Miracle-dz/UniFAR-FTUs huggingface dataset:
Chronic Granulomatous Pneumonia and Lymphocytic Responses Induced by Inhaled Beryllium Metal in A/J and C3H/HeJ Mice

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). Key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction, in which Be most likely functions as a hapten and acts as a Class II-restricted antigen, stimulating local proliferation and accumulation in the lung of Be-specific CD4+ T cells. The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2k) mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. The lungs of all Be-exposed mice had interstitial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, neutrophils in alveoli and alveolar septa, multifocal interstitial granulomas, and interstitial infiltrates of lymphocytes, plasma cells, monocytes, and macrophages. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO4 in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease.
EMPIRICAL LIKELIHOOD ESTIMATION FOR SAMPLES WITH NONIGNORABLE NONRESPONSE

Nonresponse is very common in survey sampling. Nonignorable nonresponse, a response mechanism in which the response probability of a survey variable Y depends directly on the value of Y regardless of whether Y is observed or not, is the most difficult type of nonresponse to handle. The population mean estimators ignoring the nonrespondents typically have heavy biases. This paper studies an empirical likelihood-based estimation method, with samples under nonignorable nonresponse, when an observed auxiliary categorical variable Z is available. The likelihood is semiparametric: we assume a parametric model on the response mechanism and the conditional probability of Z given Y , and a nonparametric model on the distribution of Y . When the number of Z categories is not small, a pseudo empirical likelihood method is applied to reduce the computational intensity. Asymptotic distributions of the proposed population mean estimators are derived. For variance estimation, we consider a bootstrap procedure and its consistency is established. Some simulation results are provided to assess the finite sample performance of the proposed estimators.
Finding Common Ground: A Critique of Subsumption Theory and Its Application to Small-Scale Forest Carbon Offsetting in Uganda

ABSTRACT Carbon markets as a policy tool to mitigate emissions of greenhouse gases continue to be controversial, especially in developing countries. It is thus refreshing that Carton and Andersson (2017) undertook a field investigation of a transnational forest carbon offset project in Uganda. However, I am concerned that assumptions of structural Marxism that underwrite subsumption theory may have led the authors to see the project as inherently conflict ridden and exploitative and to neglect actual benefits. Their presentation of the project’s local impact jarred with my own empirical research into this project, undertaken in 2009, as well as more recent news accounts. While my field effort preceded the authors’ by 6 years, I attribute our different interpretations largely to theoretical and methodological differences. Evidence I present below suggests considerable alignment between the interests of transnational carbon markets and Ugandan smallholder farmers. Additional fieldwork might be able to resolve these differences in interpretation.
Systematic Analysis of Bacterial Effector-Postsynaptic Density 95/Disc Large/Zonula Occludens-1 (PDZ) Domain Interactions Demonstrates Shigella OspE Protein Promotes Protein Kinase C Activation via PDLIM Proteins*

Background: PDZ domains provide specificity in protein-protein interactions in eukaryotic systems. Results: Shigella OspE, which is delivered into human cells during infection, binds PDLIM7 via a PDZ interaction and contributes to activation of PKC. Conclusion: During infection, OspE contributes to activation of PKC through PDZ-mediated binding to PDLIM7. Significance: PDZ interactions likely contribute to pathogenesis of several bacterial pathogens. Diseases caused by many Gram-negative bacterial pathogens depend on the activities of bacterial effector proteins that are delivered into eukaryotic cells via specialized secretion systems. Effector protein function largely depends on specific subcellular targeting and specific interactions with cellular ligands. PDZ domains are common domains that serve to provide specificity in protein-protein interactions in eukaryotic systems. We show that putative PDZ-binding motifs are significantly enriched among effector proteins delivered into mammalian cells by certain bacterial pathogens. We use PDZ domain microarrays to identify candidate interaction partners of the Shigella flexneri effector proteins OspE1 and OspE2, which contain putative PDZ-binding motifs. We demonstrate in vitro and in cells that OspE proteins interact with PDLIM7, a member of the PDLIM family of proteins, which contain a PDZ domain and one or more LIM domains, protein interaction domains that participate in a wide variety of functions, including activation of isoforms of protein kinase C (PKC). We demonstrate that activation of PKC during S. flexneri infection is attenuated in the absence of PDLIM7 or OspE proteins and that the OspE PDZ-binding motif is required for wild-type levels of PKC activation. These results are consistent with a model in which binding of OspE to PDLIM7 during infection regulates the activity of PKC isoforms that bind to the PDLIM7 LIM domain.
Progress with Structure–Activity Relationship modelling of occupational chemical respiratory sensitizers

Purpose of reviewThis appraises currently available computer-based (‘in silico’) models relating the molecular structure of low molecular weight compounds to their respiratory sensitization hazard. The present review places focus on the two main applications of such structure--activity relationship (SAR) models: hypotheses on disease mechanisms and toxicological prediction. Recent findingsAnalyses of the chemical structures of low molecular weight organic compounds known to have caused occupational asthma has led to the development of mechanistic alerts usually based on electrophilic reaction chemistry and protein cross-linking potential. Protein cross-linking potential has also been found to be a consistent feature of chemicals that have caused human cases of hypersensitivity pneumonitis. Stepwise iteration of quantitative SAR (QSAR) modelling has shown appreciable improvements in predictivity for occupational asthma hazard and useful prospects for practical application. A good case has also been made for the potential use of structural alert-based mechanistic SARs in predictive toxicology. SummaryFurther understanding of the molecular interactions between chemical respiratory sensitizers and components of human proteins have been obtained from in-vitro and in-silico techniques. There have been developments in both qualitative (mechanistic) SARs and QSARs, which offer potential for use in a predictive algorithm for the toxicological screening of industrial chemicals for respiratory sensitization potential.
Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence

Significance Hypervirulent strains of Clostridium difficile frequently produce the actin-ADP–ribosylating toxin Clostridium difficile transferase (CDT), which increases bacteria adherence by formation of microtubule-based protrusions. Here we report that CDT-induced protrusions contain trafficking vesicles and endoplasmic reticulum, connected to microtubules via the calcium sensor Stim1. CDT increases calcium signaling and reroutes fibronectin-containing vesicles from the basolateral to the apical side of intestinal epithelial cells, where protrusions are formed. Released fibronectin enhances adherence of bacteria. The data reassess the role of the actin cytoskeleton in bacterial adherence and infection. Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca2+ signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence.
Constructing the ‘legalities’ of encroachments in dam, canal, and stream reservations in the north-central province of Sri Lanka

ABSTRACT Encroachers on dam, canal and stream reservations in Sri Lanka have a long history, although largely neglected and sparsely investigated by academics and policy makers alike. They have been observed to degrade water resources at an alarming rate and have proven resistant to attempts of eviction. The present work attempts to employ a discourse analytical viewpoint to open up and explore the ideas, perspectives and justifications held by various social groups regarding the legality of encroachers, thus moving beyond the simplistic legal/illegal binary that has characterized previous academic inquiries on the matter. In doing so, the present work has found three competing discourses or ‘storylines’, each of which characterize encroachers in a different way. Together, these different discourses provide a platform to better understand the social practices, behaviors and motivations of the encroachers, and provide more complex and nuanced answers to the questions of ‘who they are’ and ‘what can be done about them’.
Improvement of the Thermoregulated T7 Expression System by Using the Heat‐Sensitive lacI

The thermoregulated T7 expression system was previously reported to be an effective way to produce massive amounts of recombinant proteins (Chao, Y. P.; Law, W. S.; Chen, P. T.; Hung, W. B. High production of heterologous proteins in Escherichia coli using the thermo‐regulated T7 expression system. Appl. Microbiol. Biotechnol. 2002b, 58, 446–453). To ensure its practical applicability, the system was improved for stringency with the construction of the T7 lac‐promoter‐containing plasmid associated with the thermolabile lacIgene ( lacIts). Owing to the recessive feature of lacIts, the wild‐type lacI was removed from the genome of the cell. Moreover, the cell was engineered to carry the chromosomal copy of the T7 gene 1 subject to the regulation of λPL and λPR promoters. To characterize the system, the lacZ gene was fused to the T7 lac promoter, and subsequent experiments showed that various amounts of LacZ could be synthesized in the plasmid‐bearing cell in response to heat. Among the producers, the cell with the plasmid containing lacIts (substitution of Gly265 with Asp in lacI) was able to produce the maximal LacZ, the production accounting for an amplification of more than 200‐fold over the uninduced level. A further demonstration was carried out to illustrate the practical usefulness of the developed system by producing carbamoylase on a 4000 L scale. Cultured to reach high cell density, the carbamolyase‐producing cell was shown to retain plasmids with 95% stability and to be capable of producing soluble protein equal to 13% of the total cell proteins. Overall, it illustrates the remarkable features of the developed system with tightness, high expression level, thermal inducibility, and high stability.
Translating ethical principles into outcome measures for mental health service research

Background. Mental health service research continues to use only outcome measures that are available rather than develop measures that are important. This paper argues that it is necessary to select and then define a set of ethical principles that can be operationalized and validated as outcome measures to provide a wider balance of information for health policy and clinical service decisions. Methods. The method used is to adopt a five stage procedure: (i) to select ethical principles most directly relevant for mental health services and their evaluation at the local level; (ii) to propose definitions of these principles; (iii) to validate these definitions; (iv) to translate the defined principles into operationalized outcome measures; and (v) to use these outcome measures in mental health services research, within the context of evidence-based medicine. Results. We address steps (i) and (ii) of this five-stage procedure. Nine principles are selected and defined: autonomy, continuity, effectiveness, accessibility, comprehensiveness, equity, accountability, coordination and efficiency. These principles can together be referred to as the three ACEs. Conclusions. Of these nine principles, only two (effectiveness and efficiency) have so far been fully translated into quantitative outcome measures, upon which the evidence-based medicine approach depends. We propose that further concepts also be developed into a more complete multi- dimensional range of fully operationalized outcome measures.
Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1).

AIMS Chronic atrial fibrillation (CAF) is characterized by a shortening of the plateau phase of the action potentials (AP) and a decrease in the bioavailability of nitric oxide (NO). In this study, we analysed the effects of NO on Kv4.3 (I(Kv4.3)) and on human transient outward K(+) (I(to1)) currents as well as the signalling pathways responsible for them. We also analysed the expression of NO synthase 3 (NOS3) in patients with CAF. METHODS AND RESULTS I(Kv4.3) and I(to1) currents were recorded in Chinese hamster ovary cells and in human atrial and mouse ventricular dissociated myocytes using the whole-cell patch clamp. The expression of NOS3 was analysed by western blotting. AP were recorded using conventional microelectrode techniques in mouse atrial preparations. NO and NO donors inhibited I(Kv4.3) and human I(to1) in a concentration- and voltage-dependent manner (IC(50) for NO: 375.0 +/- 48 nM) as a consequence of the activation of adenylate cyclase and the subsequent activation of the cAMP-dependent protein kinase and the serine-threonine phosphatase 2A. The density of the I(to1) recorded in ventricular myocytes from wild-type (WT) and NOS3-deficient mice (NOS3(-/-)) was not significantly different. Furthermore, the duration of atrial AP repolarization in WT and NOS3(-/-) mice was not different. The increase in NO levels to 200 nM prolonged the plateau phase of the mouse atrial AP and lengthened the AP duration measured at 20 and 50% of repolarization of the human atrial CAF-remodelled AP as determined using a mathematical model. However, the expression of NOS3 was not modified in left atrial appendages from CAF patients. CONCLUSION Our results suggested that the increase in the atrial NO bioavailability could partially restore the duration of the plateau phase of CAF-remodelled AP by inhibiting the I(to1) as a result of the activation of non-canonical enzymatic pathways.
Neighbourhood change and neighbour complaints: How gentrification and densification influence the prevalence of problems between neighbours

As people who live in closest proximity to us, the conduct of neighbours can have an impact upon our lives, even if they are relative strangers. While previous research has generally examined the positive effects of good neighbour interactions, neighbours can also be a source of nuisance, conflict and distress. In the advent of socio-structural processes of urban policy and change – such as gentrification and densification – the taken-for-granted conventions that once regulated neighbour interactions are being eroded, potentially leading to greater levels of neighbour problems and complaints. In this paper, we apply a latent modelling approach to identify subgroups of neighbourhoods based on their profiles of neighbour problems and to assess whether these subgroups are characterised by the degree of social change in the neighbourhood towards the dual processes of gentrification and densification. The findings show that high intensity problems are associated with both processes, but that class factors of gentrification are more influential than density in accounting for neighbour tensions.
Do Macro-economic Crises Determine Accounting Value Relevance?

Abstract We investigate whether the value relevance of earnings and book values in Turkey significantly changed across periods of financial uncertainty. Our enquiry differs from the mainstream literature that posits a unidirectional association determined by the ‘quality’ of individual firm accounts towards price. We find divergence in accounting value relevance components across the 1997–2012 period. Dominant value relevance shifts from earnings and negative interest rates in hyper-inflation, to the balance sheet after IFRS in 2005. On the other hand, the global financial crisis (GFC) is associated with diminished accounting value relevance for all variables. Policy issues are raised about value relevance consistency, the use of negative (low) interest rates as fiscal policies and the asymmetric application of market based valuations in emerging economies.
Agile Practices in Higher Education: A Case Study

Indian higher education is looking forward to major reforms. In the past, much of the efforts to bring in reforms have proved to be counter productive. There is so much of wastage of talent and resources that one is compelled to think whether the agile practices that have met with so much of success in manufacturing and in software industry can be of any help in education sector as well. With this guided inquiry we carried out an experiment to practice few of these principles and the results are very encouraging. In this paper we discuss the motivation behind applying agile practices in higher education and the methodology adopted by us with the help of a case study.
Brodmann's Areas 17 and 18 Brought into Stereotaxic Space—Where and How Variable?

Studies on structural-functional associations in the visual system require precise information on the location and variability of Brodmann's areas 17 and 18. Usually, these studies are based on the Talairach atlas, which does not rely on cytoarchitectonic observations, but on comparisons of macroscopic features in the Talairach brain and Brodmann's drawing. In addition, in this atlas are found only the approximate positions of cytoarchitectonic areas and not the exact borders. We have cytoarchitectonically mapped both areas in 10 human brains and marked their borders in corresponding computerized images. Borders were defined on the basis of quantitative cytoarchitecture and multivariate statistics. In addition to borders of areas 17 and 18, subparcellations within both areas were found. The cytoarchitectonically defined areas were 3-D reconstructed and transferred into the stereotaxic space of the standard reference brain. Surface rendering of the brains revealed high individual variability in size and shape of the areas and in the relationship to the free surface and sulci. Ranges and centers of gravity of both areas were calculated in Talairach coordinates. The positions of areas 17 and 18 in the stereotaxic space differed between the hemispheres. Both areas reached significantly more caudal and medial positions on the left than on the right. Probability maps were created in which the degree of overlap in each stereotaxic position was quantified. These maps of areas 17 and 18 are the first of their kind and contain precise stereotaxic information on both interhemispheric and interindividual differences.
Evolutionary Divergence of Aggregatibacter actinomycetemcomitans

Gram-negative facultative Aggregatibacter actinomycetemcomitans is an oral pathogen associated with periodontitis. The genetic heterogeneity among A. actinomycetemcomitans strains has been long recognized. This study provides a comprehensive genomic analysis of A. actinomycetemcomitans and the closely related nonpathogenic Aggregatibacter aphrophilus. Whole genome sequencing by Illumina MiSeq platform was performed for 31 A. actinomycetemcomitans and 2 A. aphrophilus strains. Sequence similarity analysis shows a total of 3,220 unique genes across the 2 species, where 1,550 are core genes present in all genomes and 1,670 are variable genes (accessory genes) missing in at least 1 genome. Phylogenetic analysis based on 397 concatenated core genes distinguished A. aphrophilus and A. actinomycetemcomitans. The latter was in turn divided into 5 clades: clade b (serotype b), clade c (serotype c), clade e/f (serotypes e and f), clade a/d (serotypes a and d), and clade e′ (serotype e strains). Accessory genes accounted for 14.1% to 23.2% of the A. actinomycetemcomitans genomes, with a majority belonging to the category of poorly characterized by Cluster of Orthologous Groups classification. These accessory genes were often organized into genomic islands (n = 387) with base composition biases, suggesting their acquisitions via horizontal gene transfer. There was a greater degree of similarity in gene content and genomic islands among strains within clades than between clades. Strains of clade e′ isolated from human were found to be missing the genomic island that carries genes encoding cytolethal distending toxins. Taken together, the results suggest a pattern of sequential divergence, starting from the separation of A. aphrophilus and A. actinomycetemcomitans through gain and loss of genes and ending with the divergence of the latter species into distinct clades and serotypes. With differing constellations of genes, the A. actinomycetemcomitans clades may have evolved distinct adaptation strategies to the human oral cavity.