The unfolding body plan of primate embryos in culture.

Improved culture of non-human primate embryos reveals the establishment of the crucial framework for subsequent development of bodily tissues and the germline in fetuses, bringing us closer to comprehending the elusive development of early human embryos

G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst

Early mouse development is regulated and accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2). Previously, we provided insights into its role in post-implantation development (Zylicz et al., 2015). Here we explore the impact of depleting the maternally inherited G9a in oocytes on development shortly after fertilisation. We show that G9a accumulates typically at 4 to 8-cell stage to promote timely repression of a subset of 4-cell stage-specific genes. Loss of maternal inheritance of G9a disrupts the gene regulatory network resulting in developmental delay and destabilisation of inner cell mass lineages by the late blastocyst stage. Our results indicate a vital role of this maternally inherited epigenetic regulator in creating conducive conditions for developmental progression and on cell fate choices.Wellcome Trust/CRUK Gurdon Institute, University of Cambridge Wellcome Trust/Medical Research Council, Stem Cell Institute, University of Cambridg

Testing the role of SOX15 in human primordial germ cell fate.

Background: Potentially novel regulators of early human germline development have been identified recently, including SOX15 and SOX17, both of which show specific expression in human primordial germ cells. SOX17 is now known to be a critical specifier of human germ cell identity. There have been suggestions, as yet without evidence, that SOX15 might also play a prominent role. The early human germline is inaccessible for direct study, but an in vitro model of human primordial germ cell-like cell (hPGCLC) specification from human embryonic stem cells (hESCs) has been developed. This enables mechanistic study of human germ cell specification using genetic tools to manipulate the levels of SOX15 and SOX17 proteins to explore their roles in hPGCLC specification. Methods: SOX15 and SOX17 proteins were depleted during hPGCLC specification from hESCs using the auxin-inducible degron system, combined with a fluorescent reporter for tracking protein levels. Additionally, SOX15 protein was overexpressed using the ProteoTuner system. Protein-level expression changes were confirmed by immunofluorescence. The impact on hPGCLC specification efficiency was determined by flow cytometry at various time points. qPCR experiments were performed to determine some transcriptional effects of SOX15 perturbations. Results: We observed specific SOX15 expression in hPGCLCs by using immunofluorescence and flow cytometry analysis. Depletion of SOX15 had no significant effect on hPGCLC specification efficiency on day 4 after induction, but there was a significant and progressive decrease in hPGCLCs on days 6 and 8. By contrast, depletion of SOX17 completely abrogated hPGCLC specification. Furthermore, SOX15 overexpression resulted in a significant increase in hPGCLC fraction on day 8. qPCR analysis revealed a possible role for the germ cell and pluripotency regulator PRDM14 in compensating for changes to SOX15 protein levels. Conclusions: SOX17 is essential for hPGCLC specification, yet SOX15 is dispensable. However, SOX15 may have a role in maintaining germ cell identity

Thromboembolic Risk in Hospitalized and Nonhospitalized COVID-19 Patients: A Self-Controlled Case Series Analysis of a Nationwide Cohort.

OBJECTIVE: To assess the associations between coronavirus disease 2019 (COVID-19) infection and thromboembolism including myocardial infarction (MI), ischemic stroke, deep vein thrombosis (DVT), and pulmonary embolism (PE). PATIENTS AND METHODS: A self-controlled case-series study was conducted covering the whole of Scotland's general population. The study population comprised individuals with confirmed (positive test) COVID-19 and at least one thromboembolic event between March 2018 and October 2020. Their incidence rates during the risk interval (5 days before to 56 days after the positive test) and the control interval (the remaining periods) were compared intrapersonally. RESULTS: Across Scotland, 1449 individuals tested positive for COVID-19 and experienced a thromboembolic event. The risk of thromboembolism was significantly elevated over the whole risk period but highest in the 7 days following the positive test (incidence rate ratio, 12.01; 95% CI, 9.91 to 14.56) in all included individuals. The association was also present in individuals not originally hospitalized for COVID-19 (incidence rate ratio, 4.07; 95% CI, 2.83 to 5.85). Risk of MI, stroke, PE, and DVT were all significantly higher in the week following a positive test. The risk of PE and DVT was particularly high and remained significantly elevated even 56 days following the test. CONCLUSION: Confirmed COVID-19 infection was associated with early elevations in risk with MI, ischemic stroke, and substantially stronger and prolonged elevations with DVT and PE both in hospital and community settings. Clinicians should consider thromboembolism, especially PE, among people with COVID-19 in the community

Associations between childhood maltreatment and psychiatric disorders: analysis from electronic health records in Hong Kong

There has been a lack of high-quality evidence concerning the association between childhood maltreatment and psychiatric diagnoses particularly for Axis II disorders. This study aimed to examine the association between childhood maltreatment exposure and Axis I and Axis II psychiatry disorders using electronic health records. In this study, the exposed group (n = 7473) comprised patients aged 0 to 19 years with a first-time record of maltreatment episode between January 1, 2001 and December 31, 2010, whereas the unexposed group (n = 26,834) comprised individuals of the same gender and age who were admitted into the same hospital in the same calendar year and month but had no records of maltreatment in the Hong Kong Clinical Data Analysis and Reporting System (CDARS). Data on their psychiatric diagnoses recorded from the date of admission to January 31, 2019 were extracted. A Cox proportional hazard regression model was fitted to estimate the hazard ratio (HR, plus 95% CIs) between childhood maltreatment exposure and psychiatric diagnoses, adjusting for age at index visit, sex, and government welfare recipient status. Results showed that childhood maltreatment exposure was significantly associated with subsequent diagnosis of conduct disorder/ oppositional defiant disorder (adjusted HR, 10.99 [95% CI 6.36, 19.01]), attention deficit hyperactivity disorder (ADHD) (7.28 [5.49, 9.65]), and personality disorders (5.36 [3.78, 7.59]). The risk of psychiatric disorders following childhood maltreatment did not vary by history of childhood sexual abuse, age at maltreatment exposure, and gender. Individuals with a history of childhood maltreatment are vulnerable to psychiatric disorders. Findings support the provision of integrated care within the primary health care setting to address the long-term medical and psychosocial needs of individuals with a history of childhood maltreatment

Origin and segregation of the human germline

Acknowledgements This work was supported by the Wellcome Investigator Awards in Science (2094)75/Z/17/Z (to MA Surani), the Wellcome Investigator Awards in Science 096738/Z/11/Z (to MA Surani), the BBSRC research grant G103986 (to MA Surani), the Croucher Postdoctoral Research Fellowship (to WWC Tang), the Wellcome 4-Yr PhD Programme in Stem Cell Biology & Medicine (2038)31/Z/16/Z (to A Castillo-Venzor) and the Cambridge Commonwealth European and International Trust (to A Castillo-Venzor), the Isaac Newton Trust (to WWC Tang), the Butterfield Awards of Great Britain Sasakawa Foundation (to T Kobayashi and MA Surani), and the Astellas Foundation for Research on Metabolic Disorders (to T Kobayashi). The marmoset embryo research is generously supported by the Wellcome Trust (WT RG89228, WT RG9242), the Centre for Trophoblast Research, the Isaac Newton Trust, and JSPS KAKENHI 15H02360, 19H05759. TE Boroviak was supported by a Wellcome Sir Henry Dale Fellowship. JC Marioni acknowledges core support from EMBL and from Cancer Research UK (C9545/A29580), which supports MD Morgan. We would like to thank Roger Barker and Xiaoling He for providing human embryonic tissues and Charles Bradshaw for bioinformatics support. We also thank The Weizmann Institute of Science for the WIS2 human PSC line and the Genomics Core Facility of CRUK Cambridge Institute for sequencing services. We thank members of the Surani laboratory for insightful comments and critical reading of the manuscript.Peer reviewedPublisher PD

Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR

We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR −/−) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37°C for up to 9 days and displayed a terminal half-life (T1/2β) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that 125I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of' 111In-labelled ch806 was demonstrated with uptake of 31%ID g−1 and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Epigenetic resetting in the human germ line entails histone modification remodeling.

Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genes and transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCs exhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signatures at most genes and TEs and the acquisition of a neutral or paused epigenetic state without transcriptional activation. Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such as evolutionarily young TEs and some developmental genes, which require H3K9me3 and H3K27me3, respectively, for efficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presents an exemplary balanced system relying on local maintenance of heterochromatic features and a lack of inductive cues