Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ...ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human "ubiquitinome" using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport.
Haumea-one of the four known trans-Neptunian dwarf planets-is a very elongated and rapidly rotating body. In contrast to other dwarf planets, its size, shape, albedo and density are not well ...constrained. The Centaur Chariklo was the first body other than a giant planet known to have a ring system, and the Centaur Chiron was later found to possess something similar to Chariklo's rings. Here we report observations from multiple Earth-based observatories of Haumea passing in front of a distant star (a multi-chord stellar occultation). Secondary events observed around the main body of Haumea are consistent with the presence of a ring with an opacity of 0.5, width of 70 kilometres and radius of about 2,287 kilometres. The ring is coplanar with both Haumea's equator and the orbit of its satellite Hi'iaka. The radius of the ring places it close to the 3:1 mean-motion resonance with Haumea's spin period-that is, Haumea rotates three times on its axis in the time that a ring particle completes one revolution. The occultation by the main body provides an instantaneous elliptical projected shape with axes of about 1,704 kilometres and 1,138 kilometres. Combined with rotational light curves, the occultation constrains the three-dimensional orientation of Haumea and its triaxial shape, which is inconsistent with a homogeneous body in hydrostatic equilibrium. Haumea's largest axis is at least 2,322 kilometres, larger than previously thought, implying an upper limit for its density of 1,885 kilograms per cubic metre and a geometric albedo of 0.51, both smaller than previous estimates. In addition, this estimate of the density of Haumea is closer to that of Pluto than are previous estimates, in line with expectations. No global nitrogen- or methane-dominated atmosphere was detected.
Abstract
Background
Ustekinumab (UST) is usually employed in Crohn’s disease (CD) after anti-tumor necrosis factor (TNF) therapy failure or if anti-TNF therapy is contraindicated. Higher UST trough ...levels have been associated with better clinical/endoscopic outcomes, so dose escalation (reducing dosing intervals or reinduction) is widely used. Intravenous (iv) maintenance has been proposed, but it has been barely assessed.
Methods
Single center, retrospective case series. All patients with CD starting treatment with UST and receiving at least one dose were eligible. Subjects started on UST in other centers or those prescribed for any indication different than IBD were excluded.
Dose escalation to iv maintenance was performed in case of lack or loss of response or persisting significant inflammation in laboratory tests, imaging or endoscopy. Following dose escalation, Harvey Bradshaw Index (HBI), fecal calprotectin and C reactive protein (CRP) were checked at each visit. UST trough levels were also assessed.
Primary outcomes were clinical remission (HBI<5) and biochemical remission (fecal calprotectin <250 mg/kg). Adverse events, and treatment persistence were also assessed.
Results
A total of 131 patients treated between May 2017 and August 2023 were included. Sixty (45.8%) patients were escalated to iv UST maintenance after a median of 14.1 (IQR: 8-50.4) weeks of UST treatment. Baseline characteristics are shown in table 1.
Patients were started on iv UST maintenance due to persistent inflammatory activity in imaging/endoscopic procedures in 21 (35%), clinical response without remission in 17 (28.3%), low trough concentrations in 16 (26.7%) and primary non-response in 6 (10%). Thirty-three (55%) were receiving sc UST every 4 weeks and 23 (38.3%) started iv maintenance directly after UST induction. At initiation of iv maintenance, patients presented a median HBI index of 4 (IQR: 2-7), a fecal calprotectin of 514 (IQR: 213-1078) mg/kg and UST trough levels of 4.8 (IQR: 3-7.3) μg/mL.
Following iv maintenance, UST trough levels increased to 10.9 (IQR: 8-17.4). Clinical remission rates increased from baseline (48.3%) at weeks 8 (79.6%, p=0.001), 24 (72%, p=0.01) and 48 (74.4%, p=0.01). However, the 10-13% increase observed in the biochemical remission rates was not statistically significant (figure 1). Treatment persistence 2 years after starting UST iv maintenance was 72.2% (95% CI: 54.7-83.8%). Only 2 infectious adverse events were observed in the whole cohort (2/131, 1.6%), both in patients receiving sc maintenance.
Conclusion
UST iv maintenance in bio-experienced patients is safe and increases clinical remission rates, although it did not achieve a relevant improvement in biochemical remission rates.
Context. The physical characterization of trans-Neptunian objects is essential for improving our understanding of the formation and evolution of our Solar System. Stellar occultation is a ...ground-based technique that can be successfully used to determine some of the TNOs' fundamental physical properties with high precision, such as size and shape. Aims: This work is aimed at constraining the size, shape, and geometric albedo of the dwarf planet candidate (307261) 2002 MS4 through the analysis of nine stellar occultation events. Using multichord detection, we also study the object's topography by analyzing the obtained limb and residuals between the observed chords and the best-fit ellipse. Metods. We predicted and organized the observational campaigns of nine stellar occultations by 2002 MS4 between 2019 and 2022, resulting in two single-chord events, four double-chord detections, and three events with between 3 and 61 positive chords. We derived the occultation light curves using differential aperture photometry, from which the star ingress and egress instants were calculated. Using 13 selected chords from the 8 August 2020 event, we determined the global elliptical limb of 2002 MS4. The best-fit ellipse, combined with the object's rotational information from the literature, sets constraints on the object's size, shape, and albedo. Additionally, we developed a new method to characterize the topography features on the object's limb. Results: The global limb has a semi-major axis of a′ = 412 ± 10 km, a semi-minor axis of b′= 385 ± 17 km, and the position angle of the minor axis is 121° ± 16°. From this instantaneous limb, we obtained 2002 MS4's geometric albedo of pV = 0.1 ± 0.025, using HV = 3.63 ± 0.05 mag and a projected area-equivalent diameter of 796 ± 24 km. Significant deviations from the fitted ellipse in the northernmost limb were detected from multiple sites, highlighting three distinct topographic features: one 11 km depth depression, followed by a 25−5+4 km height elevation next to a crater-like depression, with an extension of 322 ± 39 km and 45.1 ± 1.5 km deep. Conclusions: Our results indicate the presence of an object that is ≈138 km smaller in diameter than that derived from thermal data, possibly indicating the presence of a thus-far unknown satellite. However, within the error bars, the geometric albedo in the V-band is in agreement with the results published in the literature, even with the radiometric-derived albedo. This stellar occultation has allowed for the first multichord measurement of a large topography in a TNO. Tables B.1-B.5 are available at the CDS via anonymous ftp to cdsarc.cds.unistra.fr (ftp://130.79.128.5) or via https://cdsarc.cds.unistra.fr/viz-bin/cat/J/A+A/678/A167
ABSTRACT
On 2023 December 12, the star α Orionis will be occulted by asteroid (319) Leona. This represents an extraordinary and unique opportunity to analyse the brightness distribution of ...Betelgeuse’s photosphere with extreme angular resolution by studying light curves from different points on Earth and at different wavelengths. Here we present observations of another occultation by asteroid Leona, on 2023 September 13, whose goal was to determine Leona’s projected shape and size in preparation for the December 12th event and its interpretation. The occultation campaign was highly successful with 25 positive detections from 17 different sites and a near miss. The effective diameter in projected area derived from the positive detections was 66 ± 2 km using an elliptical fit to the instantaneous limb. The body is highly elongated, with dimensions of 79.6 ± 2.2 km × 54.8 ± 1.3 km in its long and short axis, respectively, at occultation time. This result, in combination with dense time series photometry of Leona that we recently obtained, together with archival sparse photometry, allowed us to predict the angular size of the asteroid for the Betelgeuse event and to simulate the expected brightness change. Also, an accurate position coming from the occultation is provided, to improve the orbit of Leona.
JOURNAL/nrgr/04.03/01300535-202409000-00039/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in ...that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.
From two observing runs during the 2014 summer at the Calar Alto Observatory in Almer...a (Spain) and at the Sierra Nevada Observatory in Granada (Spain), we were able to derive CCD photometry of the ...Trans-Neptunian object 2008 OG19. We analysed the time series and obtained a double-peaked light curve with a peak-to-valley amplitude of 0.437 ± 0.011 mag and a rotational period of 8.727 ± 0.003 h. This implies that this object is very elongated, closely resembling the case of Varuna. The photometry also allowed us to obtain an absolute magnitude in the R band of 4.39 ± 0.07 mag. From this result, we estimated an equivalent diameter of 2008 OG19 of 619... km using an average albedo for scattered disc objects. Finally, we interpreted the results under the assumption of hydrostatic equilibrium and found a lower limit for the density of 544... kg m^sup -3^. However, a more likely density is 609 ± 4 kg m^sup -3^ using an aspect angle of 60..., which corresponds to the most likely configuration for the spin axis with respect to the observer assuming random orientations. (ProQuest: ... denotes formulae/symbols omitted.)
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