Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Small-signal transient response and turn-on delay of polariton laser diodes

We present a theoretical description of the small-signal transient response of polariton laser diodes (pol-LDs) based on simplified coupled rate equations describing the exciton reservoir and the ground-state polariton populations. The analytic expressions derived for two pumping geometries, which are valid for all inorganic semiconductors suitable for the realization of pol-LDs, are compared to exact numerical calculations performed for the specific case of GaN-based devices. The two approaches show excellent agreement provided the current step transient remains within the small-signal limit. We report that the temporal attenuation of the envelopes of the oscillations matches half the value of the damping factor (gamma(d)) of the pol-LDs, which is proportional to the square of the oscillation relaxation resonance frequency. An explicit expression for the dependence of d g on both the exciton-photon detuning and the driving current (equivalently the optical pump power) is also obtained. In a further step, we derive the expression for the turn-on delay (t(d)) associated with the build-up of the exciton reservoir population up to its threshold value before coherent light emission occurs. We show that td has the same functional form for the two pumping geometries. It is equal to the effective exciton lifetime (tau(xeff)) weighted by a logarithmic dependence on the initial and final driving currents. In addition, tau(xeff) t is shown to be approximately equal to the exciton lifetime, which proves to be the main parameter governing the build-up of polariton lasing/condensation. Beyond electrically driven polariton lasers, we highlight that the temporal shape of the transients could also be easily tested by monitoring the time dependence of the output power of optically pumped polariton lasers subjected to a sudden increase in the continuous wave pump power within the small-signal limit

A novel class of coherent light emitters: polariton lasers

The specificities of polariton lasers-a new generation of coherent light-emitting devices where the relaxation of the bosonic quasiparticles responsible for the light emission, the polaritons, is stimulated whereas the photon emission process issued from the radiative decay of those polaritons is purely spontaneous-are reviewed. It is shown that the practical realization of such devices able to operate at room temperature would most likely rely on wide bandgap semiconductors (inorganic or organic ones) exhibiting highly stable excitons/polaritons. Using III-nitrides, the most advanced of the candidates to date, an electrically driven multiple quantum well polariton laser would display a threshold current density down to similar to 100 A cm(-2), a value more than one order of magnitude lower than that of state of the art GaN-based edge-emitting laser diodes. For the sake of comparison, the main features of optically pumped polariton lasers available that differ from those of their conventional counterparts, namely vertical cavity surface-emitting lasers, are also discussed

III-nitride photonic cavities

Owing to their wide direct bandgap tenability, III-nitride (III-N) compound semiconductors have been proven instrumental in the development of blue light-emitting diodes that led to the so-called solid-state lighting revolution and blue laser diodes that are used for optical data storage. Beyond such conventional optoelectronic devices, in this review, we explore the progress made in the past 15 years with this low refractive index material family for the realization of microdisks as well as 2D and 1D photonic crystal (PhC) membrane cavities. Critical aspects related to their design and fabrication are first highlighted. Then, the optical properties of passive PhC structures designed for near-infrared such as their quality factor and their mode volume are addressed. Additional challenges dealing with fabrication pertaining to structures designed for shorter wavelengths, namely the visible to ultraviolet spectral range, are also critically reviewed and analyzed. Various applications ranging from second and third harmonic generation to microlasers and nanolasers are then discussed. Finally, forthcoming challenges and novel fields of application of III-N photonic cavities are commented

Probing alloy formation using different excitonic species: The particular case of InGaN

Since the 1960s, alloys are grouped into two classes, featuring bound states in the bandgap (I - GaP:N, ZnTe:O, etc.) or additional, non-discrete, band states (II - SiGe, GaAsP, InGaAs, etc.). Therefore, one can observe either a rich and informative zoo of excitons bound to isoelectronic impurities (I), or the typical bandedge emission of a semiconductor that shifts and broadens with rising isoelectronic doping (II). Because no such strongly localized excitons are found in the photoluminescence (PL) spectra of the investigated bulk In(x)Ga(1-x)N epilayers ( 0 ≤ x ≤ 2.4%, 100 nm thick, growth on bulk GaN substrates), we suggest to utilize shallow impurities as a tool to study the distribution of isoelectronic centers. By micro-PL, we directly observe an entire hierarchy of bound excitons related to silicon-indium complexes as individual, energetically sharp emission lines appear (full width at half-maximum ≈ 300μeV). In order to exemplify our approach, we determine nanoscopic parameters of the InGaN alloy like the exciton diffusion length. We expect that our spectroscopic analysis represents a general pathway for studying mixed crystal alloys associated to class II, which approaches the high level of spectroscopic sophistication evidenced in literature for class I alloys

Continuous Wave Blue Lasing in III-Nitride Nanobeam Cavity on Silicon

IIIV photonics on silicon is an active and promising research area. Here, we demonstrate room-temperature (RT) lasing in short-wavelength III-nitride photonic crystal nanobeam cavities grown on silicon featuring a single InGaN quantum well (QW). In the low-absorption QW region, high quality factors in excess of 104 are measured, while RT blue lasing under continuous-wave optical pumping is reported in the high-absorption wavelength range, hence the high QW gain region. Lasing characteristics are well accounted for by the large spontaneous emission coupling factor (beta > 0.8) inherent to the nanobeam geometry and the large InGaN QW material gain. Our work illustrates the high potential of III-nitrides on silicon for the realization of low power nanophotonic devices with a reduced footprint that would be of prime interest for fundamental lightmatter interaction studies and a variety of lab-on-a-chip applications including biophotonics