In this letter, we report the performance of high-κ /metal gate nanowire (NW) transistors without junctions fabricated with a channel thickness of 9 nm and sub-15-nm gate length and NW width. ...Near-ideal subthreshold slope (SS) and extremely low leakage currents are demonstrated for ultrascaled gate lengths with a high on-off ratio (I on /I off ) >; 10 6 . For the first time, an SS lower than 70 mV/dec is achieved at LG = 13 nm for n-type and p-type transistors, highlighting excellent electrostatic integrity of trigate junctionless NW MOSFETs.
Summary
Background
A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome (‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic ...syndrome’).
Objectives
To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome.
Methods
One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow‐up, were recorded.
Results
The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow‐up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild‐to‐moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C‐reactive protein levels and less frequent chondritis). The 5‐year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis.
Conclusions
VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.
What is already known about this topic?
VEXAS syndrome is a recently described autoinflammatory disease related to UBA1 mutation. The clinical phenotype includes patients with thrombosis, fever, chondritis, neutrophilic dermatosis and MDS.
What does this study add?
The main clinical features of VEXAS patients remain recurrent fever (64.7% vs. 72%, in original description by Beck et al.), skin lesions (83.6% vs. 88%), lung infiltrates (49.1% vs. 72%), unprovoked thrombosis (35.5% vs. 44%), with new features such as arthralgia (28.4%), ocular involvement (40.5%) or lymph node enlargement (34.5%), expanding the previous clinical phenotype of VEXAS syndrome.
We identified 3 clusters of VEXAS syndrome, including an MDS‐related phenotype; mild‐to‐moderate disease with less fever, chondritis and thromboembolism, and one with more ‘inflammatory' profile characterized by cutaneous vasculitis lesions and relapsing profile.
A phenotype–genotype association was observed for UBA1 p.Met41Leu which was associated with less ‘inflammatory' and mild‐to‐moderate phenotype and better overall prognosis.
Linked Comment: L.T. Nicholson and L.M. Madigan. Br J Dermatol 2022; 186:392–393.
Plain language summary available online
Argonaute proteins repress gene expression and defend against foreign nucleic acids using short RNAs or DNAs to specify the correct target RNA or DNA sequence. We have developed single-molecule ...methods to analyze target binding and cleavage mediated by the Argonaute:guide complex, RISC. We find that both eukaryotic and prokaryotic Argonaute proteins reshape the fundamental properties of RNA:RNA, RNA:DNA, and DNA:DNA hybridization—a small RNA or DNA bound to Argonaute as a guide no longer follows the well-established rules by which oligonucleotides find, bind, and dissociate from complementary nucleic acid sequences. Argonautes distinguish substrates from targets with similar complementarity. Mouse AGO2, for example, binds tighter to miRNA targets than its RNAi cleavage product, even though the cleaved product contains more base pairs. By re-writing the rules for nucleic acid hybridization, Argonautes allow oligonucleotides to serve as specificity determinants with thermodynamic and kinetic properties more typical of RNA-binding proteins than of RNA or DNA.
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•Argonaute changes the rate of target finding by pre-organizing a region of its guide•Seed pairing is required for rapid target finding and stable binding•AGO2 releases its cleaved products by destabilizing their interaction with the guide•RISC makes its guide behave more like an RNA-binding protein and less like free RNA
Argonaute proteins reshape how oligonucleotides find, bind, and dissociate from complementary nucleic acid sequences. By re-writing the rules, Argonautes allow oligonucleotides to serve as specificity determinants with thermodynamic and kinetic properties more typical of RNA-binding proteins.
Argonaute proteins loaded with microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC), which represses target RNA expression. Predicting the biological ...targets, specificity, and efficiency of both miRNAs and siRNAs has been hamstrung by an incomplete understanding of the sequence determinants of RISC binding and cleavage. We applied high-throughput methods to measure the association kinetics, equilibrium binding energies, and single-turnover cleavage rates of mouse AGO2 RISC. We find that RISC readily tolerates insertions of up to 7 nt in its target opposite the central region of the guide. Our data uncover specific guide:target mismatches that enhance the rate of target cleavage, suggesting novel siRNA design strategies. Using these data, we derive quantitative models for RISC binding and target cleavage and show that our in vitro measurements and models predict knockdown in an engineered cellular system.
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•Binding energies, association, and cleavage rates measured for >40,000 RISC targets•AGO2 tolerates large insertions in the target opposite the central region of the guide•Some guide:target mismatches enhance the single-turnover RISC cleavage rate•In vitro measured biochemical parameters explain knockdown in cells
By high-throughput, quantitative characterization of binding and cleavage for >40,000 distinct RISC targets, Becker et al. reveal principles of miRNA regulation and siRNA function. These data enable construction of quantitative models of binding and cleavage and are used to explain mRNA knockdown in cells.
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