Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining ...mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer.
Context.
Shadows in scattered light images of protoplanetary disks are a common feature and support the presence of warps or misalignments between disk regions. These warps are possibly caused by an ...inclined (sub-)stellar companion embedded in the disk.
Aims.
We aim to study the morphology of the protoplanetary disk around the Herbig Ae star HD 139614 based on the first scattered light observations of this disk, which we model with the radiative transfer code
MCMax3D
.
Methods.
We obtained
J
- and
H
-band observations that show strong azimuthal asymmetries in polarized scattered light with VLT/SPHERE. In the outer disk, beyond ~30 au, a broad shadow spans a range of ~240 deg in position angle, in the east. A bright ring at ~16 au also shows an azimuthally asymmetric brightness, with the faintest side roughly coincidental with the brightest region of the outer disk. Additionally, two arcs are detected at ~34 and ~50 au. We created a simple four-zone approximation to a warped disk model of HD 139614 in order to qualitatively reproduce these features. The location and misalignment of the disk components were constrained from the shape and location of the shadows they cast.
Results.
We find that the shadow on the outer disk covers a range of position angles too wide to be explained by a single inner misaligned component. Our model requires a minimum of two separate misaligned zones – or a continuously warped region – to cast this broad shadow on the outer disk. A small misalignment of ~4° between adjacent components can reproduce most of the observed shadow features.
Conclusions.
Multiple misaligned disk zones, potentially mimicking a warp, can explain the observed broad shadows in the HD 139614 disk. A planetary mass companion in the disk, located on an inclined orbit, could be responsible for such a feature and for the dust-depleted gap responsible for a dip in the SED.
Context.
Hydrodynamical simulations of planet-disk interactions suggest that planets may be responsible for a number of the substructures frequently observed in disks in both scattered light and dust ...thermal emission. Despite the ubiquity of these features, direct evidence of planets embedded in disks and of the specific interaction features like spiral arms within planetary gaps are still rare.
Aims.
In this study we discuss recent observational results in the context of hydrodynamical simulations in order to infer the properties of a putative embedded planet in the cavity of a transition disk.
Methods.
We imaged the transition disk SR 21 in
H
-band in scattered light with SPHERE/IRDIS and in thermal dust emission with ALMA band 3 (3 mm) observations at a spatial resolution of 0.1″. We combine these datasets with existing Band 9 (430
μ
m) and Band 7 (870
μ
m) ALMA continuum data.
Results.
The Band 3 continuum data reveals a large cavity and a bright ring peaking at 53 au strongly suggestive of dust trapping. The ring shows a pronounced azimuthal asymmetry, with a bright region in the northwest that we interpret as a dust overdensity. A similarly asymmetric ring is revealed at the same location in polarized scattered light, in addition to a set of bright spirals inside the millimeter cavity and a fainter spiral bridging the gap to the outer ring. These features are consistent with a number of previous hydrodynamical models of planet-disk interactions, and suggest the presence of a ∼1
M
Jup
planet at 44 au and PA = 11 deg. This makes SR21 the first disk showing spiral arms inside the millimeter cavity, and the first disk for which the location of a putative planet can be precisely inferred.
Conclusions.
The main features of SR 21 in both scattered light and thermal emission are consistent with hydrodynamical predictions of planet-disk interactions. With the location of a possible planet being well constrained by observations, it is an ideal candidate for follow-up observations to search for direct evidence of a planetary companion still embedded in its disk.
The wear resistance of several thermoplastic polyurethanes (TPUs) having different chemical nature and micronscale arrangement of the hard and soft segments has been investigated by means of erosion ...and abrasion tests. The goal was correlating the erosion performances of the materials to their macroscopic mechanical properties. Unlike conventional tests, such as hardness and tensile measurements, viscoelastic analysis proved to be a valuable tool to study the erosion resistance of TPUs. In particular, a strict correlation was found between the erosion rate and the high-frequency (~107 Hz) loss modulus. The latter reflects the actual ability of TPU to dissipate the impact energy of the erodent particles.
In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile ...of NOTCH1-mutated (NOTCH1-mut) versus NOTCH1 wild-type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by the upregulation of genes related to ribosome biogenesis, such as nucleophosmin 1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by ethylenediaminetetraacetic acid or by coculture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as a mediator of NOTCH1 effects over NPM1 and RNP expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.
The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and ...surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon micro-environmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1(+) (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL.
Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ...ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies.
Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk.
The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases.
Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
In chronic lymphocytic leukemia (CLL), NOTCH1 mutations have been associated with clinical resistance to the anti-CD20 rituximab, although the mechanisms behind this peculiar behavior remain to be ...clarified. In a wide CLL series (n=692), we demonstrated that CLL cells from NOTCH1-mutated cases (87/692) were characterized by lower CD20 expression and lower relative lysis induced by anti-CD20 exposure in vitro. Consistently, CD20 expression by CLL cells was upregulated in vitro by γ-secretase inhibitors or NOTCH1-specific small interfering RNA and the stable transfection of a mutated (c.7541-7542delCT) NOTCH1 intracellular domain (NICD-mut) into CLL-like cells resulted in a strong downregulation of both CD20 protein and transcript. By using these NICD-mut transfectants, we investigated protein interactions of RBPJ, a transcription factor acting either as activator or repressor of NOTCH1 pathway when respectively bound to NICD or histone deacetylases (HDACs). Compared with controls, NICD-mut transfectants had RBPJ preferentially complexed to NICD and showed higher levels of HDACs interacting with the promoter of the CD20 gene. Finally, treatment with the HDAC inhibitor valproic acid upregulated CD20 in both NICD-mut transfectants and primary CLL cells. In conclusion, NOTCH1 mutations are associated with low CD20 levels in CLL and are responsible for a dysregulation of HDAC-mediated epigenetic repression of CD20 expression.
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