Specific interactions between a human CD4+ clone and autologous CD4+ bifunctional immunoregulatory clones.
The cellular communications between a human CD4+ clone and autologous CD4+ clones induced with the first clone are described. The autoreactive clones proliferated after stimulation with the inducer clone, but not after stimulation with autologous clones expressing irrelevant specificities. The inducer clone markedly lost its ability to interact with the autoreactive clones after the modulation of its T-cell receptor. The proliferation of the autoreactive clones stimulated with the inducer clone was blocked by anti-DR monoclonal antibody. Collectively, these findings indicate that the autoreactive clones recognize idiotypic-like determinants on the receptor of the inducer clone in conjunction with DR antigen. The regulatory activity of the autoreactive clones was assayed by co-cultivation with their target inducer clone. The autoreactive clones were not committed to a single program, they could either suppress or enhance the proliferation of the target cells depending on the state of activation of the target cells. Activated target cells were suppressed whereas non-activated cells were enhanced. It is predicted that antagonistic cytokines released from the autoreactive clones exert differential effects on the target clone.


"Knowing is better": preferences of diverse older adults for discussing prognosis.
Prognosis is critical in individualizing care for older adults with late life disability. Evidence suggests that preferences for prognostic information may be culturally determined. Yet little is known about the preferences of diverse elders for discussing prognosis. To determine the preferences for discussing prognosis of a diverse sample of older adults with late-life disability. We interviewed 60 older adults with mean age 78 and mean 2.5 Activities of Daily Living dependencies. Participants were recruited from San Francisco's On Lok program, the first Program of All-inclusive Care for the Elderly (PACE). Participants were interviewed in English, Spanish, and Cantonese, and responded to scenarios in which their doctors estimated they had 5 years and 1 year left to live. Open-ended questions explored the reasons for their responses. Results were analyzed qualitatively using grounded theory. Sixty-five percent of participants wanted to discuss the prognosis if their doctor estimated they had <5 years to live and 75% if the estimate was <1 year. Three themes were prominent among patients who wanted to discuss prognosis: to prepare, to make the most of the life they had left, and to make medical or health-related decisions. Those who preferred not to discuss prognosis described emotional difficulty, the uncertainty of prognosis, or that it would not be useful. Nearly all participants said that doctors should not make assumptions based on race or ethnicity, though differences between ethnic groups emerged. Most patients in this diverse sample of disabled elders were interested in discussing prognosis, while a substantial minority was not. Among those participants who preferred to discuss prognosis, many said that prognostic information would be important as they made difficult medical and personal decisions in late-life. Clinicians should inquire about preferences for discussing prognosis before sharing prognostic estimates.


Correcting gene expression data when neither the unwanted variation nor the factor of interest are observed.
When dealing with large scale gene expression studies, observations are commonly contaminated by sources of unwanted variation such as platforms or batches. Not taking this unwanted variation into account when analyzing the data can lead to spurious associations and to missing important signals. When the analysis is unsupervised, e.g. when the goal is to cluster the samples or to build a corrected version of the dataset--as opposed to the study of an observed factor of interest--taking unwanted variation into account can become a difficult task. The factors driving unwanted variation may be correlated with the unobserved factor of interest, so that correcting for the former can remove the latter if not done carefully. We show how negative control genes and replicate samples can be used to estimate unwanted variation in gene expression, and discuss how this information can be used to correct the expression data. The proposed methods are then evaluated on synthetic data and three gene expression datasets. They generally manage to remove unwanted variation without losing the signal of interest and compare favorably to state-of-the-art corrections. All proposed methods are implemented in the bioconductor package RUVnormalize.


A comparison of ankle taping methods.
Four different types of ankle tapings were applied to a model of the human ankle joint. The model was constructed so that it contained a hinge to represent the ankle joint and had an external shape identical to a real ankle and foot. A mechanical testing machine was used to apply moments to the model at a controlled loading rate. From these tests, the deflection and torque to failure and the tangent stiffness were determined. Loadings of an ankle joint in vivo revealed that the angular deflection to initiate pain was approximately 8 degrees. Only the figure eight and full tapings could withstand 8 degrees of angular displacement on the ankle model prior to failure. Analysis of athletic trauma revealed that torques of 420 Nm could be applied to the ankle joint. Only the figure eight taping with three or more wraps has adequate strength to withstand this moment, and thus this taping is recommended. In practice, tapings failed by shearing away from the surface of the foot of shrinking rather than by rupture of the tape.


In Planta Single-Molecule Pull-Down Reveals Tetrameric Stoichiometry of HD-ZIPIII:LITTLE ZIPPER Complexes.
Deciphering complex biological processes markedly benefits from approaches that directly assess the underlying biomolecular interactions. Most commonly used approaches to monitor protein-protein interactions typically provide nonquantitative readouts that lack statistical power and do not yield information on the heterogeneity or stoichiometry of protein complexes. Single-molecule pull-down (SiMPull) uses single-molecule fluorescence detection to mitigate these disadvantages and can quantitatively interrogate interactions between proteins and other compounds, such as nucleic acids, small molecule ligands, and lipids. Here, we establish SiMPull in plants using the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII) and LITTLE ZIPPER (ZPR) interaction as proof-of-principle. Colocalization analysis of fluorophore-tagged HD-ZIPIII and ZPR proteins provides strong statistical evidence of complex formation. In addition, we use SiMPull to directly quantify YFP and mCherry maturation probabilities, showing these differ substantially from values obtained in mammalian systems. Leveraging these probabilities, in conjunction with fluorophore photobleaching assays on over 2000 individual complexes, we determined HD-ZIPIII:ZPR stoichiometry. Intriguingly, these complexes appear as heterotetramers, comprising two HD-ZIPIII and two ZPR molecules, rather than heterodimers as described in the current model. This surprising result raises new questions about the regulation of these key developmental factors and is illustrative of the unique contribution SiMPull is poised to make to in planta protein interaction studies.


BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design.
The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.


Mobilizing monocytes to cross-present circulating viral antigen in chronic infection.
Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8+ T cells specific for MHC-I-restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivo-isolated APCs did not constitutively activate HBV-specific CD8+ T cells. However, differentiation of HBsAg+ CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells.


Adverse radiation effects in volume-staged radiosurgery for large arteriovenous malformations: a multiinstitutional study.
The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs). This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic. Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE. Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.


Robert Knox and the anatomy of beauty.
Robert Knox (1791-1862) is typically remembered as the Edinburgh anatomist to whom the murderers Burke and Hare sold the bodies of their victims. This association brought Knox infamy and damaged his life and career. Before the Burke and Hare scandal, Knox was one of the most famous, original and influential anatomists in Britain. He was also something of a dandy with a sophisticated appreciation of the visual arts. His most significant writings on artistic subjects were his books A Manual of Artistic Anatomy and Great Artists and Great Anatomists: A Biographical and Philosophical Study. Knox's interesting and independently minded opinions on the central artistic questions of his day were taken seriously by his contemporaries. His demotion in the official history of anatomy following his involvement with Burke and Hare, however, also removed him from the history of art theory in 19th century Britain. Knox was such a magnetic and impressive figure, though, that he has to be brought back to his era and his era is not complete without him. This paper discusses how Knox's writings on anatomy and biology shaped his contributions to art theory. It is a first step towards returning Knox, the art theorist, to the cultural life of 19th century Britain.


A model-based approach for identifying signatures of ancient balancing selection in genetic data.
While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates.


Effects of prenatal and perinatal exposure to fine air pollutants and maternal fish consumption on the occurrence of infantile eczema.
As there is a scarcity of evidence on potential hazards and preventive factors for infantile eczema operating in the prenatal period, the main goal of this study was to assess the role of prenatal exposure to fine particulate matter and environmental tobacco smoke (ETS) in the occurrence of infant eczema jointly with the possible modulating effect of maternal fish consumption. The study sample consisted of 469 women enrolled during pregnancy, who gave birth to term babies (>36 weeks of gestation). Among all pregnant women recruited, personal measurements of fine particulate matter (PM₂.₅) were performed over 48 h in the second trimester of pregnancy. After delivery, every 3 months in the first year of the newborn's life, a detailed, standardized, face-to-face interview was administered to each mother, in the process of which a trained interviewer recorded any history of infantile eczema and data on potential environmental hazards. The estimated risk of eczema related to higher prenatal exposure to fine particulate matter (PM₂.₅ > 53.0 μg/m³) and postnatal ETS as well as the protective effect of maternal fish intake were adjusted for potential confounders in a multivariable logistic regression model. While the separate effects of higher prenatal PM₂.₅ and postnatal ETS exposure were not statistically significant, their joint effect appeared to have a significant influence on the occurrence of infantile eczema [odds ratio 2.39, 95% confidence interval (CI) 1.10-5.18]. With maternal fish intake of more than 205 g/week, the risk of eczema decreased by 43% (odds ratio 0.57, 95% CI 0.35-0.93). The incidence rate ratio (IRR) for eczema symptoms, estimated from the Poisson regression model, was increased with both higher exposure to prenatal PM₂.₅ and postnatal ETS (IRR 1.55, 95% CI 0.99-2.44) and in children of atopic mothers (IRR 1.35, 95% CI 1.04-1.75) but was lower in girls (IRR 0.78, 95% CI 0.61-1.00). The observed preventive effect of fish consumption on the frequency of eczema symptoms was consistent with the results of the logistic analysis (IRR 0.72, 95% CI 0.52-0.99). The findings indicate that higher prenatal exposure to fine particulate matter combined with postnatal exposure to ETS may increase the risk of infant eczema, while maternal fish intake during pregnancy may reduce the risk of infantile eczema.


Performance of the European System for Cardiac Operative Risk Evaluation II: a meta-analysis of 22 studies involving 145,592 cardiac surgery procedures.
A systematic review of the European System for Cardiac Operative Risk Evaluation (euroSCORE) II performance for prediction of operative mortality after cardiac surgery has not been performed. We conducted a meta-analysis of studies based on the predictive accuracy of the euroSCORE II. We searched the Embase and PubMed databases for all English-only articles reporting performance characteristics of the euroSCORE II. The area under the receiver operating characteristic curve, the observed/expected mortality ratio, and observed-expected mortality difference with their 95% confidence intervals were analyzed. Twenty-two articles were selected, including 145,592 procedures. Operative mortality occurred in 4293 (2.95%), whereas the expected events according to euroSCORE II were 4802 (3.30%). Meta-analysis of these studies provided an area under the receiver operating characteristic curve of 0.792 (95% confidence interval, 0.773-0.811), an estimated observed/expected ratio of 1.019 (95% confidence interval, 0.899-1.139), and observed-expected difference of 0.125 (95% confidence interval, -0.269 to 0.519). Statistical heterogeneity was detected among retrospective studies including less recent procedures. Subgroups analysis confirmed the robustness of combined estimates for isolated valve procedures and those combined with revascularization surgery. A significant overestimation of the euroSCORE II with an observed/expected ratio of 0.829 (95% confidence interval, 0.677-0.982) was observed in isolated coronary artery bypass grafting and a slight underestimation of predictions in high-risk patients (observed/expected ratio 1.253 and observed-expected difference 1.859). Despite the heterogeneity, the results from this meta-analysis show a good overall performance of the euroSCORE II in terms of discrimination and accuracy of model predictions for operative mortality. Validation of the euroSCORE II in prospective populations needs to be further studied for a continuous improvement of patients' risk stratification before cardiac surgery.


Robustly estimating the marginal likelihood for cognitive models via importance sampling.
Recent advances in Markov chain Monte Carlo (MCMC) extend the scope of Bayesian inference to models for which the likelihood function is intractable. Although these developments allow us to estimate model parameters, other basic problems such as estimating the marginal likelihood, a fundamental tool in Bayesian model selection, remain challenging. This is an important scientific limitation because testing psychological hypotheses with hierarchical models has proven difficult with current model selection methods. We propose an efficient method for estimating the marginal likelihood for models where the likelihood is intractable, but can be estimated unbiasedly. It is based on first running a sampling method such as MCMC to obtain samples for the model parameters, and then using these samples to construct the proposal density in an importance sampling (IS) framework with an unbiased estimate of the likelihood. Our method has several attractive properties: it generates an unbiased estimate of the marginal likelihood, it is robust to the quality and target of the sampling method used to form the IS proposals, and it is computationally cheap to estimate the variance of the marginal likelihood estimator. We also obtain the convergence properties of the method and provide guidelines on maximizing computational efficiency. The method is illustrated in two challenging cases involving hierarchical models: identifying the form of individual differences in an applied choice scenario, and evaluating the best parameterization of a cognitive model in a speeded decision making context. Freely available code to implement the methods is provided. Extensions to posterior moment estimation and parallelization are also discussed.


Hydrogen-rich saline mitigates pressure overload-induced cardiac hypertrophy and atrial fibrillation in rats via the JAK-STAT signalling pathway.
To investigate if hydrogen-rich saline (HRS), which has been shown to have antioxidant and anti-inflammatory properties, could mitigate cardiac remodelling and reduce the incidence of atrial fibrillation (AF) in the rat model of cardiac hypertrophy. Pressure overload was induced in rats by abdominal aortic constriction (AAC). The animals were separated into four groups: sham; AAC group; AAC plus low dose HRS (LHRS); AAC plus high dose HRS (HHRS). The sham and AAC groups received normal saline intraperitoneally and the LHRS and HHRS groups received 3 or 6 ml/kg HRS daily for six weeks, respectively. In vitro research was also performed using cardiotrophin-1 (CT-1)-induced hypertrophy of cultured neonatal rat cardiomyocytes. Cardiac hypertrophy was successfully induced by AAC and low and high dose HRS mitigated the pressure overload as shown by lower heart and atrial weights in these treatment groups. AF incidence and duration of the HRS groups were also significantly lower in the HRS groups compared with the AAC group. Atrial fibrosis was also reduced in the HRS groups and the JAK-STAT signalling pathway was down-regulated. In vitro experiments showed that hydrogen-rich medium mitigated the CT-1-induced cardiomyocyte hypertrophy with a similar effect as the JAK specific antagonists AG490. HRS was found to mitigate cardiac hypertrophy induced by pressure overload in rats and reduce atrial fibrosis and AF which was possibly achieved via inhibition of the JAK-STAT signalling pathway.


Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression.
Vascular endothelial growth factor (VEGF) is an important factor mediating tumour angiogenesis. VEGF mRNA is differentially expressed in bladder cancer with high expression in superficial tumours (stage pTa and pT1) contrasting with low expression in muscle invasive tumours (stage > or = pT2). To investigate mechanisms regulating VEGF expression in bladder cancer, VEGF mRNA and protein were measured in normal bladder (n = 12) and primary bladder cancers (n = 57). VEGF protein levels correlated with mRNA expression in normal bladder (r = 0.68, P = 0.02) and bladder cancer (r = 0.46, P = 0.0007). Whilst VEGF mRNA expression was threefold higher in superficial compared to muscle invasive bladder cancers (P = 0.0001) there was no difference in VEGF protein (P = 0.81). Accordingly, the median protein:mRNA ratios increased more than 15-fold with increasing tumour stage (P < 0.0001) suggesting translational regulation. Expression of the eukaryotic initiation factor-4E (elF-4E), a factor implicated in the translational regulation of VEGF, was greater in tumours than normal bladder (P < 0.0001) and correlated with VEGE protein:mRNA ratios (n = 43, r = 0.54, P = 0.0004) pointing to its role in the regulation of VEGF. In superficial tumours (n = 37) high expression of eIF-4E was associated with a poor prognosis and reduced stage progression-free survival (P = 0.04, Cox proportional hazards model). The study demonstrates that eIF-4E may be involved in translational regulation of VEGF in bladder cancer and might have a role as a prognostic factor in bladder cancer.


TBAI-catalyzed oxidative synthesis of benzamides from acetophenones and carbinols.
An interesting and convenient procedure for the oxidative transformation of acetophenones and carbinols to primary benzamides has been developed. By using tetra-n-butylammonium iodide (TBAI) as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant, the desired benzamides were isolated in moderate to good yields in aqueous solution. Notably, not only acetophenones but also propiophenones can be applied as substrates as well. Hence, we believe that this new procedure is not just a catalytic version of the iodine-based method.


Aortopulmonary collateral flow volume affects early postoperative outcome after Fontan completion: a multimodality study.
Aortopulmonary collaterals are a frequent phenomenon in patients after bidirectional cavopulmonary connection. The aortopulmonary collateral flow volume can be quantified using cardiac magnetic resonance imaging. However, the significance of aortopulmonary collateral flow for the postoperative outcome after total cavopulmonary connection is unclear and was sought to be determined. The data from 33 patients were prospectively studied with cardiac magnetic resonance, echocardiography, and cardiac catheterization before the total cavopulmonary connection operation. The early postoperative outcomes after total cavopulmonary connection completion were recorded. Aortopulmonary collateral flow was 1.59 L/min/m(2) ± 0.65 L/min/m(2) (range, 0.54 L/min/m(2)-3.34 L/min/m(2)), constituting 43% ± 13% (range, 12-87%) of pulmonary blood flow and 35% ± 12% (range, 11-62%) of the cardiac index, resulting in a pulmonary blood flow/systemic blood flow ratio of 1.06 ± 0.17 (range, 0.79-1.55). The aortopulmonary collateral flow correlated with pulmonary blood flow/systemic blood flow ratio (r = 0.69, P < .0001), oxygen saturation (r = 0.42, P = .018), and cardiac index (r = 0.53, P = .002). Of the 36 patients, 24 underwent fenestrated total cavopulmonary connection during the study period. The aortopulmonary collateral flow, relative to the cardiac index, correlated with the duration of hospital stay (r = 0.48, P = .02) and pleural drainage (r = 0.45, P = .03). Patients whose pleural drainage lasted 1 week or less had less aortopulmonary collateral flow before the Fontan operation than those with a longer period until chest tube removal (1.23 L/min/m(2) ± 0.38 L/min/m(2) vs 1.73 L/min/m(2) ± 0.76 L/min/m(2); P = .03). Compared with a contemporary group of total cavopulmonary connection patients with fenestration in their extracardiac conduit who were studied prospectively, with a similar protocol, the bidirectional cavopulmonary connection had a greater amount of aortopulmonary collateral flow (1.59 L/min/m(2) ± 0.65 L/min/m(2) vs 1.30 L/min/m(2) ± 0.57 L/min/m(2), P = .04). Patients after bidirectional cavopulmonary connection routinely acquire a large amount of aortopulmonary collateral flow. The hemodynamic consequences of aortopulmonary collateral flow translate into adverse outcomes early after total cavopulmonary connection completion.


NosL is a dedicated copper chaperone for assembly of the CuZ center of nitrous oxide reductase.
Nitrous oxide reductase (N2OR) is the terminal enzyme of the denitrification pathway of soil bacteria that reduces the greenhouse gas nitrous oxide (N2O) to dinitrogen. In addition to a binuclear CuA site that functions in electron transfer, the active site of N2OR features a unique tetranuclear copper cluster bridged by inorganic sulfide, termed CuZ. In copper-limited environments, N2OR fails to function, resulting in truncation of denitrification and rising levels of N2O released by cells to the atmosphere, presenting a major environmental challenge. Here we report studies of nosL from Paracoccus denitrificans, which is part of the nos gene cluster, and encodes a putative copper binding protein. A Paracoccus denitrificans ΔnosL mutant strain had no denitrification phenotype under copper-sufficient conditions but failed to reduce N2O under copper-limited conditions. N2OR isolated from ΔnosL cells was found to be deficient in copper and to exhibit attenuated activity. UV-visible absorbance spectroscopy revealed that bands due to the CuA center were unaffected, while those corresponding to the CuZ center were significantly reduced in intensity. In vitro studies of a soluble form of NosL without its predicted membrane anchor showed that it binds one Cu(i) ion per protein with attomolar affinity, but does not bind Cu(ii). Together, the data demonstrate that NosL is a copper-binding protein specifically required for assembly of the CuZ center of N2OR, and thus represents the first characterised assembly factor for the CuZ active site of this key environmental enzyme, which is globally responsible for the destruction of a potent greenhouse gas.


Type 1 autoimmune hepatitis presenting with severe autoimmune neutropenia.
Autoimmune hepatitis (AIH) is a progressive, chronic liver disease characterized by unresolving hepatocellular inflammation of autoimmune origin. The clinical spectrum may vary from asymptomatic presentation, to non-specific symptoms such as fatigue, arthralgias, nausea and abdominal pain, to acute severe liver disease. AIH is characterized by the presence of interface hepatitis and portal plasma cell infiltration on histological examination, hypergammaglobulinemia, and positive autoantibodies. AIH is associated with other autoimmune diseases and its course is often accompanied by various non-specific hematological disorders. However, the coexistence of autoimmune neutropenia (AIN) is infrequent. We present a case of a female patient diagnosed with type 1 AIH and agranulocytosis on presentation. A diagnosis of AIN was established, based on the patient's sex, the underlying liver disease, the absence of alternative causes, the presence of atypical anti-neutrophil cytoplasmic antibodies in patient's serum and the favorable and dose-dependent treatment of both pathologic entities with corticosteroids and mycophenolate mofetil.


Ocean acidification alters fish-jellyfish symbiosis.
Symbiotic relationships are common in nature, and are important for individual fitness and sustaining species populations. Global change is rapidly altering environmental conditions, but, with the exception of coral-microalgae interactions, we know little of how this will affect symbiotic relationships. We here test how the effects of ocean acidification, from rising anthropogenic CO2 emissions, may alter symbiotic interactions between juvenile fish and their jellyfish hosts. Fishes treated with elevated seawater CO2 concentrations, as forecast for the end of the century on a business-as-usual greenhouse gas emission scenario, were negatively affected in their behaviour. The total time that fish (yellowtail scad) spent close to their jellyfish host in a choice arena where they could see and smell their host was approximately three times shorter under future compared with ambient CO2 conditions. Likewise, the mean number of attempts to associate with jellyfish was almost three times lower in CO2-treated compared with control fish, while only 63% (high CO2) versus 86% (control) of all individuals tested initiated an association at all. By contrast, none of three fish species tested were attracted solely to jellyfish olfactory cues under present-day CO2 conditions, suggesting that the altered fish-jellyfish association is not driven by negative effects of ocean acidification on olfaction. Because shelter is not widely available in the open water column and larvae of many (and often commercially important) pelagic species associate with jellyfish for protection against predators, modification of the fish-jellyfish symbiosis might lead to higher mortality and alter species population dynamics, and potentially have flow-on effects for their fisheries.


Improved anal Cytology Sampling: Tush Brush Compared With Dacron Swab.
The objective of this study was to determine the performance characteristics of the Tush brush (TB) compared with a saline moistened Dacron swab (DS) as anal cytology sampling devices. TB and DS anal cytology tests were randomly collected from 146 patients presenting for anal cytology. High-resolution anoscopy and biopsies were obtained as indicated. Sensitivity and specificity as well as rates of satisfactory specimens were determined for each method using the areas under the receiver operating characteristic curve (AUCROC) and McNemar's test, respectively. Perceived discomfort of each device was determined using a visual analog scale and compared using a paired t test. The adjudicated AUCROC, sensitivity, and specificity were greater, but not significantly different, for the brush (0.63, 85.5, and 40.0, respectively) compared with the swab (0.50, 79.6, and 33.3, respectively) when the anal biopsy results were considered the criterion standard. In the 1 subject diagnosed with anal cancer, the swab cytology result was normal, but the brush result was abnormal. Specimen adequacy was 95.2% for the brush and 93.2% for the swab. Mean discomfort (visual analog scale) scores were swab 28.5 mm versus brush 35.6 mm (p = .0003) with both scores within the minimal to moderate discomfort range. Anal cytology AUCROC, sensitivity, and specificity in detecting anal neoplasia were greater using the TB when compared with the DS. A novel anal cytology sampling device designed specifically to increase the detection of anal neoplasia would be clinically beneficial.


Impact of supplemental private health insurance on dialysis and outcomes.
The influence of health insurance systems on the treatment of end-stage kidney disease (ESKD) patients ispoorly understood. We investigated how supplemental private health insurance (PHI) coverage impacted ESKD treatment modalitiesand patient outcomes. The influence of health insurance systems on the treatment of end-stage kidney disease (ESKD) patients is poorly understood. We investigated how supplemental private health insurance (PHI) coverage impacted ESKD treatment modalities and patient outcomes. All adult patients commencing ESKD treatment in New South Wales, Australia from 2000 to 2010 were identified using the Australia and New Zealand Dialysis and Transplant Registry. Data were linked to the state hospitalisation dataset to obtain insurance status, allowing the comparisons of mortality, ESKD treatment modality and health service utilisation between privately insured and public patients. The cohort of 5737 patients included 38% (n = 2152) with PHI. At 1 year after ESKD treatment initiation, PHI patients had lower mortality (hazard ratio 0.84, 95% confidence interval (CI) 0.74-0.95, P = 0.01), were more likely to be receiving home haemodialysis (HD) (odds ratio (OR) 1.38, 95% CI 1.01-1.89, P = 0.04), to have been transplanted (OR 1.75, 95% CI 1.25-2.46, P = 0.001) and used fewer hospital days (incidence rate ratio 0.85, 95% CI 0.74-0.96, P = 0.01). After adjustment, PHI patients were more likely to initiate ESKD treatment with facility-based HD (OR 1.22, 95% CI 1.01-1.46, P = 0.03) but were less likely to be started on peritoneal dialysis (OR 0.81, 95% CI 0.67-0.98, P = 0.03). Our findings suggest that supplemental PHI in Australia is associated with lower-risk ESKD treatment attributes and improved health outcomes. A greater understanding of the treatment pathways that deliver these outcomes may inform treatment for the broader ESKD treatment population.


ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic.
Autophagy is an inducible autodigestive process that allows cells to recycle proteins and other materials for survival during stress and nutrient deprived conditions. The kinase ULK1 is required to activate this process. ULK1 phosphorylates a number of target proteins and regulates many cellular processes including the early secretory pathway. Recently, ULK1 has been demonstrated to phosphorylate Sec16 and affects the transport of serotonin transporter at the ER exit sites (ERES), but whether ULK1 may affect the transport of other cargo proteins and general secretion has not been fully addressed. In this study, we identified Sec23A, a component of the COPII vesicle coat, as a target of ULK1 phosphorylation. Elevated autophagy, induced by amino acid starvation, rapamycin, or overexpression of ULK1 caused aggregation of the ERES, a region of the ER dedicated for the budding of COPII vesicles. Transport of cargo proteins was also inhibited under these conditions and was retained at the ERES. ULK1 phosphorylation of Sec23A reduced the interaction between Sec23A and Sec31A. We identified serine 207, serine 312 and threonine 405 on Sec23A as ULK1 phosphorylation sites. Among these residues, serine 207, when changed to phospho-deficient and phospho-mimicking mutants, most faithfully recapitulated the above-mentioned effects of ULK1 phospho-regulation. These findings identify Sec23A as a new target of ULK1 and uncover a mechanism of coordinating intracellular protein transport and autophagy.


Prenatal exposure to an environmentally relevant mixture of Canadian Arctic contaminants decreases male reproductive function in an aging rat model.
Elevated levels of organochlorines (OC) have been reported in Inuit populations in the Arctic. We hypothesized that prenatal exposure to a Canadian Arctic OC mixture adversely affects male reproductive function and health with age. Sprague-Dawley female rats (F0) were gavaged with an environmentally relevant concentration of an Arctic OC mixture or corn oil (Control) during mating with untreated males until parturition (F1 litters). After postnatal day (PND) 90, the weights of the OC F1 males differed dramatically relative to Controls (P<0.05; n=10) and they exhibited respiratory distress. Except for possible thinning of the alveolar barrier, histological observation of the lungs revealed no apparent pathology to explain the respiratory distress. At PND 365, OC F1 males had reduced relative reproductive organ weights and lower sperm quality than Controls (P<0.05). At PND 90, OC F1 males were subfertile (P<0.05), but were infertile at PND 365. In conclusion, environmentally relevant prenatal OC exposure reduced reproductive function and health in aging male rats, providing new insight into the effects of early-life exposures to these contaminants.


Gene-expression signature predicts postoperative recurrence in stage I non-small cell lung cancer patients.
About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. The purpose of this study is to develop and validate a novel gene-expression signature that can predict tumor recurrence of stage I NSCLC patients. Cox proportional hazards regression analysis was performed to identify recurrence-related genes and a partial Cox regression model was used to generate a gene signature of recurrence in the training dataset -142 stage I lung adenocarcinomas without adjunctive therapy from the Director's Challenge Consortium. Four independent validation datasets, including GSE5843, GSE8894, and two other datasets provided by Mayo Clinic and Washington University, were used to assess the prediction accuracy by calculating the correlation between risk score estimated from gene expression and real recurrence-free survival time and AUC of time-dependent ROC analysis. Pathway-based survival analyses were also performed. 104 probesets correlated with recurrence in the training dataset. They are enriched in cell adhesion, apoptosis and regulation of cell proliferation. A 51-gene expression signature was identified to distinguish patients likely to develop tumor recurrence (Dxy = -0.83, P<1e-16) and this signature was validated in four independent datasets with AUC >85%. Multiple pathways including leukocyte transendothelial migration and cell adhesion were highly correlated with recurrence-free survival. The gene signature is highly predictive of recurrence in stage I NSCLC patients, which has important prognostic and therapeutic implications for the future management of these patients.


Two dimensional crystallization of three solid lipid A-diphosphate phases.
Surface-tension-induced liquid-crystal growth of monomeric lipid A-diphosphate in aqueous dispersions is reported as a function of concentration, (c), and temperature, (T), and at low ionic strength (10(-3) M). As the temperature was varied, a solid-liquid transition was revealed in the surface layer at a fixed lipid A-diphosphate bulk concentration. Here, the development of different two-dimensional (2-d) faceted crystal morphologies was observed and, as growth proceeded, these faceted 2-d crystals became unstable. Selected area electron microscopy diffraction (SAED) and X-ray diffraction (XRD) measurements of the faceted 2-d crystalline lipid A-diphosphate layers exhibited a pseudohexagonal molecular arrangement. The crystalline layer was a smectic F, S(F), phase below the critical temperature, T(C), and a smectic I, S(I), phase above T(C) (15 °C). Both phases could be described in terms of the same C-centered monoclinic unit cell. The in-plane order extended for a limited distance although the layers were coupled. The analysis of the SAED patterns revealed short-range order in the S(F) phase (5-15 °C), but long-range order in the S(I) phase, for the temperature range 15-30 °C. The observed 2-d solid hexatic phase and the 2-d liquid hexatic phase had correlation lengths of 220 Å. This, the hexatic phase, displayed short-range in-plane positional order and quasi long-range, sixfold bond-orientational order. The S(I) phase showed long-range order characteristics of a hexatic 2-d crystal. The two-, four-, or six-layer crystalline lipid A-diphosphate films exhibited 2-d hexatic order and 6n-fold bond-orientational order. These films did not evolve into the S(F) phase, demonstrating that the two phases were thermodynamically distinct. A finite tilt angle of φ = 15° was calculated for the lipid A-diphosphate molecule; the tilt was toward the small side of the rectangular 2-d lattice. The constraint of six close-packed acyl chains in two distinct phases with the same symmetry suggests that the S(F) → S(I) transition was first-order.


Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies.
This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.


Scanxiety.
Scanxiety is a term that has penetrated the vernacular medical vocabulary as a descriptor of the particular distress reported by patients who are scheduled for imaging to assess disease status. Patients fear failure of current treatments, return of disease or progression, the need for new treatments, and the prospect of demise. Stress related to imaging is frequent, may be persistent, and is linked to decreased quality of life. (PsycINFO Database Record


Understanding dignity: experiences of impairment in an exercise facility.
Dignity, as an essential quality of being human, has been overlooked in exercise contexts. The aim of this interpretative phenomenological study was to understand the meaning of dignity and its importance to exercise participation. The experiences of 21 adults (11 women and 10 men) from 19 to 65 yr of age who experience disability, who attended a specialized community exercise facility, were gathered using the methods of focus-group and one-on-one interviews, visual images, and field notes. The thematic analysis revealed 4 themes: the comfort of feeling welcome, perceptions of otherness, negotiating public spaces, and lost autonomy. Dignity was subjectively understood and nurtured through the respect of others. Indignities occurred when enacted social and cultural norms brought dignity to consciousness through humiliation or removal of autonomy. The specialized exercise environment promoted self-worth and positive self-beliefs through shared life experiences and a norm of respect.


Visual analysis of cardiac 4D MRI blood flow using line predicates.
Four-dimensional MRI is an in vivo flow imaging modality that is expected to significantly enhance the understanding of cardiovascular diseases. Among other fields, 4D MRI provides valuable data for the research of cardiac blood flow and with that the development, diagnosis, and treatment of various cardiac pathologies. However, to gain insights from larger research studies or to apply 4D MRI in the clinical routine later on, analysis techniques become necessary that allow to robustly identify important flow characteristics without demanding too much time and expert knowledge. Heart muscle contractions and the particular complexity of the flow in the heart imply further challenges when analyzing cardiac blood flow. Working toward the goal of simplifying the analysis of 4D MRI heart data, we present a visual analysis method using line predicates. With line predicates precalculated integral lines are sorted into bundles with similar flow properties, such as velocity, vorticity, or flow paths. The user can combine the line predicates flexibly and by that carve out interesting flow features helping to gain overview. We applied our analysis technique to 4D MRI data of healthy and pathological hearts and present several flow aspects that could not be shown with current methods. Three 4D MRI experts gave feedback and confirmed the additional benefit of our method for their understanding of cardiac blood flow.


Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent mechanism.
Δ⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT(3A) receptors (h5-HT(3A)Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC₅₀ values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT(3A)Rs. In these cells, CBD and THC did not stimulate specific [³⁵S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT(3A)Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT(3A)R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT(3A) receptors through a mechanism that is dependent on receptor desensitization.


Normal growth of Arabidopsis requires cytosolic invertase but not sucrose synthase.
The entry of carbon from sucrose into cellular metabolism in plants can potentially be catalyzed by either sucrose synthase (SUS) or invertase (INV). These 2 routes have different implications for cellular metabolism in general and for the production of key metabolites, including the cell-wall precursor UDPglucose. To examine the importance of these 2 routes of sucrose catabolism in Arabidopsis thaliana (L.), we generated mutant plants that lack 4 of the 6 isoforms of SUS. These mutants (sus1/sus2/sus3/sus4 mutants) lack SUS activity in all cell types except the phloem. Surprisingly, the mutant plants are normal with respect to starch and sugar content, seed weight and lipid content, cellulose content, and cell-wall structure. Plants lacking the remaining 2 isoforms of SUS (sus5/sus6 mutants), which are expressed specifically in the phloem, have reduced amounts of callose in the sieve plates of the sieve elements. To discover whether sucrose catabolism in Arabidopsis requires INVs rather than SUSs, we further generated plants deficient in 2 closely related isoforms of neutral INV predicted to be the main cytosolic forms in the root (cinv1/cinv2 mutants). The mutant plants have severely reduced growth rates. We discuss the implications of these findings for our understanding of carbon supply to the nonphotosynthetic cells of plants.


Validation of the Paediatric Hearing Impairment Caregiver Experience (PHICE) Questionnaire.
The paediatric hearing impairment caregiver experience (PHICE) questionnaire is a 68-item instrument that assesses the stress experienced by caregivers of children with hearing impairment (HI). While the questionnaire has been validated in the United States, it may need to be modified for use in the Singapore context due to the differing healthcare system, costing and culture related to caregiving for children with HI. This study aims to modify and validate the PHICE questionnaire to increase its relevance and ease of use in Singapore. The original PHICE questionnaire was filled out by 127 caregivers of HI children managed at the otolaryngology clinic of the National University Hospital (NUH). An expert panel was convened to assess the questionnaire for its suitability for use in Singapore. Exploratory factor analysis was conducted to evaluate the underlying factor structure of the original PHICE questionnaire. Items with high cross-loadings were removed and a new factor structure was adopted which was further analysed using confirmatory factor analysis (CFA). Cronbach's alpha (α) was computed to determine the internal consistency of the new subscales. Items that are less relevant in Singapore and those with high cross-loadings were removed. A 5-factor structure with only 42 items remaining and corresponding to the factors: " Policy", "Healthcare", "Education", "Support" and "Adaptation" was adopted. CFA suggests a good model fit for the modified questionnaire, improved from the 8-factor structure of the original PHICE. Cronbach's α were high (>0.7) for each new subscale. The original PHICE questionnaire has been shortened and reorganised in terms of the subscales composition. The resulting instrument is structurally valid and internally consistent. It is a simple and useful tool for identifying factors related to caregiving that can negatively impact rehabilitation outcomes for children with HI in Singapore. Removal of some sign language items makes this modified version less useful for caregivers, places or countries where sign language is the main focus of rehabilitation for children with HI.


The effects of liver denervation on the regulation of hepatic biliary secretion.
Effects of liver denervation on bile formation were studied in eight dogs prepared with chronic biliary fistulas. The animals were studied in the basal state, after feeding, and during infusion of glucagon 50 ng/kg/min, secretin 2 U/kg/hr, or somatostatin 200 ng/kg/min. After this first set of experiments the animals underwent a total hepatic denervation that consisted of section of the hepatic ligaments and a careful dissection of the portal vein, hepatic artery, and common duct with stripping of all the surrounding connective tissue and topical application of phenol. The above experiments were then repeated. Denervation did not modify bile flow, or bile salts, cholesterol, or phospholipid concentration or output. Biliary response to glucagon and secretin was similar before and after denervation. Somatostatin had an anticholerectic effect in both intact and denervated animals, but significantly reduced bile salt output only in the intact dogs. Feeding had a choleretic effect pre- and postdenervation, and the infusion of somatostatin following feeding decreased bile flow to the same degree before and after denervation. In the intact animals the output of all three biliary lipids was reduced by somatostatin after feeding but they were unaffected by somatostatin after denervation. Moreover, cholesterol and phospholipid outputs were stable after feeding in intact animals, but significantly decreased after denervation. 14C-erythritol clearance studies indicated no change in the canalicular component of bile flow with denervation, except again during somatostatin suppression of feeding. These data indicate that basal bile flow is normal after denervation but that innervation may play an important role in the modulation of responses to somatostatin and more complex stimuli such as feeding.


Crystal structure of a S-adenosyl-L-methionine-dependent O-methyltransferase-like enzyme from Aspergillus flavus.
S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases) are widely distributed among almost all organisms and often characterized with conserved Rossmann fold, TIM barrel, and D×G×G×G motif. However, some MTases show no methyltransferase activity. In the present study, the crystal structure of LepI, one MTase-like enzyme isolated from A. flavus that catalyzes pericyclic reactions, was investigated to determine its structure-function relationship. The overall structure of LepI in complex with the SAM mimic S-adenosyl-L-homocysteine (SAH) (PDB ID: 6IV7) indicated that LepI is a tetramer in solution. The residues His133, Arg197, Arg295, and Asp296 located near the active site can form hydrogen bonds with the substrate, thus participating in catalytic reactions. The binding of SAH in LepI is almost identical to that in other resolved MTases; however, the location of catalytic residues differs significantly. Phylogenetic trials suggest that LepI proteins share a common ancestor in plants and algae, which may explain the conserved SAM-binding site. However, the accelerated evolution of A. flavus has introduced both functional and structural changes in LepI. More importantly, the residue Arg295, which is unique to LepI, might be a key determinant for the altered enzymatic behavior. Collectively, the differences in the composition of catalytic residues, as well as the unique tetrameric form of LepI, define its unique enzymatic behavior. The present work provides an additional understanding of the structure-function relationship of MTases and MTase-like enzymes.


Impact of severe acute respiratory syndrome on the status of lung cancer chemotherapy patients and a correlation of the signs and symptoms.
Our aim was to describe the impact of severe acute respiratory syndrome (SARS) on the status and chemotherapy of non-small-cell lung cancer (NSCLC) patients who had entered clinical trials, and to review how to differentiate the signs and symptoms of SARS from lung cancer and its treatment-related toxicities. A prospective case series involving 79 NSCLC patients who were enrolled in clinical trials undergoing chemotherapy at Taipei Veterans General Hospital, between April 1 and July 15, 2003, was studied. Whether or not there existed a delay, omission, or refusal of scheduled chemotherapy, was recorded. Whether or not our patients had been suspected of or treated as having SARS, was recorded. The patients filled out questionnaires regarding lung cancer treatment and the risk of getting SARS from the hospital. Among these patients, five were placed in an isolation unit to rule out SARS infection during this period of time, and no patient was documented to have suffered from a SARS infection after examinations. Of 373 scheduled chemotherapy injections in 79 patients, a delay in treatment occurred only 10 times. Three patients refused further chemotherapy because of a fear of getting SARS if they visited the hospital. Fifty-eight patients responded to our questionnaires. Thirty-seven patients (63.8%) were afraid of visiting hospital during this SARS infection period. Twenty-one patients (36.2%) felt that a SARS infection was more severe and fatal than their lung cancer. In conclusion, SARS is a new disease entity that is highly contagious. Its clinical manifestations overlap with the signs and symptoms of lung cancer. Thus, a clear differentiation between the two conditions is needed, especially for those patients who are under active anti-cancer treatment.


Medicinal chemistry of the epigenetic diet and caloric restriction.
The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulation have been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance because of the concept that external factors such as nutrition and diet may possess the ability to alter gene expression without modifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane (SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending the human lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake while concurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging process through histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposed as two important mechanisms that modulate and potentially slow the progression of age-related diseases such as cardiovascular disease (CVD), cancer, obesity, Alzheimer's and osteoporosis to name a few. While many investigators have examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases, their epigenetic effects and their medicinal chemistry.


Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19.
Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.


Strain-programmable fiber-based artificial muscle.
Artificial muscles may accelerate the development of robotics, haptics, and prosthetics. Although advances in polymer-based actuators have delivered unprecedented strengths, producing these devices at scale with tunable dimensions remains a challenge. We applied a high-throughput iterative fiber-drawing technique to create strain-programmable artificial muscles with dimensions spanning three orders of magnitude. These fiber-based actuators are thermally and optically controllable, can lift more than 650 times their own weight, and withstand strains of >1000%. Integration of conductive nanowire meshes within these fiber-based muscles offers piezoresistive strain feedback and demonstrates long-term resilience across >105 deformation cycles. The scalable dimensions of these fiber-based actuators and their strength and responsiveness may extend their impact from engineering fields to biomedical applications.


Effects of placebo on bench throw performance of Paralympic weightlifting athletes: a pilot study.
The aim of the present study was to analyse the effects of placebo on bench throw performance in Paralympic weightlifting athletes. The study involved four Paralympic weightlifting male athletes (age: 40.25 ± 9.91 years, weight: 60.5 ± 8.29 kg, height: 1.60 ± 0.15 m) that visited the laboratory in three occasions, separated by 72 h. In the first session, the athletes were tested for bench press one repetition maximum (1RM). The other two sessions were performed in a randomized counter-balanced order and involved bench throw tests performed either after taking placebo while being informed that the capsule contained caffeine or without taking any substance (control). The bench throw tests were performed with loads corresponding to 50, 60, 70 and 80% of the bench press 1RM. According to the results, mean velocity (∆: 0.08 m/s, ES 0.36, p < 0.05) and mean propulsive velocity (∆: 0.11 m/s, ES 0.49, p < 0.05) at 50% of 1RM were significantly higher during placebo than control (p < 0.05). However, there were no difference between control and placebo for 60, 70 and 80% of 1RM (p > 0.05). Our results suggest that placebo intake, when the athletes were informed they were taking caffeine, might be an efficient strategy to improve the performance of explosive movements in Paralympic weightlifting athletes when using low-loads. This brings the possibility of using placebo in order to increase performance, which might reduce the risks associated with ergogenic aids, such as side-effects and positive doping testing.


Cellular response to phase-separated blends of tyrosine-derived polycarbonates.
Two-dimensional thin films consisting of homopolymer and discrete compositional blends of tyrosine-derived polycarbonates were prepared and characterized in an effort to elucidate the nature of different cell responses that were measured in vitro. The structurally similar blends were found to phase separate after annealing with domain sizes dependent on the overall composition. The thin polymer films were characterized with the use of atomic force microscopy (AFM), water contact angles, and time-of-flight secondary ion mass spectrometry (TOF-SIMS) and significant changes in roughness were measured following the annealing process. Genetic expression profiles of interleukin-1beta and fibronectin in MC3T3-E1 osteoblasts and RAW 264.7 murine macrophages were measured at several time points, demonstrating the time and composition-dependent nature of the cell responses. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) depicted upregulation of the fibronectin gene copy numbers in each of the blends relative to the homopolymers. Moreover, the interleukin-1beta expression profile was found to be compositionally dependent. The data suggest strongly that optimal composition and processing conditions can significantly affect the acute inflammatory and extracellular matrix production responses.


Residency Training in Robotic General Surgery: A Survey of Program Directors.
Robotic surgery continues to expand in minimally invasive surgery; however, the literature is insufficient to understand the current training process for general surgery residents. Therefore, the objectives of this study were to identify the current approach to and perspectives on robotic surgery training. An electronic survey was distributed to general surgery program directors identified by the Accreditation Council for Graduate Medical Education website. Multiple choice and open-ended questions regarding current practices and opinions on robotic surgery training in general surgery residency programs were used. 20 program directors were surveyed, a majority being from medium-sized programs (4-7 graduating residents per year). Most respondents (73.68%) had a formal robotic surgery curriculum at their institution, with 63.16% incorporating simulation training. Approximately half of the respondents believe that more time should be dedicated to robotic surgery training (52.63%), with simulation training prior to console use (84.21%). About two-thirds of the respondents (63.16%) believe that a formal robotic surgery curriculum should be established as a part of general surgery residency, with more than half believing that exposure should occur in postgraduate year one (55%). A formal robotics curriculum with simulation training and early surgical exposure for general surgery residents should be given consideration in surgical residency training.


Current perceptions of respite care: experiences of family and informal carers of people with a learning disability.
Access to regular, high-quality respite care has a beneficial impact on a carer's ability to fulfil their caring role, but provision varies widely. The current study aims to report family and informal carers' perceptions of respite care services offered to them by their local authority. A mixed method, triangulated design, yielded both quantitative and qualitative data. Members of a parent/carer federation were sent a questionnaire which included a section on 'respite care'; 151 of 647 responded. Two focus groups were held with 15 carers who had previously completed the questionnaire. The majority of carers reported that their respite needs were not being met. Unmet needs were hampered by the lack of information regarding criteria for access to respite. Discrepancies were evident between professionals and carers on a shared definition of respite care. Carers were unsure of exactly which activities constituted respite care and for whom the service was being provided.


Astringency is a trigeminal sensation that involves the activation of G protein-coupled signaling by phenolic compounds.
Astringency is an everyday sensory experience best described as a dry mouthfeel typically elicited by phenol-rich alimentary products like tea and wine. The neural correlates and cellular mechanisms of astringency perception are still not well understood. We explored taste and astringency perception in human subjects to study the contribution of the taste as well as of the trigeminal sensory system to astringency perception. Subjects with either a lesion or lidocaine anesthesia of the Chorda tympani taste nerve showed no impairment of astringency perception. Only anesthesia of both the lingual taste and trigeminal innervation by inferior alveolar nerve block led to a loss of astringency perception. In an in vitro model of trigeminal ganglion neurons of mice, we studied the cellular mechanisms of astringency perception. Primary mouse trigeminal ganglion neurons showed robust responses to 8 out of 19 monomeric phenolic astringent compounds and 8 polymeric red wine polyphenols in Ca(2+) imaging experiments. The activating substances shared one or several galloyl moieties, whereas substances lacking the moiety did not or only weakly stimulate responses. The responses depended on Ca(2+) influx and voltage-gated Ca(2+) channels, but not on transient receptor potential channels. Responses to the phenolic compound epigallocatechin gallate as well as to a polymeric red wine polyphenol were inhibited by the Gαs inactivator suramin, the adenylate cyclase inhibitor SQ, and the cyclic nucleotide-gated channel inhibitor l-cis-diltiazem and displayed sensitivity to blockers of Ca(2+)-activated Cl(-) channels.


Ephedrine versus phenylephrine: prevention of hypotension during spinal block for cesarean section and effects on the fetus.
Hypotension during spinal block for cesarean section is secondary to the sympathetic blockade and aorto-caval compression by the uterus and it can be deleterious to both the fetus and the mother. Ephedrine and phenylephrine improve venous return after sympathetic blockade during the spinal block. The objective of this study was to compare the efficacy of ephedrine and phenylephrine in the prevention and treatment of maternal hypotension during spinal block and to evaluate their side effects and fetal changes. Sixty patients undergoing spinal block with bupivacaine and sufentanil for cesarean section were randomly divided in two groups to receive prophylactic ephedrine (Group E, n = 30, dose = 10 mg) or phenylephrine (Group P, n = 30, dose = 80 microg). Hypotension (blood pressure equal or lower than 80% of baseline values) was treated with bolus administration of the vasoconstrictor at 50% of the initial dose. The incidence of hypotension, reactive hypertension, bradycardia, and vomiting, and Apgar scores on the 1st and 5th minutes, and blood gases of the umbilical cord blood were evaluated. The mean dose of ephedrine used was 14.8 +/- 3.8 mg and of phenylephrine was 186.7 +/- 52.9 microg. Demographic parameters and the incidence of vomiting, bradycardia, and reactive hypertension were similar in both groups. Hypotension had an incidence of 70% in Group E and 93% in Group P (p < 0.05). The mean arterial pH of the umbilical cord blood and the Apgar score in the 1st minute were lower in Group E (p < 0.05). Differences in the Apgar score in the 5th minute were not observed. Ephedrine was more effective than phenylephrine in the prevention of hypotension. Both drugs had similar incidence of side effects. Fetal repercussions were less frequent with phenylephrine and were transitory with the use of ephedrine.


Eyes on me: an fMRI study of the effects of social gaze on action control.
Previous evidence suggests that 'social gaze' can not only cause shifts in attention, but also can change the perception of objects located in the direction of gaze and how these objects will be manipulated by an observer. These findings implicate differences in the neural networks sub-serving action control driven by social cues as compared with nonsocial cues. Here, we sought to explore this hypothesis by using functional magnetic resonance imaging and a stimulus-response compatibility paradigm in which participants were asked to generate spatially congruent or incongruent motor responses to both social and nonsocial stimuli. Data analysis revealed recruitment of a dorsal frontoparietal network and the locus coeruleus for the generation of incongruent motor responses, areas previously implicated in controlling attention. As a correlate for the effect of 'social gaze' on action control, an interaction effect was observed for incongruent responses to social stimuli in sub-cortical structures, anterior cingulate and inferior frontal cortex. Our results, therefore, suggest that performing actions in a--albeit minimal--social context significantly changes the neural underpinnings of action control and recruits brain regions previously implicated in action monitoring, the reorienting of attention and social cognition.


Flow situations during everyday practice in a medical hospital ward. Results from a study based on experience sampling method.
Nursing is a constant balance between strain and stimulation and work and health research with a positive reference point has been recommended. A health-promoting circumstance for subjective experience is flow, which is a psychological state, when individuals concurrently experience happiness, motivation and cognitive efficiency. Flow situations can be identified through individuals' estimates of perceived challenge and skills. There is, to the best of our knowledge, no published study of flow among health care staff. The aim of this study was to identify flow-situations and study work-related activities and individual factors associated with flow situations, during everyday practice at a medical emergency ward in Sweden, in order to increase the knowledge on salutogenic health-promoting factors. The respondents consisted of 17 assistant nurses and 14 registered nurses, who randomly and repeatedly answered a small questionnaire, through an experience sampling method, during everyday nursing practice. The study resulted in 497 observations. Flow situations were defined as an exact match between a high challenge and skill estimation and logistic regression models were used to study different variables association to flow situations. The health care staff spent most of its working time in individual nursing care and administrative and communicative duties. The assistant nurses were more often occupied in individual nursing care, while the registered nurses were more involved in medical care and administrative and communicative duties. The study resulted in 11.5% observations of flow situations but the relative number of flow situations varied between none to 55% among the participants. Flow situations were positively related to medical care activities and individual cognitive resources. Taking a break was also positively associated with flow situations among the assistant nurses. The result showed opportunities for work-related interventions, with an adherent increase in flow situations, opportunity for experience of flow and work-related health among the nursing staff in general and among the assistant nurses in particular.


Do differences in work disability duration by interjurisdictional claim status vary by industry and jurisdictional context?
To examine whether differences in work disability duration between out-of-province and within-province workers differed by industry and jurisdictional context. Workers' compensation data were used to identify comparable lost time, work-related injury and musculoskeletal disorder claims accepted in six Canadian jurisdictions between 2006 and 2015. Out-of-province workers were identified as workers who filed claims in a different provincial jurisdiction to their province of residence. Coarsened exact matching was used to match out-of-province workers with within-province workers based on observable characteristics. Quantile regression models were used to estimate differences in cumulative disability days paid between out-of-province workers and within-province workers at different percentiles in the disability distribution, adjusting for confounders. Compared with within-province workers, out-of-province workers were paid more disability days even after matching and adjusting on observable characteristics. Differences between the two groups of workers were observed for short-duration, medium-duration and long-duration claims (differences of 1.57, 6.39, 21.42, 46.43 days at the 25th, 50th, 75th and 90th percentiles, respectively). Industry-specific models showed that differences were largest in construction, transportation and warehousing, and mining, quarrying and oil and gas extraction. Jurisdiction-specific models showed that differences were largest in the western provinces where out-of-province workers were concentrated in those sectors. Out-of-province workers are a vulnerable group with respect to risk of longer work disability duration. Workers' compensation systems, employers and healthcare providers may need to tailor specific interventions for these types of workers, particularly those employed in resource economy-dependent regions that are far from their regions of residence.


Adsorption and solar light decomposition of acetone on anatase TiO2 and niobium doped TiO2 thin films.
Adsorption and solar light decomposition of acetone was studied on nanostructured anatase TiO2 and Nb-doped TiO2 films made by sol-gel methods (10 and 20 mol % NbO2.5). A detailed characterization of the film materials show that films contain only nanoparticles with the anatase modification with pentavalent Nb oxide dissolved into the anatase structure, which is interpreted as formation of substituted Nb=O clusters in the anatase lattice. The Nb-doped films displayed a slight yellow color and an enhanced the visible light absorption with a red-shift of the optical absorption edge from 394 nm for the pure TiO2 film to 411 nm for 20 mol % NbO2.5. In-situ Fourier transform infrared (FTIR) transmission spectroscopy shows that acetone adsorbs associatively with eta1-coordination to the surface cations on all films. On Nb-doped TiO2 films, the carbonyl bonding to the surface is stabilized, which is evidenced by a lowering of the nu(C=O) frequency by about 20 cm(-1) to 1672 cm(-1). Upon solar light illumination acetone is readily decomposed on TiO2, and stable surface coordinated intermediates are formed. The decomposition rate is an order of magnitude smaller on the Nb-doped films despite an enhanced visible light absorption in these materials. The quantum yield is determined to be 0.053, 0.004 and 0.002 for the pure, 10% Nb:TiO2, and 20%Nb:TiO2, respectively. Using an interplay between FTIR and DFT calculations we show that the key surface intermediates are bidentate bridged formate and carbonate, and H-bonded bicarbonate, respectively, whose concentration on the surface can be correlated with their heats of formation and bond strength to coordinatively unsaturated surface Ti and Nb atoms at the surface. The oxidation rate of these intermediates is substantially slower than the initial acetone decomposition rate, and limits the total oxidation rate at t>7 min on TiO2, while no decrease of the rate is observed on the Nb-doped films. The rate of degradation of key surface intermediates is different on pure TiO2 and Nb-doped TiO2, but cannot explain the overall lower total oxidation rate for the Nb-doped films. Instead the inferior photocatalytic activity in Nb-doped TiO2 is attributed to an enhanced electron-hole pair recombination rate due to Nb=O cluster and cation vacancy formation.


Disentangled representation learning in cardiac image analysis.
Typically, a medical image offers spatial information on the anatomy (and pathology) modulated by imaging specific characteristics. Many imaging modalities including Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) can be interpreted in this way. We can venture further and consider that a medical image naturally factors into some spatial factors depicting anatomy and factors that denote the imaging characteristics. Here, we explicitly learn this decomposed (disentangled) representation of imaging data, focusing in particular on cardiac images. We propose Spatial Decomposition Network (SDNet), which factorises 2D medical images into spatial anatomical factors and non-spatial modality factors. We demonstrate that this high-level representation is ideally suited for several medical image analysis tasks, such as semi-supervised segmentation, multi-task segmentation and regression, and image-to-image synthesis. Specifically, we show that our model can match the performance of fully supervised segmentation models, using only a fraction of the labelled images. Critically, we show that our factorised representation also benefits from supervision obtained either when we use auxiliary tasks to train the model in a multi-task setting (e.g. regressing to known cardiac indices), or when aggregating multimodal data from different sources (e.g. pooling together MRI and CT data). To explore the properties of the learned factorisation, we perform latent-space arithmetic and show that we can synthesise CT from MR and vice versa, by swapping the modality factors. We also demonstrate that the factor holding image specific information can be used to predict the input modality with high accuracy. Code will be made available at https://github.com/agis85/anatomy_modality_decomposition.


What is the private sector? Understanding private provision in the health systems of low-income and middle-income countries.
Private health care in low-income and middle-income countries is very extensive and very heterogeneous, ranging from itinerant medicine sellers, through millions of independent practitioners-both unlicensed and licensed-to corporate hospital chains and large private insurers. Policies for universal health coverage (UHC) must address this complex private sector. However, no agreed measures exist to assess the scale and scope of the private health sector in these countries, and policy makers tasked with managing and regulating mixed health systems struggle to identify the key features of their private sectors. In this report, we propose a set of metrics, drawn from existing data that can form a starting point for policy makers to identify the structure and dynamics of private provision in their particular mixed health systems; that is, to identify the consequences of specific structures, the drivers of change, and levers available to improve efficiency and outcomes. The central message is that private sectors cannot be understood except within their context of mixed health systems since private and public sectors interact. We develop an illustrative and partial country typology, using the metrics and other country information, to illustrate how the scale and operation of the public sector can shape the private sector's structure and behaviour, and vice versa.


Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.
Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose- and time-dependent manner. This inhibition resulted in apoptosis induction, G(2)-M arrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation.


Magnetic resonance imaging findings of spinal intramedullary spirocercosis.
Spirocerca lupi is a nematode infecting dogs in tropical and subtropical areas. Aberrant S. lupi migration to different body organs, including the spinal cord, has been documented. To date, the diagnosis of aberrant spinal cord migration was made at post-mortem examination or as an incidental finding, during spinal surgery. We describe two dogs with acute asymmetric paraparesis that were subsequently diagnosed with spinal cord spirocercosis. In magnetic resonance (MR) images of the spine, T2 hyperintense lesions were seen in the spinal cord of both dogs. The lesions appeared isointense on T1-weighted images and focal enhancement was detected after gadolinium administration. The MR imaging findings were compatible with focal inflammation, presumably along the parasite migration tract. Gross and microscopic pathologic findings confirmed the diagnosis of aberrant spinal intramedullary migration of S. lupi in one dog, and in the other dog, the clinical and imaging findings were supportive of this diagnosis.


Experimental tests of a simple diffusion model for the estimation of scattering and absorption coefficients of turbid media from time-resolved diffuse reflectance measurements.
When a picosecond light pulse is incident upon a turbid medium such as tissue, the temporal distribution of diffusely reflected and transmitted photons depends on the optical absorption and scattering properties of the medium. From diffusion theory it is possible to derive analytic expressions for the pulse shape in terms of the optical interaction coefficients of a homogeneous semi-infinite medium. Experimental tests of this simple model in tissue-simulating liquid phantoms of different geometries are presented here. The results of these tests show that, in a semi-infinite phantom, the application of the diffusion model provides estimates of the absorption and transport-scattering coefficients that are accurate to better than 10%. Comparable accuracy was also obtained with this simple model for finite slab, cylindrical, and spherical volumes as long as the objects were of sufficient size. For smaller volumes the absorption coefficient was overestimated because of the significant loss of photons at the bounda ries of the object.


General surgical operations in the United States. 1979 to 1984.
Utilizing data from the National Center for Health Statistics, an in-depth analysis of numbers of general surgical operations from 1979 to 1984 was performed. During the study period, there was an increase in the total number of general surgical operations of 7%. During the same five-year period the number of general surgeons increased by 13%. The 25 most common general surgical operations constitute 71% of all general surgical operations. In 1983, general surgical operations represented 27% of all surgical procedures completed in this country. These statistics illustrate the dynamics of general surgical practice. They show that the number of general surgical operations has minimally increased over the last five years, despite a constantly increasing number of general surgeons. If current trends continue, then future individual operative workloads will decrease with possible adverse effects on the quality of general surgical care.


Factors associated with the sexual behavior of Canadian Aboriginal young people and their implications for health promotion.
We examined factors associated with having ever had sex, having more than 1 lifetime sexual partner, and condom nonuse at last incident of sexual intercourse among Canadian Aboriginal young people. We conducted a secondary analysis of data from the 2003 British Columbia Adolescent Health Survey, a cross-sectional survey of young people in grades 7 through 12. Of 1140 young Aboriginal men, 34% had ever had sex; of these, 63% had had more than 1 sexual partner, and 21% had not used a condom at their last incident of sexual intercourse. Of 1336 young Aboriginal women, 35% had ever had sex; of these, 56% had had more than 1 sexual partner, and 41% had not used a condom at their last incident of sexual intercourse. Frequent substance use, having been sexually abused, and having lived on a land reservation were strongly associated with sexual behavior outcomes. Feeling connected to family was strongly associated with increased condom use. Sexual behavior change interventions for Aboriginal young people must move beyond the individual and incorporate interpersonal and structural dimensions. Interventions to reduce substance use and sexual abuse and promote feelings of family connectedness in this population should be explored. Young people living on land reserves need special attention.


Antiepileptic drugs and psychopathology of epilepsy: an update.
Anti-epileptic drugs (AEDs) continue to be the mainstay of epilepsy treatment, but the benefits of seizure control need to be weighed carefully against possible adverse effects, which can include behavioral problems and psychiatric disorders. In this paper, the associations between AEDs and psychosis, depression and behavioral changes are reviewed. The concept of forced normalization and its clinical counterpart, alternative psychosis, are also discussed. Depression seems to be linked with AEDs potentiating GABAergic neurotransmission in patients with limbic system abnormalities such as hippocampal sclerosis. Psychoses have been described as associated with several of the new AEDs, and they are often seen in a setting in which previously refractory patients suddenly become seizure-free. In general terms, the use of AEDs in monotherapy, adopting slow titration schedules and low doses when possible, can significantly reduce the occurrence of behavioral adverse effects. A previous history of psychiatric disorder or a familial predisposition are important risk factors and should be always considered when choosing the appropriate AED.


BLOOD PLASMA PROTEIN PRODUCTION AND UTILIZATION : THE INFLUENCE OF AMINO ACIDS AND OF STERILE ABSCESSES.
When blood plasma proteins are depleted by bleeding with return of the washed red blood cells (plasmapheresis) it is possible to bring dogs to a steady state of hypoproteinemia and a uniform plasma protein production on a basal low protein diet. These dogs are clinically normal. Introduction of variables into their standardized life gives insight into the production of plasma protein. Casein retested as the basal protein in the ration may show high yield of plasma protein, equal to 33 per cent of the protein fed. This equals the potency of liver protein (17 to 33 per cent) and approaches the utilization of plasma protein by mouth (40 per cent). Zein has no effect upon plasma protein regeneration but when it is supplemented with cystine, tryptophane, lysine, and glycine, there is a doubling of the liver basal plasma protein production and a retention of the fed protein nitrogen. Threonine does not modify the above reaction. Liver protein supplemented with cystine, leucine, glutamic acid, and glycine in the basal diet yields double the amount of new formed plasma protein compared with liver alone. This combination is then as potent as plasma protein itself when given by mouth-40 per cent utilization. Tyrosine or lysine, arginine, and isoleucine do not modify the above responses. Methionine is not as effective as cystine in supplementing gelatin and tyrosine to produce plasma protein. Cystine, leucine, and glutamic acid appear to be of primary importance in the building of new plasma protein in these experiments. Plasma protein formation is dependent upon materials coming from the body reserve and from the diet. Given an exhaustion of the reserve store there is very little plasma protein produced during a protein fast (3 to 6 gm. per week). A turpentine abscess does not modify this fasting plasma protein reaction. Homologous plasma given by vein will promptly correct experimental hypoproteinemia due to bleeding. It will maintain nitrogen equilibrium and replenish protein stores. Even during hypoproteinemia plasma protein may promptly pass out of the circulation to supply body needs for protein. Perhaps the most significant concept which derives from all these experiments is the fluidity of the body protein (including plasma protein)-a ready give and take between the protein depots-a "dynamic equilibrium" of body protein.


High-luminosity multipass cell for infrared imaging spectroscopy.
An original imaging multipass cell for infrared spectroscopy has been designed and built. The cell design is aimed at overcoming intrinsic sensitivity limitations associated with the low specific spectral radiance power of blackbody sources. Owing to the implemented low f number, the detector collects a large amount of the energy emitted over a wide angle by a blackbody source. In addition, the adopted optical configuration allows maintenance of the same spatial distribution of the radiance pattern at the cell entrance and exit (imaging capability) within an aperture area of several square millimeters. This feature allows the use of uncollimated blackbody-type emitter arrays and infrared sensor arrays coupled with linear, spectrally variable filters, and performance of spectroscopic measurements of infrared absorption for low concentrated gases detection. In the present design the cell has an f number of about 2, and the optical path is ten times larger than the cell length.


Learning the Gestalt rule of collinearity from object motion.
The Gestalt principle of collinearity (and curvilinearity) is widely regarded as being mediated by the long-range connection structure in primary visual cortex. We review the neurophysiological and psychophysical literature to argue that these connections are developed from visual experience after birth, relying on coherent object motion. We then present a neural network model that learns these connections in an unsupervised Hebbian fashion with input from real camera sequences. The model uses spatiotemporal retinal filtering, which is very sensitive to changes in the visual input. We show that it is crucial for successful learning to use the correlation of the transient responses instead of the sustained ones. As a consequence, learning works best with video sequences of moving objects. The model addresses a special case of the fundamental question of what represents the necessary a priori knowledge the brain is equipped with at birth so that the self-organized process of structuring by experience can be successful.


Identification of two quorum-sensing systems in Sinorhizobium meliloti.
Sinorhizobium meliloti is a free-living soil bacterium which is capable of establishing a symbiotic relationship with the alfalfa plant (Medicago sativa). This symbiosis involves a network of bacterium-host signaling, as well as the potential for bacterium-bacterium communication, such as quorum sensing. In this study, we characterized the production of N-acyl homoserine lactones (AHLs) by two commonly used S. meliloti strains, AK631 and Rm1021. We found that AK631 produces at least nine different AHLs, while Rm1021 produces only a subset of these molecules. To address the difference in AHL patterns between the strains, we developed a novel screening method to identify the genes affecting AHL synthesis. With this screening method, chromosomal groEL (groELc) was shown to be required for synthesis of the AHLs that are unique to AK631 but not for synthesis of the AHLs that are made by both AK631 and Rm1021. We then used the screening procedure to identify a mutation in a gene homologous to traM of Agrobacterium tumefaciens, which was able to suppress the phenotype of the groELc mutation. A traR homolog was identified immediately upstream of traM, and we propose that its gene product requires a functional groELc for activity and is also responsible for inducing the synthesis of the AHLs that are unique to AK631. We show that the traR/traM locus is part of a quorum-sensing system unique to AK631 and propose that this locus is involved in regulating conjugal plasmid transfer. We also present evidence for the existence of a second quorum-sensing system, sinR/sinI, which is present in both AK631 and Rm1021.


PPAR Genomics and Pharmacogenomics: Implications for Cardiovascular Disease.
The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly advancing field. This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.