronized to the original AP. By measuring the delay-dependent photoelectron spectrum we obtain an interferogram that contains both quantum beats as well as multipath interference. Analysis of the interferogram allows us to determine the bound WP components with a spectral resolution much better than the inverse of the AP duration.


Determinants of bird species richness, endemism, and island network roles in Wallacea and the West Indies: is geography sufficient or does current and historical climate matter?
Island biogeography has greatly contributed to our understanding of the processes determining species' distributions. Previous research has focused on the effects of island geography (i.e., island area, elevation, and isolation) and current climate as drivers of island species richness and endemism. Here, we evaluate the potential additional effects of historical climate on breeding land bird richness and endemism in Wallacea and the West Indies. Furthermore, on the basis of species distributions, we identify island biogeographical network roles and examine their association with geography, current and historical climate, and bird richness/endemism. We found that island geography, especially island area but also isolation and elevation, largely explained the variation in island species richness and endemism. Current and historical climate only added marginally to our understanding of the distribution of species on islands, and this was idiosyncratic to each archipelago. In the West Indies, endemic richness was slightly reduced on islands with historically unstable climates; weak support for the opposite was found in Wallacea. In both archipelagos, large islands with many endemics and situated far from other large islands had high importance for the linkage within modules, indicating that these islands potentially act as speciation pumps and source islands for surrounding smaller islands within the module and, thus, define the biogeographical modules. Large islands situated far from the mainland and/or with a high number of nonendemics acted as links between modules. Additionally, in Wallacea, but not in the West Indies, climatically unstable islands tended to interlink biogeographical modules. The weak and idiosyncratic effect of historical climate on island richness, endemism, and network roles indicates that historical climate had little effects on extinction-immigration dynamics. This is in contrast to the strong effect of historical climate observed on the mainland, possibly because surrounding oceans buffer against strong climate oscillations and because geography is a strong determinant of island richness, endemism and network roles.


Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest.
Central aortic pressure gives better insight into ventriculo-arterial coupling and better prognosis of cardiovascular complications than peripheral pressures. Therefore transfer functions (TF), reconstructing aortic pressure from peripheral pressures, are of great interest. Generalized TFs (GTF) give useful results, especially in larger study populations, but detailed information on aortic pressure might be improved by individualization of the TF. We found earlier that the time delay, representing the travel time of the pressure wave between measurement site and aorta is the main determinant of the TF. Therefore, we hypothesized that the TF might be individualized (ITF) using this time delay. In a group of 50 patients at rest, aged 28-66 yr (43 men), undergoing diagnostic angiography, ascending aortic pressure was 119 +/- 20/70 +/- 9 mmHg (systolic/diastolic). Brachial pressure, almost simultaneously measured using catheter pullback, was 131 +/- 18/67 +/- 9 mmHg. We obtained brachial-to-aorta ITFs using time delays optimized for the individual and a GTF using averaged delay. With the use of ITFs, reconstructed aortic pressure was 121 +/- 19/69 +/- 9 mmHg and the root mean square error (RMSE), as measure of difference in wave shape, was 4.1 +/- 2.0 mmHg. With the use of the GTF, reconstructed pressure was 122 +/- 19/69 +/- 9 mmHg and RMSE 4.4 +/- 2.0 mmHg. The augmentation index (AI) of the measured aortic pressure was 26 +/- 13%, and with ITF and GTF the AIs were 28 +/- 12% and 30 +/- 11%, respectively. Details of the wave shape were reproduced slightly better with ITF but not significantly, thus individualization of pressure transfer is not effective in resting patients.