Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156134/2/ajt15814_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156134/1/ajt15814.pd

Psycho-Neuro-Endocrine-Immunological Basis of the Placebo Effect: Potential Applications beyond Pain Therapy

The placebo effect can be defined as the improvement of symptoms in a patient after the administration of an innocuous substance in a context that induces expectations regarding its effects. During recent years, it has been discovered that the placebo response not only has neurobiological functions on analgesia, but that it is also capable of generating effects on the immune and endocrine systems. The possible integration of changes in different systems of the organism could favor the well-being of the individuals and go hand in hand with conventional treatment for multiple diseases. In this sense, classic conditioning and setting expectations stand out as psychological mechanisms implicated in the placebo effect. Recent advances in neuroimaging studies suggest a relationship between the placebo response and the opioid, cannabinoid, and monoaminergic systems. Likewise, a possible immune response conditioned by the placebo effect has been reported. There is evidence of immune suppression conditioned through the insular cortex and the amygdala, with noradrenalin as the responsible neurotransmitter. Finally, a conditioned response in the secretion of different hormones has been determined in different studies; however, the molecular mechanisms involved are not entirely known. Beyond studies about its mechanism of action, the placebo effect has proved to be useful in the clinical setting with promising results in the management of neurological, psychiatric, and immunologic disorders. However, more research is needed to better characterize its potential use. This review integrates current knowledge about the psycho-neuro-endocrine-immune basis of the placebo effect and its possible clinical applications

CT-Based Local Distribution Metric Improves Characterization of COPD

Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRM(fSAD) has been observed. We postulate that representing the 3D PRM(fSAD) data as a single scalar quantity (relative volume of PRM(fSAD)) oversimplifies the original 3D data, limiting its potential to detect the subtle progression of COPD as well as varying subtypes. In this study, we propose a new approach to analyze PRM. Based on topological techniques, we generate 3D maps of local topological features from 3D PRM(fSAD) classification maps. We found that the surface area of fSAD (S(fSAD)) was the most robust and significant independent indicator of clinically meaningful measures of COPD. We also confirmed by micro-CT of human lung specimens that structural differences are associated with unique S(fSAD) patterns, and demonstrated longitudinal feature alterations occurred with worsening pulmonary function independent of an increase in disease extent. These findings suggest that our technique captures additional COPD characteristics, which may provide important opportunities for improved diagnosis of COPD patients

Cartografía digital de suelos a escala de predio.

La Cartografía Digital de Suelos (CDS) usando el entorno y lenguaje de programación R constituye una metodología de trabajo impulsada desde la FAO para realizar predicciones de propiedades del suelo a escala nacional. Esta realiza predicciones a partir de la interrelación entre las propiedades del suelo y datos ambientales mediante el uso de diferentes modelos geoestadísticos. En este trabajo empleamos el algoritmo de aprendizaje automático Quantile Regression Forests. El objetivo de esta contribución es probar esta metodología a escala de predio en el Campo Experimental de la UNLu. Las propiedades mapeadas fueron pH y carbono orgánico total (COT). Para ello se muestrearon 150 sitios a dos profundidades, de 0 a 10 cm y de 10 a 20 cm y se emplearon como predictores covariables ambientales derivados del Modelo Digital del Terreno externo del Instituto Geográfico Nacional (IGN) de 5 metros de resolución espacial. Las predicciones de pH mostraron un R2 ajustado de 43% de 0 a 10 cm y de 54% de 0 a 20 cm, a diferencia de las de COT que estuvieron por debajo del 10%. Los resultados muestran que la CDS resultó una metodología válida que puede aplicarse a escala de predio con una densidad de observaciones de 2 por ha. y predictores de 5 metros de resolución espacial.Fil: Tenti Vuegen, LM Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Suelos; ArgentinaFil: Irigoin, Julieta. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Suelos; Argentina. Universidad Nacional de Lujan. Departamento Tecnología; ArgentinaFil: Montes Galban, E. Universidad Nacional de Luján, Departamento de Tecnología, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) ArgentinaFil: Trabichet, Florencia Cecilia. Universidad Nacional de Luján. Departamento de Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bulos, Laura. Universidad Nacional de Luján. Departamento de Tecnología. Edafología; ArgentinaFil: Wagner, V. Universidad Nacional de Luján. Departamento de Tecnología. Edafología; ArgentinaFil: Petrasek, M.R. Universidad Nacional de Luján. Departamento de Tecnología. Edafología; ArgentinaFil: Ramírez, J.A. Universidad Nacional de Luján. Departamento de Tecnología. Edafología; ArgentinaFil: Bonvecchi, Virginia B. Universidad Nacional de Luján. Departamento de Tecnología. Edafología; Argentin

Solution Structure of Polymerase μ's BRCT Domain Reveals an Element Essential for Its Role in Nonhomologous End Joining †

The solution structure and dynamics of the BRCT domain from human DNA polymerase μ, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein—protein interactions between factors required for the cellular response to DNA damage. The pol μ BRCT domain is atypical in that, unlike other reported BRCT structures, the pol μ BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol μ BRCT domain has some unique characteristics, particularly the presence of > 10% proline residues, it forms the characteristic αβα sandwich, in which three alpha helices are arrayed around a central four-stranded β-sheet. The structure of helix α1 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting that this element may play a role in mediating interactions of pol μ with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol μ to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol μ BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol μ and TdT support the conclusion that they participate in NHEJ as alternate polymerases

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E214k, has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E214k were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E214k mRNA and protein levels in gastrocnemius muscle with increases of 6–8-fold for C2 and two-fold for E214k between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25–27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18–20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E214k mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss

Dispersal and reproductive careers of male mountain gorillas in Bwindi Impenetrable National Park, Uganda

Dispersal is a key event in the life of an animal and it influences individual reproductive success. Male mountain gorillas exhibit both philopatry and dispersal, resulting in a mixed one-male and multimale social organization. However, little is known about the relationship between male dispersal or philopatry and reproductive careers in Bwindi mountain gorillas. Here we analyze data spanning from 1993 to 2017 on social groups in Bwindi Impenetrable National Park, Uganda to examine the proportion of males that disperse, age of dispersal, pathways to attaining alpha status, fate of dispersing males and philopatric males, and male tenure length as well as make comparisons of these variables to the Virunga mountain gorilla population. We report previously undocumented cases of dispersal by immature males and old males and we also observed the only known case of a fully mature male immigrating into a breeding group. We used genetic tracking of known individuals to estimate that a minimum of 25% of males that disperse to become solitary males eventually form new groups. No differences were found between the Bwindi and Virunga population in the age of male dispersal, the proportion of males that disperse, the age of alpha male acquisition, and dominance tenure length. The lack of differences may be due to small sample sizes or because the observed ecological variability does not lead to life history differences between the populations. Males in both populations follow variable strategies to attain alpha status leading to the variable one-male and multimale social organization, including dispersal to become solitary and eventually form a group, via group fissioning, usurping another alpha male, or inheriting the alpha position when a previous group leader dies

DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials

Structural Analysis of the UBA Domain of X-linked Inhibitor of Apoptosis Protein Reveals Different Surfaces for Ubiquitin-Binding and Self-Association

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. PRINCIPAL FINDINGS: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha1 and helix alpha2, separate from the ubiquitin-binding surface. CONCLUSION: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.published_or_final_versio