We present observations of the young multiple system UX Tauri to look for circumstellar disks and for signs of dynamical interactions. We obtained SPHERE/IRDIS deep differential polarization images ...in the
J
and
H
bands. We also used ALMA archival CO data. Large extended spirals are well detected in scattered light coming out of the disk of UX Tau A. The southern spiral forms a bridge between UX Tau A and C. These spirals, including the bridge connecting the two stars, all have a CO (3–2) counterpart seen by ALMA. The disk of UX Tau C is detected in scattered light. It is much smaller than the disk of UX Tau A and has a major axis along a different position angle, suggesting a misalignment. We performed
PHANTOM
SPH hydrodynamical models to interpret the data. The scattered light spirals, CO emission spirals and velocity patterns of the rotating disks, and the compactness of the disk of UX Tau C all point to a scenario in which UX Tau A has been perturbed very recently (∼1000 years) by the close passage of UX Tau C.
Commensal bacteria in the colon may play a role in colorectal cancer (CRC) development. Recent studies from North America showed that
Fusobacterium nucleatum
(
Fn
) infection is over-represented in ...disease tissue versus matched normal tissue in CRC patients. Using quantitative real-time polymerase chain reaction (qPCR) of DNA extracted from colorectal tissue biopsies and surgical resections of three European cohorts totalling 122 CRC patients, we found an over-abundance of
Fn
in cancerous compared to matched normal tissue (
p
< 0.0001). To determine whether
Fn
infection is an early event in CRC development, we assayed
Fn
in colorectal adenoma (CRA) tissue from 52 Irish patients. While for all CRAs the
Fn
level was not statistically significantly higher in disease versus normal tissue (
p
= 0.06), it was significantly higher for high-grade dysplasia (
p
= 0.015). As a secondary objective, we determined that CRC patients with low
Fn
levels had a significantly longer overall survival time than patients with moderate and high levels of the bacterium (
p
= 0.008). The investigation of
Fn
as a potential non-invasive biomarker for CRC screening showed that, while
Fn
was more abundant in stool samples from CRC patients compared to adenomas or controls, the levels in stool did not correlate with cancer or adenoma tissue levels from the same individuals. This is the first study examining
Fn
in the colonic tissue and stool of European CRC and CRA patients, and suggests
Fn
as a novel risk factor for disease progression from adenoma to cancer, possibly affecting patient survival outcomes. Our results highlight the potential of
Fn
detection as a diagnostic and prognostic determinant in CRC patients.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost ...advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.
Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with ...the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.
We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.
Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.
The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.
Herpes zoster is a localized skin infection caused by reactivation of latent varicella-zoster virus. Tissue-resident T cells likely control skin infections. Zoster provides a unique opportunity to ...determine if focal reinfection of human skin boosts local or disseminated antigen-specific tissue-resident T cells. Here, we show virus-specific T cells are retained over one year in serial samples of rash site and contralateral unaffected skin of individuals recovered from zoster. Consistent with zoster resolution, viral DNA is largely undetectable on skin from day 90 and virus-specific B and T cells decline in blood. In skin, there is selective infiltration and long-term persistence of varicella-zoster virus-specific T cells in the rash site relative to the contralateral site. The skin T cell infiltrates express the canonical tissue-resident T cell markers CD69 and CD103. These findings show that zoster promotes spatially-restricted long-term retention of antigen-specific tissue-resident T cells in previously infected skin.
Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ...ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.
Abstract On 2022 February 15–16, multiple spacecraft measured one of the most intense solar energetic particle (SEP) events observed so far in Solar Cycle 25. This study provides an overview of ...interesting observations made by multiple spacecraft during this event. Parker Solar Probe (PSP) and BepiColombo were close to each other at 0.34–0.37 au (a radial separation of ∼0.03 au) as they were impacted by the flank of the associated coronal mass ejection (CME). At about 100° in the retrograde direction and 1.5 au away from the Sun, the radiation detector on board the Curiosity surface rover observed the largest ground-level enhancement on Mars since surface measurements began. At intermediate distances (0.7–1.0 au), the presence of stream interaction regions (SIRs) during the SEP arrival time provides additional complexities regarding the analysis of the distinct contributions of CME-driven versus SIR-driven events in observations by spacecraft such as Solar Orbiter and STEREO-A, and by near-Earth spacecraft like ACE, SOHO, and WIND. The proximity of PSP and BepiColombo also enables us to directly compare their measurements and perform cross-calibration for the energetic particle instruments on board the two spacecraft. Our analysis indicates that energetic proton measurements from BepiColombo and PSP are in reasonable agreement with each other to within a factor of ∼1.35. Finally, this study introduces the various ongoing efforts that will collectively improve our understanding of this impactful, widespread SEP event.
We present multipoint observations of earthward moving dipolarization fronts and energetic particle injections from NASAs Magnetospheric Multiscale mission with a focus on electron acceleration. From ...a case study during a substorm on 02 August 2015, we find that electrons are only accelerated over a finite energy range, from a lower energy threshold at approx. 7-9 keV up to an upper energy cutoff in the hundreds of keV range. At energies lower than the threshold energy, electron fluxes decrease, potentially due to precipitation by strong parallel electrostatic wavefields or initial sources in the lobes. Electrons at energies higher than the threshold are accelerated cumulatively by a series of impulsive magnetic dipolarization events. This case demonstrates how the upper energy cutoff increases, in this case from approx. 130 keV to >500 keV, with each depolarization/injection during sustained activity. We also present a simple model accounting for these energy limits that reveals that electron energization is dominated by betatron acceleration.
Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia ...through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 µg/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 µg/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.
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•Realistic synthetic 1D NMR spectra for robust performance on experimental spectra.•An implicit regularization through automatic labeling of synthetic spectra.•A custom data ...pre-processing for high dynamic range regions and broad lines.•A deep neural network that handles broad lines, crowded regions, and HDR spectra.•A fully automated method that yields expert-level quality sparse deconvolution results.
The analysis of nuclear magnetic resonance (NMR) spectra to detect peaks and characterize their parameters, often referred to as deconvolution, is a crucial step in the quantification, elucidation, and verification of the structure of molecular systems. However, deconvolution of 1D NMR spectra is a challenge for both experts and machines. We propose a robust, expert-level quality deep learning-based deconvolution algorithm for 1D experimental NMR spectra. The algorithm is based on a neural network trained on synthetic spectra. Our customized pre-processing and labeling of the synthetic spectra enable the estimation of critical peak parameters. Furthermore, the neural network model transfers well to the experimental spectra and demonstrates low fitting errors and sparse peak lists in challenging scenarios such as crowded, high dynamic range, shoulder peak regions as well as broad peaks. We demonstrate in challenging spectra that the proposed algorithm is superior to expert results.
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