Analysis of neuronal activity in the hippocampus of behaving animals has revealed cells acting as 'Time Cells', which exhibit selective spiking patterns at specific time intervals since a triggering ...event, and 'Distance Cells', which encode the traversal of specific distances. Other neurons exhibit a combination of these features, alongside place selectivity. This study aims to investigate how the task performed by animals during recording sessions influences the formation of these representations. We analyzed data from a treadmill running study conducted by Kraus et al., 2013, in which rats were trained to run at different velocities. The rats were recorded in two trial contexts: a 'fixed time' condition, where the animal ran on the treadmill for a predetermined duration before proceeding, and a 'fixed distance' condition, where the animal ran a specific distance on the treadmill. Our findings indicate that the type of experimental condition significantly influenced the encoding of hippocampal cells. Specifically, distance-encoding cells dominated in fixed-distance experiments, whereas time-encoding cells dominated in fixed-time experiments. These results underscore the flexible coding capabilities of the hippocampus, which are shaped by over-representation of salient variables associated with reward conditions.
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas ...(HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.
Interest in pre-Quaternary paleosols has increased over the past decade, in large part, because they have proved to be beneficial in solving diverse geological problems. The majority of paleosols are ...described from continental deposits, most commonly from alluvial strata. Criteria for recognizing these paleosols have been extensively described; however, classifying them has proved more complicated. Pre-Quaternary paleosols are generally classified according to one or more modern soil classification systems, although one new classification has been proposed exclusively for paleosols to avoid problems using the modern soil classifications. In addition to taxonomic classification, paleosols can be categorized according to the interplay among deposition, erosion, and the rate of pedogenesis when they formed. Paleosols can be solitary if they formed during a period of landscape stability following the development of an unconformity. Such paleosols are commonly thick and extremely well developed. More commonly, paleosols are vertically stacked or multistory because they formed in sedimentary systems undergoing net aggradation. If erosion was insignificant and sedimentation was rapid and unsteady, compound paleosols generally formed. If the rate of pedogenesis exceeded the rate of deposition, composite paleosols developed. Thick, cumulative paleosols indicate that erosion was insignificant and that sedimentation was relatively steady. Both autogenic and allogenic processes can influence depositional and erosion patterns and, thus, affect the kinds of soils that form. Consequently, paleosols can help to interpret the history of sediment deposition and the autogenic and allogenic processes that influenced a sedimentary basin. Paleosols are also helpful in stratigraphic studies, including sequence stratigraphic analyses. They are used for stratigraphic correlations at the local and basinal scale, and some workers have calculated sediment accumulation rates based on the degree of paleosol development. In addition to their stratigraphic applications, paleosols can be used to interpret landscapes of the past by analyzing paleosol–landscape associations at different spatial scales, ranging from local to basin-wide in scope. At the local scale, lateral changes in paleosol properties are largely the result of variations in grain size and topography. At the scale of the sedimentary basin, paleosols in different locations differ because of basinal variations in topography, grain size, climate, and subsidence rate. Paleosols are used to reconstruct ancient climates, even to estimate ancient mean annual precipitation (MAP) and mean annual temperature (MAT). Ancient climatic conditions can be interpreted from modern soil analogs or by identifying particular pedogenic properties that modern studies show to have climatic significance. Stable carbon and oxygen isotopes are also used to interpret ancient climate, and some effort has been made to estimate MAT from isotopic composition. On the basis of modern soil analogs, paleo-precipitation has been estimated from the depth at which calcic horizons originally formed. Finally, paleosol carbonates have been used to estimate ancient atmospheric CO
2 values.
Objectives
To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data.
Materials and methods
We included all patients starting ...treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non‐randomized registry study.
Results
The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log‐transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247‐0.523), P < .001.
Conclusions
The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log‐transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.
Objectives
To investigate anti‐proliferatory activity of a selected N,N‐(8‐hydroxyquinoline)methyl‐substituted benzylamine (JLK1486) on melanoma cells and to characterize its mechanism of cell ...population growth inhibition.
Materials and methods
In vitro cultures of B16F10 (mouse melanoma) cells were used as a model to characterize anti‐proliferatory activity of JLK1486 using MTT growth assay, trypan blue viability assessment, cell cycle analysis, melanin production, β‐galactosidase and acridine orange staining.
Results
Proliferating B16F10 and also MeWo (human melanoma) cells were strongly growth inhibited by JLK1486, displaying IC50 values of 196 nm and 110 nm respectively. Anti‐proliferatory effects were independent of cell death and were characterized by a distinct accumulation of cells in G0/G1 phase. Tyrosinase activity and relative melanin content remained unchanged indicating that the anti‐proliferatory activity was not due to phenotype differentiation. Although treated B16F10 cells stained strongly positive for senescence marker β‐galactosidase, cells regained near normal proliferatory activity after removal of JLK1486. Increased acridine orange staining and presence of perinuclear vacuoles suggested induction of autophagy in B16F10 cells. Furthermore, JLK1486 pre‐treatment completely abolished melphalan and antimycin A‐induced apoptosis.
Conclusion
JLK1486 provides a promising chemical scaffold to develop new anti‐melanoma drugs or combination therapies, due to its potent inhibition of cell proliferation and induction of autophagy, at pharmacologically relevant concentrations.
Glioblastoma IDH wildtype is the most frequent brain tumor in adults. It shows a highly malignant behavior and devastating outcomes. To date, there is still no targeted therapy available; thus, ...patients' median survival is limited to 12-15 months. Epithelial growth factor receptor (
) is an interesting targetable candidate in advanced precision medicine for brain tumor patients. In this study, we performed integrated epigenome-wide DNA-methylation profiling of 866,895 methylation specific sites in 50 glioblastoma IDH wildtype samples, comparing
amplified and non-amplified glioblastomas. We found 9849 significantly differentially methylated CpGs (DMCGs) with Δβ ≥ 0.1 and
-value < 0.05 in
amplified, compared to
non-amplified glioblastomas. Of these DMCGs, 2380 were annotated with tiling (2090), promoter (117), gene (69) and CpG islands (104); 7460 are located at other loci. Interestingly, the list of differentially methylated genes allocated eleven functionally relevant RNAs: five miRNAs (miR1180, miR1255B1, miR126, miR128-2, miR3125), two long non-coding RNAs (LINC00474, LINC01091), and four antisense RNAs (EPN2-AS1, MNX1-AS2, NKX2-2-AS1, WWTR1-AS1). Gene ontology (GO) analysis showed enrichment of "DNA replication-dependent nucleosome assembly", "chromatin silencing at rDNA", "regulation of gene silencing by miRNA", "DNA packaging", "posttranscriptional gene silencing", "gene silencing by RNA", "negative regulation of gene expression, epigenetic", "regulation of gene silencing", "protein-DNA complex subunit organization", and "DNA replication-independent nucleosome organization" pathways being hypomethylated in
amplified glioblastomas. In summary, dissecting the methylomes of
amplified and non-amplified glioblastomas revealed altered DNA replication, DNA packaging, chromatin silencing and gene silencing pathways, opening potential novel targets for future precision medicine.
Calsenilin is a calcium ion (Ca
2+
)-binding protein involved in regulating the intracellular concentration of Ca
2+
, a second messenger that controls multiple cellular signaling pathways. The ...ryanodine receptor (RyR) amplifies Ca
2+
signals entering the cytoplasm by releasing Ca
2+
from endoplasmic reticulum (ER) stores, a process termed calcium-induced calcium release (CICR). Here, we describe a novel mechanism, in which calsenilin controls the activity of neuronal RyRs. We show calsenilin co-localized with RyR2 and 3 in the ER of mouse hippocampal and cortical neurons using immunocytochemistry. The underlying protein-protein interaction between calsenilin and the RyR was determined in mouse central nervous system (CNS) neurons using immunoprecipitation studies. The functional relevance of this interaction was assayed with single-channel electrophysiology. At low physiological Ca
2+
concentrations, calsenilin binding to the cytoplasmic face of neuronal RyRs decreased the RyR’s open probability, while calsenilin increased the open probability at high physiological Ca
2+
concentrations. This novel molecular mechanism was studied further at the cellular level, where faster release kinetics of caffeine-induced Ca
2+
release were measured in SH-SY5Y neuroblastoma cells overexpressing calsenilin. The interaction between calsenilin and neuronal RyRs reveals a new regulatory mechanism and possibly a novel pharmacological target for the control of Ca
2+
release from intracellular stores.
Other causes include hypoperfusion secondary to aortic dissection, cardiac arrest, atherothrombotic disease, emboli, vasculitis, sickle cell disease, hypercoagulability, arteriovenous malformations, ...intervertebral disc herniation, and cocaine-induced vasospasm 2. Lower extremity neurological exam on discharge Power Hip flexion Knee extension Plantar flexion Dorsiflexion Hallux extension RLE 5 5 5 5 5 LLE 4 4 4 2 1 Sensory LLE light touch intact but diminished compared to RLE up to inguinal ligament, LLE loss of temperature up to inguinal ligament, LLE vibration intact in MTP joints, RLE normal sensation Gait Marked LLE foot drop with walker needed for ambulation RLE, right lower extremity; LLE, left lower extremity. ...only 2 of the 28 patients had unilateral lesions in the peripheral distribution of the ASA with a majority of MRIs demonstrating infarction of the central territory of the ASA. The unilateral nature of the injury and deficits highlight the complexity of the anterior blood supply of the spinal cord. Since the ASA supplies the cord bilaterally, unilateral injury suggests local hypotension to a susceptible region of cord.
State of the art: leadless ventricular pacing Steinwender, C.; Lercher, P.; Schukro, C. ...
Journal of interventional cardiac electrophysiology,
01/2020, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background
Cardiac pacing has been shown to improve quality of life and prognosis of patients with bradycardia for almost 60 years. The latest innovation in pacemaker therapy was miniaturization of ...generators to allow leadless pacing directly in the right ventricle. There is a long history and extensive experience of leadless ventricular pacing in Austria. However, no recommendations of national or international societies for indications and implantation of leadless opposed to transvenous pacing systems have been published so far.
Results
A national expert panel of skilled implanters gives an overview on the two utilized leadless cardiac pacing systems and highlights clinical advantages as well as current knowledge of performance and complication rates of leadless pacing. Furthermore, a national consensus for Austria is presented, based on recent studies and current know-how, specifically including indications for leadless pacing, management of infection, suggestions for qualification, and training of the operators and technical standards.
Conclusions
Leadless pacing systems can be implanted successfully with a low complication rate, if suggestions for indications and technical requirements are followed.
Condensed abstract
An overview of the two utilized leadless cardiac pacing systems is given, specifically highlighting clinical advantages as well as current knowledge of performance and complication rates. Furthermore, a national consensus for Austria is presented, specifically including indications for leadless pacing, management of infection, and suggestions for qualification and technical standards.
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