Treatment-free remission in chronic myeloid leukemia.
Tyrosine kinase inhibitors (TKIs) represent a major breakthrough in the treatment of chronic myeloid leukemia (CML). Thanks to these agents, CML has been transformed from a disease with limited treatment options and a dismal prognosis into a more indolent disease with survival comparable to that of the general population. The need for ongoing TKI therapy remains controversial for several reasons, including cost and toxicity. Studies in CML patients with a sustained deep molecular response have demonstrated that stopping TKI therapy is feasible and safe. Given the heterogeneity of results reported in clinical trials, practice guidelines for optimal patient selection and proper monitoring after discontinuation of TKIs are proposed outside of clinical trials. Current data available show that 40% to 60% of patients who stop therapy relapse; molecular relapses typically occur within 6 months, but nearly all relapsing patients regain response upon reinitiation of the TKI. Several factors that predict for relapse have been investigated. Duration of prior TKI therapy, achievement of deep molecular response, depth of molecular response, prior interferon treatment, and Sokal risk score have been shown to be potential predictors for relapse. Leukemia stem cells that are resistant to TKIs, and that persist despite undetectable BCR/ABL1 transcript levels, likely are responsible for disease relapse after discontinuation. Efforts geared toward better identification of low levels of BCR/ABL1 transcript using new techniques such as digital polymerase chain reaction, along with eradicating CML clones using combination therapies with agents such as pegylated interferon or venetoclax with TKIs, will hopefully lead to a functional cure of this disease.


Effectiveness of stretching exercise versus kinesiotaping in improving length of the pectoralis minor: A systematic review and network meta-analysis.
Shortness of the pectoralis minor (PM) is a potential mechanism underlying shoulder impingement syndrome. Few studies have examined the effects of kinesiotaping and stretching exercise on PM length or index. This systematic review and network meta-analysis investigated the effects of stretching exercise and kinesiotaping on PM length and index in adults. This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomised controlled trials including adults with or without symptomatic shoulders were included. Heterogeneity between studies was assessed using I2 statistics, and publication bias was evaluated by constructing a funnel plot. We extracted data from six randomised controlled trials that included 263 participants (age range: 18-50 years). Compared with usual care, kinesiotaping resulted in greater improvement in PM length (mean difference, 1.15 cm; 95% confidence interval [CI]: 0.20-2.10 cm). Compared with usual care and kinesiotaping, proprioceptive neuromuscular facilitation (PNF) stretching increased PMI significantly, with a mean difference of 1.40 (95% CI: 1.17-1.63) and 1.08 (95% CI: 0.29-1.87) cm, respectively. Compared with no intervention, kinesiotaping is beneficial for lengthening the PM. Intervention with static stretching alone has no effect on PM length. Compared with kinesiotaping alone and no intervention, PNF stretching increases PMI.


National Hospital Discharge Survey: 2000 annual summary with detailed diagnosis and procedure data.
This report presents national estimates for 2000 and selected trend data on the use of non-Federal short-stay hospitals in the United States. Estimates are provided by demographic characteristics of patients discharged, geographic region, ownership and bed size of hospitals, principal expected source of payment, conditions diagnosed, and surgical and nonsurgical procedures performed. The estimates are based on data collected through the National Hospital Discharge Survey. The survey has been conducted annually by the National Center for Health Statistics since 1965. In 2000, data were collected for approximately 313,000 discharges. Of the 481 eligible non-Federal short-stay hospitals in the sample, 434 (90 percent) responded to the survey. Measurements of hospital use include number and rate of discharges and days of care, and the average length of stay. The population estimates used to compute rates were based on the 1990 Census. Estimates of first-listed diagnoses, days of care, all-listed diagnoses, and all-listed procedures are presented according to their code number in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). An estimated 31.7 million inpatients were discharged from non-Federal short-stay hospitals in 2000. These patients used an estimated 155.9 million days of care. Females had 19.2 million discharges compared with 12.5 million for males. Fifty-four percent of all discharges under age 65 years had a principal expected source of payment from a private source, and 22 percent were covered by Medicaid. Discharge rates per 1,000 population ranged from 85.4 in the West to 135.5 in the Northeast. The leading discharge diagnosis was delivery for patients under age 65 years and heart disease for those 65 years of age and over. The rate of discharges with coronary artery bypass graft for males was 2.4 times the rate for females, and males had almost twice the female rate for discharges with removal of coronary artery obstruction. Hospital stays were 1 day or less for 15 percent of women with deliveries in 2000, compared with 37 percent in 1995.


Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.
Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-gamma, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1beta, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-beta, tumor necrosis factor [alpha], or transforming growth factor beta). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.


Aldosterone and cortisol predict medium-term left ventricular remodelling following myocardial infarction.
Mineralocorticoid receptor (MR) antagonists improve cardiovascular outcomes in patients with heart failure complicating acute myocardial infarction (AMI) and in chronic heart failure. It is unclear whether these beneficial effects are due solely to aldosterone blockade, as MR has a similar affinity for cortisol. We examined the relationships between plasma and urinary steroid hormones and left ventricular (LV) remodelling in patients with LV dysfunction following AMI. Plasma concentrations of renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and 24 h urinary excretion rates of tetrahydroaldosterone (THAldo) and total cortisol metabolites were measured in 93 patients at a mean of 46 h following AMI prior to contrast-enhanced cardiac magnetic resonance (ceCMR). Patients were then randomized to 24 weeks of placebo or eplerenone therapy in addition to standard treatment, after which ceCMR was repeated. In placebo-treated patients, aldosterone, NT-proBNP, and excretion rates of THAldo and total cortisol metabolites were univariate predictors of remodelling (i.e. change in LV end-systolic volume index); aldosterone (P = 0.040) and total cortisol metabolite excretion (P = 0.038) remained independent predictors on multivariate analysis. None of the measured biomarkers predicted remodelling in the presence of eplerenone. Plasma and urinary aldosterone measures, and urinary cortisol metabolites, were not only related to larger infarct volumes and greater infarct remodelling over time, but were also higher in patients with microvascular obstruction on baseline ceCMR. Aldosterone and cortisol are associated with medium-term LV remodelling when measured early after AMI. The beneficial effects of MR antagonism may relate to blockade of both aldosterone- and cortisol-induced MR activation.


Prognostic value of electrocardiographic abnormalities in adults from the Brazilian longitudinal study of adults' health.
Cardiovascular diseases (CVDs) are highly preventable non-communicable diseases. ECG is a potential tool for risk stratification with respect to CVD. Our aim was to evaluate ECG's role in all-cause and cardiovascular mortality prediction. Participants from the Brazilian Longitudinal Study of Adult Health, free of known CVD at baseline were included. A 12-lead ECG was obtained at baseline (2008-2010). Participants were followed up to 2018 by annual interviews. Deaths were independently reviewed. Cox as well as Fine and Grey multivariable regression models were applied to evaluate if the presence of any major electrocardiographic abnormality (MEA), defined according to the Minnesota Code system, would predict total and cardiovascular deaths. We also evaluated the Net Reclassification Index of adding MEA to the Systematic Coronary Risk Evaluation (SCORE). The 13 428 participants (median age 51 years, 45% men) were followed up for 8±1 years. All-cause and cardiovascular mortality occurred in 2.8% and 1.2% of the population, respectively. Prevalent MEA was an independent predictor of overall (HR=2.3, 95% CI 1.7 to 2.9) and cardiovascular mortality (HR=4.6, 95% CI 3.0 to 7.0) after adjustments for age, race, education and traditional cardiovascular risk factors. Adding MEA to the SCORE resulted in 9% mis-reclassification in the non-event subgroup and 33% correct reclassification in those with a fatal cardiovascular event. Presence of MEA was an independent predictor of overall and cardiovascular mortality. ECG may have a role in risk prediction of cardiovascular mortality in primary care.


Developmental expression of sodium entry pathways in rat nephron.
During the past several years, sites of expression of ion transport proteins in tubules from adult kidneys have been described and correlated with functional properties. Less information is available concerning sites of expression during tubule morphogenesis, although such expression patterns may be crucial to renal development. In the current studies, patterns of renal axial differentiation were defined by mapping the expression of sodium transport pathways during nephrogenesis in the rat. Combined in situ hybridization and immunohistochemistry were used to localize the Na-Pi cotransporter type 2 (NaPi2), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the thiazide-sensitive Na-Cl cotransporter (NCC), the Na/Ca exchanger (NaCa), the epithelial sodium channel (rENaC), and 11beta-hydroxysteroid dehydrogenase (11HSD). The onset of expression of these proteins began in post-S-shape stages. NKCC2 was initially expressed at the macula densa region and later extended into the nascent ascending limb of the loop of Henle (TAL), whereas differentiation of the proximal tubular part of the loop of Henle showed a comparatively retarded onset when probed for NaPi2. The NCC was initially found at the distal end of the nascent distal convoluted tubule (DCT) and later extended toward the junction with the TAL. After a period of changing proportions, subsegmentation of the DCT into a proximal part expressing NCC alone and a distal part expressing NCC together with NaCa was evident. Strong coexpression of rENaC and 11HSD was observed in early nascent connecting tubule (CNT) and collecting ducts and later also in the distal portion of the DCT. Ontogeny of the expression of NCC, NaCa, 11HSD, and rENaC in the late distal convolutions indicates a heterogenous origin of the CNT. These data present a detailed analysis of the relations between the anatomic differentiation of the developing renal tubule and the expression of tubular transport proteins.


Med12 gain-of-function mutation causes leiomyomas and genomic instability.
Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (MED12) exon 2 variants are associated with uterine leiomyomas; however, the causality of MED12 variants, their genetic mode of action, and their role in genomic instability have not been established. Here, we generated a mouse model that conditionally expresses a Med12 missense variant (c.131G>A) in the uterus and demonstrated that this alteration alone promotes uterine leiomyoma formation and hyperplasia in both WT mice and animals harboring a uterine mesenchymal cell-specific Med12 deletion. Compared with WT animals, expression of Med12 c.131G>A in conditional Med12-KO mice resulted in earlier onset of leiomyoma lesions that were also greater in size. Moreover, leiomyomatous, Med12 c.131G>A variant-expressing uteri developed chromosomal rearrangements. Together, our results show that the common human leiomyoma-associated MED12 variant can cause leiomyomas in mice via a gain of function that drives genomic instability, which is frequently observed in human leiomyomas.


Impact of a Microbial Pest Control Product Containing Bacillus thuringiensis on Brood Development and Gut Microbiota of Apis mellifera Worker Honey Bees.
To avoid potential adverse side effects of chemical plant protection products, microbial pest control products (MPCP) are commonly applied as biological alternatives. This study aimed to evaluate the biosafety of a MPCP with the active organism Bacillus thuringiensis ssp. aizawai (strain: ABTS-1857). An in-hive feeding experiment was performed under field-realistic conditions to examine the effect of B. thuringiensis (B. t.) on brood development and the bacterial abundance of the core gut microbiome (Bifidobacterium asteroids, Gilliamella apicola, the group of Lactobacillus and Snodgrasella alvi) in Apis mellifera worker bees. We detected a higher brood termination rate and a non-successful development into worker bees of treated colonies compared to those of the controls. For the gut microbiome, all tested core members showed a significantly lower normalized abundance in bees of the treated colonies than in those of the controls; thus, a general response of the gut microbiome may be assumed. Consequently, colony exposure to B. t. strain ABTS-1857 had a negative effect on brood development under field-realistic conditions and caused dysbiosis of the gut microbiome. Further studies with B. t.-based products, after field-realistic application in bee attractive crops, are needed to evaluate the potential risk of these MPCPs on honey bees.


Analysis of differentiation of mouse hemopoietic stem cells in culture by sequential replating of paired progenitors.
Blast cell colonies seen in cultures of spleen cells from 5-fluorouracil-treated mice provide a highly enriched population of primitive hemopoietic progenitors. Our recent studies of the differentiation potentials of the paired daughter cells of these progenitors showed different patterns of differentiation in the colonies produced by the separated daughter cells. In this study, we carried out sequential micromanipulation of paired progenitors followed by cytologic examinations of the colonies derived from these progenitors. Of the total 94 evaluable cultures, consisting of three or more colonies, 52 consisted of macrophage colonies and one consisted of megakaryocyte colonies. In the remaining 41 cultures, diverse combinations of colonies revealing heterogeneous compositions of cell lineages were identified. Presumptive genealogic trees of the differentiation of hemopoietic progenitors constructed for the latter group of cultures suggested that monopotent progenitors may be derived from pluripotent progenitors in two ways: (1) directly during one cell division of pluripotent cells or (2) as a result of progressive lineage restriction during successive division of the pluripotent progenitors. The results also suggested that some of the oligopotent progenitors are capable of limited self-renewal.


Suicide and Microglia: Recent Findings and Future Perspectives Based on Human Studies.
Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.


α-Bisabolol protects against β-adrenergic agonist-induced myocardial infarction in rats by attenuating inflammation, lysosomal dysfunction, NLRP3 inflammasome activation and modulating autophagic flux.
Emerging evidence demonstrates that NLRP3 inflammasome activation, lysosomal dysfunction, and impaired autophagic flux play a crucial role in the pathophysiology of myocardial infarction (MI). Therapeutic strategies targeting NLRP3 activation, lysosomal enzyme release and correcting autophagy have shown beneficial effects in suppressing early inflammatory responses in cardiovascular diseases. Thus, the agents, which inhibit NLRP3 activation and correct lysosome dysfunction and impaired autophagic flux, can be potential drugs for MI. The present study evaluated the effects and elucidated the NLRP3 inflammasome mediated mechanism of α-bisabolol, a dietary sesquiterpene alcohol in a rat model of isoproterenol (ISO)-induced MI. In the present study, male albino Wistar rats were pre- and co-treated with intraperitoneal injection of α-bisabolol (25 mg kg-1) daily for 10 days along with the subcutaneous injection of ISO (85 mg kg-1) at an interval of 24 h for two days (9th and 10th day). ISO injections induced MI as evidenced by the elevated cardiac marker enzyme in serum and altered oxidative stress markers in the total heart and lysosomal fractions. ISO also caused activation of NLRP3 inflammasomes mediating TLR4-NFκB/MAPK signaling pathways and lysosomal dysfunction along with induction and release of proinflammatory cytokines. Interestingly, treatment with α-bisabolol favorably corrected the morphological, histopathological, ultrastructural, biochemical and molecular abnormalities induced by ISO-induced MI in rats. Furthermore, the ultrastructural studies also confirmed the improvement in the autophagic mechanism. The findings of the present study clearly demonstrate that α-bisabolol attenuates oxidative stress and inflammation by inhibiting NLRP3 inflammasome activation and TLR4-NFκB/MAPK signaling pathways along with correcting lysosomal dysfunction and impaired autophagic flux. The underlying pharmacological and molecular mechanism of cardioprotection was attributed to its antioxidant, free radical scavenging and anti-inflammatory properties.


Anti-inflammatory properties of exenatide in human pancreatic islets.
Exenatide is an analog of the incretin hormone glucagon-like peptide (GLP-1) that is used for the treatment of T2D for their metabolic effects. In addition to its insulinotropic effects, exenatide increases functional islet mass and improves their survival. Improved outcomes have been reported in recent clinical islet transplantation trials for the treatment of type 1 diabetes. The purpose of this study was to investigate whether exenatide has anti-inflammatory properties in human islets. Exenatide treatment improved islet function, significantly reduced content of inflammation-related molecules (tissue factor, IFN-γ, IL-17, IL-1β, and IL-2) and caspase 3 activation, whereas increased phosphorylation of ERK1/2, STAT3, and Akt in vitro. Immunostaining showed expression of GLP-1R in β-cells but not in α-cells. IL-1β colocalized with GLP-1R in β-cells. Induction of serine proteinase inhibitor 9 (PI-9) was detected after exposure of human islets to exenatide in vitro and after transplantation into immunodeficient mice. GLP-1 induced PI-9 expression in vitro but to a lower extent than exenatide. This effect was partially blocked by the antagonist exendin-9 in vitro. As assessed by immunostaining PI-9 is mostly expressed in β-cells but not in α-cells. In conclusion, we describe anti-inflammatory and cytoprotective properties of exenatide in human islets. Exenatide-mediated PI-9 expression, the only known granzyme B inhibitor, unveils potential immunoregulatory properties.


A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock.
The regulation of monocyte function and the inhibition of TNF-alpha production during bacterial sepsis are critical in attenuating adverse host responses to endotoxemia. To study the function of a novel receptor tyrosine kinase, mer, that is expressed in monocytes, we generated mice (merkd) that lack the signaling tyrosine kinase domain. Upon LPS challenge, merkd animals died of endotoxic shock (15/17, 88.2%), whereas control wild-type mice survived (1/15, 6.7% died). Susceptible merkd mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher levels of TNF-alpha found in the serum of merkd mice as compared with wild-type control animals. Death due to LPS-induced endotoxic shock in merkd mice was blocked by administration of anti-TNF-alpha Ab, suggesting that overproduction of this cytokine was principally responsible for the heightened suseptibility. The increase in TNF-alpha production appeared to be the result of a substantial increase in the LPS-dependent activation of NF-kappa B nuclear translocation resulting in greater TNF-alpha production by macrophages from merkd mice. Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-alpha secretion and attenuating endotoxic shock.


Communication Between Cardiomyocytes and Fibroblasts During Cardiac Ischemia/Reperfusion and Remodeling: Roles of TGF-β, CTGF, the Renin Angiotensin Axis, and Non-coding RNA Molecules.
Communication between cells is a foundational concept for understanding the physiology and pathology of biological systems. Paracrine/autocrine signaling, direct cell-to-cell interplay, and extracellular matrix interactions are three types of cell communication that regulate responses to different stimuli. In the heart, cardiomyocytes, fibroblasts, and endothelial cells interact to form the cardiac tissue. Under pathological conditions, such as myocardial infarction, humoral factors released by these cells may induce tissue damage or protection, depending on the type and concentration of molecules secreted. Cardiac remodeling is also mediated by the factors secreted by cardiomyocytes and fibroblasts that are involved in the extensive reciprocal interactions between these cells. Identifying the molecules and cellular signal pathways implicated in these processes will be crucial for creating effective tissue-preserving treatments during or after reperfusion. Numerous therapies to protect cardiac tissue from reperfusion-induced injury have been explored, and ample pre-clinical research has attempted to identify drugs or techniques to mitigate cardiac damage. However, despite great success in animal models, it has not been possible to completely translate these cardioprotective effects to human applications. This review provides a current summary of the principal molecules, pathways, and mechanisms underlying cardiomyocyte and cardiac fibroblast crosstalk during ischemia/reperfusion injury. We also discuss pre-clinical molecules proposed as treatments for myocardial infarction and provide a clinical perspective on these potential therapeutic agents.


Tuberculosis control has failed in South Africa--time to reappraise strategy.
South Africa's rate of tuberculosis (TB) has increased over the last 20 years, to now having the third-highest TB burden in the world. The TB control programme has primarily focused on effective case management of passively presenting TB cases, and progress has been recorded towards international treatment targets. While outcomes for notified TB cases have improved, this strategy failed to contain the TB epidemic. South Africa has the highest per capita annual risk of TB disease of comparably sized countries globally, and its communities have extremely high TB transmission rates. The rates of TB infection of children and adolescents are now similar to those reported 100 years ago in Europe long before chemotherapy became available. High rates of HIV testing of TB patients in Cape Town allows analysis of TB notification data stratified by age, type of TB and HIV status, and a better understanding of TB epidemiology. TB infection prevalence data from Cape Town communities allow estimation of the prevailing force of TB infection and, together with TB notification and prevalence data, the effective number of secondary infections and case finding proportions can be estimated. This better understanding of the major drivers of the TB epidemic allows reasons to be identified for failure of the present strategy. New control strategies can also be identified, that must be accompanied by novel TB control targets.


What Makes Parkour Unique? A Narrative Review Across Miscellaneous Academic Fields.
Parkour is a growing sport that mostly involves jumping, vaulting over obstacles, and climbing in a non-dedicated setting. The authors gathered all known relevant literature across miscellaneous academic fields in order to define parkour with regard to other sports disciplines. Parkour is a lifestyle sport, and as such provides an alternative to mainstream sports, away from strict rules, standardized settings, and necessary competitions. Traceurs (parkour adepts) consider the city as a playground and as an outlet for their creativity, but they also have a strong taste for hard and individualized challenges. They usually train on non-specific structures, at ground level. Although their social background is not clear, they are mostly young and male. Traceurs are stronger than recreational athletes, especially in eccentric exercises. However, their endurance skills may be below average. One of the core specificities of parkour is its precision constraint at landing, which turns a standing long jump into a precision jump, regulated in flight so as to prepare for landing. The running precision jump follows the same landing pattern, and its flight phase contrasts with long jump techniques. Injuries, which are not more frequent than in other sports, often occur at landing and to lower limb extremities. This risk is mitigated by targeting the landing area with the forefoot instead of letting the heel hit the ground like in gymnastics, or with rolling in order to dissipate the impact. Overall, parkour focuses on adaptability to new environments, which leads to specific techniques that have not yet been extensively addressed by the literature.


Acidification reduced growth rate but not swimming speed of larval sea urchins.
Swimming behaviors of planktonic larvae impact dispersal and population dynamics of many benthic marine invertebrates. This key ecological function is modulated by larval development dynamics, biomechanics of the resulting morphology, and behavioral choices. Studies on ocean acidification effects on larval stages have yet to address this important interaction between development and swimming under environmentally-relevant flow conditions. Our video motion analysis revealed that pH covering present and future natural variability (pH 8.0, 7.6 and 7.2) did not affect age-specific swimming of larval green urchin Strongylocentrotus droebachiensis in still water nor in shear, despite acidified individuals being significantly smaller in size (reduced growth rate). This maintenance of speed and stability in shear was accompanied by an overall change in size-corrected shape, implying changes in swimming biomechanics. Our observations highlight strong evolutionary pressure to maintain swimming in a varying environment and the plasticity in larval responses to environmental change.


The trajectory of gray matter development in Broca's area is abnormal in people who stutter.
The acquisition and mastery of speech-motor control requires years of practice spanning the course of development. People who stutter often perform poorly on speech-motor tasks thereby calling into question their ability to establish the stable neural motor programs required for masterful speech-motor control. There is evidence to support the assertion that these neural motor programs are represented in the posterior part of Broca's area, specifically the left pars opercularis. Consequently, various theories of stuttering causation posit that the disorder is related to a breakdown in the formation of the neural motor programs for speech early in development and that this breakdown is maintained throughout life. To date, no study has examined the potential neurodevelopmental signatures of the disorder across pediatric and adult populations. The current study aimed to fill this gap in our knowledge. We hypothesized that the developmental trajectory of cortical thickness in people who stutter would differ across the lifespan in the left pars opercularis relative to a group of control participants. We collected structural magnetic resonance images from 116 males (55 people who stutter) ranging in age from 6 to 48 years old. Differences in cortical thickness across ages and between patients and controls were investigated in 30 brain regions previously implicated in speech-motor control. An interaction between age and group was found for the left pars opercularis only. In people who stutter, the pars opercularis did not demonstrate the typical maturational pattern of gradual gray matter thinning with age across the lifespan that we observed in control participants. In contrast, the developmental trajectory of gray matter thickness in other regions of interest within the neural network for speech-motor control was similar for both groups. Our findings indicate that the developmental trajectory of gray matter in left pars opercularis is abnormal in people who stutter.


Pes Anserinus Syndrome Caused by Osteochondroma in Paediatrics: A Case Series Study.
Osteochondroma is a common benign bone tumor, protruding from the underlying normal bone. Osteochondromas can cause pain depending on their location and size. The pes anserinus is located at the proximal medial side of the tibia, where the tendinous insertions of the sartorius, gracilis and semitendinosus muscles collectively attach. Pes anserinus syndrome, or anserine bursitis, is a painful condition of the pes anserinus, and is more common in adults typically with overweight females. The occurrence of pes anserinus syndrome is rare in the paediatric population. In the current case series, five patients with pes anserinus syndrome due to proximal tibial osteochondroma are reported. Pain was present in all cases, with snapping in one case. The average age of the patients was 13 ± 1.2 years, ranging from 12 to 15 years. Three patients had a single osteochondroma, and two patients had hereditary multiple exostoses. The sizes of the osteochondromas on plain radiographs varied from 0.5 to 2.5 cm, with an average of 1.46 ± 0.83 cm. All lesions characteristically were located at the medial-posterior edge of the proximal tibia. The symptoms resolved in four cases with surgical resection, and persisted in one non-resected patient. The characteristic location of the osteochondroma causes pes anserinus syndrome, even though the lesion is small. The diagnosis of osteochondroma or pes anserinus syndrome may be overlooked when it occurs in a paediatric population. The symptoms seem to be consistent, and resection of the osteochondroma is necessary for treatment.


Impact of CB1 Receptor Deletion on Visual Responses and Organization of Primary Visual Cortex in Adult Mice.
The endocannabinoids (eCBs) and their receptors are expressed in the cortex of developing animals where they act as a neuromodulating system during critical stages of brain development such as cell proliferation and migration, and axon guidance. Little is known on the impact of the cannabinoid system on cortical map formation and receptive field properties of cortical sensory neurons. The present study evaluates in vivo the functional organization of the primary visual cortex (V1) of mice lacking cannabinoid CB1R receptor (cnr1-/-). Using optical imaging of intrinsic signals, azimuth, and elevation maps of cnr1-/- mice were compared with their wild-type littermates (cnr1+/+). Topographic maps were affected in mutant mice as they exhibited narrower visual field and changes in the shape of V1. CB1R exerted its action in an axis dependent manner as all changes were observed in the azimuth axis. Spatial frequency and contrast sensitivity were also compared between the two groups. Both properties were affected by the chronic lacking of CB1R as mutant mice exhibited a significantly lower contrast sensitivity as well as lower spatial frequency selectivity. Taken together, these results suggest an important role for CB1R in cortical map formation. Our results also clearly demonstrate the impact of CB1R in the development of visual properties of primary visual cortex neurons. Because psychoactive effects of cannabis consumption on visual experience are mediated mainly through CB1R, our results could possibly explain neuronal mechanisms involved in those perceptual changes.


Direct and correlated responses to two-stage selection for ovulation rate and number of fully formed pigs at birth in swine.
Our objectives were to estimate responses and genetic parameters for ovulation rate, number of fully formed pigs at birth, and other production traits following two-stage selection for increased ovulation rate and number of fully formed pigs. Eight generations of selection were practiced in each of two lines. One selection line was derived from a line that previously selected eight generations for an index to increase ovulation rate and embryonic survival (the IOL pigs). The other selection line was derived from the unselected control line of the index selection experiment (the COL pigs). The control line (C) was continued with random selection. Due to previous selection, Line IOL had greater ovulation rate (4.24 +/- 0.38 and 4.14 +/- 0.29 ova) and litter size (1.97 +/- 0.39 and 1.06 +/- 0.38 pigs) at Generation 0 of two-stage selection than did Lines COL and C. In Stage 1, all gilts from 50% of the largest litters were retained. Approximately 50% of them were selected for ovulation rate in Stage 2. Gilts selected for ovulation rate were mated to boars selected from the upper one-third of the litters for litter size. At Generations 7 and 8, differences in mean EBV for ovulation rate and litter size between Lines IOL and C were 6.20 +/- 0.29 ova and 4.66 +/- 0.38 pigs; differences between Lines COL and C were 2.26 +/- 0.29 ova and 2.79 +/- 0.39 pigs; and differences between Lines IOL and COL were 3.94 +/- 0.26 ova and 1.86 +/- 0.39 pigs. Regressions of line mean EBV on generation number were 0.27 +/- 0.07 ova and 0.35 +/- 0.06 pigs in Line IOL; 0.30 +/- 0.06 ova and 0.29 +/- 0.05 pigs in Line COL; and 0.01 +/- 0.07 ova and 0.02 +/- 0.05 pigs in Line C. Correlated responses were decreased age at puberty and increased number of pigs born alive, number of mummified pigs, prenatal loss, and individual and litter birth weight. Two-stage selection for ovulation rate and number of pigs per litter is a promising procedure to improve litter size in swine.


Autonomous expression of c-myc in BC3H1 cells partially inhibits but does not prevent myogenic differentiation.
Myogenic differentiation is obligatorily coupled to withdrawal of myoblasts from the cell cycle and is inhibited by specific polypeptide growth factors. To investigate the potential involvement of c-myc in the control of myogenesis, the BC3H1 muscle cell line was stably transfected with a simian virus 40 promoter:c-myc chimeric gene. In quiescent cells in 0.5% serum, the exogenous c-myc gene was expressed at a level more than threefold greater than the level of endogenous c-myc in undifferentiated, proliferating cells of the parental line in 20% serum. The transfected myc gene partially inhibited the expression of both muscle creatine kinase and the nicotinic acetylcholine receptor, but was not sufficient to prevent the induction of these muscle differentiation products upon mitogen withdrawal.


N-terminal pro-atrial natriuretic peptide measurement in plasma suggests covalent modification.
The N-terminal fragment of cardiac-derived pro-B-type natriuretic peptide is a glycosylated polypeptide. It is unknown whether N-terminal pro-atrial natriuretic peptide (proANP) fragments are also covalently modified. We therefore evaluated the clinical performance of 2 distinctly different proANP assays on clinical outcome. We examined 474 elderly patients with symptoms of heart failure presenting in a primary healthcare setting. Samples were analyzed with an automated immunoluminometric midregion proANP (MR-proANP) assay and a new processing-independent assay (PIA) developed in our laboratory. The results were compared with Bland-Altman plots, and clinical performance was assessed by generating ROC curves for different clinical outcomes. Despite linear regression results indicating a good correlation (r = 0.85; P < 0.0001), the PIA measured considerably more proANP than the MR-proANP assay (mean difference, 663 pmol/L; SD, 478 pmol/L). In contrast, the clinical performances of the 2 assays [as assessed by the area under the ROC curve (AUC)] in detecting left ventricular dysfunction were similar [proANP PIA, 0.71 (95% CI, 0.63-0.79); MR-proANP assay, 0.74 (95% CI, 0.66-0.81); P = 0.32]. The prognostic ability to report cardiovascular mortality during a 10-year follow-up revealed AUC values of 0.66 (95% CI, 0.60-0.71) for the proANP PIA and 0.69 (95% CI, 0.63-0.74) for the MR-proANP assay (P = 0.08, for comparing the 2 assays). Our data suggest that N-terminal proANP fragments in patient plasma differ from the calibrator peptides used but that the difference does not affect ROC curves in an elderly cohort of patients with mild to moderate heart failure. We suggest that human N-terminal proANP fragments can be covalently modified.


Biological control of wheat root diseases by the CLP-producing strain Pseudomonas fluorescens HC1-07.
Pseudomonas fluorescens HC1-07, previously isolated from the phyllosphere of wheat grown in Hebei province, China, suppresses the soilborne disease of wheat take-all, caused by Gaeumannomyces graminis var. tritici. We report here that strain HC1-07 also suppresses Rhizoctonia root rot of wheat caused by Rhizoctonia solani AG-8. Strain HC1-07 produced a cyclic lipopeptide (CLP) with a molecular weight of 1,126.42 based on analysis by electrospray ionization mass spectrometry. Extracted CLP inhibited the growth of G. graminis var. tritici and R. solani in vitro. To determine the role of this CLP in biological control, plasposon mutagenesis was used to generate two nonproducing mutants, HC1-07viscB and HC1-07prtR2. Analysis of regions flanking plasposon insertions in HC1-07prtR2 and HC1-07viscB revealed that the inactivated genes were similar to prtR and viscB, respectively, of the well-described biocontrol strain P. fluorescens SBW25 that produces the CLP viscosin. Both genes in HC1-07 were required for the production of the viscosin-like CLP. The two mutants were less inhibitory to G. graminis var. tritici and R. solani in vitro and reduced in ability to suppress take-all. HC1-07viscB but not HC-07prtR2 was reduced in ability to suppress Rhizoctonia root rot. In addition to CLP production, prtR also played a role in protease production.


Field strength and frequency tunable, two-way rotation of liquid crystal micro-particles dispersed in a liquid crystal host.
Liquid crystal (LC) micro-particles are functional materials possessing anisotropies of LCs originating from their inner molecular alignment, and are fabricated by polymerizing pre-aligned rod-like molecules in the LC state. Here we demonstrate field strength and frequency tunable two-way rotation control of LC micro-particles in a LC host, and unravel its mechanism by theoretically calculating the contributing free energies. Cuboid-shaped micro-particles with inner molecular alignment along the long axis are fabricated via two-photon excited direct laser writing, and dispersed in a dual-frequency (DF) LC to be electrically driven by a voltage applied in the in-plane direction of the cell. Under an electric field, the particles rotate either clockwise or anticlockwise to align the inner molecular alignment parallel or perpendicular to the applied field; however, unlike conventional LCs, the rotation direction depends not only on the frequency, but also on the strength of the field. The complex motion is found to be the result of a delicate balance between the elastic energy of the host LC around the particle and the electrostatic energies of the host and the particle. Understanding complex rotational motion in LC/LC-particle composites is a step towards the development of advanced switching materials with superior performance.


Characterization of newcastle disease viruses in wild and domestic birds in Luxembourg from 2006 to 2008.
Newcastle disease virus (NDV) is one of the most important viral diseases of birds. Wild birds constitute a natural reservoir of low-virulence viruses, while poultry are the main reservoir of virulent strains. Exchange of virus between these reservoirs represents a risk for both bird populations. Samples from wild and domestic birds collected between 2006 and 2010 in Luxembourg were analyzed for NDV. Three similar avirulent genotype I strains were found in ducks during consecutive years, suggesting that the virus may have survived and spread locally. However, separate introductions cannot be excluded, because no recent complete F gene sequences of genotype I from other European countries are available. Detection of vaccine-like strains in wild waterbirds suggested the spread of vaccine strains, despite the nonvaccination policy in Luxembourg. Among domestic birds, only one chicken was positive for a genotype II strain differing from the LaSota vaccine and exhibiting a so-far-unrecognized fusion protein cleavage site of predicted low virulence. Three genotype VI strains from pigeons were the only virulent strains found. The circulation of NDV in wild and free-ranging domestic birds warrants continuous surveillance because of increased concern that low-virulence wild-bird viruses could become more virulent in domestic populations.


Upper gastrointestinal tract polyps in familial adenomatosis coli.
Upper gastrointestinal tract polyps were sought prospectively using endoscopy and biopsy in 34 patients with familial adenomatosis coli belonging to 18 unrelated families. Gastric and/or duodenal polyps, usually small and multiple, occurred in 28 patients (82%). Histologically verified extracolonic adenomas were present in 19 patients (56%). Gastric adenomas, all in the antrum, and duodenal adenomas occurred in four (12%) and 16 (48%) patients, respectively. In one patient, a duodenal adenocarcinoma and a bile duct adenoma were also found, and one patient had an adenocarcinoma of the bile ducts. Multiple non-neoplastic polyps were found in 19 patients (56%), most often in the stomach and also in the duodenum in 12 patients; they co-existed often with adenomas. In addition, there were nine patients with ileal polyps, most of them showing lymphoid hyperplasia but also one with adenomas. It is suggested that familial adenomatosis affects the whole gastrointestinal tract, not only the colon and rectum as believed earlier. Although upper gastrointestinal tract adenomas are not as consistent and multiple as those in the colon, and probably do not require prophylactic surgery, regular lifelong endoscopic follow up is warranted because of obviously increased cancer risk.


Origins of the insect enteric nervous system: differentiation of the enteric ganglia from a neurogenic epithelium.
The enteric nervous system (ENS) of the moth Manduca sexta is organized into two distinct cellular domains: an anterior domain that includes several small ganglia on the surface of the foregut, and a more posterior domain consisting of a branching nerve plexus (the enteric plexus) that spans the foregut-midgut boundary. Previously, we showed that the neurons of the posterior domain, the enteric plexus, are generated from a large placode that invaginates from the caudal lip of the foregut; subsequently, the cells become distributed throughout the enteric plexus by a sequence of active migration. We now demonstrate that the neurons of the anterior domain, the cells of the enteric ganglia, arise via a distinct developmental sequence. Shortly after the foregut has begun to form, three neurogenic zones differentiate within the foregut epithelium and give rise to chains of cells that emerge onto the foregut surface. The three zones are not sites of active mitosis, as indicated by the absence of labelling with a thymidine analogue and by clonal analyses using intracellularly injected dyes. Rather, the zones serve as loci through which epithelial cells are recruited into a sequence of delamination and neuronal differentiation. As they emerge from the epithelium, the cells briefly become mitotically active, each cell dividing once or twice. In this manner, they resemble the midline precursor class of neural progenitors in the insect central nervous system more than neuroblast stem cells. The progeny of these zone-derived precursors then gradually coalesce into the ganglia and nerves of the anterior ENS. Although this reorganization results in some variability in the precise configuration of neurons within the ganglia, the overall morphology of the ganglia is highly stereotyped, consisting of cortical layers of cells that surround a ventral neuropil. In addition, a number of the neurons within the frontal and hypocerebral ganglia express identifiable phenotypes in a manner that is similar to many cells of the insect central nervous system. These observations indicate that the differentiation of the enteric ganglia in Manduca involves an unusual combination of features seen during the formation of other regions of the nervous system and, as such, constitutes a distinct program of neurogenesis.


Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment.
The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverses the stemness of CRC to overcome these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44/CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer.


Organ-specific physiological responses to acute physical exercise and long-term training in humans.
Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.


The early years of pathology as a specialty in Singapore.
During the first 86 years of Singapore's medical history (1819 to 1905), nobody was officially designated a "pathologist" although pathology was practised. All pathological work (purely medical or forensic) was done by non-specialist doctors. Representative cases are quoted so that conclusions can be drawn regarding what pathological practice was like and the problems faced. In 1905, the Governor, concerned about the high death rate in Singapore, consulted the Principal Civil Medical Officer, who advised that the most effective means to reduce the death rate was the establishment of a Department of Pathology with a full-time specialist pathologist in charge. Dr GA Finlayson was appointed the first Government Pathologist, responsible for all the hospitals in Singapore. He was also appointed Lecturer in Pathology in the Medical School. Work in the Pathology Department increased by leaps and bounds, and no research was possible. The first Annual Report of the Department (1907) is quoted in some detail to show the scope of the work done, reflecting the public health conditions of Singapore a hundred years ago. The Department gradually expanded and more staff were recruited. The new position of Government Bacteriologist was created. This officer served under the Government Pathologist in the Pathology Department.


Duodenum clamping trauma induces significant postoperative intraperitoneal adhesions on a rat model.
The purpose of this study was to investigate the histological and morphological changes in the first two postoperative weeks on a rat intraperitoneal adhesion model induced by duodenum clamping trauma. The rat model of postoperative intraperitoneal adhesions was established in 48 male Wistar rats by laparotomy, followed by the duodenum clamping trauma. Rats were sacrificed respectively on 1(st), 3(rd), 5(th), 7(th) and 14(th) day after the operation. The control rats were sacrificed immediately after the operation (0 day). Then the intraperitoneal adhesions were assessed macroscopically. Histopathology and immunohistochemistry were performed to evaluate the fibrosis, inflammatory responses, neovascularization, and cells infiltration in adhesion tissues. In addition, the changes of the mesothelium covering the surgical sites were examined by scanning electron microscopy. Our study revealed that duodenum clamping trauma induced by mosquito hemostat can result in significant postoperative intraperitoneal adhesions formation. The extent and tenacity of intraperitoneal adhesions reached their peaks on 3(rd) and 5(th) days, respectively. Histopathological examination showed that all rats developed inflammatory responses at the clamped sites of duodenum, which was most prominent on 1(st) day; the scores of fibrosis and vascular proliferation increased slowly from 3(rd) to 5(th) day. Myofibroblasts proliferated significantly in the adhesion tissues from 3(rd) day, which were examined by immunohistochemical method. And the mesothelium covering the surgical sites and the adhesion tissues healed on 7(th) day. This study suggests that clamping trauma to the duodenum can result in significant postoperative intraperitoneal adhesions formation, which represents an ideal rat model for intraperitoneal adhesions research and prevention. And myofibroblasts may play an important role in the forming process of intraperitoneal adhesions.


Development of single-nucleotide polymorphism markers for Bromus tectorum (Poaceae) from a partially sequenced transcriptome.
Bromus tectorum (Poaceae) is an annual grass species that is invasive in many areas of the world but most especially in the U.S. Intermountain West. Single-nucleotide polymorphism (SNP) markers were developed for use in investigating the geospatial and ecological diversity of B. tectorum in the Intermountain West to better understand the mechanisms behind its successful invasion. Normalized cDNA libraries from six diverse B. tectorum individuals were pooled and sequenced using 454 sequencing. Ninety-five SNP assays were developed for use on 96.96 arrays with the Fluidigm EP1 genotyping platform. Verification of the 95 SNPs by genotyping 251 individuals from 12 populations is reported, along with amplification data from four related Bromus species. These SNP markers are polymorphic across populations of B. tectorum, are optimized for high-throughput applications, and may be applicable to other, related Bromus species.


Nonequilibrium localization and the interplay between disorder and interactions.
We study the nonequilibrium interplay between disorder and interactions in a closed quantum system. We base our analysis on the notion of dynamical state-space localization, calculated via the Loschmidt echo. Although real-space and state-space localization are independent concepts in general, we show that both perspectives may be directly connected through a specific choice of initial states, namely, maximally localized states (ML-states). We show numerically that in the noninteracting case the average echo is found to be monotonically increasing with increasing disorder; these results are in agreement with an analytical evaluation in the single particle case in which the echo is found to be inversely proportional to the localization length. We also show that for interacting systems, the length scale under which equilibration may occur is upper bounded and such bound is smaller the greater the average echo of ML-states. When disorder and interactions, both being localization mechanisms, are simultaneously at play the echo features a non-monotonic behaviour indicating a non-trivial interplay of the two processes. This interplay induces delocalization of the dynamics which is accompanied by delocalization in real-space. This non-monotonic behaviour is also present in the effective integrability which we show by evaluating the gap statistics.


Incoming pathogens team up with harmless 'resident' bacteria.
Microbial diseases occur as a result of multifarious host-pathogen interactions. However, invading pathogens encounter a large number of different harmless and beneficial bacterial species, which colonize and reside in the host. Surprisingly, there has been little study of the possible interactions between incoming pathogens and the resident bacterial community. Recent studies have revealed that resident bacteria assist different types of incoming pathogens via a wide variety of mechanisms including cell-cell signaling, metabolic interactions, evasion of the immune response and a resident-to-pathogen switch. This calls for serious consideration of pathogen-microbe interactions in the host with respect to disease severity and progression.


Infection with versus exposure to Taenia solium: what do serological test results tell us?
Taenia solium cysticercosis is an endemic zoonosis in many developing countries. Serological tests are the most appropriate diagnostic tools to understand the transmission dynamics of the parasite, but the performances of these methods in such a setting are not known. A south Ecuadorian human population living in an endemic area was tested using three common serological tests. Because none of them is a gold standard, a Bayesian Latent Class analysis was used to estimate the test characteristics. Two definitions of a case were considered to differentiate between prevalence of current infection and prior exposure to the parasite. Differences between the performances of the same test in function of the definition of a case were observed. This study shows that test results and prior information should be interpreted carefully in a Bayesian analysis framework, particularly when the latter is based on clinical studies.


Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology.
Developing blood-based tests is appealing for non-invasive disease diagnosis, especially when biopsy is difficult, costly, and sometimes not even an option. Tumor-derived exosomes have attracted increasing interest in non-invasive cancer diagnosis and monitoring of treatment response. However, the biology and clinical value of exosomes remains largely unknown due in part to current technical challenges in rapid isolation, molecular classification and comprehensive analysis of exosomes. Here we developed a new microfluidic approach to streamline and expedite the exosome analysis pipeline by integrating specific immunoisolation and targeted protein analysis of circulating exosomes. Compared to the conventional methods, our approach enables selective subpopulation isolation and quantitative detection of surface and intravesicular biomarkers directly from a minimally invasive amount of plasma samples (30 μL) within ~100 min with markedly improved detection sensitivity. Using this device, we demonstrated phenotyping of exosome subpopulations by targeting a panel of common exosomal and tumor-specific markers and multiparameter analyses of intravesicular biomarkers in the selected subpopulation. We were able to assess the total expression and phosphorylation levels of IGF-1R in non-small-cell lung cancer patients by probing plasma exosomes as a non-invasive alternative to conventional tissue biopsy. We foresee that the microfluidic exosome analysis platform will form the basis for critically needed infrastructures for advancing the biology and clinical utilization of exosomes.


Foxo3 Promotes Apoptosis of B Cell Receptor-Stimulated Immature B Cells, Thus Limiting the Window for Receptor Editing.
Central tolerance checkpoints are critical for the elimination of autoreactive B cells and the prevention of autoimmunity. When autoreactive B cells encounter their Ag at the immature B cell stage, BCR cross-linking induces receptor editing, followed by apoptosis if edited cells remain autoreactive. Although the transcription factor Foxo1 is known to promote receptor editing, the role of the related factor Foxo3 in central B cell tolerance is poorly understood. We find that BCR-stimulated immature B cells from Foxo3-deficient mice demonstrate reduced apoptosis compared with wild type cells. Despite this, Foxo3-/- mice do not develop increased autoantibodies. This suggests that the increased survival of Foxo3-/- immature B cells allows additional rounds of receptor editing, resulting in more cells "redeeming" themselves by becoming nonautoreactive. Indeed, increased Igλ usage and increased recombining sequence recombination among Igλ-expressing cells were observed in Foxo3-/- mice, indicative of increased receptor editing. We also observed that deletion of high-affinity autoreactive cells was intact in the absence of Foxo3 in the anti-hen egg lysozyme (HEL)/membrane-bound HEL model. However, Foxo3 levels in B cells from systemic lupus erythematosus (SLE) patients were inversely correlated with disease activity and reduced in patients with elevated anti-dsDNA Abs. Although this is likely due in part to increased B cell activation in these SLE patients, it is also possible that low-affinity B cells that remain autoreactive after editing may survive inappropriately in the absence of Foxo3 and become activated to secrete autoantibodies in the context of other SLE-associated defects.


Integrating contact network structure into tuberculosis epidemiology in meerkats in South Africa: Implications for control.
Empirical studies that integrate information on host contact patterns with infectious disease transmission over time are rare. The aims of this study were to determine the relative importance of intra-group social interactions in the transmission of tuberculosis (TB; Mycobacterium bovis infection) in a population of wild meerkats (Suricata suricatta) in South Africa, and to use this information to propose an evidence-based intervention strategy to manage this disease. Detailed behavioural observations of all members of eight meerkat groups (n=134 individuals) were made over 24 months from January 2006 to December 2007. Social network analysis of three types of interaction (aggression, foraging competitions and grooming) revealed social structure to be very stable over time. Clustering of interactions was positively correlated with group size for both aggression (r=0.73) and grooming interactions (r=0.71), suggesting that infections may spread locally within clusters of interacting individuals but be limited from infecting all members of large groups by an apparent threshold in connections between different clusters. Repeated biological sampling every three months of all members of one social group (n=37 meerkats) was undertaken to quantify individual changes in M. bovis infection status. These empirical data were used to construct a dynamic network model of TB transmission within a meerkat group. The results indicated that grooming (both giving and receiving) was more likely than aggression to be correlated with M. bovis transmission and that groomers were at higher risk of infection than groomees. Intervention strategies for managing TB in meerkats that focus on those individuals engaging in the highest amount of grooming are therefore proposed.


Effects of gonadotrophin surge-attenuating factor on the two pools of gonadotrophin-releasing hormone-induced luteinizing hormone secretion in vitro.
In order to study the in-vitro mechanism of action of gonadotrophin surge-attenuating factor (GnSAF), ovine pituitary monolayers were incubated for 48 h either with steroid-free follicular fluid from women in whom ovulation had been induced or oestradiol or progesterone. Monolayers were also incubated with 10-30 and > 30 kDa follicular fluid fractions. The effect of these preparations on gonadotrophin-releasing hormone (GnRH)-induced luteinizing hormone (LH) secretion was then determined by incubation with GnRH for between 15 and 240 min. Incubation with steroid-free follicular fluid resulted in the significant attenuation of both the acutely releasable LH pool (LH 54.3 +/- 3.0% of control secretion at 15 min of GnRH incubation) and the reserve LH pool (LH 36.8 +/- 1.6% of control secretion at 240 min GnRH incubation). The 10-30 kDa follicular fluid fraction had similar effects while the > 30 kDa follicular fluid fraction significantly stimulated GnRH-induced LH secretion, with concentrations up to 134.0 +/- 8.6% of controls. Oestradiol or progesterone at doses of 1000 nmol/l/well did not significantly reduce any aspect of GnRH-induced LH secretion (never < 95.1 +/- 15.1% of controls). These results demonstrate that GnSAF markedly attenuates both the acutely releasable and reserve pools of GnRH-induced LH secretion. Inhibin, oestradiol and progesterone are not responsible for the marked attenuation of either the initial or reserve pools of GnRH-induced LH secretion.


Evaluating a Sexual Health Patient Education Resource.
This article shares the findings of an evaluation of a patient teaching resource for sexual health entitled Everything Nobody Tells You About Cancer Treatment and Your Sex Life: From A to Z, which was accomplished through systematic conceptualization, construction, and evaluation with women diagnosed with breast or gynecologic cancer. This resource, which has evolved from patient-focused research and has been tested in the clinical setting, can be used in patient education and support. Oncology professionals are committed to addressing quality-of-life concerns for patients across the trajectory of illness. Sexuality is a key concern for patients and impacts relationships and overall quality of life. Through careful assessment, patient education, and support, clinicians can ensure that sexuality is respected as an essential part of patient-centered care.


The strength of the strongest ties in collaborative problem solving.
Complex problem solving in science, engineering, and business has become a highly collaborative endeavor. Teams of scientists or engineers collaborate on projects using their social networks to gather new ideas and feedback. Here we bridge the literature on team performance and information networks by studying teams' problem solving abilities as a function of both their within-team networks and their members' extended networks. We show that, while an assigned team's performance is strongly correlated with its networks of expressive and instrumental ties, only the strongest ties in both networks have an effect on performance. Both networks of strong ties explain more of the variance than other factors, such as measured or self-evaluated technical competencies, or the personalities of the team members. In fact, the inclusion of the network of strong ties renders these factors non-significant in the statistical analysis. Our results have consequences for the organization of teams of scientists, engineers, and other knowledge workers tackling today's most complex problems.


A Fragment of Apolipoprotein E4 Leads to the Downregulation of a CXorf56 Homologue, a Novel ER-Associated Protein, and Activation of BV2 Microglial Cells.
Despite the fact that harboring the apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer's disease (AD), the exact mechanism by which apoE4 contributes to disease progression remains unknown. Recently, we demonstrated that a 151 amino-terminal fragment of apoE4 (nApoE41-151) localizes within the nucleus of microglia in the human AD brain, suggesting a potential role in gene expression. In the present study, we investigated this possibility utilizing BV2 microglia cells treated exogenously with nApoE41-151. The results indicated that nApoE41-151 leads to morphological activation of microglia cells through, at least in part, the downregulation of a novel ER-associated protein, CXorf56. Moreover, treatment of BV2 cells with nApoE41-151 resulted in a 68-fold increase in the expression of the inflammatory cytokine, TNFα, a key trigger of microglia activation. In this regard, we also observed a specific binding interaction of nApoE41-151 with the TNFα promoter region. Collectively, these data identify a novel gene-regulatory pathway involving CXorf56 that may link apoE4 to microglia activation and inflammation associated with AD.


New Genus Fibralongavirus in Siphoviridae Phages of Staphylococcus pseudintermedius.
Bacteriophages of the significant veterinary pathogen Staphylococcus pseudintermedius are rarely described morphologically and genomically in detail, and mostly include phages of the Siphoviridae family. There is currently no taxonomical classification for phages of this bacterial species. Here we describe a new phage designated vB_SpsS_QT1, which is related to phage 2638A originally described as a Staphylococcus aureus phage. Propagating strain S. aureus 2854 of the latter was reclassified by rpoB gene sequencing as S. pseudintermedius 2854 in this work. Both phages have a narrow but different host range determined on 54 strains. Morphologically, both of them belong to the family Siphoviridae, share the B1 morphotype, and differ from other staphylococcal phage genera by a single long fibre at the terminus of the tail. The complete genome of phage vB_SpsS_QT1 was sequenced with the IonTorrent platform and expertly annotated. Its linear genome with cohesive ends is 43,029 bp long and encodes 60 predicted genes with the typical modular structure of staphylococcal siphophages. A global alignment found the genomes of vB_SpsS_QT1 and 2638A to share 84% nucleotide identity, but they have no significant similarity of nucleotide sequences with other phage genomes available in public databases. Based on the morphological, phylogenetic, and genomic analyses, a novel genus Fibralongavirus in the family Siphoviridae is described with phage species vB_SpsS_QT1 and 2638A.


Well-being and employee health-how employees' well-being scores interact with demographic factors to influence risk of hospitalization or an emergency room visit.
The goal of this study was to determine the relationship between individual well-being and risk of a hospital event in the subsequent year. The authors hypothesized an inverse relationship in which low well-being predicts higher likelihood of hospital use. The study specifically sought to understand how well-being segments and demographic variables interact in defining risk of a hospital event (inpatient admission or emergency room visit) in an employed population. A retrospective study design was conducted with data from 8835 employees who completed a Well-Being Assessment questionnaire based on the Gallup-Healthways Well-Being Index. Cox proportional hazards models were used to examine the impact of Individual Well-Being Score (IWBS) segments and member demographics on hazard ratios (HRs) for a hospital event during the 12 months following assessment completion. Significant main effects were found for the influence of IWBS segments, sex, education, and relationship status on HRs of a hospital event, but not for age. However, further analysis revealed significant interactions between age and IWBS segments (P=0.005) and between age and sex (P<0.0001), indicating that the effects for IWBS segments and sex on HRs of a hospital event are mediated through their relationship with age. Overall, the strong relationship between low well-being and higher risk of an event in employees ages 44 years and older is mitigated in younger age groups. These results suggest that youth attenuates the risk engendered in poor well-being; therefore, methods to maintain or improve well-being as individuals age presents a strong opportunity for reducing hospital events.


Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family.
Sarcomeric myosin heavy chain (MyHC) is the major contractile protein of striated muscle. Six tandemly linked skeletal MyHC genes on chromosome 17 and two cardiac MyHC genes on chromosome 14 have been previously described in the human genome. We report the identification of three novel human sarcomeric MyHC genes on chromosomes 3, 7, and 20, which are notable for their atypical size and intron-exon structure. Two of the encoded proteins are structurally most like the slow-beta MyHC, whereas the third one is closest to the adult fast IIb isoform. Data from pairwise comparisons of aligned coding sequences imply the existence of ancestral genomes with four sarcomeric genes before the emergence of a dedicated smooth muscle MyHC gene. To further address the evolutionary relationships of the distinct sarcomeric and nonsarcomeric rod sequences, we have identified and further annotated human genomic DNA sequences corresponding to 14 class-II MyHCs. An extensive analysis provides a timeline for intron gain and loss, gene contraction and expansion, and gene conversion among genes encoding class-II myosins. One of the novel human genes is found to have introns at positions shared only with the molluscan catchin/MyHC gene, providing evidence for the structure of a pre-Cambrian ancestral gene.


Interactions between dorsolateral and ventromedial prefrontal cortex underlie context-dependent stimulus valuation in goal-directed choice.
External circumstances and internal bodily states often change and require organisms to flexibly adapt valuation processes to select the optimal action in a given context. Here, we investigate the neurobiology of context-dependent valuation in 22 human subjects using functional magnetic resonance imaging. Subjects made binary choices between visual stimuli with three attributes (shape, color, and pattern) that were associated with monetary values. Context changes required subjects to deviate from the default shape valuation and to integrate a second attribute to comply with the goal to maximize rewards. Critically, this binary choice task did not involve any conflict between opposing monetary, temporal, or social preferences. We tested the hypothesis that interactions between regions of dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) implicated in self-control choices would also underlie the more general function of context-dependent valuation. Consistent with this idea, we found that the degree to which stimulus attributes were reflected in vmPFC activity varied as a function of context. In addition, activity in dlPFC increased when context changes required a reweighting of stimulus attribute values. Moreover, the strength of the functional connectivity between dlPFC and vmPFC was associated with the degree of context-specific attribute valuation in vmPFC at the time of choice. Our findings suggest that functional interactions between dlPFC and vmPFC are a key aspect of context-dependent valuation and that the role of this network during choices that require self-control to adjudicate between competing outcome preferences is a specific application of this more general neural mechanism.


On the subjective acceptance during cardiovascular magnetic resonance imaging at 7.0 Tesla.
This study examines the subjective acceptance during UHF-CMR in a cohort of healthy volunteers who underwent a cardiac MR examination at 7.0T. Within a period of two-and-a-half years (January 2012 to June 2014) a total of 165 healthy volunteers (41 female, 124 male) without any known history of cardiac disease underwent UHF-CMR. For the assessment of the subjective acceptance a questionnaire was used to examine the participants experience prior, during and after the UHF-CMR examination. For this purpose, subjects were asked to respond to the questionnaire in an exit interview held immediately after the completion of the UHF-CMR examination under supervision of a study nurse to ensure accurate understanding of the questions. All questions were answered with "yes" or "no" including space for additional comments. Transient muscular contraction was documented in 12.7% of the questionnaires. Muscular contraction was reported to occur only during periods of scanning with the magnetic field gradients being rapidly switched. Dizziness during the study was reported by 12.7% of the subjects. Taste of metal was reported by 10.1% of the study population. Light flashes were reported by 3.6% of the entire cohort. 13% of the subjects reported side effects/observations which were not explicitly listed in the questionnaire but covered by the question about other side effects. No severe side effects as vomiting or syncope after scanning occurred. No increase in heart rate was observed during the UHF-CMR exam versus the baseline clinical examination. This study adds to the literature by detailing the subjective acceptance of cardiovascular magnetic resonance imaging examinations at a magnetic field strength of 7.0T. Cardiac MR examinations at 7.0T are well tolerated by healthy subjects. Broader observational and multi-center studies including patient cohorts with cardiac diseases are required to gain further insights into the subjective acceptance of UHF-CMR examinations.


Self-perceived oral health among 19-year-olds in two Swedish counties.
The primary purpose of the present study, which focused on a census of 19-year-olds (2006) attending dental clinics in two Swedish counties, was to describe the frequency distribution of clinically- and self-perceived oral health indicators in terms of DSa (Decayed Surfaces approximal), four global dimensions of oral health and one'all-embracing' oral health measure, according to county of residence and gender. A second purpose was to examine to what extent the clinical indicator of oral health and the global dimensions of self-perceived oral health contribute to the explainable variance of the global single-item indicator. Finally, the study examined whether or not the association of clinically- and self-perceived oral health indicators with the single global oral health indicator varied as a function of gender and place of residence. The study base was 46.5% (n=3658) of all children attending for dental checks (n=7866). The questionnaire included thirteen questions, divided into four global dimensions. These were Knowledge, Quality of life, Social and Function. There was also one 'all-embracing' oral health question, one question about gender and finally information about clinically-registered disease. The findings of this study were that females reported more serious problems than males in the Social and Quality of life dimensions and there were differences between counties in knowledge about oral diseases. The group with poor self-reported oral health in the 'all-embracing' oral health question had significantly more problems with all global dimensions, especially Quality of life and Social dimensions. Statistically-significant two-way interactions occurred between county and Knowledge and between county and Quality of life. This study supports the idea of one or several questions concerning self-perceived oral health to be used as a complement to the traditional epidemiological clinical registration of oral diseases.


Pushing spatial and temporal resolution for functional and diffusion MRI in the Human Connectome Project.
The Human Connectome Project (HCP) relies primarily on three complementary magnetic resonance (MR) methods. These are: 1) resting state functional MR imaging (rfMRI) which uses correlations in the temporal fluctuations in an fMRI time series to deduce 'functional connectivity'; 2) diffusion imaging (dMRI), which provides the input for tractography algorithms used for the reconstruction of the complex axonal fiber architecture; and 3) task based fMRI (tfMRI), which is employed to identify functional parcellation in the human brain in order to assist analyses of data obtained with the first two methods. We describe technical improvements and optimization of these methods as well as instrumental choices that impact speed of acquisition of fMRI and dMRI images at 3T, leading to whole brain coverage with 2 mm isotropic resolution in 0.7 s for fMRI, and 1.25 mm isotropic resolution dMRI data for tractography analysis with three-fold reduction in total dMRI data acquisition time. Ongoing technical developments and optimization for acquisition of similar data at 7 T magnetic field are also presented, targeting higher spatial resolution, enhanced specificity of functional imaging signals, mitigation of the inhomogeneous radio frequency (RF) fields, and reduced power deposition. Results demonstrate that overall, these approaches represent a significant advance in MR imaging of the human brain to investigate brain function and structure.


Miss to the right: the effect of attentional asymmetries on goal-kicking.
Cerebral asymmetries for spatial attention generate a bias of attention--causing lines to be bisected to the left or right in near (within reach) and far (outside reach) space, respectively. This study explored whether the rightward deviation for bisecting lines in far space extends to tasks where a ball is aimed between two goal-posts. Kicking was assessed in a laboratory and a real-life setting. In the laboratory setting, 212 participants carried out three conditions: (a) kick a soccer ball at a single goal post, (b) kick a soccer ball between two goal posts and (c) use a stick to indicate the middle between two goal posts. The goals were placed at a distance of 4.0 m. There was no deviation in the one-goal kicking condition--demonstrating that no asymmetries exist in the perceptual motor system when aiming at a single point. When kicking or pointing at the middle between two goal posts, rightward deviations were observed. In the real-world setting, the number of misses to the left or right of goal (behinds) in the Australian Rules football for the 2005-2009 seasons was assessed. The data showed more rightward deviations for kicks at goal. Combined, the studies suggest that the rightward deviation for lines placed in far space extends to the kicking of a football in laboratory and real-life settings. This asymmetry in kicking builds on a body of research showing that attentional asymmetries impact everyday activities.


Effects of Hemp Extract on Markers of Wellness, Stress Resilience, Recovery and Clinical Biomarkers of Safety in Overweight, But Otherwise Healthy Subjects.
We determined the effects of a commercially available, GRAS (Generally Recognized As Safe) by independent conclusion, CBD-containing hemp oil extract on stress resilience, perceived recovery, mood, affect, body composition, and clinical safety markers in healthy human subjects.Methods: Using a randomized, placebo-controlled, double-blind design, 65 overweight, but otherwise healthy men and women (35.2 ± 11.4 years, 28.5 ± 3.3 kg/m2) ingested either Hemp Oil Extract [Hemp, 60 mg/d PlusCBDTM Extra Strength Hemp Extract Oil (15 mg hemp-derived CBD)] or a placebo (PLA) every day for six weeks while continuing to follow their normal diet and physical activity patterns. Outcome variables included changes in stress resilience, a 14-item panel of various psychometric parameters, heart-rate variability, plasma chromogranin A, body composition, and general markers of health. Data were analyzed using mixed factorial ANOVA, t-tests with 95% confidence intervals, and effect sizes (ES).Results: HDL cholesterol significantly improved in the Hemp group (p = 0.004; ES = 0.75). No other statistically significant group x time interaction effects were observed. Statistical tendencies for between-group differences were found for 'I Get Pleasure From Life' (p = 0.06, ES = 0.48) and 'Ability to Cope with Stress' (p = 0.07, ES = 0.46). Sleep quality (Hemp, p = 0.005, ES = 0.54) and sleep quantity (Hemp, p = 0.01, ES = 0.58) exhibited significant within-group changes. All values for hepato-renal function, cardiovascular health, fasting blood lipids, and whole blood cell counts remained within normal clinical limits with no between-group differences over time being identified.Conclusions: Hemp supplementation improved HDL cholesterol, tended to support psychometric measures of perceived sleep, stress response, and perceived life pleasure and was well tolerated with no clinically relevant safety concerns. Registered at clinicaltrials.gov: NCT04294706.


The prevalence of refractive error and visual impairment among New Zealand children in a community with significant socioeconomic disadvantage: is current preschool vision screening effective?
To examine the prevalence of refractive error and visual impairment and evaluate the efficacy of B4 School Check (B4SC) vision screening, in a cohort of predominantly New Zealand Māori and Pacific children from a community with socioeconomic disadvantage. A cross-sectional investigation of children in the Welcome-to-School study. Participants received a comprehensive eye examination at six to seven years of age. Refractive error and amblyopia were identified and compared with B4SC vision screening results. One-hundred and fourteen children were assessed: 21.9% Māori, 57.9% Pacific and 20.2% Other. Over 30% of children had significant refractive error. Eighty-nine percent received a B4SC; 26.3% of children who passed the B4SC had significant refractive error. Seven children (6.1%) had amblyopia risk factors: none passed the B4SC, four were referred, one was identified for rescreening and two were not screened. Refractive errors were common in this cohort. For those screened, the B4SC was effective at identifying children with amblyopia risk factors but poor at detecting refractive errors potentially affecting academic performance. The efficacy of the programme was limited by the number of children screened, inequity of screening and the mismatch between the aims of the vision screening test and the overall rationale for the B4SC.


Long-term quality of life and risk factors for recurrence after laparoscopic repair of paraesophageal hernia.
Laparoscopic repair of paraesophageal hernia (PEH) has been shown to result in excellent relief of symptoms and improved quality of life (QOL) despite a relatively high radiographically identified recurrence rate. To assess potential risk factors for recurrence and long-term change in QOL after laparoscopic repair of PEH. This was a prospective study of 111 patients who underwent elective laparoscopic repair of type III PEH with biological mesh buttressed over a primary cruroplasty from April 3, 2009, through July 31, 2014, at the Department of Surgery, Johns Hopkins University of Medicine. We administered a modified version of a validated gastroesophageal reflux disease-specific QOL tool to patients before and at 2, 12, and 36 months after the procedure. Higher QOL scores represent greater severity of symptoms. An upper gastrointestinal tract barium-contrast radiographic examination was performed at 1 year to assess for recurrence. Demographic factors, comorbidities, and preoperative radiographic findings were analyzed as possible indicators for recurrence using logistic regression. Quality of life, measured by the gastroesophageal reflux disease-specific QOL tool, and recurrence, defined as a PEH of greater than 2 cm. Median patient age was 61 years, 63.1% of patients were women, and 81.1% of patients were white. Four patients required reoperation, of which only 1 was for symptomatic recurrent PEH. The mean follow-up time for the 36-month QOL assessment was 43.5 months. The overall preoperative and 2-, 12-, and 36-month QOL scores were 28.50, 10.18, 9.74, and 10.58, respectively (P < .001). Recurrences were found in 19 of the 70 patients (27%) who completed the 1-year radiographic examination. Compared with baseline, all individual symptoms improved significantly except for early satiety (mean [SD] score, 3.18 [1.88] at baseline vs 2.07 [1.70] at the 36-month follow-up; P = .07), nausea (1.69 [1.63] vs 0.77 [1.25]; P = .08), pain with swallowing (1.06 [1.50] vs 0.53 [0.90]; P = .73), and bloating/gas (3.28 [1.71] vs 2.23 [1.72]; P = .05) at the 36-month QOL assessment. Although not statistically significant, preoperative hernias containing most of the stomach were more likely to recur after repair when compared with those involving gastric cardia and fundus (odds ratio, 3.74 [95% CI, 0.93-15.14]; P = .06). Overall, laparoscopic repair of PEH with biological mesh results in excellent long-term QOL. The cause of recurrence is likely multifactorial and individualized to each patient. Further evaluation of novel techniques and unidentified patient factors is needed.


The Uptick in Income Segregation: Real Trend or Random Sampling Variation?
Recent studies have reported a reversal of an earlier trend in income segregation in metropolitan regions, from a decline in the 1990s to an increase in the 2000-2010 decade. This finding reinforces concerns about the growing overall income inequality in the U.S. since the 1970s. Yet the evidence may be systematically biased to show an upward trend because the effective sample for the American Community Survey (ACS) is much smaller than it was for Census 2000, to which it is being compared. There is a possibility that the apparent changes in disparities across census tracts result partly from a higher level of sampling variation and bias due to the smaller sample. This study uses 100% microdata from the 1940 census to simulate the impact of different sampling rates on estimates of several measures of segregation and to propose and test the effectiveness of approaches to correcting the bias. It then applies those approaches to publicly available data for 2000 and 2007-2011. The reduction in sample sizes associated with the ACS results in exaggeration of evidence for increasing income segregation for all measures tested here, especially for subgroups (African Americans are studied here as an example). The methods of correction applied here will yield more conclusive and unbiased results when applied to the original sample data that is held internally by the Census Bureau.


Experimental Evaluation of Seaweeds as a Vector for Microplastics into Marine Food Webs.
The ingestion of microplastics has been shown for a great variety of marine organisms. However, benthic marine mesoherbivores such as the common periwinkle Littorina littorea have been largely disregarded in studies about the effects of microplastics on the marine biota, probably because the pathway for microplastics to this functional group of organisms was not obvious. In laboratory experiments we showed that the seaweed Fucus vesiculosus retains suspended microplastics on its surface. The numbers of microplastics that adhered to the algae correlated with the concentrations of suspended particles in the water. In choice feeding assays L. littorea did not distinguish between algae with adherent microplastics and clean algae without microplastics, indicating that the snails do not recognize solid nonfood particles in the submillimeter size range as deleterious. In periwinkles that were feeding on contaminated algae, microplastics were found in the stomach and in the gut. However, no microplastics were found in the midgut gland, which is the principle digestive organ of gastropods. Microplastics in the fecal pellets of the periwinkles indicate that the particles do not accumulate rapidly inside the animals but are mostly released with the feces. Our results provide the first evidence that seaweeds may represent an efficient pathway for microplastics from the water to marine benthic herbivores.


'I would never have done it if it hadn't been digital': a qualitative study on patients' experiences of a digital management programme for hip and knee osteoarthritis in Sweden.
To investigate the experiences of a digital management programme for hip and knee osteoarthritis (OA), including education and exercises as well as an option to chat with an assigned physical therapist for feedback, questions and support. This study was conducted at a regional hospital in the southern part of Sweden. Nineteen patients (10 women), median age of 66 (q1-q3, 57-71) years, with confirmed hip or knee OA were interviewed after completing their first 6 weeks in the programme, using a semistructured interview guide. The interviews were transcribed verbatim and were qualitatively analysed using systematic text condensation. Three categories emerged during the interviews:(1) Management options for mitigating the consequences of OA; (2) Experiences of the digital programme and (3) Perceived effects of the digital programme over time. The participants had mostly positive experiences of the programme. Particularly important for these experiences were no waiting list, the flexibility of taking part in the programme with regards to location and time and the possibility to have daily contact with a physical therapist. These aspects were also emphasised as advantages compared with traditional care. Digital management of OA, including education and exercise, was experienced as a valid alternative to traditional treatment in enabling the implementation of OA guidelines in a wider community. Easy access, exercising at one's own convenience, flexible options, daily follow-up and support by a physical therapist were mentioned as the most important features. In addition, the results will contribute to further development and improvement of digital OA management programmes.


Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer.
Protein conformation and orientation in the lipid membrane plays a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (Aβ) in a lipid membrane. We observed that after the helical peptide was initially half-embedded in the extracelluar leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the Aβ was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with θu (-4/3), where θu is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The Aβ was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3β oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet.


Genome-wide association analysis of avian resistance to Campylobacter jejuni colonization identifies risk locus spanning the CDH13 gene.
The enteropathogen Campylobacter jejuni is a major worldwide health and economic burden, being one of the leading causes of bacterial gastroenteritis and commonly linked to postinfectious onset of autoimmune disease. Chickens are a major vector for human infection and even though variation in avian colonization level is heritable, no previous studies have identified regions of the genome associated with colonization resistance. We performed a genome-wide association study of resistance to C. jejuni colonization in the avian intestine by controlling for population structure, which revealed a risk locus with genome-wide significance spanning the T-cadherin (CDH13) gene. A second possible risk locus was also identified close to calmodulin (CALM1), a calcium-activated modulator of cadherin function. In addition, gene expression analysis of mRNA sequencing profiles revealed that the relative expression of the two genes is significantly associated with colonization resistance. Functional studies have previously demonstrated involvement of cadherins and calmodulin in C. jejuni intracellular invasion and colonization of human intestinal epithelial cells in vitro. Consistent with this finding, our analysis reveals that variation surrounding these genes is associated with avian colonization resistance in vivo and highlights their potential as possible targets for control of the bacterium in avian and human populations.


Whole-plant mineral partitioning throughout the life cycle in Arabidopsis thaliana ecotypes Columbia, Landsberg erecta, Cape Verde Islands, and the mutant line ysl1ysl3.
Minimal information exists on whole-plant dynamics of mineral flow through Arabidopsis thaliana or on the source tissues responsible for mineral export to developing seeds. Understanding these phenomena in a model plant could help in the development of nutritionally enhanced crop cultivars. A whole-plant partitioning study, using sequential harvests, was conducted to characterize growth and mineral concentrations and contents of rosettes, cauline leaves, stems, immature fruit, mature fruit hulls, and seeds of three WT lines (Col-0, Ler, and Cvi) and one mutant line (Col-0::ysl1ysl3). Shoot mineral content increased throughout the life cycle for all minerals, although tissue-specific mineral partitioning differed between genotypes. In particular, iron (Fe), zinc (Zn), and copper (Cu) were aberrantly distributed in ysl1ysl3. Remobilization was observed for several minerals from various tissues, including cauline leaves and silique hulls, but the amounts were generally far below the total mineral accretion observed in seeds. When YSL1 and YSL3 are nonfunctional, Cu, Fe, and Zn are not effectively remobilized from, or do not effectively pass through, leaf and maternal fruit tissues. With respect to seed mineral accretion in Arabidopsis, continued uptake and translocation of minerals to source tissues during seed fill are as important, if not more important, than remobilization of previously stored minerals.