Plxnd1 Expression in Thymocytes Regulates Their Intrathymic Migration While That in Thymic Endothelium Impacts Medullary Topology

An important role for plexinD1 in thymic development is inferred from studies of germline Plxnd1 knockout (KO) mice where mislocalized CD69+ thymocytes as well as ectopic thymic subcapsular medullary structures were observed. Given embryonic lethality of the Plxnd1−/− genotype, fetal liver transplantation was employed in these prior analyses. Such embryonic hematopoietic reconstitution may have transferred Plxnd1 KO endothelial and/or epithelial stem cells in addition to Plxnd1 KO lymphoid progenitors, thereby contributing to that phenotype. Here we use Plxnd1flox/flox mice crossed to pLck-Cre, pKeratin14-Cre, or pTek-Cre transgenic animals to create cell-type specific conditional knockout (CKO) lines involving thymocytes (D1ThyCKO), thymic epithelium (D1EpCKO), and thymic endothelium (D1EnCKO), respectively. These CKOs allowed us to directly assess the role of plexinD1 in each lineage. Loss of plexinD1 expression on double positive (DP) thymocytes leads to their aberrant migration and cortical retention after TCR-mediated positive selection. In contrast, ectopic medulla formation is a consequence of loss of plexinD1 expression on endothelial cells, in turn linked to dysregulation of thymic angiogenesis. D1EpCKO thymi manifest neither abnormality. Collectively, our findings underscore the non-redundant roles for plexinD1 on thymocytes and endothelium, including the dynamic nature of medulla formation resulting from crosstalk between these thymic cellular components

Sharp constants in weighted trace inequalities on Riemannian manifolds

We establish some sharp weighted trace inequalities W^{1,2}(\rho^{1-2\sigma}, M)\hookrightarrow L^{\frac{2n}{n-2\sigma}}(\pa M) on $n+1$ dimensional compact smooth manifolds with smooth boundaries, where $\rho$ is a defining function of $M$ and $\sigma\in (0,1)$. This is stimulated by some recent work on fractional (conformal) Laplacians and related problems in conformal geometry, and also motivated by a conjecture of Aubin.Comment: 34 page

Long-range temporal correlations of broadband EEG oscillations for depressed subjects following different hemispheric cerebral infarction

Abnormal long-range temporal correlation (LRTC) in EEG oscillation has been observed in several brain pathologies and mental disorders. This study examined the relationship between the LRTC of broadband EEG oscillation and depression following cerebral infarction with different hemispheric lesions to provide a novel insight into such depressive disorders. Resting EEGs of 16 channels in 18 depressed (9 left and 9 right lesions) and 21 non-depressed (11 left and 10 right lesions) subjects following cerebral infarction and 19 healthy control subjects were analysed by means of detrended fluctuation analysis, a quantitative measurement of LRTC. The difference among groups and the correlation between the severity of depression and LRTC in EEG oscillation were investigated by statistical analysis. The results showed that LRTC of broadband EEG oscillations in depressive subjects was still preserved but attenuated in right hemispheric lesion subjects especially in left pre-frontal and right inferior frontal and posterior temporal regions. Moreover, an association between the severity of psychiatric symptoms and the attenuation of the LRTC was found in frontal, central and temporal regions for stroke subjects with right lesions. A high discriminating ability of the LRTC in the frontal and central regions to distinguish depressive from non-depressive subjects suggested potential feasibility for LRTC as an assessment indicator for depression following right hemispheric cerebral infarction. Different performance of temporal correlation in depressed subjects following the two hemispheric lesions implied complex association between depression and stroke lesion location.</p

Preliminarily Static Analysis of CFETR Central Solenoid Magnet System

Conceptual design of China Fusion Engineering Test Reactor (CFETR) Central Solenoid (CS) coil had been started in Institute of Plasma Physics, Chinese Academy of Sciences. The highest field of CS coil is 17.2 T when the running current is 60 kA. CS magnet system mainly consists of 8 Nb3Sn coils compressed with 8 sets of preload structure. The functions of the preload structure are to apply an enough axial compression to the CS coils and to have a mechanical rigidity against the repulsive force between 8 Nb3Sn coils. This paper describes structural design of CFETR CS magnet system. A global finite element model is created based on the design geometry data to investigate the mechanical property of CFETR CS preload structure and support structure under the different operating conditions. 2D finite element model under electromagnetic is created to calculate the stress on the conductor jacket and turn insulation.</p

Thr 163 Phosphorylation Causes Mcl-1 Stabilization when Degradation is Independent of the Adjacent GSK3-Targeted Phosphodegron, Promoting Drug Resistance in Cancer

The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance – effects that can be suppressed by inhibition of ERK activation

Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Over-expression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.<br/

Efeito da adição de látex nas pastas de cimento branco no estado endurecido

Este trabalho investiga o impacto da utilização de látex poliméricos em propriedades de pastas de cimento Portland branco no estado endurecido. Para tanto, foram utilizados dois látex com propriedades físico-químicas distintas: EVA (etileno de vinil acetato) em pó redispersível, e SAE (estireno acrílico) na forma de emulsão. As pastas foram preparadas com relação água/cimento constante de 0,40, e as quantidades de látex foram variadas, de 5% a 20% de constituintes ativos em relação à massa de cimento. Apesar de os látex poliméricos terem afetado negativamente a reação de hidratação do cimento de forma distinta, houve aumento na resistência mecânica e redução da absorção de água e da permeabilidade ao vapor, com maior teor látex/cimento

The Canine Papillomavirus and Gamma HPV E7 Proteins Use an Alternative Domain to Bind and Destabilize the Retinoblastoma Protein

The high-risk HPV E6 and E7 proteins cooperate to immortalize primary human cervical cells and the E7 protein can independently transform fibroblasts in vitro, primarily due to its ability to associate with and degrade the retinoblastoma tumor suppressor protein, pRb. The binding of E7 to pRb is mediated by a conserved Leu-X-Cys-X-Glu (LXCXE) motif in the conserved region 2 (CR2) of E7 and this domain is both necessary and sufficient for E7/pRb association. In the current study, we report that the E7 protein of the malignancy-associated canine papillomavirus type 2 encodes an E7 protein that has serine substituted for cysteine in the LXCXE motif. In HPV, this substitution in E7 abrogates pRb binding and degradation. However, despite variation at this critical site, the canine papillomavirus E7 protein still bound and degraded pRb. Even complete deletion of the LXSXE domain of canine E7 failed to interfere with binding to pRb in vitro and in vivo. Rather, the dominant binding site for pRb mapped to the C-terminal domain of canine E7. Finally, while the CR1 and CR2 domains of HPV E7 are sufficient for degradation of pRb, the C-terminal region of canine E7 was also required for pRb degradation. Screening of HPV genome sequences revealed that the LXSXE motif of the canine E7 protein was also present in the gamma HPVs and we demonstrate that the gamma HPV-4 E7 protein also binds pRb in a similar way. It appears, therefore, that the type 2 canine PV and gamma-type HPVs not only share similar properties with respect to tissue specificity and association with immunosuppression, but also the mechanism by which their E7 proteins interact with pRb

Towards Investigating Residual Hearing Loss: Quantification of Fibrosis in a Novel Cochlear OCT Dataset

Objective: Cochlear implants (CIs) are bionic prostheses that restores hearing via electrical stimulation of the auditory nerve. Hybrid CIs, which use electroacoustic stimulation (EAS), combine residual low-frequency acoustic hearing with CI electrical stimulation. Intracochlear fibrosis, which forms in response to the presence of the implant, may impede residual hearing function and gradually reduce the efficacy of EAS. It is therefore a translational objective to study the formation of cochlear fibrosis in rodents, with the goal of reducing fibrotic burden and improving outcomes for CI patients. Methods: We generate and annotate a novel dataset of optical coherence tomography (OCT) images from chronically implanted guinea pigs as part of an ongoing study focused on implant induced fibrosis. Objectively assessing fibrotic burden in this model, with high resolution and repeatability, presents an obvious use case for computer-vision methods. Results: We present the results of several state-of-the-art semantic segmentation models and compare their efficacy for identifying cochlear fibrosis and other relevant annotations, using a new library of manually segmented OCT images. Conclusions: We find that the best performance is achieved by using a modified version of the well-known UNET architecture (which we term 2D-OCT-UNET) that operates on the upscaled OCT input resolution. Significance: For the first time, we have successfully applied computer vision techniques to an OCT dataset of implanted cochleae with fibrosis. Using this deep learning model, the cochlear fibrotic burden calculation can be reliably carried out as we verify in our experimental section. The dataset and the project code are available here:https://github.com/juliadietlmeier/CF-OCT-segmentation