Glass Beads in Iron Age Britain: a social approach

Studies of Iron Age artefacts from Britain tend to be dominated either by the study of metalwork, or pottery. This thesis presents a study not only of a different material, but also a different type of object: glass beads. These are found in a range of different sizes, shapes, colours, and employ a variety of different decorative motifs. Thus far, glass beads have been studied through typology (Guido 1978a) and compositional analysis (Bertini 2012; Henderson 1982), yet a thorough analysis of the social context of glass beads remains absent. Through an analysis of glass beads from four key study regions in Britain, this thesis aims not only to address regional differences in appearance and chronology, but also to explore the role that this object played within the networks and relationships that constructed Iron Age society. It seeks to understand how they were used during their lives and how they came to be deposited within the archaeological record, in order to establish the social processes that glass beads were bound within. The results indicate that glass beads were a strongly regionalised artefact, potentially reflecting differing local preferences for colour and motif. In addition, glass beads, in combination with several other types of object, were integral to Middle Iron Age dress. Given that the first century BC is often seen as a turning point in terms of settlements and material culture, this supports the possibility of strong continental exchange during an earlier period for either glass beads or raw materials. However, by the Late Iron Age in the first century BC and early first century AD, their use had severely diminished

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

CD4 and CD8 T cell proliferation and differentiation in response to Listeria monocytogenes infection

Mounting evidence suggests that the mechanisms that regulate T cell proliferation, acquisition of effector function, and memory cell formation and maintenance are different for CD4 and CD8 T cells. We compared the proliferation of adoptively transferred TCR transgenic CD4 and CD8 T cells in response to Listeria monocytogenes (LM) infection and found that CD4 T cells undergo limited division, differentiation, and clonal expansion in comparison to CD8 T cells. To further investigate these differences, we developed an adoptive transfer system that enables the visualization of primary polyclonal T cell responses. Surprisingly, we observed a difference in the extent of division between transferred monoclonal CD4 T cells and polyclonal CD4 T cells in response to LM infection. Adoptively transferred TCR transgenic CD4 T cells divided a limited number of times in response to LM infection while transferred CD4 T cells from C57BL/6 mice divided extensively under the same infection conditions. Titration of transferred TCR transgenic CD4 T cells revealed that reducing the precursor frequency increased the mean number of divisions underwent by these cells and increased the percent of responding CD4 T cells that differentiated into effector CD4 T cells as determined by IFN-γ secretion. Moreover, the transfer of a low number of naive TCR transgenic CD4 T cells provided better protection against LM infection in the liver than the transfer of a large number of the same cells. In contrast, adoptively transferred TCR transgenic CD8 T cells and polyclonal CD8 T cells from C57BL/6 mice both divided and differentiated extensively following infection. Thus, clonal competition induced by abnormally high precursor frequencies limits the extent of division and differentiation of CD4 T cells more than CD8 T cells. These results also show that CD4 T cell division and differentiation is quite extensive in response to LM infection and that the adoptive transfer of TCR transgenic CD4 T cells may underestimate the extent of a natural CD4 T cell response. However, despite this robust response, our data indicates that CD4 T cells provide only limited protection against LM infection in comparison to CD8 T cells

CD4 and CD8 T cell proliferation and differentiation in response to Listeria monocytogenes infection

Mounting evidence suggests that the mechanisms that regulate T cell proliferation, acquisition of effector function, and memory cell formation and maintenance are different for CD4 and CD8 T cells. We compared the proliferation of adoptively transferred TCR transgenic CD4 and CD8 T cells in response to Listeria monocytogenes (LM) infection and found that CD4 T cells undergo limited division, differentiation, and clonal expansion in comparison to CD8 T cells. To further investigate these differences, we developed an adoptive transfer system that enables the visualization of primary polyclonal T cell responses. Surprisingly, we observed a difference in the extent of division between transferred monoclonal CD4 T cells and polyclonal CD4 T cells in response to LM infection. Adoptively transferred TCR transgenic CD4 T cells divided a limited number of times in response to LM infection while transferred CD4 T cells from C57BL/6 mice divided extensively under the same infection conditions. Titration of transferred TCR transgenic CD4 T cells revealed that reducing the precursor frequency increased the mean number of divisions underwent by these cells and increased the percent of responding CD4 T cells that differentiated into effector CD4 T cells as determined by IFN-γ secretion. Moreover, the transfer of a low number of naive TCR transgenic CD4 T cells provided better protection against LM infection in the liver than the transfer of a large number of the same cells. In contrast, adoptively transferred TCR transgenic CD8 T cells and polyclonal CD8 T cells from C57BL/6 mice both divided and differentiated extensively following infection. Thus, clonal competition induced by abnormally high precursor frequencies limits the extent of division and differentiation of CD4 T cells more than CD8 T cells. These results also show that CD4 T cell division and differentiation is quite extensive in response to LM infection and that the adoptive transfer of TCR transgenic CD4 T cells may underestimate the extent of a natural CD4 T cell response. However, despite this robust response, our data indicates that CD4 T cells provide only limited protection against LM infection in comparison to CD8 T cells