Lineage frequency time series reveal elevated levels of genetic drift in SARS-CoV-2 transmission in England.

Genetic drift in infectious disease transmission results from randomness of transmission and host recovery or death. The strength of genetic drift for SARS-CoV-2 transmission is expected to be high due to high levels of superspreading, and this is expected to substantially impact disease epidemiology and evolution. However, we don't yet have an understanding of how genetic drift changes over time or across locations. Furthermore, noise that results from data collection can potentially confound estimates of genetic drift. To address this challenge, we develop and validate a method to jointly infer genetic drift and measurement noise from time-series lineage frequency data. Our method is highly scalable to increasingly large genomic datasets, which overcomes a limitation in commonly used phylogenetic methods. We apply this method to over 490,000 SARS-CoV-2 genomic sequences from England collected between March 2020 and December 2021 by the COVID-19 Genomics UK (COG-UK) consortium and separately infer the strength of genetic drift for pre-B.1.177, B.1.177, Alpha, and Delta. We find that even after correcting for measurement noise, the strength of genetic drift is consistently, throughout time, higher than that expected from the observed number of COVID-19 positive individuals in England by 1 to 3 orders of magnitude, which cannot be explained by literature values of superspreading. Our estimates of genetic drift suggest low and time-varying establishment probabilities for new mutations, inform the parametrization of SARS-CoV-2 evolutionary models, and motivate future studies of the potential mechanisms for increased stochasticity in this system.

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase.

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-µM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays.

Phylogenomic early warning signals for SARS-CoV-2 epidemic waves.

BACKGROUND: Epidemic waves of coronavirus disease 2019 (COVID-19) infections have often been associated with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Rapid detection of growing genomic variants can therefore serve as a predictor of future waves, enabling timely implementation of countermeasures such as non-pharmaceutical interventions (social distancing), additional vaccination (booster campaigns), or healthcare capacity adjustments. The large amount of SARS-CoV-2 genomic sequence data produced during the pandemic has provided a unique opportunity to explore the utility of these data for generating early warning signals (EWS). METHODS: We developed an analytical pipeline (Transmission Fitness Polymorphism Scanner - designated in an R package mrc-ide/tfpscanner) for systematically exploring all clades within a SARS-CoV-2 virus phylogeny to detect variants showing unusually high growth rates. We investigated the use of these cluster growth rates as the basis for a variety of statistical time series to use as leading indicators for the epidemic waves in the UK during the pandemic between August 2020 and March 2022. We also compared the performance of these phylogeny-derived leading indicators with a range of non-phylogeny-derived leading indicators. Our experiments simulated data generation and real-time analysis. FINDINGS: Using phylogenomic analysis, we identified leading indicators that would have generated EWS ahead of significant increases in COVID-19 hospitalisations in the UK between August 2020 and March 2022. Our results also show that EWS lead time is sensitive to the threshold set for the number of false positive (FP) EWS. It is often possible to generate longer EWS lead times if more FP EWS are tolerated. On the basis of maximising lead time and minimising the number of FP EWS, the best performing leading indicators that we identified, amongst a set of 1.4 million, were the maximum logistic growth rate (LGR) amongst clusters of the dominant Pango lineage and the mean simple LGR across a broader set of clusters. In the case of the former, the time between the EWS and wave inflection points (a conservative measure of wave start dates) for the seven waves ranged between a 20-day lead time and a 7-day lag, with a mean lead time of 5.4 days. The maximum number of FP EWS generated prior to a true positive (TP) EWS was two and this only occurred for two of the seven waves in the period. The mean simple LGR amongst a broader set of clusters also performed well in terms of lead time but with slightly more FP EWS. INTERPRETATION: As a result of the significant surveillance effort during the pandemic, early detection of SARS-CoV-2 variants of concern Alpha, Delta, and Omicron provided some of the first examples where timely detection and characterisation of pathogen variants has been used to tailor public health response. The success of our method in generating early warning signals based on phylogenomic analysis for SARS-CoV-2 in the UK may make it a worthwhile addition to existing surveillance strategies. In addition, the method may be translatable to other countries and/or regions, and to other pathogens with large-scale and rapid genomic surveillance. FUNDING: This research was funded in whole, or in part, by the Wellcome Trust (220885_Z_20_Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. KOD, OB, VBF and EMV acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. RMC acknowledges funding from the Wellcome Trust Collaborators Award (206298/Z/17/Z).

Genetic evidence for the association between COVID-19 epidemic severity and timing of non-pharmaceutical interventions.

Unprecedented public health interventions including travel restrictions and national lockdowns have been implemented to stem the COVID-19 epidemic, but the effectiveness of non-pharmaceutical interventions is still debated. We carried out a phylogenetic analysis of more than 29,000 publicly available whole genome SARS-CoV-2 sequences from 57 locations to estimate the time that the epidemic originated in different places. These estimates were examined in relation to the dates of the most stringent interventions in each location as well as to the number of cumulative COVID-19 deaths and phylodynamic estimates of epidemic size. Here we report that the time elapsed between epidemic origin and maximum intervention is associated with different measures of epidemic severity and explains 11% of the variance in reported deaths one month after the most stringent intervention. Locations where strong non-pharmaceutical interventions were implemented earlier experienced much less severe COVID-19 morbidity and mortality during the period of study.

Genomic epidemiology of a densely sampled COVID-19 outbreak in China.

Analysis of genetic sequence data from the SARS-CoV-2 pandemic can provide insights into epidemic origins, worldwide dispersal, and epidemiological history. With few exceptions, genomic epidemiological analysis has focused on geographically distributed data sets with few isolates in any given location. Here, we report an analysis of 20 whole SARS- CoV-2 genomes from a single relatively small and geographically constrained outbreak in Weifang, People's Republic of China. Using Bayesian model-based phylodynamic methods, we estimate a mean basic reproduction number (R 0) of 3.4 (95% highest posterior density interval: 2.1-5.2) in Weifang, and a mean effective reproduction number (Rt) that falls below 1 on 4 February. We further estimate the number of infections through time and compare these estimates to confirmed diagnoses by the Weifang Centers for Disease Control. We find that these estimates are consistent with reported cases and there is unlikely to be a large undiagnosed burden of infection over the period we studied.

Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England.

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.

Database of epidemic trends and control measures during the first wave of COVID-19 in mainland China.

OBJECTIVES: In this data collation study, we aimed to provide a comprehensive database describing the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19) throughout the main provinces in China. METHODS: From mid-January to March 2020, we extracted publicly available data regarding the spread and control of COVID-19 from 31 provincial health authorities and major media outlets in mainland China. Based on these data, we conducted descriptive analyses of the epidemic in the six most-affected provinces. RESULTS: School closures, travel restrictions, community-level lockdown, and contact tracing were introduced concurrently around late January but subsequent epidemic trends differed among provinces. Compared with Hubei, the other five most-affected provinces reported a lower crude case fatality ratio and proportion of critical and severe hospitalised cases. From March 2020, as the local transmission of COVID-19 declined, switching the focus of measures to the testing and quarantine of inbound travellers may have helped to sustain the control of the epidemic. CONCLUSIONS: Aggregated indicators of case notifications and severity distributions are essential for monitoring an epidemic. A publicly available database containing these indicators and information regarding control measures is a useful resource for further research and policy planning in response to the COVID-19 epidemic.

Evidence of initial success for China exiting COVID-19 social distancing policy after achieving containment.

Background: The COVID-19 epidemic was declared a Global Pandemic by WHO on 11 March 2020. By 24 March 2020, over 440,000 cases and almost 20,000 deaths had been reported worldwide. In response to the fast-growing epidemic, which began in the Chinese city of Wuhan, Hubei, China imposed strict social distancing in Wuhan on 23 January 2020 followed closely by similar measures in other provinces. These interventions have impacted economic productivity in China, and the ability of the Chinese economy to resume without restarting the epidemic was not clear. Methods: Using daily reported cases from mainland China and Hong Kong SAR, we estimated transmissibility over time and compared it to daily within-city movement, as a proxy for economic activity. Results: Initially, within-city movement and transmission were very strongly correlated in the five mainland provinces most affected by the epidemic and Beijing. However, that correlation decreased rapidly after the initial sharp fall in transmissibility. In general, towards the end of the study period, the correlation was no longer apparent, despite substantial increases in within-city movement. A similar analysis for Hong Kong shows that intermediate levels of local activity were maintained while avoiding a large outbreak. At the very end of the study period, when China began to experience the re-introduction of a small number of cases from Europe and the United States, there is an apparent up-tick in transmission. Conclusions: Although these results do not preclude future substantial increases in incidence, they suggest that after very intense social distancing (which resulted in containment), China successfully exited its lockdown to some degree. Elsewhere, movement data are being used as proxies for economic activity to assess the impact of interventions. The results presented here illustrate how the eventual decorrelation between transmission and movement is likely a key feature of successful COVID-19 exit strategies.

The impact of COVID-19 and strategies for mitigation and suppression in low- and middle-income countries.

The ongoing coronavirus disease 2019 (COVID-19) pandemic poses a severe threat to public health worldwide. We combine data on demography, contact patterns, disease severity, and health care capacity and quality to understand its impact and inform strategies for its control. Younger populations in lower-income countries may reduce overall risk, but limited health system capacity coupled with closer intergenerational contact largely negates this benefit. Mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems, with substantial excess deaths in lower-income countries resulting from the poorer health care available. Of countries that have undertaken suppression to date, lower-income countries have acted earlier. However, this will need to be maintained or triggered more frequently in these settings to keep below available health capacity, with associated detrimental consequences for the wider health, well-being, and economies of these countries.

Rhodacyclopentanones as Linchpins for the Atom Economical Assembly of Diverse Polyheterocycles.

We outline a conceptual blueprint that provides direct and atom economical access to a wide range of complex polyheterocycles. Our method capitalizes on the ambiphilic reactivity of rhodacyclopentanones that arise upon exposure of cyclopropanes to Rh(I) catalysts and CO. Using this approach, a wide array of polycyclizations are achieved, including variants that involve powerful dearomatizations and medium ring formations.

Modular Access to Eight-Membered N-Heterocycles by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.

Aminocyclopropanes equipped with pendant nucleophiles undergo carbonylative heterocyclization triggered by C-C bond activation to generate eight-membered N-heterocycles. In these processes, intramolecular "capture" of a rhodacyclopentanone intermediate by an aryl or N-based nucleophile is followed by C-C or C-N bond-forming "collapse" to the targets. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be harnessed to enable otherwise challenging medium ring closures.

Phylogeny of the beetle supertribe Trechitae (Coleoptera: Carabidae): Unexpected clades, isolated lineages, and morphological convergence.

Using data from two nuclear ribosomal genes and four nuclear protein-coding genes, we infer a well-resolved phylogeny of major lineages of the carabid beetle supertribe Trechitae, based upon a sampling of 259 species. Patrobini is the sister group of Trechitae, but the genus Lissopogonus appears to be outside of the Patrobini + Trechitae clade. We find that four enigmatic trechite genera from the Southern Hemisphere, Bembidarenas, Argentinatachoides, Andinodontis, and Tasmanitachoides, form a clade that is the sister group of Trechini; we describe this clade as a new tribe, Bembidarenini. Bembidarenini + Trechini form the sister group of remaining trechites. Within Trechini, subtribe Trechodina is not monophyletic, as three trechodine genera from Australia (Trechobembix, Paratrechodes, Cyphotrechodes) are the sister group of subtribe Trechina. Trechini appears to have originated in the continents of the Southern Hemisphere, with almost all Northern Hemisphere lineages representing a single radiation within the subtribe Trechina. We present moderate evidence that the geographically and phylogenetically isolated genera Sinozolus (six species in the mountains of China), Chaltenia (one species in Argentina and Chile), and Phrypeus (one species in western North America) also form a clade, the tribe Sinozolini. The traditionally recognized tribe Bembidiini sens. lat., diagnosed by the presence of a subulate terminal palpomere, is shown to be polyphyletic; subulate palpomeres have arisen five times within Trechitae. Anillini is monophyletic, and the sister group of Tachyini + Pogonini + Bembidiini + Zolini + Sinozolini; within anillines, we confirm earlier results indicating the eyed New Zealand genus Nesamblyops as the sister to the rest. Sampled New World Pogonini are monophyletic, rendering the genus Pogonus non-monophyletic. Tachyina and Xystosomina are sister groups. Within Xystosomina, the New World members are monophyletic, and are sister to an Australia-New Zealand clade. The latter consists of the genus Philipis as well as taxa not previously recognized as xystosomines: Kiwitachys, the "Tachys" ectromioides group, and "Tachys" mulwalensis. Within Tachyina, the subgenus Elaphropus is not closely related to other subgenera previously placed in the genus Elaphropus; we move the other subgenera into the genus Tachyura. Tachyina with a bifoveate mentum do not form a clade; in fact, a bifoveate mentum is found in Xystosomina, Sinozolini, Trechini, Trechitae and its sister group, Patrobini. Extensive homoplasy in the morphological characters previously used as key indicators of relationship is supported by our results: in addition to multiple origins of subulate palpomeres and bifoveate menta, a concave protibial notch has arisen independently in Anillina, Xystosomina, and Tachyina. Phylogenetically and geographically isolated, species-poor lineages in Trechini, Bembidarenini, and Sinozolini may be relicts of more widespread faunas; many of these are found today on gravel or sand shores of creeks and rivers, which may be an ancestral habitat for portions of Trechitae. In addition to the description of Bembidarenini, we present a diagnosis of the newly delimited Sinozolini, and keys to the tribes of Trechitae.

MonotomidGen - A matrix-based interactive key to the New World genera of Monotomidae (Coleoptera, Cucujoidea).

A matrix-based LucidTM key is presented for the twelve genera of Monotomidae (Coleoptera: Cucujoidea) represented in the New World. A general overview is given for the features and technical specifications of an original interactive key for the identification of these genera. The list of terminal taxa included with the key provides a current summary of monotomid generic diversity for the Nearctic and Neotropical regions.

Taxonomic review of New World Tachyina (Coleoptera, Carabidae): descriptions of new genera, subgenera, and species, with an updated key to the subtribe in the Americas.

The classification of the carabid subtribe Tachyina (Trechitae: Bembidiini) is reviewed in light of newly discovered diversity from Central and South America. Described herein are three new genera (Tachyxystagen. n., Stigmatachysgen. n., Nothoderisgen. n.), two new subgenera of Meotachys (Scolistichussubgen. n., Hylotachyssubgen. n.), and two new subgenera of Elaphropus (Ammotachyssubgen. n., Idiotachyssubgen. n.). Two names previously synonymized under Polyderis (Polyderidius Jeannel, 1962) and Elaphropus (Nototachys Alluaud, 1930) are elevated to generic and subgeneric status, respectively. Eight new species are recognized: Tachyxysta howdenorum (type locality: México: Chiapas: El Aguacero, 680m); Elaphropus marchantarius (type locality: Brazil, Amazonas, Rio Solimões, Ilha de Marchantaria), Elaphropus acutifrons (type locality: Brazil: Pará, Santarém) and Elaphropus occidentalis (type locality: Perú: Loreto, Pithecia, 74°45'W 05°28'S); Stigmatachys uvea (type locality: Perú: Loreto: Campamento San Jacinto, 2°18.75'S, 75°51.77'W, 175-215m); and Meotachys riparius (type locality: Colombia: Amazonas: Leticia, 700 ft), Meotachys ballorum (type locality: Brazil: Amazonas, Rio Negro Cucui), and Meotachys rubrum (type locality: Perú: Madre de Dios: Rio Manu, Pakitza, 11°56°47'S 071°17°00'W, 356m). An updated key to the genera and subgenera of Tachyina occurring in the New World is provided, with accompanying illustrations.

ResumenLa clasificación de la subtribu Tachyina (Carabidae: Trechitae: Bembidiini) se revisa luego de diversidad que ha sido nuevamente descrita del Centro y Sur América. Aquí se describen tres géneros nuevos (Tachyxystagénero nuevo, Stigmatachysgénero nuevo, Nothoderisgénero nuevo), dos subgéneros nuevos del Meotachys (Scolistichussubgénero nuevo, Hylotachyssubgénero nuevo), y dos subgéneros nuevos del Elaphropus (Ammotachyssubgénero nuevo, Idiotachyssubgénero nuevo). Dos nombres taxonómicos previamente sinonimizados con Polyderis (Polyderidius Jeannel, 1962) y Elaphropus (Nototachys Alluaud, 1930) aquí son elevados a los niveles de género y subgénero, respectivamente. Se reconocen ochos espécies nuevos: Tachyxysta howdenorum (localidad tipo: México: Chiapas: El Aguacero, 680m); Elaphropus marchantarius (localidad tipo: Brazil, Amazonas, Rio Solimões, Ilha de Marchantaria), Elaphropus acutifrons (localidad tipo: Brazil: Pará, Santarém) and Elaphropus occidentalis (localidad tipo: Perú: Loreto, Pithecia, 74°45'W 05°28'S); Stigmatachys uvea (localidad tipo: Perú: Loreto: Campamento San Jacinto, 2°18.75'S, 75°51.77'W, 175­215m); and Meotachys riparius (localidad tipo: Colombia: Amazonas: Leticia, 700 ft), Meotachys ballorum (localidad tipo: Brazil: Amazonas, Rio Negro Cucui), and Meotachys rubrum (localidad tipo: Perú: Madre de Dios: Rio Manu, Pakitza, 11°56°47'S 071°17°00'W, 356m). Una clave actualizada con illustraciones de los géneros y subgéneros del Tachyina que ocurren en el Nuevo Mundo está incluída.