Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and cerine residues in the Epstein-Barr Virus lytic switch protein

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with various malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma. Like all herpesviruses, the EBV life cycle alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and, in the switch to the lytic cycle, this epigenetic silencing is overturned. A key event is the activation of the viral BRLF1 gene by the immediate-early protein Zta. Zta is a bZIP transcription factor that preferentially binds to specific response elements (ZREs) in the BRLF1 promoter (Rp) when these elements are methylated. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. The mutant is compromised both in vitro and in vivo for binding two methylated ZREs in Rp (ZRE2 and ZRE3), although the effect is striking only for ZRE3. Molecular modeling of Zta bound to methylated ZRE3, together with biochemical data, indicate that C189 directly contacts one of the two methyl cytosines within a specific CpG motif. The motif's second methyl cytosine (on the complementary DNA strand) is predicted to contact S186, a residue known to regulate methyl-ZRE recognition. Our results suggest that C189 regulates the enhanced interaction of Zta with methylated DNA in overturning the epigenetic control of viral latency. As C189 is conserved in many bZIP proteins, the selectivity of Zta for methylated DNA may be a paradigm for a more general phenomenon

Connectivity-based parcellation of the thalamus explains specific cognitive and behavioural symptoms in patients with bilateral thalamic infarct

A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1-weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients' lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.'s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.'s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient's frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns

Controls on gut phosphatisation : the trilobites from the Weeks Formation Lagerstätte (Cambrian; Utah)

Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace

Microfluidic impedance biosensors for monitoring a single and multiple cancer cells in anticancer drug treatments

In this work, we present a novel microfluidic impedance biosensor chip for trapping both a single and multiple cancer cells and monitoring their response to the anti-cancer drug treatment. By designing different sizes of working microelectrodes together with the V-shaped cell capture structures, a single or multiple cells are trapped on the microelectrodes surfaces. In addition, by utilizing the passive pumping method, cells can be trapped and positioned inside the microchannels without the need of using the outer micro pump or syringe. The impedance change induced by the response of cells to the anticancer drug Cisplatin treatment was successfully recorded. The proposed biosensor chip has a great potential for applications in cancer cell research, drug screening, and quantification of cancer cells from various tumor stages. The results of this study open potential research collaborations about development of cost-effective devices and lab-on-chips for early disease detection, studies of cancerous cells and their response to anti-cancer drugs to optimize cancer treatments, characterisation of mechanical properties of cells, new drug delivery mechanisms, and micro and nano manufacturing

Determinants of postnatal spleen tissue regeneration and organogenesis

Abstract The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases

Priming by Chemokines Restricts Lateral Mobility of the Adhesion Receptor LFA-1 and Restores Adhesion to ICAM-1 Nano-Aggregates on Human Mature Dendritic Cells

LFA-1 is a leukocyte specific β2 integrin that plays a major role in regulating adhesion and migration of different immune cells. Recent data suggest that LFA-1 on mature dendritic cells (mDCs) may function as a chemokine-inducible anchor during homing of DCs through the afferent lymphatics into the lymph nodes, by transiently switching its molecular conformational state. However, the role of LFA-1 mobility in this process is not yet known, despite that the importance of lateral organization and dynamics for LFA-1-mediated adhesion regulation is broadly recognized. Using single particle tracking approaches we here show that LFA-1 exhibits higher mobility on resting mDCs compared to monocytes. Lymphoid chemokine CCL21 stimulation of the LFA-1 high affinity state on mDCs, led to a significant reduction of mobility and an increase on the fraction of stationary receptors, consistent with re-activation of the receptor. Addition of soluble monomeric ICAM-1 in the presence of CCL21 did not alter the diffusion profile of LFA-1 while soluble ICAM-1 nano-aggregates in the presence of CCL21 further reduced LFA-1 mobility and readily bound to the receptor. Overall, our results emphasize the importance of LFA-1 lateral mobility across the membrane on the regulation of integrin activation and its function as adhesion receptor. Importantly, our data show that chemokines alone are not sufficient to trigger the high affinity state of the integrin based on the strict definition that affinity refers to the adhesion capacity of a single receptor to its ligand in solution. Instead our data indicate that nanoclustering of the receptor, induced by multi-ligand binding, is required to maintain stable cell adhesion once LFA-1 high affinity state is transiently triggered by inside-out signals.Peer ReviewedPostprint (published version

Narcissism and prosocial behavior

There are many motivations for prosocial behavior, some more altruistic and some more egoistic. We posit that more narcissistic people may perform prosocial acts strategically, for example, to improve their reputations or to receive something in return

Search for Pair-Produced Resonances Decaying to Quark Pairs in Proton-Proton Collisions at √s = 13 TeV

A general search for the pair production of resonances, each decaying to two quarks, is reported. The search is conducted separately for heavier resonances (masses above 400 GeV), where each of the four final-state quarks generates a hadronic jet resulting in a four-jet signature, and for lighter resonances (masses between 80 and 400 GeV), where the pair of quarks from each resonance is collimated and reconstructed as a single jet resulting in a two-jet signature. In addition, a b-tagged selection is applied to target resonances with a bottom quark in the final state. The analysis uses data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 35.9  fb⁻¹, from proton-proton collisions at a center-of-mass energy of 13 TeV. The mass spectra are analyzed for the presence of new resonances, and are found to be consistent with standard model expectations. The results are interpreted in the framework of R-parity-violating supersymmetry assuming the pair production of scalar top quarks decaying via the hadronic coupling λ′′312 or λ′′323 and upper limits on the cross section as a function of the top squark mass are set. These results probe a wider range of masses than previously explored at the LHC, and extend the top squark mass limits in the ˜t→qq′ scenario

Digital Signal Processing

Contains summary of research and reports on sixteen research projects.U.S. Navy - Office of Naval Research (Contract N00014-75-C-0852)National Science Foundation FellowshipNATO FellowshipU.S. Navy - Office of Naval Research (Contract N00014-75-C-0951)National Science Foundation (Grant ECS79-15226)U.S. Navy - Office of Naval Research (Contract N00014-77-C-0257)Bell LaboratoriesNational Science Foundation (Grant ECS80-07102)Schlumberger-Doll Research Center FellowshipHertz Foundation FellowshipGovernment of Pakistan ScholarshipU.S. Navy - Office of Naval Research (Contract N00014-77-C-0196)U.S. Air Force (Contract F19628-81-C-0002)Hughes Aircraft Company Fellowshi

Search for Standard Model Production of Four Top Quarks with Same-Sign and Multilepton Final States in Proton–proton Collisions at √s = 13 TeV

A search for standard model production of four top quarks (tt¯tt¯) is reported using events containing at least three leptons (e,μ) or a same-sign lepton pair. The events are produced in proton–proton collisions at a center-of-mass energy of 13TeV at the LHC, and the data sample, recorded in 2016, corresponds to an integrated luminosity of 35.9fb[superscript −1]. Jet multiplicity and flavor are used to enhance signal sensitivity, and dedicated control regions are used to constrain the dominant backgrounds. The observed and expected signal significances are, respectively, 1.6 and 1.0 standard deviations, and the tt¯tt¯ cross section is measured to be 16.9[superscript +13.8][subscript −11.4] fb, in agreement with next-to-leading-order standard model predictions. These results are also used to constrain the Yukawa coupling between the top quark and the Higgs boson to be less than 2.1 times its expected standard model value at 95% confidence level