Miracle-dz/UniFAR-FTUs huggingface dataset:
Using model-based proposals for fast parameter inference on discrete state space, continuous-time Markov processes

Bayesian statistics provides a framework for the integration of dynamic models with incomplete data to enable inference of model parameters and unobserved aspects of the system under study. An important class of dynamic models is discrete state space, continuous-time Markov processes (DCTMPs). Simulated via the Doob–Gillespie algorithm, these have been used to model systems ranging from chemistry to ecology to epidemiology. A new type of proposal, termed ‘model-based proposal’ (MBP), is developed for the efficient implementation of Bayesian inference in DCTMPs using Markov chain Monte Carlo (MCMC). This new method, which in principle can be applied to any DCTMP, is compared (using simple epidemiological SIS and SIR models as easy to follow exemplars) to a standard MCMC approach and a recently proposed particle MCMC (PMCMC) technique. When measurements are made on a single-state variable (e.g. the number of infected individuals in a population during an epidemic), model-based proposal MCMC (MBP-MCMC) is marginally faster than PMCMC (by a factor of 2–8 for the tests performed), and significantly faster than the standard MCMC scheme (by a factor of 400 at least). However, when model complexity increases and measurements are made on more than one state variable (e.g. simultaneously on the number of infected individuals in spatially separated subpopulations), MBP-MCMC is significantly faster than PMCMC (more than 100-fold for just four subpopulations) and this difference becomes increasingly large.
Inhibition of Ca2+‐sensitive K+ currents in NG 108‐15 cells by substance P and related tachykinins

1 The whole‐cell patch‐clamp technique was used to investigate the actions of substance P and other agonists at neurokinin (NK) receptors on voltage‐gated K+ and Ca+ channel currents in undifferentiated mouse neuroblastoma x rat glioma NG 108‐15 cells. 2 Both substance P (0.3–30 μm) and the NK1 receptor selective agonist GR73632 (10 nM‐10 μm) caused concentration‐dependent inhibition of K+ currents. GR64349 and senktide (agonists at NK2 and NK3 receptors respectively) also inhibited K+ currents, but only at concentrations which were several orders of magnitude greater than GR73632, suggesting that current inhibition was mediated via NK1 receptors. 3 Substance P and GR73632 were without effect on residual K+ currents recorded in the presence of extracellular Co2+ (4 mM) to abolish the Ca2+‐sensitive component (IKCa) of the K+ current. Ca2+ channel currents, recorded with either Ba2+ or Ca2+ as charge carrier, were unaffected by NK1, NK2 and NK3 receptor ligands. 4 Iontophoretic application of GR73632 produced a current‐dependent reduction of K+ currents. In the presence of the non‐peptide NK1 antagonists, CP‐99,994 and RP67580, and the peptide antagonist, GR82334, the current‐response relationship was reversibly shifted to the right. This indicates that the response is mediated by NK1 receptors. 5 Our results indicate that activation of NK1 receptors leads to the selective inhibition of IKCa in undifferentiated NG 108‐15 cells.
Increased Nitric Oxide Synthase Activities and l‐[3H]Arginine Uptake in Brain Following Portacaval Anastomosis

Abstract: Glutamatergic synaptic dysfunction has been proposed as a causal factor in portal‐systemic encephalopathy. Increased in vitro and in vivo glutamate release and decreased glutamate binding to NMDA receptors were previously reported in the brains of portacaval‐shunted rats. Such changes could lead to alterations in the second messenger systems coupled to glutamate receptors. As NMDA receptors have been shown to act via the nitric oxide/cyclic GMP second messenger system, we studied the activities of constitutive nitric oxide synthase (NOS), in the brains of rats following portacaval shunting. Results demonstrate that NOS activities are significantly increased in cerebellum (by 54%, p < 0.01), cerebral cortex (by 65%, p < 0.01), hippocampus (by 88%, p < 0.01), and striatum (by 64%, p < 0.01) of shunted rats compared with sham‐operated controls. As l‐arginine transport is a prerequisite for nitric oxide production, we also studied l‐[3H]arginine transport into cerebellar and cerebral cortical synaptosomes prepared from the brains of portacaval‐shunted and sham‐operated rats. l‐[3H]Arginine uptake was significantly increased (by ∼50%, p < 0.01) in both cerebellum and cortex. Increased NOS activities of neuronal and/or astrocytic origin and the resultant increased production of nitric oxide in brain could be the consequence of increased NMDA receptor activation following portacaval shunting. Furthermore, increased nitric oxide production could contribute to the increased cerebral blood flow consistently observed following portacaval shunting.
Antiplatelet Is Superior to Anticoagulant Treatment After Coronary Stenting: Fewer Coronary and Other Events Within 30 Days After Stenting

Stent prosthesis is a high efficacious method with low complication rates. However, the ideal adjunctive therapy following stent implantation remains controversial. The authors compared the effectiveness and complication rates of aspirin-ticlopidine antiplatelet therapy vs anticoagulant therapy with acenocoumarol within 30 days following stent prosthesis. They prospectively studied 404 patients following stent prosthesis while randomly receiving anticoagulant (Group A: 201 patients) vs antiplatelet treatment (Group B: 203 patients). Groups A and B were similar in demographic data (age, gender), stent location, clinical presentation, indication of stenting, and type of implanted stent. Chi-square test, t test, and Wilcoxon test for two samples were used for statistical analysis of the results. Stent implantation was attempted in 434 cases. This was successful in 70/85 (82%) of the bailout, 122/135 (90%) of the suboptimal, and 212/214 (99%) of the elective cases. In 201 patients anticoagulant treatment with acenocoumarol was administered for 4 weeks (group A), while 203 received antiplatelet treatment with ticlo pidine (group B). The need for reintervention was less and total cardiac events were fewer in group B than in group A: three (1.5%) and nine (4.4%) vs 18 (9%) and 29 (14.4%), p < 0.0008 and p < 0.006 respectively. Hemorrhagic complications and total noncardiac events were fewer in group B than in group A: six (3%) and six (3%) vs 18 (9%) and 19 (9.5%), p < 0.01 and p < 0.007 respectively. The length of hospital stay was shorter in group B than in A, p < 0.0001. In conclusion, in this study of intracoronary stenting the authors had a high success rate in 434 attempted cases. Antiplatelet therapy was accompanied by fewer cardiac and noncardiac 1 month events when compared with anticoagulant therapy, supporting its role as the adjunctive treatment of choice post- stenting for the time being.
Impact and Quantification of the Sources of Error in DNA Pooling Designs

The analysis of genome wide variation offers the possibility of unravelling the genes involved in the pathogenesis of disease. Genome wide association studies are also particularly useful for identifying and validating targets for therapeutic intervention as well as for detecting markers for drug efficacy and side effects. The cost of such large‐scale genetic association studies may be reduced substantially by the analysis of pooled DNA from multiple individuals. However, experimental errors inherent in pooling studies lead to a potential increase in the false positive rate and a loss in power compared to individual genotyping. Here we quantify various sources of experimental error using empirical data from typical pooling experiments and corresponding individual genotyping counts using two statistical methods. We provide analytical formulas for calculating these different errors in the absence of complete information, such as replicate pool formation, and for adjusting for the errors in the statistical analysis. We demonstrate that DNA pooling has the potential of estimating allele frequencies accurately, and adjusting the pooled allele frequency estimates for differential allelic amplification considerably improves accuracy. Estimates of the components of error show that differential allelic amplification is the most important contributor to the error variance in absolute allele frequency estimation, followed by allele frequency measurement and pool formation errors. Our results emphasise the importance of minimising experimental errors and obtaining correct error estimates in genetic association studies.
Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals

AbstractThere is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in-depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.
A comparison of airborne ergosterol, glucan and Air-O-Cell data in relation to physical assessments of mold damage and some other parameters.

UNLABELLED We report here a comparison of long duration air samples in 110 homes where the material collected on open faced filter cassettes was analyzed for beta 1,3-d glucan, ergosterol, cholesterol and endotoxin. These data were then compared to careful estimates of visible mold and Air-O-Cell data. All the values found except cholesterol were of a similar magnitude to values reported in the limited number of studies available. Glucan was measured with a factor G based assay of the Limulus Amebocyte Lysate followed by size exclusion chromatography. This showed that the majority of airborne glucan found in these houses was fungal in origin arising from both yeasts and intact spores, as well as hyphal and spore fragments. Hyphal and spore fragments together represented 16% of the intact spore counts but over a broad range. Correlations between airborne glucan were strong for ergosterol and visible mold. However, airborne ergosterol was more highly correlated to visible mold than glucan. Endotoxin and Air-O-Cell measurements were poorly or not related to the other measures in the study. This study provides confidence that long duration air samples of the toxin glucan and ergosterol are related to building damage. PRACTICAL IMPLICATIONS Some studies of damp buildings have shown a relationship between extent of water/mold damage and symptoms. This study compared long duration air samples for glucan and ergosterol to extent of visible mold in houses measuring also the nature of the glucans present. Both measures were highly correlated to extent of visible mold damage in the houses; ergosterol was somewhat superior. Spore counts or prevalence of Asp/Pen in Air-O-Cell samples was not related to extent of visible mold damage but the observation of hyphal fragments was more likely when mold damage was present. This indicates that rigorous assessment of mold damage is a useful measure.
Cytosolic H+ microdomain developed around AE1 during AE1‐mediated Cl−/HCO3− exchange

Non‐technical summary Most cellular processes are exquisitely sensitive to pH. Consequently our cells have a range of processes directed to control cellular pH. Plasma membrane transport proteins move acid or base across the plasma membrane to regulate pH precisely. We studied AE1 (also called Band 3) of erythrocytes and kidney cells, which rapidly transports the base, bicarbonate. AE1's high transport rate, combined with the surprisingly slow rates of H+ diffusion in cytosol, led us to wonder whether AE1 changes the pH of its local environment. The key findings were that H+ diffusion through the cytosol occurs at 0.6 μm s−1, and along the inner surface of the plasma membrane at only 0.01 μm s−1. We estimated that the size of the region of altered pH (H+ microdomain) around AE1 is 0.3 μm in diameter. pH‐regulatory transporters, like AE1, have differential effects on their immediate environment, with implications for the regulation of nearby pH‐sensitive proteins.
Infant skin physiology and development during the first years of life: a review of recent findings based on in vivo studies

Infant skin is often presented as the cosmetic ideal for adults. However, compared to adult skin it seems to be more prone to develop certain pathological conditions, such as atopic dermatitis and irritant contact dermatitis. Therefore, understanding the physiology of healthy infant skin as a point of reference is of interest both from the cosmetic as well as from the clinical point of view. Clinical research on healthy infants is, however, limited because of ethical considerations of using invasive methods and therefore until recently data has been scarce. Technical innovations and the availability of non‐invasive in vivo techniques, such as evaporimetry, electrical impedance measurement, in vivo video and confocal microscopy, and in vivo fibre‐optic based spectroscopy, opened up the field of in vivo infant skin physiology research. Studies incorporating such methods have demonstrated that compared to adult, infant skin continues to develop during the first years of life. Specifically, infant skin appears to have thinner epidermis and stratum corneum (SC) as well as smaller corneocytes at least until the second year of life. The water‐handling properties are not fully developed before the end of the first year and infant SC contains more water and less amounts of natural moisturizing factors. Such findings re‐evaluate the old notions that skin is fully matured at birth. Armed with this knowledge, we are in a position not only to better understand infant dermatological conditions but also to design better skin care products respecting the distinct qualities of infant skin.
DST studies in psychotic depression: a meta-analysis.

OBJECTIVE Although hypersecretion of cortisol has frequently been reported in psychotic depression, the findings have been mixed. The authors performed a meta-analysis of the existing studies to determine the significance of differences in nonsuppression of cortisol across studies. METHOD Fourteen studies that compared dexamethasone suppression test (DST) results in psychotic and nonpsychotic patients were examined, and a Mantel-Haenszel meta-analysis was performed. For comparison purposes, 19 studies of the DST with respect to melancholic/nonmelancholic and inpatient/outpatient distinctions were similarly reviewed. RESULTS This analysis indicated a highly significant probability that a greater rate of cortisol nonsuppression occurs in psychotic depression. The nonsuppression rate was substantially higher in patients with psychotic depression (64%) than in nonpsychotic patients (41%). In the 19 studies of melancholia, nonsuppression was less frequent (36%), and when inpatient/outpatient status was controlled, melancholic depression was not significantly associated with nonsuppression. In nonmelancholic outpatients with major depression, the nonsuppression rate was low (12%). CONCLUSIONS Among patients with major depression, psychotic depression is the subtype that is most closely associated with nonsuppression of cortisol on the DST. Hypercortisolemia is usually present in psychotic depression and may be important in understanding the pathophysiology of this syndrome.
Pre-, pro- and synbiotics

Approximately 70% of the immune system is localized in the gastrointestinal tract. The saliva and gastrointestinal secretions, as well as flora (probiotics) and supplied fibres (prebiotics), are important for optimal function. Probiotic bacteria have been shown to influence the immune system through several molecular mechanisms. Pre-, pro- and synbiotics (products produced by fermentation) offer both protection against and cure of a variety of endemic and acute diseases. This review summarizes the present experience in various forms of diarrhoea, inflammatory bowel disease, and Helicobacter infections, in intensive care patients and in connection with extensive surgery.
Modulation of Serines 17 and 24 in the LC3-interacting Region of Bnip3 Determines Pro-survival Mitophagy versus Apoptosis*

Background: Bnip3 is both a pro-apoptotic BH3-only protein and a mitochondrial autophagy receptor. Results: Serine phosphorylation of the Bnip3 LC3-interacting region (LIR) increased binding to Atg8 members and consequently mitophagy, in a manner positively regulated by Bcl-xL. Conclusion: The Bnip3 LIR activity state determines either pro-survival mitophagy or mitochondrial apoptosis. Significance: Bnip3-induced mitophagy is serine kinase-regulated and thus a targetable pathway. BH3-only proteins integrate apoptosis and autophagy pathways, yet regulation and functional consequences of pathway cross-talk are not fully resolved. The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. Here we report that phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16. Using quantitative multispectral image-based flow cytometry, we demonstrate that enhancing Bnip3-Atg8 interactions via phosphorylation-mimicked LIR mutations increased mitochondrial sequestration, lysosomal delivery, and degradation. Importantly, mitochondria were targeted by mitophagy prior to cytochrome c release, resulting in reduced cellular cytochrome c release capacity. Intriguingly, pro-survival Bcl-xL positively regulated Bnip3 binding to LC3B, sequestration, and mitochondrial autophagy, further supporting an anti-apoptotic role for Bnip3-induced mitophagy. The ensemble of these results demonstrates that the phosphorylation state of the Bnip3 LIR signals either the induction of apoptosis or pro-survival mitophagy.
Zero Lower Bound (ZLB) Economics

This paper explores zero lower bound (ZLB) economics. The ZLB is widely invoked to explain stagnation and it fits with the long tradition that argues Keynesian economics is a special case based on nominal rigidities. The ZLB represents the newest rigidity. Contrary to ZLB economics, not only does a laissez-faire monetary economy lack a mechanism for delivering the natural rate of interest, it may also lack such an interest rate. Moreover, the ZLB can be a stabilizing rigidity that prevents negative nominal interest rates exacerbating excess supply conditions.
Functional Relationships of Srb10-Srb11 Kinase, Carboxy-Terminal Domain Kinase CTDK-I, and Transcriptional Corepressor Ssn6-Tup1

ABSTRACT The Srb10-Srb11 protein kinase of Saccharomyces cerevisiae is a cyclin-dependent kinase (cdk)-cyclin pair which has been found associated with the carboxy-terminal domain (CTD) of RNA polymerase II holoenzyme forms. Previous genetic findings implicated the Srb10-Srb11 kinase in transcriptional repression. Here we use synthetic promoters and LexA fusion proteins to test the requirement for Srb10-Srb11 in repression by Ssn6-Tup1, a global corepressor. We show that srb10Δ and srb11Δ mutations reduce repression by DNA-bound LexA-Ssn6 and LexA-Tup1. A point mutation in a conserved subdomain of the kinase similarly reduced repression, indicating that the catalytic activity is required. These findings establish a functional link between Ssn6-Tup1 and the Srb10-Srb11 kinase in vivo. We also explored the relationship between Srb10-Srb11 and CTD kinase I (CTDK-I), another member of the cdk-cyclin family that has been implicated in CTD phosphorylation. We show that mutation of CTK1, encoding the cdk subunit, causes defects in transcriptional repression by LexA-Tup1 and in transcriptional activation. Analysis of the mutant phenotypes and the genetic interactions of srb10Δ and ctk1Δ suggests that the two kinases have related but distinct roles in transcriptional control. These genetic findings, together with previous biochemical evidence, suggest that one mechanism of repression by Ssn6-Tup1 involves functional interaction with RNA polymerase II holoenzyme.
Reusable Knowledge for Best Clinical Practices: Why We Have Difficulty Sharing and What We Can Do

and Objective A central challenge in clinical decision support is the difficulty in creating shareable repositories of best practice knowledge. A host of proprietary systems makes it difficult to have a widely accepted representation format. Different uses of knowledge and contextualized, workflow-specific adaptations cause the knowledge that is already in such site-specific formats to be not readily usable by others. New or updated knowledge is continually being generated. Where should such knowledge reside, what format should it reside in, and how should it be reviewed and disseminated? What are roles of knowledge providers? How does the “last mile” of adaptation to settings and proprietary formats get accomplished? This panel seeks to identify promising approaches to managing the lifecycle of knowledge generation and refinement. The aims are to facilitate the transition of new knowledge to formal representation, and the delivery of best practice knowledge in executable form to different settings, where it can be adapted to improve care processes and outcomes. Learning objectives: (1) Recognize the new and emerging methodologies for knowledge representation and knowledge management. (2) Explain the life cycle of knowledge generation/ refinement/deployment/value delivery. (3) Recognize the challenges in adaptation and widespread use.