Endosomal trafficking ensures the proper distribution of lipids and proteins to various cellular compartments, facilitating intracellular communication, nutrient transport, waste disposal, and the ...maintenance of cell structure. Retromer, a peripheral membrane protein complex, plays an important role in this process by recruiting the associated actin‐polymerizing WASH complex to establish distinct sorting domains. The WASH complex is recruited through the interaction of the VPS35 subunit of retromer with the WASH complex subunit FAM21. Here, we report the identification of two separate fragments of FAM21 that interact with VPS35, along with a third fragment that binds to the VPS29 subunit of retromer. The crystal structure of VPS29 bound to a peptide derived from FAM21 shows a distinctive sharp bend that inserts into a conserved hydrophobic pocket with a binding mode similar to that adopted by other VPS29 effectors. Interestingly, despite the network of interactions between FAM21 and retromer occurring near the Parkinson's disease‐linked mutation (D620N) in VPS35, this mutation does not significantly impair the direct association with FAM21 in vitro.
Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T‐cell lymphoma (PTCL), non‐small cell lung cancer, and ...other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer‐associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF‐dependent activation of RAC1, GEF‐independent adaptor‐like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.
Synopsis
VAV1 encodes a multifunctional signaling protein involved in both RAC1 GTPase activation and adaptor‐like functions. Mutations in this gene have recently been found in PTCL and other tumor types. Here, we have catalogued 51 VAV1 tumor‐associated mutations according to their functional impact on the downstream signaling branches of the protein. Our work has revealed that:
The VAV1 gain‐of‐function mutations belong to different subclasses according to impact on VAV1 downstream signaling.
These mutations target both expected and hitherto unknown VAV1 regulatory layers.
A VAV1 mutation representative of the most frequent functional subclass drives PTCL formation in mice.
VAV1‐driven lymphomagenesis requires cooperating signals from the catalytic‐dependent and independent pathways of the mutant protein.
The molecular features of VAV1‐driven lymphomas resemble those found in PTCL patients.
Systematic mapping of non‐passenger mutations in the multifunctional signaling factor VAV1 offers new insights into their signaling consequences and functional outcomes in vivo.
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► HMS functionalized with 30
wt.% HPW and 1% of Pt or Pd. ► Catalysts for
n-pentane hydroisomerization reaction. ► The optimal reaction temperature was 350
°C. ► The Pt catalyst was ...more active, selective and catalytically stable than Pd catalysts.
Non order structure type HMS was synthesized through a S°I° mechanism. These solids were modified by incorporation of acid (30
wt.% of tungstophosphoric acid) and metallic sites (1% of metal: Pt or Pd), and tested in the hydroisomerization reaction of
n-pentane. The catalysts were characterized by X-ray diffraction (XRD), N
2 adsorption and desorption, chemisorption of H
2, scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). For the catalyst containing Pt, the effect of reaction temperature was investigated in the range of 200–400
°C, the optimal catalytic activity was reached at 350
°C. The Pt catalyst showed higher conversion, iso-pentane yield and catalytic stability than its Pd counterpart.
The entorhinal cortex (EC) is especially vulnerable in the early stages of Alzheimer's disease (AD). In particular, cognitive deficits have been linked to alterations in the upper layers of EC. In ...the present report, we examined Layers II and III from eight human brain autopsies (four subjects with no recorded neurologic alterations and four AD cases). We used stereological methods to assess cortical atrophy of the EC and possible changes in the volume occupied by different cortical elements (neuronal and glial cell bodies; blood vessels; and neuropil). We performed 3D ultrastructural analyses of synapses using focused ion beam/scanning electron microscopy (FIB/SEM) to examine possible alterations related to AD. At the light microscope level, we found a significantly lower volume fraction occupied by neuronal bodies in Layer III and a higher volume fraction occupied by glial cell bodies in Layer II in AD cases. At the ultrastructural level, we observed that (1) there was a significantly lower synaptic density in both layers in AD cases; (2) synapses were larger and more complex in Layer II in AD cases; and (3) there was a greater proportion of small and simple synapses in Layer III in AD cases than in control individuals. These structural differences may play a role in the anatomic basis for the impairment of cognitive functions in AD.
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▶ Preparation, characterisation and screening of palladium based catalysts. ▶ Mesostructured materials were used as support of palladium catalysts. ▶ 1% Pd/SBA-15 showed high activity ...and stereo-selectivity for semi-hydrogenation of 3-hexyne. ▶ The starting 3-hexyne produces primarily
cis-3-hexene, which subsequently is either hydrogenated to hexane or isomerized to
trans-3-hexene and 2-hexenes that are found in very small amounts depending on the nature of the support used.
This paper studies the effect of mesostructured materials in the stereo-selective hydrogenation of 3-hexyne at 298
K and 40
psig pressure of H
2 over Pd-supported catalysts at different substrate:palladium (S:Pd) molar ratios. The catalysts were prepared by impregnation using a toluene solution of Pd(acac)
2 to obtain a metal content close to 1
wt.% over SBA-15 with one-dimensional hexagonal structure, MCM-48 silica with cubic structure and three-dimensional pore system and MSU-γ alumina with a lathlike particle morphology. All the supports were characterised by nitrogen adsorption–desorption isotherms at 77
K, TEM, XRD and H
2 chemisorption and TEM measurements. The reactions were found to be zero order with respect to 3-hexyne concentration. The starting 3-hexyne produces primarily
cis-3-hexene, which subsequently is either hydrogenated to hexane or isomerized to
trans-3-hexene and 2-hexenes that are found in very small amounts depending on the nature of the support used. Palladium catalysts supported on SBA-15 was the most active and selective catalyst.
This study examines the utility of Passive Integrated Transponder (PIT) tagging system in fingerlings of gilthead seabream, Sparus auratus L. Two different body positions (abdominal, dorsal) and four ...weight classes (2–3 g, 3–4 g, 4–5 g, 5–8 g) were tested in three experiments. Tag loss rate, as well as its effect on growth and mortality rates, was determined. Times of handling and healing were also assessed. Fish tagged in the abdominal cavity showed a significantly lower tag loss rate (14%) than those given dorsal muscle implants (40%). No differences were found in growth within experiment between tagged and untagged fish, their final mean weight ranging between 6–39 g and 6–38 g, respectively. There was no difference in mortality between tagged and untagged fish at any position (0–3.4% and 0–2.1%, respectively). Fish smaller than 3 g suffered significantly higher mortality (14.3%), indicating that the PIT tags are not suitable for very small individuals. PIT retention rate was 100% above 4 g, irrespective of the personal expertise in tagging. Mean tag application time was 19 s per fish. Mean wound healing time was close to 20 days. Hence, these results showed that PIT tagging of gilthead seabream above 3 g is feasible because it does not affect growth or mortality.
The stereospecific hydrogenation of phenyl alkyl acetylenes at 298
K and atmospheric pressure of hydrogen over Pd supported catalysts has been studied. The catalysts were prepared by impregnation ...Al-PILC and Ca-Mont with Pd(acac)
2 precursor, with metal content close to 1
wt.%. All the solids were characterised by nitrogen adsorption–desorption isotherms at 77
K, TPR, H
2 and CO chemisorption, XRD and TEM measurements. The reactions were found to be zero order concerning the alkyne concentration. At conversion levels up to 80% (reaction time lower than 90
min), only a limited overhydrogenation occurred. It was found that at higher reactant molecule:Pd atom ratios (R:P
=
7000), the activity is approximately half of that obtained at lower R:P (R:P
=
3500). The results suggested that the hydrogenation of phenyl alkyl acetylenes to
cis-alkene is “structure insensitive”. All catalysts displayed high selectivity to
cis-alkene isomer being the 1% Pd/Al-PILC the most active catalyst.
The stereoselective hydrogenation of phenyl alkyl acetylenes at 298
K and atmospheric pressure of hydrogen over Pd-supported catalysts has been studied. The catalysts were prepared by impregnation of Al-PILC and Ca-Mont with Pd(acac)
2 precursor, with a metal content close to 1
wt %. All the solids were characterised by nitrogen adsorption–desorption isotherms at 77
K, TPR, H
2 and CO chemisorption, XRD and TEM measurements. The reactions were found to be zero order concerning the alkyne concentration. All catalysts displayed high selectivity to
cis-alkene isomer being the 1%Pd/Al-PILC the most active catalyst.
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The liquid-phase stereoselective hydrogenation of phenyl alkyl acetylenics at 298 K and atmospheric pressure on Pd-supported catalysts has been studied. The catalysts were prepared by impregnation of ...Pd(acac)2 precursor (1 wt% of Pd) on different siliceous substrates such as amorphous SiO2, mesoporous MCM-41 and silylated MCM-41. The poisoning effect of lead incorporation on the supported palladium was also studied. All the catalysts displayed high selectivity to cis-alkene isomer, with Pd/MCM-41 being the most active catalyst. Deliberately adding lead to the base, palladium catalysts underwent changes in the selectivity to cis-alkene isomer and a significant drop in the activity. All the solids were characterized by nitrogen adsorption–desorption isotherms at 77 K, TGA, TPR, H2 and CO chemisorption, XRD, XPS, and TEM.
Abstract
We introduce the Automatic Learning for the Rapid Classification of Events (ALeRCE) broker, an astronomical alert broker designed to provide a rapid and self-consistent classification of ...large etendue telescope alert streams, such as that provided by the Zwicky Transient Facility (ZTF) and, in the future, the Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST). ALeRCE is a Chilean-led broker run by an interdisciplinary team of astronomers and engineers working to become intermediaries between survey and follow-up facilities. ALeRCE uses a pipeline that includes the real-time ingestion, aggregation, cross-matching, machine-learning (ML) classification, and visualization of the ZTF alert stream. We use two classifiers: a stamp-based classifier, designed for rapid classification, and a light curve–based classifier, which uses the multiband flux evolution to achieve a more refined classification. We describe in detail our pipeline, data products, tools, and services, which are made public for the community (see
https://alerce.science
). Since we began operating our real-time ML classification of the ZTF alert stream in early 2019, we have grown a large community of active users around the globe. We describe our results to date, including the real-time processing of 1.5 × 10
8
alerts, the stamp classification of 3.4 × 10
7
objects, the light-curve classification of 1.1 × 10
6
objects, the report of 6162 supernova candidates, and different experiments using LSST-like alert streams. Finally, we discuss the challenges ahead in going from a single stream of alerts such as ZTF to a multistream ecosystem dominated by LSST.
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