Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration. Fractalkine (FKN) is a transmembrane chemokine expressed in the CNS by neurons and signals through its unique receptor CX3CR1 present in microglia. During experimental autoimmune encephalomyelitis (EAE), CX3CR1 deficiency confers exacerbated disease defined by severe inflammation and neuronal loss. The CX3CR1 human polymorphism I249/M280 present in ∼20% of the population exhibits reduced adhesion for FKN conferring defective signaling whose role in microglia function and influence on neurons during MS remains unsolved. The aim of this study is to assess the effect of weaker signaling through hCX3CR1I249/M280 during EAE. We hypothesize that dysregulated microglial responses due to impaired CX3CR1 signaling enhance neuronal/axonal damage. We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR1I249/M280 variant. Upon EAE induction, these mice exhibited exacerbated EAE correlating with severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and ciliary neurotrophic factor during EAE in contrast to wild type mice. Our results provide validation of defective function of the hCX3CR1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation. © 2018 Cardona et al

Spontaneous expectoration of pulmonary metastases in a child with osteogenic sarcoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/1/pbc27611.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/2/pbc27611_am.pd

Tecnografias líticas do Holoceno médio na região central da América do Sul: tesselas culturais para um mosaico paleo-histórico (primeira parte)

Este trabajo, subdividido em primera y segunda parte, presenta un panorama tecnográfico del material lítico proveniente de sitios del Holoceno medio, localizados en la región central de América del Sur, específicamente de la macro-región dominada por sabanas en las tierras bajas. Este análisis fue posible a través de una revisión y reflexión sobre la información bibliográfica disponible. En base a un enfoque tecno-funcional, la descripción de los modos de manufactura de útiles líticos se basó en el reconocimiento de tres principios técnicos desde el punto de vista tecno-funcional: débitage, façonnage y affordance, así como de la consideración de la relación entre las porciones activas y prehensivas de las piezas interpretadas como útiles (denominadas también “categorías tecno-funcionales”). Como resultado se obtuvo una síntesis de las particularidades y variabilidades tecnológicas en áreas poco conocidas o documentadas en lo que se refiere a la materialidad lítica. En la primera parte del artículo, esta síntesis puso en evidencia que en los agrupamientos de los sitios del Cratón Amazónico existió un conjunto de culturas tecnicas relativamente homogéneas concentradas alrededor de los principios de débitage y façonnage. En cuanto a la gestión de la materia prima, se observa en estos sitios un aprovisionamiento local de recursos líticos

Tecnografias líticas do Holoceno médio na região central da América do Sul: tesselas culturais para um mosaico paleo-histórico (segunda parte)

Este artigo constitui a segunda parte da análise das tecnografias líticas dos sítios do Holoceno Médio em uma grande macrorregião, o setor central da América do Sul: ele abrange os grupos de sítios B, C e D. Um elemento comum em todos os conjuntos analisados é a presença de ferramentas da categoria tecnofuncional B. Com relação aos modos de produção, pode-se observar que o princípio da debitage predomina na área de análise. No entanto, sua aplicação é diversa; há conjuntos em que houve uma predeterminação na fabricação de lascas, outros em que os núcleos são reintroduzidos como suportes ou lâminas de apresentação e outros locais em que lascas de fabricação de façonagem foram reintroduzidas como ferramentas de suporte. Os demais princípios de produção também foram registrados: afordance (tanto na produção instrumental quanto em sua expressão produtiva) e façonagem são observados em sítios dos grupos A, C e D. O reconhecimento dos diferentes modos de produção é o ponto de partida para pensar em como grupos com diferentes tradições técnicas ocuparam diferentes espaços na região

CD98 Increases Renal Epithelial Cell Proliferation by Activating MAPKs

CD98 heavy chain (CD98hc) is a multifunctional transmembrane spanning scaffolding protein whose extracellular domain binds with light chain amino acid transporters (Lats) to form the heterodimeric amino acid transporters (HATs). It also interacts with β1 and β3 integrins by its transmembrane and cytoplasmic domains. This interaction is proposed to be the mechanism whereby CD98 mediates cell survival and growth via currently undefined signaling pathways. In this study, we determined whether the critical function of CD98-dependent amino acid transport also plays a role in cell proliferation and defined the signaling pathways that mediate CD98-dependent proliferation of murine renal inner medullary collecting duct (IMCD) cells. We demonstrate that downregulating CD98hc expression resulted in IMCD cell death. Utilizing overexpression studies of CD98hc mutants that either lacked a cytoplasmic tail or were unable to bind to Lats we showed that CD98 increases serum-dependent cell proliferation by a mechanism that requires the CD98hc cytoplasmic tail. We further demonstrated that CD98-dependent amino acid transport increased renal tubular epithelial cell proliferation by a mechanism that does not require the CD98hc cytoplasmic tail. Both these mechanisms of increased renal tubular epithelial cell proliferation are mediated by Erk and p38 MAPK signaling. Although increased amino transport markedly activated mTor signaling, this pathway did not alter cell proliferation. Thus, these studies demonstrate that in IMCD cells, the cytoplasmic and extracellular domains of CD98hc regulate cell proliferation by distinct mechanisms that are mediated by common MAPK signaling pathways

Assessment of humoral immunity to SARS-CoV-2 by a sample examination of medical workers in a large specialized multidisciplinary hospital

Introduction. The assessment of specific IgG antibodies to RBD Spike SARS-CoV-2 and their quantitation permit to calculate the intensity of immunity to COVID-19, i.e. to determine the level of immunity to infection, the risk of infection, the severity of the disease, as well as the ability to prevent death. Meanwhile, the protective level of antibodies is not determined. Therefore, determining the nature of immunity and quantitation of IgG antibodies to RBD Spike SARS-CoV-2 make it possible to assess the effectiveness of preventive measures and correct them in a timely manner. The aim is to determine the presence of IgG antibodies to RBD Spike SARS-CoV-2, their concentrations, and the nature of humoral immunity in different age and occupational groups of employees in a closed-type hospital after the completed vaccination with "Gam-Covid-Vac" vaccine. Materials and methods. The blood sera of 310 members of medical staff who received a full course of immunization with the "Gam-Covid-Vac" vaccine were tested using "SARS-CoV-2-ELISA-IgG" kit according to instructions provided in 21.20.23-004-28597318-2020, RU No. RZN 2021/15898. IgG antibodies to RBD Spike SARS-CoV-2 were quantitated against WHO standard NIBSC 20/136. Results. Specific IgG antibodies to RBD Spike SARS-CoV-2 were found in 92.9% of the examined individuals, including 67.4% having hybrid immunity (both vaccine- and infection- induced), and 25.5% having post-vaccination immunity after immunization with the "Gam-Covid-Vac" vaccine; 7.1% participants were nonimmune. A higher level of IgG antibodies to RBD Spike SARS-CoV-2 was detected in the group of individuals with hybrid immunity (p 0.01). Only 11.6% of employees had a protective antibody level of more than 300 BAU/ml. Discussion. Most employees with hybrid immunity were identified in the older age groups and in the junior medical staff. The results of this serological study, taking into account the age and professional aspects, can serve as the basis for adjusting preventive measures in medical institutions

Integrative multi-kinase approach for the identification of potent antiplasmodial hits

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.7CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP405996/2016-0; 400760/2014-2Sem informação2018/05926-2; 2017/02353-9; 2012/16525-2; 2017/18611-7; 2018/07007-4; 2013/13119-6; 2018/24878-9; 2015/20774-

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods: SLC3A2 was assessed at the genomic level, using METABRIC data (n=1,980), and proteomic level, using immunohistochemistry on TMA sections constructed from a large well-characterised primary BC cohort (n=2,500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results: SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple negative (TN), HER2+, and ER+ high proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p<0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p<0.001)), but only in the ER+ high proliferation (p=0.01) and triple negative (p=0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter breast cancer specific survival (p<0.001). Conclusions: SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes

A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811)

Safety and efficacy of intrapericardial (ipc) instillation of bleomycin (BLM) following pericardial drainage in patients with malignant pericardial effusion (MPE) remain unclear. Patients with pathologically documented lung cancer, who had undergone pericardial drainage for MPE within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (ipc BLM at 15 mg, followed by additional ipc BLM 10 mg every 48 h). The drainage tube was removed when daily drainage was 20 ml or less. The primary end point was survival with MPE control (effusion failure-free survival, EFFS) at 2 months. Eighty patients were enrolled, and 79 were eligible. Effusion failure-free survival at 2 months was 29% in arm A and 46% in arm B (one-sided P=0.086 by Fisher's exact test). Arm B tended to favour EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40–1.03, one-sided P=0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively. This medium-sized trial failed to show statistical significance in the primary end point. Although ipc BLM appeared safe and effective in the management of MPE, the therapeutic advantage seems modest