Recent advance in high manufacturing readiness level and high temperature CMOS mixed-signal integrated circuits on silicon carbide

A high manufacturing readiness level silicon carbide (SiC) CMOS technology is presented. The unique process flow enables the monolithic integration of pMOS and nMOS transistors with passive circuit elements capable of operation at temperatures of 300 °C and beyond. Critical to this functionality is the behaviour of the gate dielectric and data for high temperature capacitance–voltage measurements are reported for SiO2/4H-SiC (n and p type) MOS structures. In addition, a summary of the long term reliability for a range of structures including contact chains to both n-type and p-type SiC, as well as simple logic circuits is presented, showing function after 2000 h at 300 °C. Circuit data is also presented for the performance of digital logic devices, a 4 to 1 analogue multiplexer and a configurable timer operating over a wide temperature range. A high temperature micro-oven system has been utilised to enable the high temperature testing and stressing of units assembled in ceramic dual in line packages, including a high temperature small form-factor SiC based bridge leg power module prototype, operated for over 1000 h at 300 °C. The data presented show that SiC CMOS is a key enabling technology in high temperature integrated circuit design. In particular it provides the ability to realise sensor interface circuits capable of operating above 300 °C, accommodate shifts in key parameters enabling deployment in applications including automotive, aerospace and deep well drilling

Assembly defects of human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia

Mutations within subunits of the tRNA splicing endonuclease complex (TSEN) are associated with pontocerebellar hypoplasia (PCH). Here the authors show that tRNA intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers, and provide evidence that modulation of TSEN stability may contribute to PCH phenotypes.Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-angstrom resolution X-ray crystal structure of a TSEN15-34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.Genetics of disease, diagnosis and treatmen

Allaeochelys libyca, a new carettochelyine turtle from the middle miocene (Langhian) of Libya

Fossil carettochelyine turtles are well known from the Paleogene of Europe (Allaeochelys), North America and Asia (Anosteira); however, the previously known Neogene fossil record is highly fragmentary and was therefore unsuitable for taxonomic analysis. In this work, we present a new carettochelyine taxon, Allaeochelys libyca, from the Middle Miocene (Langhian) of Gebel Zelten (Libya) based on an incomplete skull and disarticulated postcranial elements. The new taxon is diagnosed relative to the extant Carettochelys insculpta based on the placement of the foramen posterius canalis carotici interni close to the fenestra postotica, the horizontal orientation of the tubercula basioccipitalis, the substantial contribution of the opisthotic to the base of the tubercula basioccipitalis, the presence of a triangular pterygoid fossa, the arrangement of the mandibular condyles along a plane and the presence of an extremely well-developed fossa at the base of the processus mandibularis. A phylogenetic analysis of pancarettochelyids confirms the monophyly of Carettochelyidae and Carettochelyinae but resulted in a paraphyletic taxon, Allaeochelys. For the sake of nomenclatural stability, we provisionally retain the genus Allaeochelys as paraphyletic relative to the extant Carettochelys insculpta

A review of the fossil record of turtles of the clade Pan-Carettochelys

Turtles of the total clade Pan-Carettochelys have a relatively poor fossil record that extends from the Early Cretaceous. The clade is only found in Asia during the Cretaceous, but spreads to Europe and North America during the Eocene. Neogene finds are restricted to Europe, Africa and Australia, whereas the only surviving species, Carettochelys insculpta, lives in New Guinea and the Northern Territories of Australia. The ecology of fossil pan-carettochelyids appears similar to that of the extant C. insculpta, although more primitive representatives were likely less adapted to brackish water. Current phylogenies only recognize three internested clades: Pan- Carettochelys, Carettochelyidae and Carettochelyinae. A taxonomic review of the group concludes that of 25 named taxa, 13 are nomina valida, 7 are nomina invalida, 3 are nomina dubia, and 2 are nomina nuda

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

Background: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods: Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings: Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding: UK Vaccine Taskforce and National Institute for Health and Care Research