Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasma membrane Toll‐like receptor activation increases bacterial uptake but abrogates endosomal Lactobacillus acidophilus induction of interferon‐β

Lactobacillus acidophilus induces a potent interferon‐β (IFN‐β) response in dendritic cells (DCs) by a Toll‐like receptor 2 (TLR2) ‐dependent mechanism, in turn leading to strong interleukin‐12 (IL‐12) production. In the present study, we investigated the involvement of different types of endocytosis in the L. acidophilus‐induced IFN‐β and IL‐12 responses and how TLR2 or TLR4 ligation by lipopolysaccharide and Pam3/4CSK4 influenced endocytosis of L. acidophilus and the induced IFN‐β and IL‐12 production. Lactobacillus acidophilus was endocytosed by constitutive macropinocytosis taking place in the immature cells as well as by spleen tyrosine kinase (Syk) ‐dependent phagocytosis but without involvement of plasma membrane TLR2. Stimulation with TLR2 or TLR4 ligands increased macropinocytosis in a Syk‐independent manner. As a consequence, incubation of DCs with TLR ligands before incubation with L. acidophilus enhanced the uptake of the bacteria. However, in these experimental conditions, induction of IFN‐β and IL‐12 was strongly inhibited. As L. acidophilus‐induced IFN‐β depends on endocytosis and endosomal degradation before signalling and as TLR stimulation from the plasma membrane leading to increased macropinocytosis abrogates IFN‐β induction we conclude that plasma membrane TLR stimulation leading to increased macropinocytosis decreases endosomal induction of IFN‐β and speculate that this is due to competition between compartments for molecules involved in the signal pathways. In summary, endosomal signalling by L. acidophilus that leads to IFN‐β and IL‐12 production is inhibited by TLR stimulation from the plasma membrane.
Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load

Abstract Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We review the evidence for mutation rate heterogeneity and explore its consequences by extending classic population genetic models to allow an arbitrary distribution of mutation rate among individuals, either with or without inheritance. With this general new framework, we rigorously establish the effects of heterogeneity at various evolutionary timescales. In a single generation, variation of mutation rate about the mean increases the probability of producing zero or many simultaneous mutations on a genome. Over multiple generations of mutation and selection, heterogeneity accelerates the appearance of both deleterious and beneficial multi-point mutants. At mutation-selection balance, higher-order mutant frequencies are likewise boosted, while lower-order mutants exhibit subtler effects; nonetheless, population mean fitness is always enhanced. We quantify the dependencies on moments of the mutation rate distribution and selection coefficients, and clarify the role of mutation rate inheritance. While typical methods of estimating mutation rate will recover only the population mean, analyses assuming mutation rate is fixed to this mean could underestimate the potential for multi-locus adaptation, including medically relevant evolution in pathogenic and cancerous populations. We discuss the potential to empirically parameterize mutation rate distributions, which have to date hardly been quantified.
Population Genomics of Paramecium Species

Population-genomic analyses are essential to understanding factors shaping genomic variation and lineage-specific sequence constraints. The dearth of such analyses for unicellular eukaryotes prompted us to assess genomic variation in Paramecium, one of the most well-studied ciliate genera. The Paramecium aurelia complex consists of ∼15 morphologically indistinguishable species that diverged subsequent to two rounds of whole-genome duplications (WGDs, as long as 320 MYA) and possess extremely streamlined genomes. We examine patterns of both nuclear and mitochondrial polymorphism, by sequencing whole genomes of 10-13 worldwide isolates of each of three species belonging to the P. aurelia complex: P. tetraurelia, P. biaurelia, P. sexaurelia, as well as two outgroup species that do not share the WGDs: P. caudatum and P. multimicronucleatum. An apparent absence of global geographic population structure suggests continuous or recent dispersal of Paramecium over long distances. Intergenic regions are highly constrained relative to coding sequences, especially in P. caudatum and P. multimicronucleatum that have shorter intergenic distances. Sequence diversity and divergence are reduced up to ∼100-150 bp both upstream and downstream of genes, suggesting strong constraints imposed by the presence of densely packed regulatory modules. In addition, comparison of sequence variation at non-synonymous and synonymous sites suggests similar recent selective pressures on paralogs within and orthologs across the deeply diverging species. This study presents the first genome-wide population-genomic analysis in ciliates and provides a valuable resource for future studies in evolutionary and functional genetics in Paramecium.
Stigma and Discrimination in an Emergency Department: Policy and practice guiding care for people who use illegal drugs

People who use illegal drugs all too often experience stigma and discrimination, criminalization and marginalization in Canada. Substance use has both immediate and chronic health consequences that may require healthcare. However, people who use illegal drugs often experience difficulty accessing equitable care, and stigma has been identified as a key barrier to access. This study explores the provision of health care by nurses in an emergency department for people who use illegal drugs, and the impact of hospital policies and procedures on nurses’ capacity to provide care. The study uses data from in-depth interviews with nurses and policy leaders, and analyses policy documents discussed by nurses in the interviews. This study found that neoliberal policies that result in downsizing of social programs means that patients come to emergency departments with a broad set of health and socials needs that extend beyond what nurses can do. The study also uncovered a lack of cultural safety for Aboriginal patients seeking care. Finally, the study discovered the existence of a culture of stigma in the emergency department. The culture of stigma is transmitted and taken up through individual
Recombination Alters the Dynamics of Adaptation on Standing Variation in Laboratory Yeast Populations

The rates and selective effects of beneficial mutations, together with population genetic factors such as population size and recombination rate, determine the outcomes of adaptation and the signatures this process leaves in patterns of genetic diversity. Previous experimental studies of microbial evolution have focused primarily on initially clonal populations, finding that adaptation is characterized by new strongly selected beneficial mutations that sweep rapidly to fixation. Here, we study evolution in diverse outcrossed yeast populations, tracking the rate and genetic basis of adaptation over time. We combine time-serial measurements of fitness and allele frequency changes in 18 populations of budding yeast evolved at different outcrossing rates to infer the drivers of adaptation on standing genetic variation. In contrast to initially clonal populations, we find that adaptation is driven by a large number of weakly selected, linked variants. Populations undergoing different rates of outcrossing make use of this selected variation differently: whereas asexual populations evolve via rapid, inefficient, and highly variable fixation of clones, sexual populations adapt continuously by gradually breaking down linkage disequilibrium between selected variants. Our results demonstrate how recombination can sustain adaptation over long timescales by inducing a transition from selection on genotypes to selection on individual alleles, and show how pervasive linked selection can affect evolutionary dynamics.
Duplication of hsp-110 Is Implicated in Differential Success of Globodera Species under Climate Change

Abstract Managing the emergence and spread of crop pests and pathogens is essential for global food security. Understanding how organisms have adapted to their native climate is key to predicting the impact of climate change. The potato cyst nematodes Globodera pallida and G. rostochiensis are economically important plant pathogens that cause yield losses of up to 50% in potato. The two species have different thermal optima that may relate to differences in the altitude of their regions of origin in the Andes. Here, we demonstrate that juveniles of G. pallida are less able to recover from heat stress than those of G. rostochiensis. Genome-wide analysis revealed that while both Globodera species respond to heat stress by induction of various protective heat-inducible genes, G. pallida experiences heat stress at lower temperatures. We use C. elegans as a model to demonstrate the dependence of the heat stress response on expression of Heat Shock Factor-1 (HSF-1). Moreover, we show that hsp-110 is induced by heat stress in G. rostochiensis, but not in the less thermotolerant G. pallida. Sequence analysis revealed that this gene and its promoter was duplicated in G. rostochiensis and acquired thermoregulatory properties. We show that hsp-110 is required for recovery from acute thermal stress in both C. elegans and in G. rostochiensis. Our findings point towards an underlying molecular mechanism that allows the differential expansion of one species relative to another closely related species under current climate change scenarios. Similar mechanisms may be true of other invertebrate species with pest status.
Dental disease evidence for agricultural intensification in the Nubian C‐Group

The results of this study reveal significantly greater frequencies of caries, periapical abscesses and ante-mortem tooth loss in the Lower Nubian C-Group (ca. 2000–1500 BC) compared with the preceding Classic/Terminal A-Group (ca. 3100–2500 BC). More severe tooth wear in the C-Group, which traditionally would be interpreted as consistent with a hunting-gathering subsistence base, can instead be attributed to grit in the diet resulting from the processing of agricultural produce with sandstone and quartzite mortars and grinding stones, and perhaps also to the intentional addition of grit to grain in order to facilitate grinding. The results of this study, when evaluated in the context of complementary archaeological and osteological evidence, indicate that both groups practised a mixed economy but that the C-Group relied more heavily on cereal cultivation.
CAR T cells: driving the road from the laboratory to the clinic

Blockbuster antibody therapies have catapulted immune‐based approaches to treat cancer into the consciousness of mainstay clinical research. On the back of this, other emerging immune‐based therapies are providing great promise. T‐cell therapy is one such area where recent trials using T cells genetically modified to express an antibody‐based chimeric antigen receptor (CAR) targeted against the CD19 antigen have demonstrated impressive responses when adoptively transferred to patients with advanced chronic lymphocytic leukemia. The general concept of the CAR T cell was devised some 20 years ago. In this relatively short period of time, the technology to redirect T‐cell function has moved at pace facilitating clinical translation; however, many questions remain with respect to developing the approach to improve CAR T‐cell therapeutic activity and also to broaden the range of tumors that can be effectively targeted by this approach. This review highlights some of the underlying principles and compromises of CAR T‐cell technology using the CD19‐targeted CAR as a paradigm and discusses some of the issues that relate to targeting solid tumors with CAR T cells.
Applied Methods of Cost-Benefit Analysis in Health Care

This book provides the reader with a comprehensive set of instructions and examples of how to perform a cost-benefit analysis (CBA) of a health intervention. Developed out of a course run by Jordan Louviere at the University of Technology, Sydney, entitled An Introduction to Stated Preference Discrete Choice Modelling it has a particular focus on the use of stated preference survey methods to identify consumer preference data, as well as the use of recent developments in cost-effectiveness analysis within a CBA framework. In doing so, the most up to date methodologies for CBA are compiled in a comprehensive manner with the aim of advancing the methodology of CBA in healthcare. ABOUT THE SERIES Series editors Alastair Gray and Andrew Briggs Economic evaluation of health intervention is a growing specialist field, and this series of practical handbooks tackles, in depth, topics superficially addressed in more general economics books. Each volume includes illustrative material, case histories and worked examples to encourage the reader to apply the methods discussed, with supporting material provided online. The series is aimed at health economists in academia, the pharmaceutical industry and the health sector, those on advanced health economics courses, and health researchers in associated fields. Contributors to this volume - F. Reed Johnson, RTI Health Solutions, Research Triangle Institute, North Carolina, USA W.L. (Vic) Adamowicz, Department of Rural Economy, University of Alberta, Canada Alastair Gray, Health Economics Research Centre, Department of Public Health, University of Oxford, UK Mathias Haefeli Achim Elfering Atul Sukthankar Norbert Boos Richard Carson Denzil G. Fiebig, School of Economics, University of New South Wales Sydney, Australia
Oxford Handbook of General Practice

[][1] Chantal Simon, Hazel Everitt, Jon Birtwistle, Brian Stevenson Oxford University Press, £22.95, pp 1060 ISBN 0 19 263270 1 Rating: ! [Graphic][2] ! [Graphic][3] ! [Graphic][4] Iremember getting a bit of a shock before my medical finals. Jovial consultants who had spent two and a half years telling us how the only thing that they had learnt at medical school was not to mix wine and beer suddenly started looking serious. When teaching us, instead of regaling us with tales of drunken stupor from their … [1]: /embed/graphic-1.gif [2]: /embed/inline-graphic-1.gif [3]: /embed/inline-graphic-2.gif [4]: /embed/inline-graphic-3.gif
Activity‐based protein profiling of hydrolytic enzymes induced by gibberellic acid in isolated aleurone layers of malting barley

During barley germination, the aleurone layer secretes most of the enzymes required to degrade the endosperm, many of which are yet to be characterized. We used activity‐based protein profiling (ABPP) to detect a range of active enzymes extracted from aleurone layers isolated from grains of a commercial malting barley variety incubated with or without gibberellic acid (GA). Enzymes found to be induced by GA were putative aleurains, cathepsin‐B‐like proteases and serine hydrolases. By using an inhibitory sugar panel, a specific active retaining β‐glycosidase in the barley aleurone was identified as a putative xylanase. Our results show that ABPP can be used rapidly to identify a variety of active enzyme isoforms in cereal aleurone without the need for enzyme purification.
Caspase‐8: regulating life and death

Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best‐known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor‐mediated activation of programmed cell death is the aspartate‐specific cysteine protease (caspase)‐8. This review describes the role of caspase‐8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase‐8 inhibits necroptosis. The importance of caspase‐8 in the development and homeostasis and the way that dysfunctional caspase‐8 may contribute to the development of malignancies in mice and humans are also explored.
AMP‐activated protein kinase‐mediated expression of heat shock protein beta 1 enhanced insulin sensitivity in the skeletal muscle

Activation of AMP‐activated protein kinase (AMPK) has been viewed as an important target for the treatment of insulin resistance. Here, by proteomic analysis, we found that expression of heat shock protein beta‐1 (HSPB1) was induced by the AMP analog 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside in palmitate‐induced insulin‐resistant cells. Overexpression of AMPKα2, or activation of AMPKα via acute/chronic exercise training, increased HSPB1 expression in the skeletal muscle. In AMPKα2−/− mice, HSPB1 expression was downregulated in the quadriceps muscles. Exercise did not increase HSPB1 expression in AMPKα2−/− mice. Moreover, overexpression of HSPB1 enhanced insulin sensitivity in palmitate‐induced insulin‐resistant cells and restored metabolic phenotypes associated with defective AMPK. Finally, HSPB1 was required for AMPK‐mediated activation of the class IIa histone deacetylases and glucose uptake in the skeletal muscle. Our results demonstrate that AMPK‐mediated HSPB1 expression enhanced insulin sensitivity in the skeletal muscle.
Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

Coordinated regulation of mRNA localization and local translation are essential steps in cellular asymmetry and function. It is increasingly evident that mRNA‐binding proteins play critical functions in controlling the fate of mRNA, including when and where translation occurs. In this review, we discuss the robust and complex roles that mRNA‐binding proteins play in the regulation of local translation that impact cellular function in vertebrates. First, we discuss the role of local translation in cellular polarity and possible links to vertebrate development and patterning. Next, we discuss the expanding role for local protein synthesis in neuronal development and function, with special focus on how a number of neurological diseases have given us insight into the importance of translational regulation. Finally, we discuss the ever‐increasing set of tools to study regulated translation and how these tools will be vital in pushing forward and addressing the outstanding questions in the field.
Assessing exposure to secondhand smoke in restaurants and bars 2 years after the smoking regulations in Beijing, China.

UNLABELLED Field observation of patron smoking behaviors and multiple sampling approaches were conducted in 79 restaurants and bars in Beijing, 2010, 2 years after implementing the governmental smoking regulations. Smoking was observed in 30 visits to 22 of the 37 nominal non-smoking venues during peak patronage times and six visits to four of the 14 nominal non-smoking sections. The median area secondhand smoke (SHS) concentrations during peak patronage time were 27, 15, 43, and 40 μg/m(3) in nominal non-smoking venues, non-smoking sections, smoking sections, and smoking venues, respectively, as indicated by the difference between indoor and outdoor PM2.5 levels; and 1.4, 0.6, 1.7, and 2.7 μg/m(3) , respectively, as indicated by airborne nicotine. In the 27 venues with sampling of different approaches and over different time periods, the median nicotine concentration was 1.8 μg/m(3) by one-hour peak patronage-time sampling, 1.1 μg/m(3) by 1-day active area sampling, 2.5 μg/m(3) by 1-day personal sampling, and 2.3 μg/m(3) by week-long passive sampling. No significant differences in nicotine levels were observed among venues/sections with different nominal smoking policies by all sampling approaches except during peak patronage time. This study showed that the 2008 Beijing governmental smoking restriction has been poorly implemented, and SHS exposures in Beijing restaurants and bars remain high. PRACTICAL IMPLICATIONS The 2008 Beijing governmental smoking restriction requires large restaurants to designate no less than 50% of their dining area as non-smoking, without defining ‘large’ or specifying how the designated smoking sections and non-smoking sections should be separated. Two years after its implementation, smoking is still commonly observed in nominally non-smoking restaurants and bars and in designated non-smoking sections, and both patrons and servers are exposed to high concentrations of secondhand smoke. These results indicate that the Beijing governmental regulation fails to protect the population from SHS exposure in restaurants and bars and that more efforts are needed to pass stronger smoking regulations and ensure better compliance in Beijing, China.
Collision coupling in the GABAB receptor–G protein–GIRK signaling cascade

The signaling cascade comprising the 4‐aminobutyrate(B) receptor (GABABR), G protein and the G protein‐gated K+ channel (GIRK) mediates neuronal inhibition in the brain. Precoupling between components of the pathway (within a permanent macromolecular complex) has been proposed, but this remains debatable. We investigated this mechanism in Xenopus oocytes by varying the expression of the GABABR. Increased expression of GABABR accelerates activation of GIRK by agonist, implying that some of the components in this cascade interact by a classical collision mechanism. We also find that GABABR has a bidirectional effect on the basal activity of the GIRK channel. Our results suggest a complex mechanism of coupling between GABABR and GIRK which involves elements of both precoupling and collision coupling.