Calmodulin antagonizes amyloid-β peptides-mediated inhibition of brain plasma membrane Ca2+-ATPase

AbstractThe synaptosomal plasma membrane Ca2+-ATPase (PMCA) plays an essential role in regulating intracellular Ca2+ concentration in brain. We have recently found that PMCA is the only Ca2+ pump in brain which is inhibited by amyloid-β peptide (Aβ), a neurotoxic peptide implicated in the pathology of Alzheimer's disease (AD) [1], but the mechanism of inhibition is lacking. In the present study we have characterized the inhibition of PMCA by Aβ. Results from kinetic assays indicate that Aβ aggregates are more potent inhibitors of PMCA activity than monomers. The inhibitory effect of Aβ could be blocked by pretreating the purified protein with Ca2+-calmodulin, the main endogenous activator of PMCA, and the activity of truncated PMCA lacking the calmodulin binding domain was not affected by Aβ. Dot-overlay experiments indicated a physical association of Aβ with PMCA and also with calmodulin. Thus, calmodulin could protect PMCA from inhibition by Aβ by burying exposed sites on PMCA, making them inaccessible to Aβ, and also by direct binding to the peptide. These results suggest a protective role of calmodulin against neuronal Ca2+ dysregulation by PMCA inhibition induced by Aβ

The identification of linker characteristics among the Venzuelan students in the United States.

The process of technology transfer is dependent on personal communication between individuals knowledgeable in new technology and who are willing to share this knowledge with others for the purpose of increasing the benefits to mankind. A modified version of a previously developed situational test for naval officers is used to determine the natural ability among Venezuelan students in the United States to transfer technical information and bring about its adoption. Emphasis is placed on locating and understanding these individuals to improve the effectiveness and efficiency of technology transfer efforts of Venezuelan agencies. Extensive analysis is performed on the results of questionnaires. Conclusions are drawn and recommendations for additional investigation are provided.http://archive.org/details/identificationof00delrCommander, Venezuelan NavyApproved for public release; distribution is unlimited

Radio-Optically- and Thermally Stimulated Luminescence of Zn(BO2)2:Tb3+ exposed to Ionizing Radiation

The optical absorption of zinc tetraborate at different concentrations of the terbium impurity (0, 0.5, 1, 2, 4, 8 mol%) was analyzed. The radioluminescence (RL) emission spectra was obtained after beta irradiation of a 90Sr/90Y source. The RL spectrum showed the characteristics bands of Tb3+ with two main emissions at 489 nm and 546 nm which corresponding to the5D4→7F6 and 5D4→7F5 transitions respectively in this ion. The OSL and TL characteristics have been analyzed. The stimulation blue light (497 nm) of a diode laser at 500 mA was used to bleach the thermoluminescent (TL) signals obtained with 5Gy of 60Co source. The two main glow peaks (79 and 161 °C) are sensitives under 497 nm stimulation, and they were shifted to higher temperature values and faded their TL intensities. Similar behavior of TL glow curves before and after OSL stimulation with blue light was observed when the samples were exposed to 30 Gy gamma dose of 137Cs irradiator. The OSL signal response was linear with the dose range of 1-10 Gy and increased their response up to 200 Gy gamma dose. The OSL shows a bleaching sensitive shallow traps and diminishing the intensity of the TL glow curves remaining a complex traps distribution. The RL, TL and OSL properties were investigated in Zn(BO2)2:Tb3+ phosphor

Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors

Comparison of gene expression in normal and glaucomatous eyes from Caucasian American and African American donors reveals differences that might reflect different susceptibility to glaucoma

Genetic networks controlling retinal injury.

PURPOSE: The present study defines genomic loci underlying coordinate changes in gene expression following retinal injury. METHODS: A group of acute phase genes expressed in diverse nervous system tissues was defined by combining microarray results from injury studies from rat retina, brain, and spinal cord. Genomic loci regulating the brain expression of acute phase genes were identified using a panel of BXD recombinant inbred (RI) mouse strains. Candidate upstream regulators within a locus were defined using single nucleotide polymorphism databases and promoter motif databases. RESULTS: The acute phase response of rat retina, brain, and spinal cord was dominated by transcription factors. Three genomic loci control transcript expression of acute phase genes in brains of BXD RI mouse strains. One locus was identified on chromosome 12 and was highly correlated with the expression of classic acute phase genes. Within the locus we identified the inhibitor of DNA binding 2 (Id2) as a candidate upstream regulator. Id2 was upregulated as an acute phase transcript in injury models of rat retina, brain, and spinal cord. CONCLUSIONS: We defined a group of transcriptional changes associated with the retinal acute injury response. Using genetic linkage analysis of natural transcript variation, we identified regulatory loci and candidate regulators that control transcript levels of acute phase genes

miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.

Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both, in sterile and non-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.This work was supported by research grants from Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional “Investing in your future” (PI17/00051 y PI17/01421) (PFIS18/0045: A.M. de los Reyes-García) (CD18/00044: S. Águila), and Fundación Séneca (19873/GERM/15). The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Fundación Pro CNIC, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. Arroyo has a research fellowship from Sociedad Española de Trombosis y Hemostasia (SETH). The MCIU supported A.dM. (predoctoral contract BES-2014-067791).S

GSE4‐loaded nanoparticles a potential therapy for lung fibrosis that enhances pneumocyte growth, reduces apoptosis and DNA damage

Idiopathic pulmonary fibrosis is a lethal lung fibrotic disease, associated with aging with a mean survival of 2-5 years and no curative treatment. The GSE4 peptide is able to rescue cells from senescence, DNA and oxidative damage, inflammation, and induces telomerase activity. Here, we investigated the protective effect of GSE4 expression in vitro in rat alveolar epithelial cells (AECs), and in vivo in a bleomycin model of lung fibrosis. Bleomycin-injured rat AECs, expressing GSE4 or treated with GSE4-PLGA/PEI nanoparticles showed an increase of telomerase activity, decreased DNA damage, and decreased expression of IL6 and cleaved-caspase 3. In addition, these cells showed an inhibition in expression of fibrotic markers induced by TGF-β such as collagen-I and III among others. Furthermore, treatment with GSE4-PLGA/PEI nanoparticles in a rat model of bleomycin-induced fibrosis, increased telomerase activity and decreased DNA damage in proSP-C cells. Both in preventive and therapeutic protocols GSE4-PLGA/PEI nanoparticles prevented and attenuated lung damage monitored by SPECT-CT and inhibited collagen deposition. Lungs of rats treated with bleomycin and GSE4-PLGA/PEI nanoparticles showed reduced expression of α-SMA and pro-inflammatory cytokines, increased number of pro-SPC-multicellular structures and increased DNA synthesis in proSP-C cells, indicating therapeutic efficacy of GSE4-nanoparticles in experimental lung fibrosis and a possible curative treatment for lung fibrotic patients

Development of Potent Cellular and Humoral Immune Responses in Long-Term Hemodialysis Patients After 1273-mRNA SARS-CoV-2 Vaccination

Long-term hemodialysis (HD) patients are considered vulnerable and at high-risk of developing severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection due to their immunocompromised condition. Since COVID-19 associated mortality rates are higher in HD patients, vaccination is critical to protect them. The response towards vaccination against COVID-19 in HD patients is still uncertain and, in particular the cellular immune response is not fully understood. We monitored the humoral and cellular immune responses by analysis of the serological responses and Spike-specific cellular immunity in COVID-19-recovered and naïve HD patients in a longitudinal study shortly after vaccination to determine the protective effects of 1273-mRNA vaccination against SARS-CoV-2 in these high-risk patients. In naïve HD patients, the cellular immune response measured by IL-2 and IFN-ɣ secretion needed a second vaccine dose to significantly increase, with a similar pattern for the humoral response. In contrast, COVID-19 recovered HD patients developed a potent and rapid cellular and humoral immune response after the first vaccine dose. Interestingly, when comparing COVID-19 recovered healthy volunteers (HV), previously vaccinated with BNT162b2 vaccine to HD patients vaccinated with 1273-mRNA, these exhibited a more robust immune response that is maintained longitudinally. Our results indicate that HD patients develop strong cellular and humoral immune responses to 1273-mRNA vaccination and argue in favor of personalized immune monitoring studies in HD patients, especially if COVID-19 pre-exposed, to adapt COVID-19 vaccination protocols for this immunocompromised population.Funding was obtained from Instituto de Salud Carlos III (ISCIII) RICORS program to RICORS2040 (RD21/0005/0001), FEDER funds; Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, grant number AESI PI21CIII_00022 to PP and Healthstar-plus -REACT-UE Grant through Segovia Arana Research Institute Puerta de Hierro Majadahonda-IDIPHIM. JO is a member of VACCELERATE (European Corona Vaccine Trial Accelerator Platform) Network, which aims to facilitate and accelerate the design and implementation of COVID-19 phase 2 and 3 vaccine trials. JO is a member of the INsTRuCT under the MSC grant agreement Nº860003 (Innovative Training in Myeloid Regulatory Cell Therapy) Consortium, a network of European scientists from academia and industry focused on developing innovative immunotherapies.S

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.This research was funded by INSTITUTO DE SALUD CARLOS III, institutional project Spain UDP and grant PT20CIII/00009.S