The mediodorsal thalamus (MD) is a higher‐order nucleus located within the central thalamus in many mammalian species. Emerging evidence from MD lesions and tracer injections suggests that the MD is ...reciprocally connected to the prefrontal cortex (PFC) and plays an essential role in specific cognitive processes and tasks. MD subdivisions (medial, central, and lateral) are poorly segregated at the molecular level in rodents, leading to a lack of MD subdivision‐specific Cre driver mice. Moreover, this lack of molecular identifiers hinders MD subdivision‐ and cell‐type‐specific circuit formation and function analysis. Therefore, using publicly available databases, we explored molecules separately expressed in MD subdivisions. In addition to MD subdivision markers, we identified several genes expressed in a subdivision‐specific combination and classified them. Furthermore, after developing medial MD (MDm) or central MD (MDc) region‐specific Cre mouse lines, we identified diverse region‐ and layer‐specific PFC projection patterns. Comparison between classified MD marker genes in mice and common marmosets, a nonhuman primate model, revealed diverging gene expression patterns. These results highlight the species‐specific organization of cell types and their projections in the MD thalamus.
The mediodorsal thalamus (MD) can be divided into three distinctive regions, which project to the different cortical areas. Here we searched for subdivision‐specific molecular markers in developing mouse MD thalamus. We made an MD region‐specific Cre mouse line based on this search, which clearly shows specific projections to PrL/IL and AID in PFC. Further, we showed molecular organization in developing common marmoset, which showed dynamic expression differences compared to mouse MD, suggesting diverse MD function and connectivity in different species.
Sepsis-associated encephalopathy (SAE), a diffuse cerebral dysfunction in the absence of direct CNS infection, is associated with increased rates of mortality and morbidity in patients with sepsis. ...Increased cytokine production and disruption of the blood-brain barrier (BBB) are implicated in the pathogenesis of SAE. The induction of pro-inflammatory mediators is driven, in part, by activation of NF-κΒ. Lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, potently activates NF-κΒ and its downstream targets, including cyclooxygenase-2 (Cox-2). Cox-2 catalyzes prostaglandin synthesis and in the brain prostaglandin, E2 is capable of inducing endothelial permeability. Depletion of polymerase δ-interacting protein 2 (Poldip2) has previously been reported to attenuate BBB disruption, possibly via regulation of NF-κΒ, in response to ischemic stroke. Here we investigated Poldip2 as a novel regulator of NF-κΒ/cyclooxygenase-2 signaling in an LPS model of SAE.
Intraperitoneal injections of LPS (18 mg/kg) were used to induce BBB disruption in Poldip2
and Poldip2
mice. Changes in cerebral vascular permeability and the effect of meloxicam, a selective Cox-2 inhibitor, were assessed by Evans blue dye extravasation. Cerebral cortices of Poldip2
and Poldip2
mice were further evaluated by immunoblotting and ELISA. To investigate the role of endothelial Poldip2, immunofluorescence microscopy and immunoblotting were performed to study the effect of siPoldip2 on LPS-mediated NF-κΒ subunit p65 translocation and Cox-2 induction in rat brain microvascular endothelial cells. Finally, FITC-dextran transwell assay was used to assess the effect of siPoldip2 on LPS-induced endothelial permeability.
Heterozygous deletion of Poldip2 conferred protection against LPS-induced BBB permeability. Alterations in Poldip2
BBB integrity were preceded by induction of Poldip2, p65, and Cox-2, which was not observed in Poldip2
mice. Consistent with these findings, prostaglandin E2 levels were significantly elevated in Poldip2
cerebral cortices compared to Poldip2
cortices. Treatment with meloxicam attenuated LPS-induced BBB permeability in Poldip2
mice, while having no significant effect in Poldip2
mice. Moreover, silencing of Poldip2 in vitro blocked LPS-induced p65 nuclear translocation, Cox-2 expression, and endothelial permeability.
These data suggest Poldip2 mediates LPS-induced BBB disruption by regulating NF-κΒ subunit p65 activation and Cox-2 and prostaglandin E2 induction. Consequently, targeted inhibition of Poldip2 may provide clinical benefit in the prevention of sepsis-induced BBB disruption.
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although ...non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
Abstract
Excitatory spiny stellate neurons are prominently featured in the cortical circuits of sensory modalities that provide high salience and high acuity representations of the environment. These ...specialized neurons are considered developmentally linked to bottom-up inputs from the thalamus, however, the molecular mechanisms underlying their diversification and function are unknown. Here, we investigated this in mouse somatosensory cortex, where spiny stellate neurons and pyramidal neurons have distinct roles in processing whisker-evoked signals. Utilizing spatial transcriptomics, we identified reciprocal patterns of gene expression which correlated with these cell-types and were linked to innervation by specific thalamic inputs during development. Genetic manipulation that prevents the acquisition of spiny stellate fate highlighted an important role for these neurons in processing distinct whisker signals within functional cortical columns, and as a key driver in the formation of specific whisker-related circuits in the cortex.
Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to ...understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)-based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.
This study evaluated the relationship between three-dimensional (3D) mean computed tomography (CT) attenuation values of ground-glass nodules (GGN) and pathological invasiveness in early lung ...adenocarcinoma. The diagnostic accuracy of 3D CT attenuation values was compared with that of two-dimensional (2D) CT attenuation values and standardised uptake value on positron-emission tomography (PET).
Surgical and radiological data from 96 pure or part-solid GGNs of <20 mm were analysed retrospectively. Mean 2D and 3D CT attenuation values of the tumours were obtained with semi-automated volumetric software. Pathological invasiveness was diagnosed according to the International Association for the Study of Lung Cancer (IASLC))/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification. Pre-invasive lesions and minimally invasive adenocarcinomas were classified as non-invasive adenocarcinoma. Univariate and multivariate analyses determined relationships between pathological invasiveness and clinical/radiological findings. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cut-off value for detecting invasive adenocarcinoma.
A total of 66 non-invasive and 30 invasive adenocarcinoma cases between 2010 and 2016 were analysed. Univariate analysis revealed four tumour invasiveness-associated predictors: maximum diameter, SUVmax, mean 2D CT attenuation value, and mean 3D CT attenuation value (p<0.05). Multivariate analysis revealed that the maximum diameter, SUVmax, and mean 3D CT attenuation value were significant predictors of pathological invasiveness (p=0.023, 0.022, 0.004). The area under the ROC curve to predict invasive adenocarcinoma for mean 3D CT attenuation value was 0.838 and the cut-off value was –489 HU.
The mean 3D CT attenuation value could distinguish pre-invasive lesions and minimally invasive adenocarcinoma from invasive adenocarcinoma.
•Pre/minimally invasive adenocarcinoma shows GGO-dominant nodule on chest CT.•Pre/minimally invasive adenocarcinomas could be candidate for sublobar resection.•Accurate radiological prediction is crucial to determine the surgical procedure.•Three-dimensional densitometric evaluation is helpful to predict tumor invasiveness.•Mean CT value calculated by 3D-CT was well correlated with pathological features.
Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has ...remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion.
Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay.
Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs.
Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.
Redox-sensitive metallic elements, Mn and Fe, are oxidized in deep sea waters and form abundant ferromanganese crusts and nodules on the world's ocean floors at ultraslow rates of growth. This ...process of oxidation and the mechanism of precipitation are yet unknown. In this paper, the results of the first successful, long-term, on-site experiment of mineral precipitation that ascertains modern, ongoing hydrogenetic deposition of oxide materials from normal seawaters at water depths of 900-4500 m of geologically active and inactive environments are presented. We succeeded in the in-situ precipitation experiment on the sea floor and characterized the precipitates using high-resolution and submicron-scale chemical, mineralogical, and structural analyses. The installed artificial plates of glass, ceramics, and plastic yielded spread-out particles of sizes varying from one to a few micrometers in diameter, of coccoid-like irregular shapes, with a maximum of 1,000-10,000 individual particles/mm
/year after 12-15 years of exposure. The results indicated a continuous substantial growth of the hydrogenetic minerals if both Mn and Fe are supplied to the bottom waters. The mineralogical, chemical, and structural properties of the precipitates are similar to those of the natural precipitates on the seabed that are made up of hydrogenetic ferromanganese crusts and nodules, together with settling sediments, suspended hydrothermal particles, or microbial precipitates from cultivated Mn-oxidizing bacteria. Our work presents new realistic insight into proposed genetic models of marine hydrogenetic ferromanganese deposits in modern diverse ocean environments.
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