An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in ...cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory.
Cognitive decline is a debilitating condition associated with not only neurodegenerative diseases but also aging in general. However, effective treatments have been slow to emerge so far. In this study, we demonstrate that epigenetic regulation of key synaptic proteins may be an underlying, yet reversible, cause of this decline. Our findings suggest that histone 3 trimethylation is a probable target for pharmacological intervention that can counteract cognitive decline in the aging brain. Finally, we provide support to the hypothesis that, by manipulating the enzyme that regulates H3K9me3 (using a newly developed specific inhibitor of SUV39H1), it is possible to alter the chromatin state of subjects and restore memory and synaptic function in the aging brain.
The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the ...normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.
Highlights • Cytokines can affect learning and memory by modulating LTP. • Cytokines modulate LTP directly in neurons, and indirectly via cell-cytokine networks. • Direct cytokine’s effect on LTP can ...be tested in cultured neurons and in synaptosomes. • Synaptosomes allow testing LTP modulation by cytokines directly at the synapse.
Evolving evidence suggests that brain inflammation and the buildup of proinflammatory cytokine increases the risk for cognitive decline and cognitive dysfunction. Interleukin-1β (IL-1β), acting via ...poorly understood mechanisms, appears to be a key cytokine in causing these deleterious effects along with a presumably related loss of long-term potentiation (LTP)-type synaptic plasticity. We hypothesized that IL-1β disrupts brain-derived neurotrophic factor (BDNF) signaling cascades and thereby impairs the formation of filamentous actin (F-actin) in dendritic spines, an event that is essential for the stabilization of LTP. Actin polymerization in spines requires phosphorylation of the filament severing protein cofilin and is modulated by expression of the immediate early gene product Arc. Using rat organotypic hippocampal cultures, we found that IL-1β suppressed BDNF-dependent regulation of Arc and phosphorylation of cofilin and cAMP response element-binding protein (CREB), a transcription factor regulating Arc expression. IL-1β appears to act on BDNF signal transduction by impairing the phosphorylation of insulin receptor substrate 1, a protein that couples activation of the BDNF receptor TrkB to downstream signaling pathways regulating CREB, Arc, and cofilin. IL-1β upregulated p38 mitogen-activated protein kinase (MAPK), and inhibiting p38 MAPK prevented IL-1β from disrupting BDNF signaling. IL-1β also prevented the formation of F-actin in spines and impaired the consolidation, but not the induction, of BDNF-dependent LTP in acute hippocampal slices. The suppressive effect of IL-1β on F-actin and LTP was prevented by inhibiting p38 MAPK. These findings define a new mechanism for the action of IL-1β on LTP and point to a potential therapeutic target to restore synaptic plasticity.
On 17 August 2017, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of ...SSS17a from 11.75 hours until 8.5 days after the merger. Over the first hour of observations, the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measured the photosphere cooling from
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kelvin, and determined a photospheric velocity of roughly 30% of the speed of light. The spectra of SSS17a began displaying broad features after 1.46 days and evolved qualitatively over each subsequent day, with distinct blue (early-time) and red (late-time) components. The late-time component is consistent with theoretical models of r-process–enriched neutron star ejecta, whereas the blue component requires high-velocity, lanthanide-free material.
Double seismic zones are ubiquitous features of subduction zones, where seismicity is distributed along two layers separated by a region with significantly less seismic activity. Dehydration ...embrittlement is thought to be responsible for earthquakes in the subducting crust (upper layer), but the case for it in the lithospheric mantle (lower layer) is less clear. We apply a recently developed relative relocation technique to characterize seismicity in 32 slab segments. The high‐precision hypocentral depths allow us to assign events to either the upper or lower layer and to separately estimate frequency size distributions for each plane. We find consistently larger b values, correlating with slab age, for the upper layer and roughly constant values for the lower. We also show that thermal parameter and plate age are the key controls on double seismic zone geometry. Our results point to a relatively dry lower layer and suggest a fundamentally different mechanism for lithospheric mantle earthquakes.
Plain Language Summary
Despite being a common feature of global seismicity, intermediate‐depth earthquakes (70–350 km in depth approximately) and their physical mechanism are not well understood. These earthquakes occur at pressures and temperatures incompatible with our current models of brittle failure. At those depths, most subducting slabs feature two separate layers of seismicity, with little activity in‐between. It is commonly believed that the release of high‐pressure fluids enables the brittle‐like behavior; however, it is not yet clear whether this mechanism can operate on both layers. We have applied a recently developed earthquake location technique to construct a new global catalog of intermediate‐depth seismicity. We use this data set to study the geometrical structure of the two layers and their statistical characteristics. Our results point to a relatively dry lithospheric mantle—lower layer—regardless of plate age, convergence velocity, or composition and suggest that the physical mechanism enabling rupture in the lower layer is fundamentally different from the one in the upper.
Key Points
Double seismic zone geometrical structure is controlled by plate age and the slab's thermal parameter
We find consistently larger b values for the upper seismicity layer, correlating with slab age, and roughly constant values for the lower
Our results are consistent with dehydration embrittlement operating in the upper layer but point to a relatively dry lithospheric mantle
ABSTRACT
We present the JWST cycle 1 53.8 h medium program FRESCO, short for ‘First Reionization Epoch Spectroscopically Complete Observations’. FRESCO covers 62 arcmin2 in each of the two ...GOODS/CANDELS fields for a total area of 124 arcmin2 exploiting JWST’s powerful new grism spectroscopic capabilities at near-infrared wavelengths. By obtaining ∼2 h deep NIRCam/grism observations with the F444W filter, FRESCO yields unprecedented spectra at R ∼ 1600 covering 3.8–5.0 µm for most galaxies in the NIRCam field of view. This setup enables emission line measurements over most of cosmic history, from strong PAH lines at z ∼ 0.2–0.5, to Pa α and Pa β at z ∼ 1–3, He i and S iii at z ∼ 2.5–4.5, H α and N ii at z ∼ 5–6.5, up to O iii and H β for z ∼ 7–9 galaxies. FRESCO’s grism observations provide total line fluxes for accurately estimating galaxy stellar masses and calibrating slit-loss corrections of NIRSpec/MSA spectra in the same field. Additionally, FRESCO results in a mosaic of F182M, F210M, and F444W imaging in the same fields to a depth of ∼28.2 mag (5σ in 0${_{.}^{\prime\prime}}$32 diameter apertures). Here, we describe the overall survey design and the key science goals that can be addressed with FRESCO. We also highlight several, early science results, including: spectroscopic redshifts of Lyman break galaxies that were identified almost 20 yr ago, the discovery of broad-line active galactic nuclei at z > 4, and resolved Pa α maps of galaxies at z ∼ 1.4. These results demonstrate the enormous power for serendipitous discovery of NIRCam/grism observations.
Though not required currently for staging, regression is a histopathologic parameter typically reported upon diagnosis of an invasive primary cutaneous melanoma. The studies examining the prognostic ...significance of regression in patient outcome have yielded controversial findings; likely because the definition and assessment of regression have not been consistent, in addition to subjectivity of pathologists' interpretation. Regression is histologically characterized by variable decrease in the number of melanoma cells accompanied by the presence of a host response consisting of dermal fibrosis, inflammatory infiltrate, melanophages, ectatic blood vessels, epidermal attenuation, and/or apoptosis of keratinocytes or melanocytes; the relative extent of these features depends on the stage of the regression. However, the magnitudes to which these individual changes must be present to meet the threshold of histologic regression have not been well defined or agreed upon, and thus, the definition and classification of histologic regression in melanoma varies considerably among institutions and even among individual pathologists. In order to determine the clinical significance of histologic analysis of regression, there is a compelling need for a universal scheme to objectively define and assess histologic regression in primary cutaneous melanoma, so that the biologic and prognostic significance of this process may be completely understood.
Sedimentary basins increase the damaging effects of earthquakes by trapping and amplifying seismic waves. Simulations of seismic wave propagation in sedimentary basins capture this effect; however, ...there exists no method to validate these results for earthquakes that have not yet occurred. We present a new approach for ground motion prediction that uses the ambient seismic field. We apply our method to a suite of magnitude 7 scenario earthquakes on the southern San Andreas fault and compare our ground motion predictions with simulations. Both methods find strong amplification and coupling of source and structure effects, but they predict substantially different shaking patterns across the Los Angeles Basin. The virtual earthquake approach provides a new approach for predicting long-period strong ground motion.
Cutaneous angiosarcoma: a current update Shustef, Elina; Kazlouskaya, Viktoryia; Prieto, Victor G ...
Journal of clinical pathology,
11/2017, Letnik:
70, Številka:
11
Journal Article
Recenzirano
Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm with variable clinical presentation. Although a distinct vascular tumour, cAS shares many overlapping histopathological features with other ...vasoformative and epithelioid tumours or ‘mimickers’. cAS shows aggressive behaviour and carries a grave prognosis, thus early diagnosis is of paramount importance to achieve the best possible outcomes. Recently, several genetic studies were conducted leading to the identification of novel molecular targets in the treatment of cAS. Herein, we present a comprehensive review of cAS with discussion of its clinical, histopathological and molecular aspects, the differential diagnosis, as well as current therapies including ongoing clinical trials.
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