Influence of bacterial extracellular polymeric substances on the formation of carbonaceous and nitrogenous disinfection byproducts.
Considering the regulatory presence of residual chlorine in water distribution systems, untreated organic matter may not be the sole contributor to disinfection byproduct (DBP) formation, given the presence of microbial biofilm with extracellular polymeric substances (EPS). This study investigated the influence of bacterial EPS on the formation of carbonaceous DBPs (C-DBPs) and nitrogenous DBPs (N-DBPs), reacting chlorine with Pseudomonas strains that produce different quantities and composition of EPS. When biomass is reacted in excess to chlorine, both C-DBPs and N-DBPs were produced without preference for speciation. However, under an excess of chlorine compared to biomass, increased EPS content led to enhanced formation of DBPs. The DBP yield of haloacetic acids (HAAs) was higher than that of trihalomethanes where dichloroacetic acid was dominant in HAA species. Additionally, chemical composition of EPS influenced the yields of DBPs. The N-DBP yield from P. putida EPS was two times higher than that of P. aeruginosa EPS, which suggested that higher organic nitrogen content in EPS contributes to higher N-DBP yield. Moreover, time-based experiments revealed that DBP formation from biomass occurs rapidly, reaching a maximum in less than four hours. Combined results suggest that bacterial EPS have significant roles in both the formation and fate of DBPs.


Far-field optical microscopy with a nanometer-scale resolution based on the in-plane image magnification by surface plasmon polaritons.
A new far-field optical microscopy capable of reaching nanometer-scale resolution is developed using the in-plane image magnification by surface plasmon polaritons. This approach is based on the optical properties of a metal-dielectric interface that may provide extremely large values of the effective refractive index neff up to 10(3) as seen by surface polaritons, and thus the diffraction limited resolution can reach nanometer-scale values of lambda/2neff. The experimental realization of the microscope has demonstrated the optical resolution better than 60 nm at 515 nm illumination wavelength.


[Endoscopic assistance in microvascular decompression of cranial nerves].
Microvascular decompression (MVD) is an effective method for treatment of trigeminal neuralgia (TN), hemifacial spasm (HFS), glossopharyngeal neuralgia (GPN). The aim of this study was to assess the role of endoscopic assistance in MVD for the treatment of cranial neuropathies. Since 2009 till 2011 133 patients with cranial neuropathies were treated by MVD in Burdenko Neurosurgical Institute, Moscow. In 22 patients (11 patients with HFS, 10 patients with TN, 1 with GPN) endoscopic assistance was applied during the MVD. We used minimally invasive retrosigmoid approach in a unilateral position. Cerebellopontine angle was explored by 30-degree or 70-degree telescope to visualize the root entry zone of trigeminal, facial or glossopharyngeal nerves and to locate the neurovascular conflict. In 9 patients with HFS and in 1 patient with TN and in another patient with GPN endoscopy discovered offending vessels that were not visible through the microscope. In all cases endoscope was used to exclude another site of compression and to verify decompression and to identify position of teflon and offending vessel after MVD. Immediately after the surgery excellent outcome was observed in 10 patients with HFS (89%), one patient was reoperated 1.5 years after first operation with positive effect. Relief of pain in early postoperative period was observed in patients with TN and GPN. There were no major complications and postoperative mortality in our series. Endoscopic assistance is very effective and helpful technique in MVD of cranial nerves, especially in cases with HFS. In this study the use of the endoscope allowed to identify the site of compression and to confirm the position of teflon after MVD.


Eco-systems biology--from the gene to the stream.
This review considers the implications for environmental health and ecosystem sustainability, of new developments in radiobiology and ecotoxicology. Specifically it considers how the non-targeted effects of low doses of radiation, which are currently being scrutinized experimentally, not only mirror similar effects from low doses of chemical stressors but may actually lead to unpredictable emergent effects at higher hierarchical levels. The position is argued that non-targeted effects are mechanistically important in coordinating phased hierarchical transitions (i.e. transitions which occur in a regulated sequence). The field of multiple stressors (both radiation and chemical) is highly complex and agents can interact in an additive, antagonist or synergistic manner. The outcome following low dose multiple stressor exposure also is impacted by the context in which the stressors are received, perceived or communicated by the organism or tissue. Modern biology has given us very sensitive methods to examine changes following stressor interaction with biological systems at several levels of organization but the translation of these observations to ultimate risk remains difficult to resolve. Since multiple stressor exposure is the norm in the environment, it is essential to move away from single stressor-based protection and to develop tools, including legal instruments, which will enable us to use response-based risk assessment. Radiation protection in the context of multiple stressors includes consideration of humans and non-humans as separate groups requiring separate assessment frameworks. This is because for humans, individual survival and prevention of cancer are paramount but for animals, it is considered sufficient to protect populations and cancer is not of concern. The need to revisit this position is discussed not only from the environmental perspective but also from the human health perspective because the importance of "pollution" (a generic term for multiple environmental stressors) as a cause of non-cancer disease is increasingly being recognized. Finally a way forward involving experimental assessment of biomarker performance to lead to a theoretical framework allowing modeling is suggested.


Autoantigen Tetramer Silences Autoreactive B Cell Populations.
Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, cross-linking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP139-151), referred to as 4-arm PLP139-151, was synthesized by copper-catalyzed azide-alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP139-151 completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP139-151 to PLP139-151-specific IgG in the mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to the free peptide. Furthermore, key PLP139-151-reactive B cells were depleted following 4-arm PLP139-151 treatment, resulting in significant reduction of proinflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP139-151 to silence autoreactive B cell populations and limit the downstream activation of effector cells.


Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction.
Serine hydroxymethyltransferase (SHMT) is an enzyme that catalyzes the reaction that converts serine to glycine. It plays an important role in one-carbon metabolism. Recently, SHMT has been shown to be associated with various diseases. Therefore, SHMT has attracted attention as a biomarker and drug target. However, the development of molecular probes responsive to SHMT has not yet been realized. This is because SHMT catalyzes an essential yet simple reaction; thus, the substrates that can be accepted into the active site of SHMT are limited. Here, we focus on the SHMT-catalyzed retro-aldol reaction rather than the canonical serine-glycine conversion and succeed in developing fluorescent and 19F NMR molecular probes. Taking advantage of the facile and direct detection of SHMT, the developed fluorescent probe is used in the high-throughput screening for human SHMT inhibitors, and two hit compounds are obtained.


Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice.
Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1β (IL-1β), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1β, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti-inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH.


Digesta kinetics in sheep and cattle fed diets with different forage to concentrate ratios at high and low intakes.
Effect of maintenance and ad libitum intakes on digesta kinetics was studied with six ruminally fistulated cows and six ruminally fistulated wethers to validate the use of sheep as a model of cattle. Complete diets were made up of ratios of alfalfa:cracked corn and soybean meal of 80:20, 55:45, and 30:70. The rate of passage of Cr-mordanted alfalfa and soybean meal in the reticulorumen was negatively related to percentage of concentrate in the diet in both species at low intakes. Passage values of particulate and liquid markers were faster at high than at low intakes in both species for all diets. Rumen liquid volume increased with intake only in the cows on the low and intermediate concentrate diets. No substantial differences were found in particulate passage values between sheep and cattle. However, liquid passage rates from the rumen and the differentials between liquid and particulate dilution rates were higher in cows than in sheep for all diets at both intakes. These results together with those for digestibility data reported in a previous communication suggest that caution should be exercised when extrapolating results from one species to the other.


The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC.
Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis. Five human lung cancer cell lines and one murine line were investigated for transforming growth factor beta inhibition via Pirfenidone by using flow cytometry, In-Cell western analysis, proliferation assays as well as comprehensive analyses of the transcriptome with subsequent bioinformatics analysis. Overall, Pirfenidone induced cell cycle arrest, down-regulated SMAD expression and reduced proliferation in lung cancer. Furthermore, cell stress pathways and pro-apoptotic signaling may be mediated by reduced expression of Survivin. A murine subcutaneous model was used to assess the in vivo drug efficacy of Pirfenidone and showed reduced tumor growth and increased infiltration of T cells and NK cells. This data warrant further clinical evaluation of Pirfenidone with advanced non-small cell lung cancer. The observed in vitro and in vivo effects point to a substantial benefit for using Pirfenidone to reactivate the local immune response and possible application in conjunction with current immunotherapies.


Lycium barbarum polysaccharides ameliorates renal injury and inflammatory reaction in alloxan-induced diabetic nephropathy rabbits.
This study was aimed to investigate the effect of Lycium barbarum polysaccharides (LBP) on renal function and inflammatory reaction in rabbits with diabetic nephropathy. Diabetes was induced by injecting alloxan (ALX). Japanese male white rabbits were randomly assigned into 5 groups: normal control group, diabetic nephropathy (DN) model group, LBP prevention group, positive control group and LBP treatment group. LBP (10mg/kg) was given to the LBP prevention group after diabetes mellitus (DM) model succeeded for 12weeks and to the LBP treatment group after DN model succeeded for 4weeks. Telmisartan (3.7mg/kg) was given to the positive group after DN model succeeded for 4weeks, and the same volume of balanced saline was given to the normal group and DN group for 12weeks. Urea nitrogen (BUN), creatinine (SCr), and C-reaction protein (CRP) in serum were detected at the end of the 12th week. The expression of MCP-1 mRNA and ICAM-1 mRNA extracted from cortex were detected by RT-PCR. Western blot analysis was carried out to examine NF-κB p65 protein expression. LBP improves the renal function and alleviates the inflammatory reaction in the kidneys of diabetic rabbits. In addition, the prevention effect of LBP is better than the treatment effect of LBP. LBP has obvious protective effect on the diabetic nephropathy rabbits' renal function and postpones the appearance and development of DN. The mechanisms may be related to the reduction the expression of MCP-1mRNA and ICAM-1mRNA by restraining the expression of NF-κB and AngII.


Increased Photochemical Efficiency in Cyanobacteria via an Engineered Sucrose Sink.
In plants, a limited capacity to utilize or export the end-products of the Calvin-Benson cycle (CB) from photosynthetically active source cells to non-photosynthetic sink cells can result in reduced carbon capture and photosynthetic electron transport (PET), and lowered photochemical efficiency. The down-regulation of photosynthesis caused by reduced capacity to utilize photosynthate has been termed 'sink limitation'. Recently, several cyanobacterial and algal strains engineered to overproduce target metabolites have exhibited increased photochemistry, suggesting that possible source-sink regulatory mechanisms may be involved. We directly examined photochemical properties following induction of a heterologous sucrose 'sink' in the unicellular cyanobacterium Synechococcus elongatus PCC 7942. We show that total photochemistry increases proportionally to the experimentally controlled rate of sucrose export. Importantly, the quantum yield of PSII (ΦII) increases in response to sucrose export while the PET chain becomes more oxidized from less PSI acceptor-side limitation, suggesting increased CB activity and a decrease in sink limitation. Enhanced photosynthetic activity and linear electron flow are detectable within hours of induction of the heterologous sink and are independent of pigmentation alterations or the ionic/osmotic effects of the induction system. These observations provide direct evidence that secretion of heterologous carbon bioproducts can be used as an alternative approach to improve photosynthetic efficiency, presumably by by-passing sink limitation. Our results also suggest that engineered microalgal production strains are valuable alternative models for examining photosynthetic sink limitation because they enable greater control and monitoring of metabolite fluxes relative to plants.


A Quasi-Metric Approach to Multidimensional Unfolding for Reducing the Occurrence of Degenerate Solutions.
In multidimensional unfolding (MDU), one typically deals with two-way, two-mode dominance data in estimating a joint space representation of row and column objects in a derived Euclidean space. Unfortunately, most unfolding procedures, especially nonmetric ones, are prone to yielding degenerate solutions where the two sets of points (row and column objects) are disjointed or separated in the derived joint space, providing very little insight as to the structure of the input data. We present a new approach to multidimensional unfolding which reduces the occurrence of degenerate solutions. We first describe the technical details of the proposed method. We then conduct a Monte Carlo simulation to demonstrate the superior performance of the proposed model compared to two non-metric procedures, namely, ALSCAL and KYST. Finally, we evaluate the performance of alternative models in two applications. The first application deals with student rank-order preferences (nonmetric data) for attending various graduate business (MBA) programs. Here, we compare the performance of our model with those of KYST and ALSCAL. The second application concerns student preference ratings (metric data) for a number of popular brands of analgesics. Here, we compare the performance of the proposed model with those of two metric procedures, namely, SMACOF-3 and GENFOLD 3. Finally, we provide some directions for future research.


Health-industry linkages for local health: reframing policies for African health system strengthening.
The benefits of local production of pharmaceuticals in Africa for local access to medicines and to effective treatment remain contested. There is scepticism among health systems experts internationally that production of pharmaceuticals in sub-Saharan Africa (SSA) can provide competitive prices, quality and reliability of supply. Meanwhile low-income African populations continue to suffer poor access to a broad range of medicines, despite major international funding efforts. A current wave of pharmaceutical industry investment in SSA is associated with active African government promotion of pharmaceuticals as a key sector in industrialization strategies. We present evidence from interviews in 2013-15 and 2017 in East Africa that health system actors perceive these investments in local production as an opportunity to improve access to medicines and supplies. We then identify key policies that can ensure that local health systems benefit from the investments. We argue for a 'local health' policy perspective, framed by concepts of proximity and positionality, which works with local priorities and distinct policy time scales and identifies scope for incentive alignment to generate mutually beneficial health-industry linkages and strengthening of both sectors. We argue that this local health perspective represents a distinctive shift in policy framing: it is not necessarily in conflict with 'global health' frameworks but poses a challenge to some of its underlying assumptions.


Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity.
Storage of erythrocytes in blood banks is associated with biochemical and morphological changes to RBCs (red blood cells). It has been suggested that these changes have potential negative clinical effects characterized by inflammation and microcirculatory dysfunction which add to other transfusion-related toxicities. However, the mechanisms linking RBC storage and toxicity remain unclear. In the present study we tested the hypothesis that storage of leucodepleted RBCs results in cells that inhibit NO (nitric oxide) signalling more so than younger cells. Using competition kinetic analyses and protocols that minimized contributions from haemolysis or microparticles, our data indicate that the consumption rates of NO increased ~40-fold and NO-dependent vasodilation was inhibited 2-4-fold comparing 42-day-old with 0-day-old RBCs. These results are probably due to the formation of smaller RBCs with increased surface area: volume as a consequence of membrane loss during storage. The potential for older RBCs to affect NO formation via deoxygenated RBC-mediated nitrite reduction was also tested. RBC storage did not affect deoxygenated RBC-dependent stimulation of nitrite-induced vasodilation. However, stored RBCs did increase the rates of nitrite oxidation to nitrate in vitro. Significant loss of whole-blood nitrite was also observed in stable trauma patients after transfusion with 1 RBC unit, with the decrease in nitrite occurring after transfusion with RBCs stored for >25 days, but not with younger RBCs. Collectively, these data suggest that increased rates of reactions between intact RBCs and NO and nitrite may contribute to mechanisms that lead to storage-lesion-related transfusion risk.


Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder.
Controversy surrounds the diagnostic categorization of generalized anxiety disorder (GAD). To examine the incidence, comorbidity, and risk patterns for anxiety and depressive disorders and to test whether developmental features of GAD more strongly support a view of this condition as a depressive as opposed to an anxiety disorder. Face-to-face, 10-year prospective longitudinal and family study with as many as 4 assessment waves. The DSM-IV Munich Composite International Diagnostic Interview was administered by clinically trained interviewers. Munich, Germany. A community sample of 3021 individuals aged 14 to 24 years at baseline and 21 to 34 years at last follow-up. Cumulative incidence of GAD, other anxiety disorders (specific phobias, social phobia, agoraphobia, and panic disorder), and depressive disorders (major depressive disorder, and dysthymia). Longitudinal associations between GAD and depressive disorders are not stronger than those between GAD and anxiety disorders or between other anxiety and depressive disorders. Survival analyses reveal that the factors associated with GAD overlap more strongly with those specific to anxiety disorders than those specific to depressive disorders. In addition, GAD differs from anxiety and depressive disorders with regard to family climate and personality profiles. Anxiety and depressive disorders appear to differ with regard to risk constellations and temporal longitudinal patterns, and GAD is a heterogeneous disorder that is, overall, more closely related to other anxiety disorders than to depressive disorders. More work is needed to elucidate the potentially unique aspects of pathways and mechanisms involved in the etiopathogenesis of GAD. Grouping GAD with depressive disorders, as suggested by cross-sectional features and diagnostic comorbidity patterns, minimizes the importance of longitudinal data on risk factors and symptom trajectories.


Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM.
Immune defect in ataxia telangiectasia patients has been attributed to either the failure of V(D)J recombination or class-switch recombination, and the chromosomal translocation in their lymphoma often involves the TCR gene. The ATM-deficient mouse exhibits fewer CD4 and CD8 single-positive T cells because of a failure to develop from the CD4(+)CD8(+) double-positive phase to the single-positive phase. Although the occurrence of chromosome 14 translocations involving TCR-δ gene in ATM-deficient lymphomas suggests that these are early events in T-cell development, a thorough analysis focusing on early T-cell development has never been performed. Here we demonstrate that ATM-deficient mouse thymocytes are perturbed in passing through the β- or γδ-selection checkpoint, leading in part to the developmental failure of T cells. Detailed karyotype analysis using the in vitro thymocyte development system revealed that RAG-mediated TCR-α/δ locus breaks occur and are left unrepaired during the troublesome β- or γδ-selection checkpoints. By getting through these selection checkpoints, some of the clones with random or nonrandom chromosomal translocations involving TCR-α/δ locus are selected and accumulate. Thus, our study visualized the first step of multistep evolutions toward lymphomagenesis in ATM-deficient thymocytes associated with T-lymphopenia and immunodeficiency.


Understanding Gas adsorption selectivity in IRMOF-8 using molecular simulation.
Grand canonical Monte Carlo simulations were used to explore the adsorption behavior of methane, ethane, ethylene, and carbon dioxide in isoreticular metal-organic frameworks, IRMOF-1, noninterpenetrated IRMOF-8, and interpenetrated IRMOF-8. The simulated isotherms are compared with experimentally measured isotherms, when available, and a good agreement is observed. In the case of IRMOF-8, the agreement is much better for the interpenetrated model than for the noninterpenetrated model, suggesting that the experimental data was obtained on an essentially interpenetrated structure. Simulations show that carbon dioxide is preferentially adsorbed over methane, and a selective adsorption at low pressures of ethane over ethylene, especially in the case of IRMOF-8, confirm recent experimental results. Analysis of simulation results on both the interpenetrated and the noninterpenetrated structures shows that interpenetration is responsible for the higher adsorbed amounts of ethane at low pressures (<100 kPa) and for the interesting selectivity for ethane in ethane/ethylene binary mixtures. Van der Waals interactions seem to be enhanced in the interpenetrated structure, favoring ethane adsorption. This indicates that interpenetrated MOF structures may be of interest for the separation of small gas molecules.


Chocolate feeding studies: a novel approach for evaluating the plasma lipid effects of stearic acid.
Milk chocolate does not adversely affect plasma lipids and lipoproteins despite its relatively high content of saturated fatty acids (SFAs). Evidence from well-controlled feeding studies indicates that this unique response is due to the high proportion of stearic acid in milk chocolate. In experimental diets containing very high amounts (eg, 280 g/d, or 10 oz/d) and more typical amounts (46.2 g, or 1.65 oz) of milk chocolate, plasma total- and low-density-lipoprotein-cholesterol concentrations are not elevated. Furthermore, isoenergetic substitution of one milk chocolate bar per day for a high-carbohydrate snack in a National Cholesterol Education Program/American Heart Association Step 1 Diet does not adversely affect the cholesterol-lowering response. These findings indicate that stearic acid is not hypercholesterolemic as are the other long-chain SFAs. Thus, as illustrated by the different results generated from the predictive equations that group all long-chain SFAs vs those that consider stearic acid separately, grouping stearic acid with other SFAs appears to misrepresent the actual blood cholesterol response.


Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing.
The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-ss showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-ss-dependent physiological and pathological matrix remodeling.


The smashHitCore Ontology for GDPR-Compliant Sensor Data Sharing in Smart Cities.
The adoption of the General Data Protection Regulation (GDPR) has resulted in a significant shift in how the data of European Union citizens is handled. A variety of data sharing challenges in scenarios such as smart cities have arisen, especially when attempting to semantically represent GDPR legal bases, such as consent, contracts and the data types and specific sources related to them. Most of the existing ontologies that model GDPR focus mainly on consent. In order to represent other GDPR bases, such as contracts, multiple ontologies need to be simultaneously reused and combined, which can result in inconsistent and conflicting knowledge representation. To address this challenge, we present the smashHitCore ontology. smashHitCore provides a unified and coherent model for both consent and contracts, as well as the sensor data and data processing associated with them. The ontology was developed in response to real-world sensor data sharing use cases in the insurance and smart city domains. The ontology has been successfully utilised to enable GDPR-complaint data sharing in a connected car for insurance use cases and in a city feedback system as part of a smart city use case.


Against the right to die.
For some patients, a right to receive euthanasia will not enhance autonomy in the morally relevant sense. Even if these patients choose wisely whether to exercise their right to die, they will still be harmed by having been given it. Perhaps, then, physicians should have permission to administer voluntary euthanasia, but patients should not have a right to receive it.


Key determinants of AIDS impact in Southern sub-Saharan Africa.
To investigate why Southern sub-Saharan Africa is more severely impacted by HIV and AIDS than other parts of sub-Saharan Africa, I conducted a review of the literature that assessed viral, host and transmission (societal) factors. This narrative review evaluates: 1) viral factors, in particular the aggregation of subtype-C HIV infections in Southern sub-Saharan Africa; 2) host factors, including unique behaviour patterns, concomitant high prevalence of sexually transmitted diseases, circumcision patterns, average age at first marriage and immunogenetic determinants; and, 3) transmission and societal factors, including levels of poverty, degrees of literacy, migrations of people, extent of political corruption, and the usage of contaminated injecting needles in community settings. HIV prevalence data and published indices on wealth, fertility, and governmental corruption were correlated using statistical software. The high prevalence of HIV in Southern sub-Saharan Africa is not explained by the unusual prevalence of subtype-C HIV infection. Many host factors contribute to HIV prevalence, including frequency of genital ulcerating sexually transmitted infections, absence of circumcision (compiled odds ratios suggest a protective effect of between 40% and 60% from circumcision), and immunogenetic loci, but no factor alone explains the high prevalence of HIV in the region. Among transmission and societal factors, the wealthiest, most literate and most educated, but also the most income-disparate, nations of sub-Saharan Africa show the highest HIV prevalence. HIV prevalence is also highest within societies experiencing significant migration and conflict as well as in those with government systems experiencing a high degree of corruption. The interactions between poverty and HIV transmission are complex. Epidemiologic studies currently do not suggest a strong role for the community usage of contaminated injecting needles. Areas meriting additional study include clade type, host immunogenetic determinants, the complex interrelationship of HIV with poverty, and the community usage of contaminated injecting needles.


Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique.
The curative potential of bronchoscopic intervention, e.g. photodynamic therapy (PDT) and brachytherapy, for resectable radiographically occult lung cancer has been reported previously. Bronchoscopic electrocautery is currently feasible using an insulated flexible bronchoscope to coagulate and vaporize tumour tissue. Since the lesions are usually small, noninvasive bronchoscopic electrocautery may be able to eradicate radiographically occult lung cancer completely. In a prospective study, 13 patients with 15 radiographically occult lung cancer lesions were treated with bronchoscopic electrocautery. The duration of follow-up was > or = 16 months. The median age of the patients was 69 yrs (range 48-79 yrs). Fibreoptic bronchoscopy under local anaesthesia was used to coagulate the occult lung cancer. Approximately 30 W of energy was applied until visible necrosis of the tumour area became apparent. There were no immediate complications. In 10 patients with 12 lesions, a complete response (CR) was obtained (CR rate 80%; 95% confidence interval (95% CI) 52-96%). Median duration of follow-up was 21 months (range 16-43 months). Bronchoscopic electrocautery did not obtain a CR in the remaining three patients, but PDT also failed to achieve CR. Two patients underwent radical resection, and the tumours were histologically confirmed to be more invasive. One patient received external radiotherapy. Three patients with a CR died during follow-up, two as a result of myocardial infarction and apoplexy, and one because of metastasis from his previously resected T3N1 primary large cell cancer. Current data show bronchoscopic electrocautery to be equally effective and potentially as curative as photodynamic therapy for treating patients with radiographically occult lung cancer. Obvious advantages are that it is an inexpensive and simple procedure, which does not cause photosensitivity.


Preventing and managing aberrant drug-related behavior in primary care: systematic review of outcomes evidence.
Several strategies for preventing, identifying, and responding to aberrant opioid-related behaviors are recommended in pain management guidelines. This systematic review evaluated data supporting basic strategies for addressing aberrant opioid-related behaviors. Risk reduction strategies were identified via a review of available guidelines. Systematic literature searches of PubMed (May 1, 2007-January 18, 2013) identified articles with evidence relevant to nine basic strategies. Reference lists from relevant articles were reviewed for additional references of interest. Levels of evidence for articles identified were graded on a four-point scale (strongest evidence = level 1; weakest evidence = level 4) using Oxford Centre for Evidence-Based Medicine Levels of Evidence criteria. Weak to moderate evidence supports the value of thorough patient assessment, risk-screening tools, controlled-substance agreements, careful dose titration, opioid dose ceilings, compliance monitoring, and adherence to practice guidelines. Moderate to strong evidence suggests that prescribing tamper-resistant opioids may help prevent misuse but may also have the unintended consequence of prompting a migration of users to other marketed opioids, heroin, or other substances. Similarly, preliminary evidence suggests that although recent regulatory and legal efforts may reduce misuse, they also impose barriers to the legitimate treatment of pain. Despite an absence of consistent, strong supporting evidence, clinicians are advised to use each of the available risk-mitigation strategies in combination in an attempt to minimize the risk of abuse in opioid treatment patients. Physicians must critically evaluate their opioid prescribing and not only increase their efforts to prevent substance abuse but also not compromise pain management in patients who benefit from it.


Predicting the DNP-SENS efficiency in reactive heterogeneous catalysts from hydrophilicity.
Identification of surfaces at the molecular level has benefited from progress in dynamic nuclear polarization surface enhanced NMR spectroscopy (DNP SENS). However, the technique is limited when using highly sensitive heterogeneous catalysts due to secondary reaction of surface organometallic fragments (SOMFs) with stable radical polarization agents. Here, we observe that in non-porous silica nanoparticles (NPs) (dparticle = 15 nm) some DNP enhanced NMR or SENS characterizations are possible, depending on the metal-loading of the SOMF and the type of SOMF substituents (methyl, isobutyl, neopentyl). This unexpected observation suggests that aggregation of the nanoparticles occurs in non-polar solvents (such as ortho-dichlorobenzene) leading to (partial) protection of the SOMF inside the interparticle space, thereby preventing reaction with bulky polarization agents. We discover that the DNP SENS efficiency is correlated with the hydrophilicity of the SOMF/support, which depends on the carbon and SOMF concentration. Nitrogen sorption measurements to determine the BET constant (CBET) were performed. This constant allows us to predict the aggregation of silica nanoparticles and consequently the efficiency of DNP SENS. Under optimal conditions, CBET > 60, we found signal enhancement factors of up to 30.


Detection of CSF 14-3-3 protein in Guillain-Barré syndrome.
To search for biologic markers in the Guillain-Barré syndrome (GBS), we studied CSF samples from patients with GBS and neuropathy of various etiologies for the presence of 14-3-3 protein. CSF samples from patients with GBS, chronic neuropathies, motor neuron disease (MND), definite sporadic Creutzfeldt-Jakob disease (sCJD), and normal control subjects were analyzed by standard immunoblot assay, using a polyclonal anti-14-3-3 antibody. CSF samples were also tested with antibodies recognizing specific isoforms of 14-3-3 proteins, either after one-dimensional or two-dimensional electrophoretic separation. A positive 14-3-3 assay was observed in 29 of 38 patients with GBS and in 4 patients with MND and other neuropathies, including 2 subjects with vasculitic neuropathy (VN). In GBS, 14-3-3 protein was detected as early as 12 to 48 hours after disease onset and showed an isoform pattern different from that encountered in patients with noninflammatory neuropathies, VN, MND, and sCJD. Immunohistochemical studies performed in archival fatal GBS cases disclosed marked 14-3-3 expression by mononuclear inflammatory infiltrates and Schwann cells. CSF 14-3-3 assay may represent a useful biologic marker in patients with Guillain-Barré syndrome.


Comparison of Three Distinct Prophylactic Agents Against Invasive Fungal Infections in Patients Undergoing Haplo-identical Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide.
Over the past decade, invasive fungal infections (IFIs) have remained an important problem in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT). The optimal approach for prophylactic antifungal therapy has yet to bedetermined. We conducted a retrospective analysis, comparing the safety and efficacy of micafungin 50mg/day vs. fluconazole 400mg/day vs. itraconazole 200mg/day as prophylaxis for adult patients with various haematological diseases receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) followed by high-dose cyclophosphamide (PT-Cy). Overall, 99 patients were identified: 30 patients received micafungin, 50 and 19 patients received itraconazole and fluconazole, respectively. After a median follow-up of 12 months (range: 1-51), proven or probable IFIs were reported in 3 patients (10%) in the micafungin, 5 patients in the itraconazole (10%) and 2 patients (11%) in the fluconazole group (p=0.998). Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 3 [6%] in the itraconazole vs. 2 [11%] in the fluconazole group, p=0.589). Four patients (13%) in the micafungin group vs 13 (26%) patients in the itraconazole group and 10 (53%) patients in the fluconazole received empirical antifungal therapy (P = 0.19). No serious adverse events related to treatment were reported by patients, and there was no treatment discontinuation because of drug-related adverse events in both groups. The present analysis shows that micafungin did better than fluconazole in preventing invasive aspergillosis after transplant in these high-risk hematological diseases, as expected. In addition, micafungin was more effective than itraconazole in preventing all IFI episodes when also considering possible fungal infections. Future prospective studies would shed light on this issue, concerning this increasingly used transplant platform.


Modulation of Cav3.2 T-type calcium channel permeability by asparagine-linked glycosylation.
Low-voltage-gated T-type calcium channels are expressed throughout the nervous system where they play an essential role in shaping neuronal excitability. Defects in T-type channel expression have been linked to various neuronal disorders including neuropathic pain and epilepsy. Currently, little is known about the cellular mechanisms controlling the expression and function of T-type channels. Asparagine-linked glycosylation has recently emerged as an essential signaling pathway by which the cellular environment can control expression of T-type channels. However, the role of N-glycans in the conducting function of T-type channels remains elusive. In the present study, we used human Cav3.2 glycosylation-deficient channels to assess the role of N-glycosylation on the gating of the channel. Patch-clamp recordings of gating currents revealed that N-glycans attached to hCav3.2 channels have a minimal effect on the functioning of the channel voltage-sensor. In contrast, N-glycosylation on specific asparagine residues may have an essential role in the conducting function of the channel by enhancing the channel permeability and / or the pore opening of the channel. Our data suggest that modulation of N-linked glycosylation of hCav3.2 channels may play an important physiological role, and could also support the alteration of T-type currents observed in disease states.


Seasonal maintenance of influenza vaccine-induced antibody response in kidney transplant recipients.
Although annual influenza vaccination is recommended for kidney transplant recipients, efficacy as reflected by serum antibody titers has not been well studied beyond 1 month in kidney transplant recipients. We performed a single-center prospective cohort study of 51 kidney transplant recipients and 102 healthy controls receiving the 2006-2007 influenza vaccine. Anti-hemagglutinin antibody titers to A/H1N1, A/H3N2, and B were measured before and 1 month after vaccination, and again at the end of influenza season. The primary outcome was the proportion of participants maintaining seroprotection (antibody titer ≥1:32) for the duration of the influenza season after influenza vaccination. Median follow-up time was 175 and 155 days in the transplant and control groups, respectively. For types A/H1N1 and B, a similar high proportion of the transplant and control groups (88.5 and 81.6% vs. 83.7 and 74.2% for A/H1N1 and B, respectively) maintained seroprotection. For type A/H3N2, significantly less of the transplant group (66.7%) versus the control group (90%) maintained a protective influenza vaccine response (odds ratio 0.21, 95% confidence interval 0.07-0.64). This difference disappeared in adjusted analyses. Actual geometric mean titers decreased significantly within both groups (p < 0.001) but this did not differ between groups. Once they have developed protective vaccine-induced antibody responses to influenza vaccine, kidney transplant recipients are able to maintain adequate protective levels of antibody compared with healthy controls.


Chemistry and biology of ferritin.
Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.


[Patient positioning on the operating table in neurosurgery: sitting or lying].
Efficacy and safety of microvascular decompression of trigeminal nerve depending on the position on the operating table were assessed in 200 neurosurgical patients in retrospective observational study It was shown that efficacy doesn't depend on positioning. Lying position eliminates probability of such complications as postural hypotension, hypotension during surgery, tension pneumocephalus and peripheral nerves injury. Sitting position increases risk of air venous embolism by 25 times. Lying position increases risk of postoperative nasal liquorrhea by 4 times, but eliminates risk of postoperative paresis of trigeminal nerve. It is also decreases risk of corneal reflex reduction by 3 times, hyperpathia by 2 times and paresthesias by 5 times, but increases probability of postoperative hyperesthesia by 4 times. Microvascular decompression of trigeminal nerve in lying position is safer than similar operation in sitting position.


What can we do for people with drug-resistant epilepsy? The 2016 Wartenberg Lecture.
Treatment goals for epilepsy are no seizures, no side effects, as soon as possible, but these goals are too often unmet. Approximately 1 million people in the United States continue to have seizures despite adequate treatment with antiseizure drugs, representing 40% of those with epilepsy, and 80% of the cost of epilepsy. Drug-resistant epilepsy (DRE) can be associated with developmental delay in infants and young children, and severe disability and morbidity in older children and adults, as well as a mortality rate 5-10 times that of the general population. While diagnosis and treatment at a full-service (levels 3 and 4) epilepsy center are demonstrated to improve seizure control, fewer than 1% of people with DRE are referred, and those who are, are referred an average of over 20 years after onset of habitual seizures. A possible reason for this is the misconception that all these epilepsy centers offer is surgery. Specialized multidisciplinary teams, consisting of neurologists, clinical neurophysiologists, neurosurgeons, neuroradiologists, psychologists, psychiatrists, social workers, and counselors, which constitute full-service epilepsy centers, can recognize and address pseudopharmacoresistance due to nonadherence, seizures that are not epilepsy, treatable underlying conditions, misdiagnosis of epilepsy syndromes, treatment with the wrong drug or wrong dosage, and lifestyle issues that are remediable. A variety of alternative treatment approaches are offered in addition to surgery, and for patients who continue to have seizures, full-service epilepsy centers have psychologists, psychiatrists, social workers, and counselors specialized in recognizing, and addressing, the psychological and social challenges experienced by people with epilepsy. Surgery for epilepsy remains, arguably, the most underutilized of all acceptable medical interventions, and the reasons for this are unclear. Often, excellent surgical candidates are not recognized as such by general neurologists, but if more patients with DRE were referred to full-service epilepsy centers, more surgical candidates would be identified by epilepsy specialists. All patients with medication-resistant epilepsy, defined as failure of 2 appropriate trials of antiseizure drugs due to inefficacy and not intolerance, who continue to be compromised by seizures deserve a timely consultation at a full-service epilepsy center. Early referral provides the best opportunity to avoid irreversible psychological and social problems, a lifetime of disability, and premature death.


A validated LC-MS-MS method for simultaneous identification and quantitation of rodenticides in blood.
A rapid, highly sensitive and specific analytical method for the extraction, identification and quantification of nine rodenticides from whole blood has been developed and validated. Commercially available rodenticides in Australia include coumatetralyl, warfarin, brodifacoum, bromadiolone, difenacoum, flocoumafen, difethialone, diphacinone and chlorophacinone. A Waters ACQUITY UPLC TQD system operating in multiple reaction monitoring mode was used to conduct the analysis. Two different ionization techniques, ES+ and ES-, were examined to achieve optimal sensitivity and selectivity resulting in detection by MS-MS using electrospray ionization in positive mode for difenacoum and brodifacoum and in negative mode for all other analytes. All analytes were extracted from 200 µL of whole blood with ethylacetate and separated on a Waters ACQUITY UPLC BEH-C18 column using gradient elution. Ammonium acetate (10 mM, pH 7.5) and methanol were used as mobile phases with a total run time of 8 min. Recoveries were between 70 and 105% with limits of detection ranging from 0.5 to 1 ng/mL. The limit of quantitation was 2 ng/mL for all analytes. Calibration curves were linear within the range 2-200 ng/mL for all analytes with the coefficient of determination ≥0.98. The application of the proposed method using liquid-liquid extraction in a series of clinical investigations and forensic toxicological analyses was successful.


Individual differences in science competence among students are associated with ventrolateral prefrontal cortex activation.
Functional neuroimaging studies have revealed that, compared with novices, science experts show increased activation in dorsolateral and ventrolateral prefrontal brain areas associated with inhibitory control mechanisms when providing scientifically valid responses in tasks related to electricity and mechanics. However, no study thus far has explored the relationship between activation of the key brain regions involved in inhibitory control mechanisms, namely the ventrolateral prefrontal cortex (VLPC) and dorsolateral prefrontal cortex (DLPC), and individual differences in conceptual science competence, while controlling for scientific training. In the present study, 24 secondary school students (11 female participants, 13 male participants) were selected from a larger pool based on their performance on a conceptual science questionnaire and were divided into groups with low and high conceptual science competence. In an fMRI block design, participants had to verify the correctness (true or false) of congruent and incongruent statements. In congruent statements, both spontaneous and scientific conceptions about given natural phenomena lead to a scientifically appropriate judgment. However, in incongruent statements, commonly held spontaneous conceptions about natural phenomena lead to a scientifically inappropriate judgment. The interaction effect reveals that students with higher conceptual science competence display stronger activation of the left VLPC and DLPC in incongruent trials than in congruent trials. These findings show that activation of the VLPC and DLPC when reasoning in incongruent situations underlies individual differences in conceptual science competence, and suggests stronger recruitment of inhibitory control mechanisms in more competent individuals.


Vascular Dysfunction in Malaria: Understanding the Role of the Endothelial Glycocalyx.
Malaria caused by Plasmodium falciparum results in over 400,000 deaths annually, predominantly affecting African children. In addition, non-falciparum species including vivax and knowlesi cause significant morbidity and mortality. Vascular dysfunction is a key feature in malaria pathogenesis leading to impaired blood perfusion, vascular obstruction, and tissue hypoxia. Contributing factors include adhesion of infected RBC to endothelium, endothelial activation, and reduced nitric oxide formation. Endothelial glycocalyx (eGC) protects the vasculature by maintaining vessel integrity and regulating cellular adhesion and nitric oxide signaling pathways. Breakdown of eGC is known to occur in infectious diseases such as bacterial sepsis and dengue and is associated with adverse outcomes. Emerging studies using biochemical markers and in vivo imaging suggest that eGC breakdown occurs during Plasmodium infection and is associated with markers of malaria disease severity, endothelial activation, and vascular function. In this review, we describe characteristics of eGC breakdown in malaria and discuss how these relate to vascular dysfunction and adverse outcomes. Further understanding of this process may lead to adjunctive therapy to preserve or restore damaged eGC and reduce microvascular dysfunction and the morbidity/mortality of malaria.


Initiation of angiogenesis by human follicular fluid.
Angiogenesis was observed and measured after injection of human follicular fluid into rabbit corneas. Undiluted human follicular fluid stimulated angiogenesis in every case, with new blood vessels visible 3 days after injection and extending 2.0 millimeters from the corneal scleral limbus into the injection site by day 15. Stimulation of angiogenesis was lost by heating or diluting the follicular fluid but was retained after charcoal stripping or dialysis. Human follicular fluid contains an angiogenic factor that may be associated with perifollicular neovascularization during folliculogenesis.


Quality of Life in Newly Diagnosed Moderate-to-Severe Ulcerative Colitis: Changes in the MOSAIK Cohort Over 1 Year.
Improving quality of life has been gaining importance in ulcerative colitis (UC) management. The aim of this study was to investigate changes in health-related quality of life (HRQL) and related factors in patients with moderate-to-severe UC. A multicenter, hospital-based, prospective study was performed using a Moderate-to-Severe Ulcerative Colitis Cohort in Korea (the MOSAIK). Changes in HRQL, evaluated using the 12-Item Short Form Health Survey (SF-12) and Inflammatory Bowel Disease Questionnaire (IBDQ), were analyzed at the time of diagnosis and 1 year later. In a sample of 276 patients, the mean age was 38.4 years, and the majority of patients were male (59.8%). HRQL tended to increase in both the IBDQ and SF-12 1 year after diagnosis. A higher partial Mayo score was significantly related to poorer HRQL on the IBDQ and SF-12 in a linear mixed model (p<0.01). Inflammatory markers such as C-reactive protein (CRP) or erythrocyte sedimentation rate also showed a negative correlation on HRQL (p<0.05). Patients whose IBDQ score improved by 16 or more (71.2%) in 1 year were younger, tended to be nonsmokers, and had a lower partial Mayo score and CRP than those whose IBDQ score did not. There was no significant association between HRQL and disease extent, treatments at diagnosis, or the highest treatment step during the 1-year period. Optimally controlled disease status improves HRQL in patients with moderate-to-severe UC. The partial Mayo score and inflammatory markers may be potential indicators reflecting the influence of UC on patient`s daily lives.


Synergy between selection for production and longevity and the use of extended lactation: insights from a resource allocation model in a dairy goat herd.
Although most of the genetic progress in production efficiency is achieved through selection at a global scale, locally, farm managers can also influence the selection process to better match genotypes and their varying herd environment. This study focused on the influence of a particular management decision--the use of extended lactation (EL) in dairy goat production systems--as it affects the survival and reproduction rates at the herd level, which may then shape different long-term selection responses. The objective was to understand and quantify the influences of EL and variability in achieved intake level on the responses to selection for production, reproduction, and longevity. An animal model of resource allocation between life functions was applied to the dairy goat. It predicts the trajectory of change in the herd genetic composition as affected by the feeding level and the selection pressure applied by the manager. During 40 yr, goats were selected for milk yield, reproduction, and, with a different selection weight for age (WAGE), for longevity. Under varying achieved intake levels, increasing WAGE improved the survival rate but a nonlinear effect was observed for the average milk yield and BCS. When moderately increasing WAGE from 0, resources were reallocated from lactation towards body reserves and survival, which led to a trade-off at the herd level between improving survival and BCS and increasing milk yield. When further increasing WAGE, old females became systematically preferred regardless of their reproductive status and the proportion of EL in the herd increased. Females undergoing EL had reduced energetic costs of reproduction, which improved their probability of survival. Across generations, an increased herd incidence of EL led to a relaxation of the selection pressure on the resource allocation to body reserves, which is normally imposed by the manager's priority to achieve successful reproduction at each mating. As selection for longevity progressed, the incidence of high-producing females increased within the herd, driving a long-term trend in increased milk production. Thus, the use of EL as a management tool led to an alleviation of the trade-off between milk yield progress and survival improvement. Although the model simplifies the underlying physiology of nutrient allocation, it provides insights into how farm manager strategies can influence the development of genotype × environment interactions and promote herd robustness.


Regulatory effect of SOCS on NF-kappaB activity in murine monocytes/macrophages.
The suppressor of cytokine signaling (SOCS) group of proteins has been implicated in regulation of various cytokine signaling and in a negative crosstalk between distinct signaling pathways. Interleukin-10 (IL-10) and LPS were known to induce expression of SOCS-3 in neutrophils and monocytes/macrophages. IL-10 was also reported to inhibit a proinflammatory signal-induced NF-kappaB activation in monocytes and peripheral T lymphocytes. The effects of increased SOCS-3 expression upon IL-10 regulation of NF-kappaB activation have not yet been demonstrated. Here we examined the effects of SOCS-3 on NF-kappaB activity. SOCS-3 did not induce any alterations in NF-kappaB activity induced by LPS or TNF-alpha. However, it enhanced RelA-dependent kappaB promoter activity when cotransfected with RelA. Similar results were observed with SOCS-1. In contrast, SOCS-2 did not show any regulatory effects on RelA activity. Analysis of C-terminal truncation mutants of SOCS-1 and SOCS-3 demonstrated that the SOCS box and its N-terminal region, a less well-conserved linker region were important for SOCS-3 activation of RelA. In contrast, the SOCS box itself was critical for SOCS-1 to activate RelA. These results suggest that SOCS proteins can enhance the effects of NF-kappaB/Rel proteins, and therefore, further modulate immune and inflammatory responses.


Adenine and guanine nucleotide metabolism during platelet storage at 22 degrees C.
Adenine and guanine nucleotide metabolism of platelet concentrates (PCs) was studied during storage for transfusion at 22 +/- 2 degrees C over a 7-day period using high-pressure liquid chromatography. There was a steady decrease in platelet adenosine triphosphate (ATP) and adenosine diphosphate (ADP), which was balanced quantitatively by an increase in plasma hypoxanthine. As expected, ammonia accumulated along with hypoxanthine but at a far greater rate. A fall in platelet guanosine triphosphate (GTP) and guanosine diphosphate (GDP) paralleled the fall in ATP + ADP. When adenine was present in the primary anticoagulant, it was carried over into the PC and metabolized. ATP, GTP, total adenine nucleotides, and total guanine nucleotides declined more slowly in the presence of adenine than in its absence. With adenine, the increase in hypoxanthine concentration was more rapid and quantitatively balanced the decrease in adenine and platelet ATP + ADP. Plasma xanthine rose during storage but at a rate that exceeded the decline in GTP + GDP. When platelet ATP + ADP was labeled with 14C-adenine at the initiation of storage, half of the radioactivity was transferred to hypoxanthine (45%) and GTP + GDP + xanthine (5%) by the time storage was completed. The isotopic data were consistent with the presence of a radioactive (metabolic) and a nonradioactive (storage) pool of ATP + ADP at the initiation of storage with each pool contributing approximately equally to the decline in ATP + ADP during storage. The results suggested a continuing synthesis of GTP + GDP from ATP + ADP, explaining the slower rate of fall of GTP + GDP relative to the rate of rise of plasma xanthine. Throughout storage, platelets were able to incorporate 14C-hypoxanthine into both adenine and guanine nucleotides but at a rate that was only one fourth the rate of hypoxanthine accumulation. All of these data should be helpful in improving the function and viability of PC as currently stored for 5 days, in devising methods for storage beyond 5 days, and in the development of synthetic media for PC storage.


Memory and imprinting effects in multienzyme complexes--I. Isolation, dissociation, and reassociation of a phosphoribulokinase-glyceraldehyde-3-phosphate dehydrogenase complex from Chlamydomonas reinhardtii chloroplasts.
A bienzyme complex made up of phosphoribulokinase and glyceraldehyde-3-phosphate dehydrogenase has been isolated and purified from chloroplasts of Chlamydomonas reinhardtii. The complex contains four phosphoribulokinase and eight glyceraldehyde-3-phosphate dehydrogenase polypeptide chains. As phosphoribulokinase is dimeric and glyceraldehyde-3-phosphate dehydrogenase tetrameric, it is concluded that the complex comprises two phosphoribulokinase and two glyceraldehyde-3-phosphate dehydrogenase molecules. Its overall molecular mass is 460 kDa, which is in excellent agreement with its stoichiometry. Moreover, owing to the nature of the two enzymes, this complex must catalyse two nonconsecutive reactions. The bienzyme complex tended to spontaneously dissociate into the free enzymes upon dilution. This dissociation process was considerably promoted by reducing agents such as dithiothreitol or reduced thioredoxin. The kinetics of the dissociation process induced by dithiothreitol or reduced thioredoxin were paralleled by an increase of activity of phosphoribulokinase. The dissociation of the complex was reversible. If oxidized phosphoribulokinase and glyceraldehyde-3-phosphate dehydrogenase were mixed, a certain amount of the complex was formed. The reconstituted complex displayed properties that were indistinguishable from those of the native complex extracted from chloroplasts of Chlamydomonas reinhardtii. These results suggest that the concentration of the complex in vivo must vary depending on the light intensity.


Alcohol consumption and lung cancer risk among Japanese: a meta-analysis.
t is unknown what biologic mechanism may be responsible for the harmful effects of alcohol, though several have been suggested. Alcohol consumption is an established risk factor for cancers of the oral cavity, pharynx, larynx, esophagus and liver. However, epidemiologic studies have not provided consistent evidence on the effect of alcohol consumption on the risk of lung cancer. To evaluate the role of alcohol consumption in the risk of lung cancer among Japanese, the authors performed a meta-analysis of existing epidemiological studies. The authors first examined whether current alcohol consumption could potentially increase the risk of lung cancer without considering confounding factors. The summary risk estimate based on then random effects model for current consumption was 0.65 (95% confidence interval (CI) = 0.53 - 0.77). This risk estimate might be biased due to uncontrolled confounders, especially smoking cigarettes which is highly correlated with alcohol consumption. After adjustment for cigarette smoking, the summary risk estimate based on the random effects model for current alcohol consumption was no longer statistically significant (summary risk = 1.00, 95% CI = 0.73 - 1.26). Our results do not indicate that alcohol consumption serves as a major risk factor for lung cancer among Japanese. Additional studies with detailed assessments of alcohol consumption and potential confounding factors will undoubtedly lead to a better understanding of the role of alcohol consumption in lung cancer development.


Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.
Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters--pre-multifocal, spherical, and rim-enhancing, names reflecting their image features--were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.


Communication, disability, and the ICF-CY.
The child's interactions with persons in the proximal environment constitute the context for development of communication. Within early close relationships, the child acquires communication skills; developmental outcomes are defined by the continuous dynamic interactions of the child, the experiences provided by the family and close environment, and the use of different means of augmentative and alternative communication (AAC). Communication problems manifest in a variety of ways and at different levels of severity. The nature of problems differs as a function of the child's age and diagnosed condition, the communication skills of interaction partners, and the availability of communication aids. The focus for assessment and intervention may be the child, the family, the close environment and/or the interactions between them. Clarifying these varied functions and environmental factors is crucial for appropriate assessment and provision of augmentative and alternative communication (AAC) interventions. This paper reviews issues in assessment and intervention for children in need of AAC and presents the World Health Organizations' (WHO) International Classification of Functioning, Disability and Health version for Children and Youth (ICF-CY) as a tool to enhance assessment and intervention in the AAC field.


Phage-Assisted Continuous Evolution and Selection of Enzymes for Chemical Synthesis.
Ligand-dependent biosensors are valuable tools for coupling the intracellular concentrations of small molecules to easily detectable readouts such as absorbance, fluorescence, or cell growth. While ligand-dependent biosensors are widely used for monitoring the production of small molecules in engineered cells and for controlling or optimizing biosynthetic pathways, their application to directed evolution for biocatalysts remains underexplored. As a consequence, emerging continuous evolution technologies are rarely applied to biocatalyst evolution. Here, we develop a panel of ligand-dependent biosensors that can detect a range of small molecules. We demonstrate that these biosensors can link enzymatic activity to the production of an essential phage protein to enable biocatalyst-dependent phage-assisted continuous evolution (PACE) and phage-assisted continuous selection (PACS). By combining these phage-based evolution and library selection technologies, we demonstrate that we can evolve enzyme variants with improved and expanded catalytic properties. Finally, we show that the genetic diversity resulting from a highly mutated PACS library is enriched for active enzyme variants with altered substrate scope. These results lay the foundation for using phage-based continuous evolution and selection technologies to engineer biocatalysts with novel substrate scope and reactivity.


Electroconvulsive Shock Does Not Impair the Reconsolidation of Cued and Contextual Pavlovian Threat Memory.
Existing memories, when retrieved under certain circumstances, can undergo modification through the protein synthesis-dependent process of reconsolidation. Disruption of this process can lead to the weakening of a memory trace, an approach which is being examined as a potential treatment for disorders characterized by pathological memories, such as Post-Traumatic Stress Disorder. The success of this approach relies upon the ability to robustly attenuate reconsolidation; however, the available literature brings into question the reliability of the various drugs used to achieve such a blockade. The identification of a drug or intervention that can reliably disrupt reconsolidation without requiring intracranial access for administration would be extremely useful. Electroconvulsive shock (ECS) delivered after memory retrieval has been demonstrated in some studies to disrupt memory reconsolidation; however, there exists a paucity of literature characterizing its effects on Pavlovian fear memory. Considering this, we chose to examine ECS as an inexpensive and facile means to impair reconsolidation in rats. Here we show that electroconvulsive seizure induction, when administered after memory retrieval, (immediately, after 30 min, or after 1 h), does not impair the reconsolidation of cued or contextual Pavlovian fear memories. On the contrary, ECS administration immediately after extinction training may modestly impair the consolidation of fear extinction memory.


Ontogeny of a tessellated surface: Carapace growth of the longhorn cowfish Lactoria cornuta.
Biological armors derive their mechanical integrity in part from their geometric architectures, often involving tessellations: individual structural elements tiled together to form surface shells. The carapace of boxfish, for example, is composed of mineralized polygonal plates, called scutes, arranged in a complex geometric pattern and nearly completely encasing the body. In contrast to artificial armors, the boxfish exoskeleton grows with the fish; the relationship between the tessellation and the gross structure of the armor is therefore critical to sustained protection throughout growth. To clarify whether or how the boxfish tessellation is maintained or altered with age, we quantify architectural aspects of the tessellated carapace of the longhorn cowfish Lactoria cornuta through ontogeny (across nearly an order of magnitude in standard length) and in a high-throughput fashion, using high-resolution microCT data and segmentation algorithms to characterize the hundreds of scutes that cover each individual. We show that carapace growth is canalized with little variability across individuals: rather than continually adding scutes to enlarge the carapace surface, the number of scutes is surprisingly constant, with scutes increasing in volume, thickness, and especially width with age. As cowfish and their scutes grow, scutes become comparatively thinner, with the scutes at the edges (weak points in a boxy architecture) being some of the thickest and most reinforced in younger animals and thinning most slowly across ontogeny. In contrast, smaller scutes with more variable curvature were found in the limited areas of more complex topology (e.g., around fin insertions, mouth, and anus). Measurements of Gaussian and mean curvature illustrate that cowfish are essentially tessellated boxes throughout life: predominantly zero curvature surfaces comprised of mostly flat scutes, and with scutes with sharp bends used sparingly to form box edges. Since growth of a curved, tiled surface with a fixed number of tiles would require tile restructuring to accommodate the surface's changing radius of curvature, our results therefore illustrate a previously unappreciated advantage of the odd boxfish morphology: by having predominantly flat surfaces, it is the box-like body form that in fact permits a relatively straightforward growth system of this tessellated architecture (i.e., where material is added to scute edges). Our characterization of the ontogeny and maintenance of the carapace tessellation provides insights into the potentially conflicting mechanical, geometric, and developmental constraints of this species but also perspectives into natural strategies for constructing mutable tiled architectures.


Spectroscopic studies on the photooxidation of calf-lens gamma-crystallin.
The photooxidation of calf gamma-crystallin has been investigated in (a) riboflavin-sensitized reaction and (b) direct photolysis of the tryptophan residues of the protein at 300 nm. Partial insolubilization of the protein is evident by the increase in turbidity of the photolyzed protein solution. The turbidity is diminished when anaerobic conditions are used for irradiation. Spectroscopic studies on the soluble phase of the photolyzed protein reveal significant changes in the near-UV circular dichroism spectrum, suggesting that changes in the tertiary structure of the protein precede insolubilization. Isoelectric focusing analyses reveal that the gamma-crystallin polypeptides have more acidic pI's after photooxidation under both conditions. The insoluble protein is highly crosslinked into dimers and higher oligomers via covalent, non-disulfide crosslinks, but inter-subunit crosslinking is negligible in the soluble phase of the photolyzed protein. The mechanism of photooxidation involves the generation of H2O2 in the riboflavin-sensitized reaction. In the direct photolysis of tryptophan residues by 300 nm irradiation, there is a rapid disruption of the protein structure, apparently by the oxidation of the hydrophobic tryptophan residues.


[Occupational exposure of physical therapists to electric and magnetic fields and the efficacy of Faraday cages].
Measure physical therapists' exposure to the electric and magnetic fields produced by 17 shortwave diathermy devices in physical therapy clinics in the city of Presidente Prudente, São Paulo State, Brazil. Compare the observed values with the exposure levels recommended by the International Commission on Non-ionizing Radiation Protection (ICNIRP). Observe the efficacy of Faraday cages as a means of protecting physical therapists from exposure to oscillating electric and magnetic fields. Electric and magnetic field measurements were taken at four points during actual physical therapy sessions: in proximity to the operator's pelvis and head, the devices' electrical cables, and the electrodes. The measuring equipment was a Wandel & Goltermann EMR-200. The values obtained in proximity to the electrodes and cables were 10 to 30 times higher than ICNIRP's recommended occupational reference levels. In the shortwave diathermy treatment rooms with Faraday cages, the fields were even higher than in treatment rooms not so equipped-principally the magnetic field, where the values were more than 100 times higher than the ICNIRP exposure limit. The electric and magnetic field intensities obtained in this study are generally above the exposure levels recommend in ICNIRP standards. It was also observed that the Faraday cage offers physical therapists no protection, and instead, increases their level of exposure.


Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements.
Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non-invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long-term effect of successful antiviral treatment, using LSM, in HCV-infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P-value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P-value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment.


Developing a Novel Parameter Estimation Method for Agent-Based Model in Immune System Simulation under the Framework of History Matching: A Case Study on Influenza A Virus Infection.
Since they can provide a natural and flexible description of nonlinear dynamic behavior of complex system, Agent-based models (ABM) have been commonly used for immune system simulation. However, it is crucial for ABM to obtain an appropriate estimation for the key parameters of the model by incorporating experimental data. In this paper, a systematic procedure for immune system simulation by integrating the ABM and regression method under the framework of history matching is developed. A novel parameter estimation method by incorporating the experiment data for the simulator ABM during the procedure is proposed. First, we employ ABM as simulator to simulate the immune system. Then, the dimension-reduced type generalized additive model (GAM) is employed to train a statistical regression model by using the input and output data of ABM and play a role as an emulator during history matching. Next, we reduce the input space of parameters by introducing an implausible measure to discard the implausible input values. At last, the estimation of model parameters is obtained using the particle swarm optimization algorithm (PSO) by fitting the experiment data among the non-implausible input values. The real Influeza A Virus (IAV) data set is employed to demonstrate the performance of our proposed method, and the results show that the proposed method not only has good fitting and predicting accuracy, but it also owns favorable computational efficiency.


Endothelial Nitric Oxide Synthase Regulates Lymphatic Valve Specification By Controlling β - catenin Signaling During Embryogenesis.
Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (gene name: Nos3 ) is a well characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. We used global Nos3 -/- mice and cultured hdLECs to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of β-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of β-catenin target proteins in vivo and in vitro . However, pharmacological inhibition of NO production did not reproduce these effects. Coimmunoprecipitation experiments reveal that eNOS forms a complex with β-catenin and their association is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and rescued the loss of valve specification in the eNOS knockouts. In conclusion, we demonstrate a novel, nitric oxide-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS forms a complex with β-catenin to regulate its nuclear translocation and thereby transcriptional activity.


Tamoxifen induces deregulation of [Ca2+] in human breast cancer cells.
Tamoxifen is a clinically useful estrogen antagonist at or below 10(-6) M concentration. However, above this concentration tamoxifen exerts non-ER mediated cytotoxicity. Such cytotoxic effects are lethal or sublethal. The lethal effects lead to cell death while the sublethal effects may lead to cellular transformation and response modification participating in the process of tumor resistance or even tumor stimulation. Deregulation of intracellular ionized calcium ([Ca2+]i) could lead to genomic instability and deregulation of oncogene expression which might participate in the process of carcinogenesis and/or tumor promotion. Tamoxifen may cause tumor stimulation due to deregulation of [Ca2+]i or its consequences such as activity of protein kinase C, calmodulin and related protein kinases. Precise understanding of such mechanism is important for avoiding tamoxifen induced tumor resistance or tumor stimulation. The deregulation of [Ca2+]i was studied on fluo-3/AM loaded MCF-7 human breast cancer cells following acute and chronic treatment of tamoxifen and calcium ionophore ionomycin. The elevation of [Ca2+]i preceded the death of MCF-7 cells following treatment with ionomycin as previously reported on other cells. Tamoxifen above 10(-6) M also caused an increase in [Ca2+]i preceding the death of MCF-7 cells. However, below this concentration, tamoxifen caused a decrease in [Ca2+]i without any signs of cytotoxicity. The present data clearly demonstrate a tamoxifen-induced increase in [Ca2+]i and cell death only at the concentration-range in which non-E R mediated cytotoxicity is reported.


[Congenital familial dwarfism with cephaloskeletal dysplasia (Taybi-Linder syndrome)].
The authors report the case of an infant presenting with a syndrome associating dwarfism, microcephaly, facial dysmorphy and important skeletal abnormalities consisting of radiologic changes concerning the skull, long bones, vertebrae, pelvis, ribs, metacarpus and metatarsus. Severe cerebral atrophy and neurologic involvement were responsible for death in the first year of life. This rare syndrome is likely to have an autosomal recessive transmission.


Optimizing Chemically Induced Resistance in Tomato Against Botrytis cinerea.
Resistance-inducing chemicals can offer broad-spectrum disease protection in crops, but can also affect plant growth and interactions with plant-beneficial microbes. We have evaluated different application methods of β-aminobutyric acid (BABA) and jasmonic acid (JA) for long-lasting induced resistance in tomato against Botrytis cinerea. In addition, we have studied nontarget effects on plant growth and root colonization by arbuscular mycorrhizal fungi (AMF). Germinating seeds for 1 week in BABA- or JA-containing solutions promoted seed germination efficiency, did not affect plant growth, and induced resistance in 4-week-old plants. When formulating BABA and JA in carboxymethyl cellulose seed coating, only BABA was able to induce resistance in 4-week-old plants. Root treatment of 1-week-old seedlings with BABA or JA also induced resistance in 4-week-old plants. However, this seedling treatment repressed plant growth at higher concentrations of the chemicals, which was particularly pronounced in hydroponically grown plants after BABA treatment. Both seed coating with BABA, and seedling treatments with BABA or JA, did not affect AMF root colonization in soil-grown tomato. Our study has identified commercially feasible application methods of BABA and JA, which induce durable disease resistance in tomato without concurrent impacts on plant growth or colonization by plant-beneficial AMF.


Exploring service users experiences of remotely delivered CBT interventions in primary care during COVID-19: An interpretative phenomenological analysis.
Primary Care Mental Health Services (PMHCS) aim to provide accessible and effective psychological interventions. However, there is a scarcity of qualitative research focused on patients' experiences. Service users' experience can inform development of accessible, high-quality mental health services. Nine semi-structured interviews were analysed from Primary Care Mental Health users in Northern Scotland using Interpretative Phenomenological Analysis (IPA). Four superordinate themes were generated: Orientating to treatment, Intervention features, Change enablers, and Impact. The results identified both facilitators and barriers associated with access and psychological change; and narratives around CBT acceptability, outcomes and remote delivery. The role of GPs emerged as a key determinant of access to PMHCS. The therapeutic relationship contributed to person-centred care provision, idiosyncratic change processes and self-empowerment. A personal commitment to engage with homework was described as a crucial change enabler. Findings are discussed in relation to existing literature, practical implications and suggestions for future research.


Mechanism of Particle-Mediated Inhibition of Demetalation for Single-Atom Catalytic Sites in Acidic Electrochemical Environments.
Demetalation, caused by the electrochemical dissolution of metal atoms, poses a significant challenge to the practical application of single-atom catalytic sites (SACSs) in proton exchange membrane-based energy technologies. One promising approach to inhibit SACS demetalation is the use of metallic particles to interact with SACSs. However, the mechanism underlying this stabilization remains unclear. In this study, we propose and validate a unified mechanism by which metal particles can inhibit the demetalation of Fe SACSs. Metal particles act as electron donors, decreasing the Fe oxidation state by increasing the electron density at the FeN4 position, thereby strengthening the Fe-N bond, and inhibiting electrochemical Fe dissolution. Different types, forms, and contents of metal particles increase the Fe-N bond strength to varying extents. A linear correlation between the Fe oxidation state, Fe-N bond strength, and electrochemical Fe dissolution amount supports this mechanism. Our screening of a particle-assisted Fe SACS led to a 78% reduction in Fe dissolution, enabling continuous operation for up to 430 h in a fuel cell. These findings contribute to the development of stable SACSs for energy applications.


Laser-EXAFS: Fast Extended X-ray Absorption Fine Structure Spectroscopy with a Single Pulse of Laser-Produced X-rays.
The extended x-ray absorption fine structure (EXAFS) spectrum of aluminum has been measured with a nanosecond pulse of soft x-rays generated by a laser-produced plasma. This technique provides a practical alternative to synchrotorn radiation for the acquisition of EXAFS data. It also provides a unique capability for the analysis of molecular structure in highly transient chemical species.


Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Ca(v)2.3 calcium channels.
Here, we describe a new mechanism by which glutamate (Glu) and trace metals reciprocally modulate activity of the Ca(v)2.3 channel by profoundly shifting its voltage-dependent gating. We show that zinc and copper, at physiologically relevant concentrations, occupy an extracellular binding site on the surface of Ca(v)2.3 and hold the threshold for activation of these channels in a depolarized voltage range. Abolishing this binding by chelation or the substitution of key amino acid residues in IS1-IS2 (H111) and IS2-IS3 (H179 and H183) loops potentiates Ca(v)2.3 by shifting the voltage dependence of activation toward more negative membrane potentials. We demonstrate that copper regulates the voltage dependence of Ca(v)2.3 by affecting gating charge movements. Thus, in the presence of copper, gating charges transition into the "ON" position slower, delaying activation and reducing the voltage sensitivity of the channel. Overall, our results suggest a new mechanism by which Glu and trace metals transiently modulate voltage-dependent gating of Ca(v)2.3, potentially affecting synaptic transmission and plasticity in the brain.


Synthesis, conformational analysis, and spectroscopic characterization of peptides based on Daf, the first rigid transition-metal receptor, cyclic C(alpha,alpha)-disubstituted glycine.
Three series of terminally protected model oligopeptides to the nonamer level, based on 9-amino-4,5-diazafluorene-9-carboxylic acid, the first rigid bipyridine-type C(alpha,alpha)-disubstituted glycine, and either Gly, L-Ala, or Aib residues were synthesized by solution methods and fully characterized. The molecular structures of two derivatives and one tripeptide were determined in the crystal state by x-ray diffraction. Moreover, the solution preferred conformations of these peptides were assessed by Fourier transform infrared absorption and (1)H-NMR techniques. A comparison with the known structural tendencies of the strictly related C(alpha,alpha)-disubstituted glycyl residues 1-aminocyclopentane-1-carboxylic acid and 9-aminofluorene-9-carboxylic acid is made, and the implications for the use of the 9-amino-4,5-diazafluorene-9-carboxylic acid residue in conformationally constrained analogs of bioactive peptides are briefly examined. A spectroscopic (uv absorption, fluorescence, CD) characterization of this novel heteroaromatic C(alpha,alpha)-disubstituted glycine is also reported. Finally, preliminary conformational data and membrane activity measurements are discussed for an analog of the lipopeptaibol antibiotic [L-Leu(11)-OMe] trichogin GA IV in which a 9-amino-4,5-diazafluorene-9-carboxylic acid residue was synthetically incorporated in position 1 (replacing the original Aib residue).


[Hereditary deficit of antithrombin III].
Antithrombin III is a well-known coagulation inhibitor. Its heterozygous deficit is demonstrated through concentrations reduced about by 50 p. 100. On a clinical level, about 40 p. 100 to 70 p. 100 patients present with deep venous thrombosis (visceral on the whole) and pulmonary embolisms from puberty. There are both qualitative and quantitative deficits, these appearing to be mostly frequent. Only calculation of activity in the presence of heparin (co-factor of heparin) enables to diagnose these two types of deficits. Treatment performed includes both AT III concentrated agents and heparin in severe cases. Recurrences prevention is performed thanks to antivitamins K. If surgical treatment or delivery, a prevention of any incidents thanks to a vicarious therapy (AT III concentrated agent) is to be used.


Prior-Attention Residual Learning for More Discriminative COVID-19 Screening in CT Images.
We propose a conceptually simple framework for fast COVID-19 screening in 3D chest CT images. The framework can efficiently predict whether or not a CT scan contains pneumonia while simultaneously identifying pneumonia types between COVID-19 and Interstitial Lung Disease (ILD) caused by other viruses. In the proposed method, two 3D-ResNets are coupled together into a single model for the two above-mentioned tasks via a novel prior-attention strategy. We extend residual learning with the proposed prior-attention mechanism and design a new so-called prior-attention residual learning (PARL) block. The model can be easily built by stacking the PARL blocks and trained end-to-end using multi-task losses. More specifically, one 3D-ResNet branch is trained as a binary classifier using lung images with and without pneumonia so that it can highlight the lesion areas within the lungs. Simultaneously, inside the PARL blocks, prior-attention maps are generated from this branch and used to guide another branch to learn more discriminative representations for the pneumonia-type classification. Experimental results demonstrate that the proposed framework can significantly improve the performance of COVID-19 screening. Compared to other methods, it achieves a state-of-the-art result. Moreover, the proposed method can be easily extended to other similar clinical applications such as computer-aided detection and diagnosis of pulmonary nodules in CT images, glaucoma lesions in Retina fundus images, etc.


Alternative outcomes create biased expectations regarding the received outcome: Evidence from event-related potentials.
After choosing between uncertain options, one might get feedback on both the outcome of the chosen option and the outcome of the unchosen option (the alternative). Behavioral research has shown that in such cases people engage in outcome comparison, and that the alternative outcome influences the way one evaluates his own received outcome. Moreover, this influence differs whether one was responsible or not for the choice made. In two studies, we looked for the electrophysiological correlates of outcome comparison. Subjects chose one of two boxes shown on the screen, each box contained a gain or a loss. The alternative outcome was always revealed first, followed by the received outcome. In half of the trials the software picked one box instead of subjects. We tested whether the feedback-related negativity (FRN) and the P3 elicited by the received reflect outcome comparison. As expected, we found that the FRN and P3 were more positive when the received outcome was a gain (vs. a loss). The FRN and P3 were also sensitive to the value of the alternative outcome, but contrary to our predictions, they were more positive when the alternative outcome was a gain (vs. a loss). As the FRN and P3 are sensitive to expectations, we hypothesized that our findings might result from subjects' biased expectations: subjects might have wrongly believed that a good (bad) alternative outcome signaled a bad (good) received outcome. This hypothesis, coined as the Alternative Omen Effect, was confirmed in parallel in a series of behavioral experiments: people see an illusory negative correlation between the uncorrelated outcomes of choice options (reported in Marciano-Romm et al. (2016)). A challenge for future research will be to disentangle the effects of expectation from those of outcome comparison.