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Author(s): Alan Watson (corresponding author) [1] [illus. 1] For decades, physicists have puzzled over why the Universe contains more matter than antimatter -- essentially, how it is that we are [...]

Successful pregnancies rely on adaptations within the mother.sup.1, including marked changes within the immune system.sup.2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy.sup.3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK.sup.4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T.sub.reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T.sub.reg cells through RANK in a manner that depends on AIRE.sup.+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T.sub.reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T.sub.reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T.sub.reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T.sub.reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T.sub.reg cells during pregnancy, and expand the functional role of maternal T.sub.reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes., Author(s): Magdalena Paolino [sup.1] [sup.2] [sup.3] , Rubina Koglgruber [sup.1] , Shane J. F. Cronin [sup.1] , Iris Uribesalgo [sup.1] , Esther Rauscher [sup.1] , Jürgen Harreiter [sup.4] , Michael [...]

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1–3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4–6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.By demonstrating a computational approach to restore the clinical efficacy of a COVID-19 antibody, the potential to rapidly update clinical antibodies is explored. [ABSTRACT FROM AUTHOR]

Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain.sup.1,2. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine--a tryptophan metabolite that blocks antitumour immunity--inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity. Tetrahydrobiopterin (BH4) is an enzyme co-factor that is involved in the nervous system; it is shown here to also function in T cell activation and proliferation, with roles in autoimmunity, allergic inflammation and cancer., Author(s): Shane J. F. Cronin [sup.1] [sup.2] [sup.3] , Corey Seehus [sup.2] [sup.3] , Adelheid Weidinger [sup.4] , Sebastien Talbot [sup.2] [sup.3] [sup.5] , Sonja Reissig [sup.6] , Markus Seifert [...]

Change history: Owing to the misidentification of compound 22 in the original Letter, changes have been made to Fig. 5, Extended Data Fig. 2 and the main text; see accompanying Amendment., Author(s): Jaroslaw M. Granda [sup.1] , Liva Donina [sup.1] , Vincenza Dragone [sup.1] , De-Liang Long [sup.1] , Leroy Cronin [sup.1] Author Affiliations: (1) School of Chemistry, University of Glasgow, [...]

A dual-function helicase-nuclease, typified by RecBCD in Escherichia coli, acts on free DNA ends during bacterial double-stranded break repair until it reaches a [chi] sequence at which it pauses before continuing with modified enzymatic properties; here several crystal structures of the related AddAB enzyme from Bacillus subtilis bound to [chi]-containing DNA are presented, offering insight into [chi] recognition and its effect on DNA translocation. Taming a rampant nuclease In bacterial double-stranded DNA break repair, the free ends are initially acted upon by a dual function helicase/nuclease, typified by the RecBCD enzyme of Escherichia coli. As RecBCD unwinds DNA, it eventually encounters a polar octameric sequence known as Chi ([chi]), which causes attenuation and a change in specificity of the nuclease activity. Dale Wigley and colleagues have now solved several structures of AddAB, a related enzyme from Bacillus subtilis, bound to [chi]-containing DNA. These structures offer insight into the translocation process, the recognition of [chi], and the pausing that occurs when [chi] is recognized. In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequence [chi] (Chi).sup.1,2 and is catalysed by either an AddAB- or RecBCD-type helicase-nuclease (reviewed in refs 3, 4). These enzyme complexes unwind and digest the DNA duplex from the broken end until they encounter a [chi] sequence.sup.5, whereupon they produce a 3' single-stranded DNA tail onto which they initiate loading of the RecA protein.sup.6. Consequently, regulation of the AddAB/RecBCD complex by [chi] is a key control point in DNA repair and other processes involving genetic recombination. Here we report crystal structures of Bacillus subtilis AddAB in complex with different [chi]-containing DNA substrates either with or without a non-hydrolysable ATP analogue. Comparison of these structures suggests a mechanism for DNA translocation and unwinding, suggests how the enzyme binds specifically to [chi] sequences, and explains how [chi] recognition leads to the arrest of AddAB (and RecBCD) translocation that is observed in single-molecule experiments.sup.7,8,9., Author(s): Wojciech W. Krajewski [sup.1] [sup.3] , Xin Fu [sup.1] , Martin Wilkinson [sup.1] , Nora B. Cronin [sup.1] , Mark S. Dillingham [sup.2] , Dale B. Wigley [sup.1] Author [...]

The discovery of chemical reactions is an inherently unpredictable and time-consuming process.sup.1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy.sup.2. Reaction prediction based on high-level quantum chemical methods is complex.sup.3, even for simple molecules. Although machine learning is powerful for data analysis.sup.4,5, its applications in chemistry are still being developed.sup.6. Inspired by strategies based on chemists' intuition.sup.7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert.sup.8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.A robot instructed by a machine learning algorithm and coupled with real-time spectroscopic systems provides fast and accurate reaction outcome predictions and reactivity assessments, leading to the discovery of new reactions., Author(s): Jaroslaw M. Granda [sup.1] , Liva Donina [sup.1] , Vincenza Dragone [sup.1] , De-Liang Long [sup.1] , Leroy Cronin [sup.1] Author Affiliations:(1) School of Chemistry, University of Glasgow, Glasgow, [...]

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia (1). Introduction of ABL1 kinase inhibitors (for example, imatinib) [...]

Flash memory devices--that is, non-volatile computer storage media that can be electrically erased and reprogrammed--are vital for portable electronics, but the scaling down of metal-oxide-semiconductor (MOS) flash memory to sizes of below ten nanometres per data cell presents challenges. Molecules have been proposed to replace MOS flash memory (1), but they suffer from low electrical conductivity, high resistance, low device yield, and finite thermal stability, limiting their integration into current MOS technologies. Although great advances have been made in the pursuit of molecule-based flash memory (2), there are a number of significant barriers to the realization of devices using conventional MOS technologies (3-7). Here we show that core-shell polyoxometalate (POM) molecules (8) can act as candidate storage nodes for MOS flash memory. Realistic, industry-standard device simulations validate our approach at the nanometre scale, where the device performance is determined mainly by the number of molecules in the storage media and not by their position. To exploit the nature of the core-shell POM clusters, we show, at both the molecular and device level, that embedding [[[(Se(IV)[O.sub.3]).sub.2]].sup.4-] as an oxidizable dopant in the cluster core allows the oxidation of the molecule to a [[Se[(V).sub.2][O.sub.6]].sup.2-] moiety containing a {Se(v)-Se(v)} bond (where curly brackets indicate a moiety, not a molecule) and reveals a new 51 oxidation state for selenium. This new oxidation state can be observed at the device level, resulting in a new type of memory, which we call 'write-once-erase'. Taken together, these results show that POMs have the potential to be used as a realistic nanoscale flash memory. Also, the configuration of the doped POM core may lead to new types of electrical behaviour (9-11). This work suggests a route to the practical integration of configurable molecules in MOS technologies as the lithographic scales approach the molecular limit (12)., To engineer the flash memory devices, we selected a core-shell POM 'Dawson-like' archetype as the functional part of the switching node with the general formula [[[M.sub.18][O.sub.54][(X[O.sub.n]).sup.2]].sup.m-] (where M = Mo [...]

In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequence χ (Chi) (1,2) and is catalysed by either an AddAB- or RecBCD-type helicase-nuclease (reviewed in refs 3, 4). These enzyme complexes unwind and digest the DNA duplex from the broken end until they encounter a χ sequence (5), whereupon they produce a 3' single-stranded DNA tail onto which they initiate loading of the RecA protein (6). Consequently, regulation of the AddAB/ RecBCD complex by χ is a key control point in DNA repair and other processes involving genetic recombination. Here we report crystal structures of Bacillus subtilis AddAB in complex with different χ-containing DNA substrates either with or without a non-hydrolysable ATP analogue. Comparison of these structures suggests a mechanism for DNA translocation and unwinding, suggests how the enzyme binds specifically to χ sequences, and explains how χ recognition leads to the arrest of AddAB (and RecBCD) translocation that is observed in single-molecule experiments (7-9)., We have previously determined the crystal structures of initiation complexes of AddAB and RecBCD bound to a DNA end (10,11). We have now crystallized AddAB in a translocation-like state by [...]

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy (1). New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies (2). Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity invivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology (3). This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases., Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice results in [CD8.sup.+] T-cell-mediated rejection of primary tumours in several different models (4-6). In a control [...]

CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis (1). The ~120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamilyofsmall GTPases, nuclear lamins, the γ-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases (2). The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (3) (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum (4,5). Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane α-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located ~10 Å into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane α-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs., Reel is a type II CAAX prenyl endopeptidase that was first identified in Saccharomyces cerevisiae together with the type I CAAX-processing enzyme, Ste24p (also known as ZMPSTE24 or Afc1p) (4,6). [...]

Author(s): P. J. Talling (corresponding author) [1]; R. B. Wynn [2]; D. G. Masson [2]; M. Frenz [2]; B. T. Cronin [3]; R. Schiebel [2]; A. M. Akhmetzhanov [2]; S. [...]

The history of the Arctic Ocean during the Cenozoic era (0-65 million years ago) is largely unknown from direct evidence. Here we present a Cenozoic palaeoceanographic record constructed from >400 m of sediment core from a recent drilling expedition to the Lomonosov ridge in the Arctic Ocean. Our record shows a palaeoenvironmental transition from a warm 'greenhouse' world, during the late Palaeocene and early Eocene epochs, to a colder 'icehouse' world influenced by sea ice and icebergs from the middle Eocene epoch to the present. For the most recent ~14 Myr, we find sedimentation rates of 1-2 cm per thousand years, in stark contrast to the substantially lower rates proposed in earlier studies; this record of the Neogene reveals cooling of the Arctic that was synchronous with the expansion of Greenland ice (~3.2 Myr ago) and East Antarctic ice (~14 Myr ago). We find evidence for the first occurrence of ice-rafted debris in the middle Eocene epoch (~45 Myr ago), some 35 Myr earlier than previously thought; fresh surface waters were present at ~49 Myr ago, before the onset of ice-rafted debris. Also, the temperatures of surface waters during the Palaeocene/Eocene thermal maximum (~55 Myr ago) appear to have been substantially warmer than previously estimated. The revised timing of the earliest Arctic cooling events coincides with those from Antarctica, supporting arguments for bipolar symmetry in climate change. The Cenozoic Arctic Ocean Little was known about the environmental history of the Arctic Ocean before the 2004 ACEX ocean drilling expedition. Now a 430-metre sea floor sediment core has been recovered and its analysis, reported this week, provides a 56-million-year climate record spanning the transition from a warm 'greenhouse' to a colder 'icehouse' world. Several key events are identified during the Cenozoic: surface waters during the Palaeocene/Eocene thermal maximum (55 million years ago) were much warmer than previous estimates; surface-water freshening confirms an intensified hydrological cycle about 49 million years ago; and the first ice-rafted debris occurred 45 million years ago, 35 million years earlier than was thought. The revised timings for the earliest Arctic cooling events coincide with those for Antarctica, supporting suggestions that global climate changed symmetrically about the poles. Analysis of Arctic Ocean sediment core spanning more than 50 million years identifies several key features of Arctic climate history -- the revised timing of the earliest Arctic cooling events implied by this record coincides with those from Antarctica, supporting arguments that climate change is symmetric about the Earth's polar regions., Author(s): Kathryn Moran [sup.1] [sup.31] , Jan Backman [sup.2] , Henk Brinkhuis [sup.3] , Steven C. Clemens [sup.4] , Thomas Cronin [sup.5] , Gerald R. Dickens [sup.6] , Frédérique Eynaud [...]

Author(s): Jeremy Field (corresponding author) [1]; Adam Cronin [1]; Catherine Bridge [1] Helpers in primitively eusocial and cooperatively breeding animal societies forfeit their own reproduction to rear the offspring of [...]

Author(s): Laura N. Borodinsky (corresponding author); Cory M. Root; Julia A. Cronin; Sharon B. Sann; Xiaonan Gu; Nicholas C. Spitzer The determination of neuronal phenotypes is a substantial developmental challenge, [...]

CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clpl ([Clp1.sup.K/K]) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues [Clp1.sup.K/K] mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53., RNA molecules undergo co- and post-transcriptional processing, leading to mature, functional RNAs. In mammals and archaea CLP1 proteins are kinases that phosphorylate the 5' hydroxyl ends of RNA (1-3). Human [...]

Type IV secretion systems are secretion nanomachines spanning the two membranes of Gram-negative bacteria. Three proteins, Vir137, Vir139 and VirB10, assemble into a 1.05 megadalton (MDa) core spanning the inner and outer membranes. This core consists of 14 copies of each of the proteins and forms two layers, the I and O layers, inserting in the inner and outer membrane, respectively. Here we present the crystal structure of a ~0.6 MDa outer-membrane complex containing the entire O layer. This structure is the largest determined for an outer-membrane channel and is unprecedented in being composed of three proteins. Unexpectedly, this structure identifies VirB10 as the outer-membrane channel with a unique hydrophobic double-helical transmembrane region. This structure establishes VirB10 as the only known protein crossing both membranes of Gram-negative bacteria. Comparison of the cryo-electron microscopy (cryo-EM) and crystallographic structures points to conformational changes regulating channel opening and closing., Type IV secretion (T4S) systems are used by Gram-negative bacteria in a variety of processes, ranging from the delivery of virulence factors into eukaryotic cells to conjugative transfer of genetic [...]

Author(s): Mark Pagani (corresponding author) [1, 7]; Nikolai Pedentchouk [1, 7]; Matthew Huber [2, 7]; Appy Sluijs [3]; Stefan Schouten [4]; Henk Brinkhuis [3]; Jaap S. Sinninghe Damsté [4, 5]; [...]

Author(s): L. Eichinger [1, 23]; J. A. Pachebat [1, 2, 23]; G. Glöckner [3, 23]; M.-A. Rajandream [4, 23]; R. Sucgang [5, 23]; M. Berriman [4]; J. Song [5]; R. [...]

An Amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Shane J. F. Cronin [sup.1] [sup.2] [sup.3] , Corey Seehus [sup.2] [sup.3] , Adelheid Weidinger [sup.4] , Sebastien Talbot [sup.2] [sup.3] [sup.5] , Sonja Reissig [sup.6] , Markus Seifert [...]

Author(s): N. Hall (corresponding author) [1]; A. Pain [1]; M. Berriman [1]; C. Churcher [1]; B. Harris [1]; D. Harris [1]; K. Mungall [1]; S. Bowman [1, 2]; R. Atkin [...]

Author(s): S. D. Bentley (corresponding author) [1]; K. F. Chater [2]; A.-M. Cerdeño-Tárraga [1]; G. L. Challis [2, 3]; N. R. Thomson [1]; K. D. James [1]; D. E. Harris [...]

Author(s): V. Wood [1]; R. Gwilliam [1]; M.-A. Rajandream (corresponding author) [1]; M. Lyne [1]; R. Lyne [1]; A. Stewart [2]; J. Sgouros [2]; N. Peat [3]; J. Hayles [3]; [...]

The chemical structure formatting in Fig. 5 has been corrected online., Author(s): Jaroslaw M. Granda [sup.1] , Liva Donina [sup.1] , Vincenza Dragone [sup.1] , De-Liang Long [sup.1] , Leroy Cronin [sup.1] Author Affiliations:(1) School of Chemistry, University of Glasgow, Glasgow, [...]

Author(s): J. Parkhill (corresponding author) [1]; G. Dougan (corresponding author) [2]; K. D. James [1]; N. R. Thomson [1]; D. Pickard [2]; J. Wain [2]; C. Churcher [1]; K. L. [...]

Author(s): J. Parkhill (corresponding author) [1]; B. W. Wren [2]; N. R. Thomson [1]; R. W. Titball [3]; M. T. G. Holden [1]; M. B. Prentice [4]; M. Sebaihia [1]; [...]

It has been possible to identify the sequence of chromosome 2 from the Columbia ecotype of Arabidopsis thaliana in two gap-free assemblies of 3.6 Mb and 16 Mb. The two assemblies terminate in blocks of 180-bp repeats, with the repeats representing the inner boundaries of the completed sequence. Within the genetically defined centromere, there is a stretch of 270 kb of sequence that is almost identical to that of the Arabidopsis mitochondrial gene. It cannot be established whether the observed sequence polymorphisms are the result of divergence of the insertion from the mitochondrial genome or of differences among ecotypes.

Pliocene deep-sea North Atlantic benthic ostracod species diversity has been found to be associated to solar insolation changes caused by 41,000-yr cycles of Earth's obliquity. There is also a correlation between temporal changes in diversity and independent climate indicators of benthic foraminiferal oxygen-isotope ratios and ostracod Mg:Ca ratios. There was no support for the stability-time hypothesis in relation to control of deep-sea benthic diversity by cyclic climate change at timescales of 10(super 3)-10(super 4)yr.

Author(s): Robert N. Jinks (corresponding author) [1]; Tara L. Markley [1]; Elizabeth E. Taylor [1]; Gina Perovich [2]; Ana I. Dittel [2]; Charles E. Epifanio [2]; Thomas W. Cronin [3] [...]

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.Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages. [ABSTRACT FROM AUTHOR]