Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Background: Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment. Methods: SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR. Results: One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60 % of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate. Conclusion: Within the IFN treated SPMS population, 60 % of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment

Notes on Photomontage

Introduction (English) Grete Stern (Wuppertal, 1904-Buenos Aires, 1999) was a disciple of Walter Peterhans, the proponent of the Neues Sehen (New Vision), who was responsible for the first course on photography at the Bauhaus (Dessau, 1929). In Berlin, at the beginning of the 1930s, she associated with Ellen Rosenberg (later Auerbach) in the photographic studio ringl+pit, where they operated with photomontage and photocollage in advertising and portrait following the experiments of the New Vi..

Differential associations between distinct components of cognitive function and mobility: implications for understanding aging, turning and dual-task walking

Objective: Cognition and mobility are interrelated. However, this association can be impacted by the specific facets of cognition and mobility that are measured, and further by the different task conditions, e.g., single- versus dual-task walking, under which these associations are evaluated. Systematically studying the multiple facets of cognitive-mobility associations under both the task conditions is critical because both cognition and mobility change with age and pose significant risks associated with falls, morbidity, and disability. Methods: Using a cross-sectional, prospective study design, data from 124 healthy adults [mean age (SD) = 61.51 (11.90); mean education (SD) = 15.94 (2.18)] were collected. A comprehensive battery of cognitive tests was administered, and gait was assessed using a small, lightweight, three-axis accelerometer with a gyroscope. Analytical Plan: Data were transformed, and only relatively strong relationships survived after strict statistical criteria adjusting for multiple comparisons were applied. Spearman rho correlation coefficients were used to examine the matrix of correlations between the cognitive-motor variables while adjusting for age and gender. Results: Executive functions, processing speed, and language were associated with distinct facets of variability, pace, and asymmetry, especially under the dual-task walking condition. Both turns and transitions were also associated with cognition during the Timed Up and Go Task. Conclusion: Our results extend converging evidence of the involvement of executive functions and processing speed in specific aspects of mobility, along with the role of language. The study has important implications for aging in terms of both assessment and rehabilitation of cognition and gait as well as for the emerging dual-tasking theories and the role of the neural pathways involved in mobility

Anticipatory feelings: Neural correlates and linguistic markers

This review introduces anticipatory feelings (AF) as a new construct related to the process of anticipation and prediction of future events. AF, defined as the state of awareness of physiological and neurocognitive changes that occur within an oganism in the form of a process of adapting to future events, are an important component of anticipation and expectancy. They encompass bodily-related interoceptive and affective components and are influenced by intrapersonal and dispositional factors, such as optimism, hope, pessimism, or worry. In the present review, we consider evidence from animal and human research, including neuroimaging studies, to characterize the brain structures and brain networks involved in AF. The majority of studies reviewed revealed three brain regions involved in future oriented feelings: 1) the insula; 2) the ventromedial prefrontal cortex (vmPFC); and 3) the amygdala. Moreover, these brain regions were confirmed by a meta-analysis, using a platform for large-scale, automated synthesis of fMRI data. Finally, by adopting a neurolinguistic and a big data approach, we illustrate how AF are expressed in language

Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases (n = 69; 49%), hematology (n = 68; 48%), and others (n = 41; 29%). BCT was performed in 57% (n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% (n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome

Persistent ER Stress Induces the Spliced Leader RNA Silencing Pathway (SLS), Leading to Programmed Cell Death in Trypanosoma brucei

Trypanosomes are parasites that cycle between the insect host (procyclic form) and mammalian host (bloodstream form). These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR). However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS) pathway. SLS elicits shut-off of spliced leader RNA (SL RNA) transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER) stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD), evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS) production, increase in cytoplasmic Ca2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM). ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

A moda no MASP de Pietro Maria Bardi (1947-1987)

O objetivo deste artigo é evidenciar a centralidade das ações ligadas à moda e à formação da Seção de Costumes do MASP no projeto de museu e na concepção de arte de Pietro Maria Bardi no período 1947-1987, e como tais ações teriam sido relevantes para a instituição de uma visualidade e uma história para a moda nacional. Demonstra-se como a trajetória de P. M. Bardi na Itália, ou seja, sua atuação como galerista e comerciante de artes, jornalista, bem como seu contato com a ideologia e as ações do Regime Fascista no campo das artes e da moda, influenciou diretamente suas ações em relação ao design de moda. Essas ideias e experiências foram fundamentais para direcionar sua atuação no MASP e, em especial suas iniciativas na área do design. Nota-se ainda como a atuação de Bardi no campo do design de moda foi também influenciada pelas ideias propagadas pela Bauhaus e Le Corbusier, assim como por seu olhar estrangeiro, que acaba por levá-lo a recuperar, nas referentes iniciativas, as tradições e a cultura brasileiras, gerando uma produção que dialoga com o modernismo brasileiro, uma vez que usa a experiência internacional para valorizar o nacional