Splanchnic vein thrombosis in myeloproliferative neoplasms: Pathophysiology and molecular mechanisms of disease

Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients

Role for polo-like kinase 4 in mediation of cytokinesis.

The mitotic protein polo-like kinase 4 (PLK4) plays a critical role in centrosome duplication for cell division. By using immunofluorescence, we confirm that PLK4 is localized to centrosomes. In addition, we find that phospho-PLK4 (pPLK4) is cleaved and distributed to kinetochores (metaphase and anaphase), spindle midzone/cleavage furrow (anaphase and telophase), and midbody (cytokinesis) during cell division in immortalized epithelial cells as well as breast, ovarian, and colorectal cancer cells. The distribution of pPLK4 midzone/cleavage furrow and midbody positions pPLK4 to play a functional role in cytokinesis. Indeed, we found that inhibition of PLK4 kinase activity with a small-molecule inhibitor, CFI-400945, prevents translocation to the spindle midzone/cleavage furrow and prevents cellular abscission, leading to the generation of cells with polyploidy, increased numbers of duplicated centrosomes, and vulnerability to anaphase or mitotic catastrophe. The regulatory role of PLK4 in cytokinesis makes it a potential target for therapeutic intervention in appropriately selected cancers

Oral microbiota of periodontal health and disease and their changes after nonsurgical periodontal therapy

This study examined the microbial diversity and community assembly of oral microbiota in periodontal health and disease and after nonsurgical periodontal treatment. The V4 region of 16S rRNA gene from DNA of 238 saliva and subgingival samples of 21 healthy and 48 diseased subjects was amplified and sequenced. Among 1979 OTUs identified, 28 were overabundant in diseased plaque. Six of these taxa were also overabundant in diseased saliva. Twelve OTUs were overabundant in healthy plaque. There was a trend for disease-associated taxa to decrease and health-associated taxa to increase after treatment with notable variations among individual sites. Network analysis revealed modularity of the microbial communities and identified several health- and disease-specific modules. Ecological drift was a major factor that governed community turnovers in both plaque and saliva. Dispersal limitation and homogeneous selection affected the community assembly in plaque, with the additional contribution of homogenizing dispersal for plaque within individuals. Homogeneous selection and dispersal limitation played important roles, respectively, in healthy saliva and diseased pre-treatment saliva between individuals. Our results revealed distinctions in both taxa and assembly processes of oral microbiota between periodontal health and disease. Furthermore, the community assembly analysis has identified potentially effective approaches for managing periodontitis

VLBA Observations of Sub-Parsec Structure in Mrk 231: Interaction between a Relativistic Jet and a BAL Wind

We report on the first high frequency VLBI observations of the nearby broad absorption line quasar (BALQSO), Mrk 231. Three epochs of observations were achieved at 15 GHz and 22 GHz, two of these included 43 GHz observations as well. The nuclear radio source is resolved as a compact double. The core component experienced a strong flare in which the flux density at 22 GHz increased by $> 150$ (45 mJy) in three months. Theoretical models of the flare imply that the emission is likely enhanced by very strong Doppler boosting of a highly relativistic ejecta with a kinetic energy flux, $Q \sim 3 \times 10^{43} \mathrm{ergs/sec}$. Combining our data with two previous epochs of 15 GHz data, shows marginal evidence for the slow advance of the secondary component (located $\approx 0.97$ pc from the core) over a 9.4 year span. We estimate that the long term time averaged kinetic energy flux of the secondary at $\bar{Q}\approx 10^{42}\mathrm{ergs/sec}$. Low frequency VLBA observations indicate that the secondary is seen through a shroud of free-free absorbing gas with an emission measure of $\approx 10^{8} \mathrm{cm}^{-6}\mathrm{pc}$. The steep spectrum secondary component appears to be a compact radio lobe that is associated with a working surface between the ram-pressure confined jet, and a dense medium that is likely to be the source of the free-free absorption. The properties of the dense gas are consistent with the temperatures, displacement from the nucleus and the column density of total hydrogen commonly associated with the BAL wind.Comment: To appear in Ap

Comparison of sequential indicator simulation, object modelling and multiple-point statistics in reproducing channel geometries and continuity in 2D with two different spaced conditional datasets

Fluvial sediments with multi-scale channels are difficult to model using classical two-point statistical methods, e.g. sequential indicator simulation (SIS) or object-based modelling (ObjM). Multiple-point statistics (MPS) has been used to generate facies, fracture and porosity distributions based on pattern statistics derived from training datasets. However, the ability of these three methods to reproduce channel geometry and continuity is not clear, especially when using differently spaced conditional data. This paper presents a case study to compare the application of these three methods in reproducing channels from a section of Amazon River based on two differently spaced conditional data sets. Results show that: the reproduction accuracy is similar between MPS and SIS; MPS provides the most connected channel facies (or most channel continuity) as compared to SIS and ObjM; and using a hand-drawn facies based on the sampling points yield a similar accuracy to that achieved by using the reality facies distribution as the training image. Finally, we conclude that the application of MPS does not significantly increase the reproduction accuracy when compared to SIS channel models; however, MPS can generate realistic models with respect to channel geometry and continuity

ThicknessTool: automated ImageJ retinal layer thickness and profile in digital images

To develop an automated retina layer thickness measurement tool for the ImageJ platform, to quantitate nuclear layers following the retina contour. We developed the ThicknessTool (TT), an automated thickness measurement plugin for the ImageJ platform. To calibrate TT, we created a calibration dataset of mock binary skeletonized mask images with increasing thickness masks and different rotations. Following, we created a training dataset and performed an agreement analysis of thickness measurements between TT and two masked manual observers. Finally, we tested the performance of TT measurements in a validation dataset of retinal detachment images. In the calibration dataset, there were no differences in layer thickness between measured and known thickness masks, with an overall coefficient of variation of 0.00%. Training dataset measurements of immunofluorescence retina nuclear layers disclosed no significant differences between TT and any observer's average outer nuclear layer (ONL) (p = 0.998), inner nuclear layer (INL) (p = 0.807), and ONL/INL ratio (p = 0.944) measurements. Agreement analysis showed that bias between TT vs. observers' mean was lower than between any observers' mean against each other in the ONL (0.77 ± 0.34 µm vs 3.25 ± 0.33 µm) and INL (1.59 ± 0.28 µm vs 2.82 ± 0.36 µm). Validation dataset showed that TT can detect significant and true ONL thinning (p = 0.006), more sensitive than manual measurement capabilities (p = 0.069). ThicknessTool can measure retina nuclear layers thickness in a fast, accurate, and precise manner with multi-platform capabilities. In addition, the TT can be customized to user preferences and is freely available to download

Cortical Microhemorrhages Cause Local Inflammation but Do Not Trigger Widespread Dendrite Degeneration

Microhemorrhages are common in the aging brain, and their incidence is correlated with increased risk of neurodegenerative disease. Past work has shown that occlusion of individual cortical microvessels as well as large-scale hemorrhages can lead to degeneration of neurons and increased inflammation. Using two-photon excited fluorescence microscopy in anesthetized mice, we characterized the acute and chronic dynamics of vessel bleeding, tissue compression, blood flow change, neural degeneration, and inflammation following a microhemorrhage caused by rupturing a single penetrating arteriole with tightly-focused femtosecond laser pulses. We quantified the extravasation of red blood cells (RBCs) and blood plasma into the brain and determined that the bleeding was limited by clotting. The vascular bleeding formed a RBC-filled core that compressed the surrounding parenchymal tissue, but this compression was not sufficient to crush nearby brain capillaries, although blood flow speeds in these vessels was reduced by 20%. Imaging of cortical dendrites revealed no degeneration of the large-scale structure of the dendritic arbor up to 14 days after the microhemorrhage. Dendrites close to the RBC core were displaced by extravasating RBCs but began to relax back one day after the lesion. Finally, we observed a rapid inflammatory response characterized by morphology changes in microglia/macrophages up to 200 µm from the microhemorrhage as well as extension of cellular processes into the RBC core. This inflammation persisted over seven days. Taken together, our data suggest that a cortical microhemorrhage does not directly cause significant neural pathology but does trigger a sustained, local inflammatory response