Abstract
The hippocampus is a very heterogeneous brain structure with different mechanical properties reflecting its functional variety. In particular, adult neurogenesis in rodent hippocampus has ...been associated with specific viscoelastic properties in vivo and ex vivo. Here, we study the microscopic mechanical properties of hippocampal subregions using ex vivo atomic force microscopy (AFM) in correlation with the expression of GFP in presence of the nestin promoter, providing a marker of neurogenic activity. We further use magnetic resonance elastography (MRE) to investigate whether in vivo mechanical properties reveal similar spatial patterns, however, on a much coarser scale. AFM showed that tissue stiffness increases with increasing distance from the subgranular zone (p = 0.0069), and that stiffness is 39% lower in GFP than non-GFP regions (p = 0.0004). Consistently, MRE showed that dentate gyrus is, on average, softer than Ammon´s horn (shear wave speed = 3.2 ± 0.2 m/s versus 4.4 ± 0.3 m/s, p = 0.01) with another 3.4% decrease towards the subgranular zone (p = 0.0001). The marked reduction in stiffness measured by AFM in areas of high neurogenic activity is consistent with softer MRE values, indicating the sensitivity of macroscopic mechanical properties in vivo to micromechanical structures as formed by the neurogenic niche of the hippocampus.
A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship ...between PD-L1 expression and the natural course of disease are controversial and sparse.
To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era.
Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001).
It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.
Carotid artery disease is frequent and can result in chronic modest hypoperfusion of the brain. If no transient ischemic attack or stroke occur, it is classified asymptomatic. In the long-term, ...though, it can lead to cognitive impairment. Fostering cerebral remodeling after carotid artery occlusion might be a new concept of treatment. Paracrine Interleukin 6 (IL-6) can induce such remodeling processes at early stages. However, it has neurodegenerative long-term effects. With this exploratory study, we investigated the effect of paracrine IL-6 on cerebral remodeling in early stages after asymptomatic carotid artery occlusion to identify new treatment targets.
To mimic a human asymptomatic carotid artery disease, we used a mouse model of unilateral common carotid artery (CCA) occlusion. We developed a mouse model for inducible paracrine cerebral IL-6 expression (Cx30-Cre-ERT2;FLEX-IL6) and induced IL-6 2 days after CCA occlusion. We studied the effects of paracrine IL-6 after CCA occlusion on neuronal connectivity using diffusion tensor imaging and on local proteome regulations of the hypo-perfused striatum and contralateral motor cortex using mass spectrometry of laser capture micro-dissected tissues. Paracrine IL-6 induced cerebral remodeling leading to increased inter-hemispheric connectivity and changes in motor system connectivity. We identified changes in local protein abundance which might have adverse effects on functional outcome such as upregulation of Synuclein gamma (Sncg) or downregulation of Proline Dehydrogenase 1 (Prodh). However, we also identified changes in local protein abundance having potentially beneficial effects such as upregulation of Caprin1 or downregulation of GABA transporter 1 (Gat1).
Paracrine cerebral IL-6 at early stages induces changes in motor system connectivity and the proteome after asymptomatic CCA occlusion. Our results may help to distinguish unfavorable from beneficial IL-6 dependent protein regulations. Focusing on these targets might generate new treatments to improve long-term outcome in patients with carotid artery disease.
The perception-filter model posits that the generation of medically-unexplained symptoms is associated with (I.) more intense afferent bodily signals, (II.) impaired filter system activity to ...differentiate relevant from irrelevant signals, and (III.) altered perception of bodily signals. We tested these assumptions for cardiac perception in patients with somatoform disorders (SFD), patients with major depressive disorder (MDD) and healthy control (HC) individuals. Heart rate (variability; HR/HRV) and blood pressure served as indicators of bodily signals (I.); heartbeat-evoked potentials (HEPs) assessed during a heartbeat counting task (HCT) and a distraction task indicated filter system activity (II.); interoceptive accuracy (IAc) in the HCT was interpreted as an index of perception (III.). All indicators were assessed before and after a socially-evaluated cold pressor stress task (SECPT) and a control intervention. SFD patients (n = 24) showed higher average HR and diastolic blood pressure, as well as lower HRV than HC individuals (n = 22), but there were no differences in HEPs or IAc. Neither were there significant differences between the SFD and the MDD groups (n = 24), nor any stress effect on HEPs or IAc. Our findings suggest that increased intensity of bodily signals (I.) is the only model assumption that could be supported for patients with fully-developed SFD.
•We investigated interoception in somatoform disorders (SFD) and depression (MDD).•SFD and MDD patients had higher heart rate (HR) and blood pressure than controls.•Heartbeat-evoked potentials did not differ between SFD, MDD patients and controls.•Cardiac interoception did not differ between SFD, MDD patients and controls.•Acute stress did not affect heartbeat-evoked potentials and cardiac interoception.
In this paper we've equipped a cylindrical end-effector with an array of capacitive sensors in order to implement 3D contour following. During the task, using proximity servoing, the sensors are ...aligned parallel to the surface and kept at a target distance. In addition, due to the spatial resolution, it's possible to estimate the surface's curvature in two dimensions along the rows and columns of the array. We show how a compound movement can be derived from both curvatures that pre-aligns the end-effector in each step, yielding a predictive component for the control scheme. We evaluate our approach with different geometries and show that the curvature information produces smooth contour following paths. We show that the system can handle speeds up to 150mms -1 .
The unsteady boundary layer behavior of a supercritical laminar airfoil model, which undergoes limit cycle oscillations in pitch, is investigated by the application of hot-film anemometry. The data ...basis is a 2D flutter experiment under transonic flow conditions. The laminar airfoil model was elastically mounted with a single degree of freedom in pitch and performed self-excited limit cycle oscillations at a Mach number of
Ma
=
0.73
and a Reynolds number of
Re
≈
2
×
10
6
. An analysis of the hot-film signals on the basis of the quasi-wall shear stress is carried out, with which the boundary layer state for steady and unsteady flow is resolved. An algorithm is presented which allows an automated detection of the transition position, so that a correlation between airfoil motion and transition location movement can be quantified. A sudden movement of the boundary layer transition is observed at the upper and lower reversal points of the limit cycle oscillation, while in parts of the up- and downstroke of the laminar airfoil a shock-induced transition occurs. During the limit cycle oscillation, a delayed response of the boundary layer occurs, resulting in a significant phase lag between the movement of the boundary layer transition and the motion of the laminar airfoil.
Abstract
Patients with multiple sclerosis consistently show widespread changes in functional connectivity. Yet, alterations are heterogeneous across studies, underscoring the complexity of functional ...reorganization in multiple sclerosis. Here, we aim to provide new insights by applying a time-resolved graph-analytical framework to identify a clinically relevant pattern of dynamic functional connectivity reconfigurations in multiple sclerosis. Resting-state data from 75 patients with multiple sclerosis (N = 75, female:male ratio of 3:2, median age: 42.0 ± 11.0 years, median disease duration: 6 ± 11.4 years) and 75 age- and sex-matched controls (N = 75, female:male ratio of 3:2, median age: 40.2 ± 11.8 years) were analysed using multilayer community detection. Local, resting-state functional system and global levels of dynamic functional connectivity reconfiguration were characterized using graph-theoretical measures including flexibility, promiscuity, cohesion, disjointedness and entropy. Moreover, we quantified hypo- and hyper-flexibility of brain regions and derived the flexibility reorganization index as a summary measure of whole-brain reorganization. Lastly, we explored the relationship between clinical disability and altered functional dynamics. Significant increases in global flexibility (t = 2.38, PFDR = 0.024), promiscuity (t = 1.94, PFDR = 0.038), entropy (t = 2.17, PFDR = 0.027) and cohesion (t = 2.45, PFDR = 0.024) were observed in patients and were driven by pericentral, limbic and subcortical regions. Importantly, these graph metrics were correlated with clinical disability such that greater reconfiguration dynamics tracked greater disability. Moreover, patients demonstrate a systematic shift in flexibility from sensorimotor areas to transmodal areas, with the most pronounced increases located in regions with generally low dynamics in controls. Together, these findings reveal a hyperflexible reorganization of brain activity in multiple sclerosis that clusters in pericentral, subcortical and limbic areas. This functional reorganization was linked to clinical disability, providing new evidence that alterations of multilayer temporal dynamics play a role in the manifestation of multiple sclerosis.
Von Schwanenflug et al. investigate functional reorganization of brain dynamics in multiple sclerosis, their spatial distribution and their relationship to clinical impairment. Patients show clinically relevant increases in functional dynamics that cluster in pericentral, subcortical and limbic regions, with the most significant increases in areas showing low dynamics in controls.
Graphical Abstract
Graphical abstract
Vascular endothelial cadherin (VE‐cadherin) mediates contact inhibition of cell growth in quiescent endothelial cell layers. Searching for proteins that could be involved in VE‐cadherin signaling, we ...found the cytosolic C‐terminal Src kinase (Csk), a negative regulator of Src family kinases. We show that Csk binds via its SH2 domain to the phosphorylated tyrosine 685 of VE‐cadherin. VE‐cadherin recruits Csk to cell contacts and both proteins can be co‐precipitated from cell lysates of transfected cells and endothelial cells. Association of VE‐cadherin and Csk in endothelial cells increased with increasing cell density. CHO cells expressing the tyrosine replacement mutant VE‐cadherin‐Y685F grow to higher cell densities than cells expressing wild‐type VE‐cadherin. Overexpression of Csk in these cells under an inducible promoter inhibits cell proliferation in the presence and absence of VE‐cadherin, but not in the presence of VE‐cadherin‐Y685F. Reduction of Csk expression by RNA interference enhances endothelial cell proliferation. Our results suggest that the phosphorylated tyrosine residue 685 of VE‐cadherin and probably the binding of Csk to this site are involved in inhibition of cell growth triggered by cell density.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an ...early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes
and
, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.
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