LFA-1 Engagement Triggers T Cell Polarization at the HIV-1 Virological Synapse

HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined. Here, we use a reductionist bead-coupled antibody assay as a model of the VS and show that cross-linking the integrin LFA-1 alone is sufficient to induce active T cell polarization and recruitment of the microtubule organizing center (MTOC) in HIV-1-infected cells. Mutant cell lines coupled with inhibitors demonstrated that LFA-1-induced polarization was dependent on the T cell kinase ZAP70. Notably, immunofluorescent staining of viral proteins revealed an accumulation of surface Env at sites of LFA-1 engagement, with intracellular Env localized to a Golgi compartment proximal to the polarized MTOC. Furthermore, blocking LFA-1-induced MTOC polarization through ZAP70 inhibition prevented intracellular Env polarization. Taken together, these data reveal that LFA-1 is a key determinant in inducing dynamic T cell remodeling to the VS and suggest a model in which LFA-1 engagement triggers active polarization of the MTOC and the associated Env-containing secretory apparatus to sites of cell-cell contact to support polarized viral assembly and egress for efficient cell-cell spread. IMPORTANCE: HIV-1 causes AIDS by spreading within immune cells and depletion of CD4 T lymphocytes. Rapid spread between these cells occurs by highly efficient cell-cell transmission that takes place at virological synapses (VS). VS are characterized by striking T cell remodeling that is spatially associated with polarized virus assembly and budding at sites of cell contact. Here, we show that the integrin LFA-1 triggers organelle polarization and viral protein recruitment, facilitating formation of the VS, and that this requires the T cell kinase ZAP70. Taken together, these data suggest a mechanism by which HIV-1-infected T cells sense and respond to cell contact to polarize viral egress and promote cell-cell spread. Understanding how cell-cell spread is regulated may help reveal therapeutic targets to specifically block this mode of HIV-1 dissemination

Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies

OBJECTIVE: To summarise the evidence of associations between dietary factors and incidence of type 2 diabetes and to evaluate the strength and validity of these associations. DESIGN: Umbrella review of systematic reviews with meta-analyses of prospective observational studies. DATA SOURCES: PubMed, Web of Science, and Embase, searched up to August 2018. ELIGIBILITY CRITERIA: Systematic reviews with meta-analyses reporting summary risk estimates for the associations between incidence of type 2 diabetes and dietary behaviours or diet quality indices, food groups, foods, beverages, alcoholic beverages, macronutrients, and micronutrients. RESULTS: 53 publications were included, with 153 adjusted summary hazard ratios on dietary behaviours or diet quality indices (n=12), food groups and foods (n=56), beverages (n=10), alcoholic beverages (n=12), macronutrients (n=32), and micronutrients (n=31), regarding incidence of type 2 diabetes. Methodological quality was high for 75% (n=115) of meta-analyses, moderate for 23% (n=35), and low for 2% (n=3). Quality of evidence was rated high for an inverse association for type 2 diabetes incidence with increased intake of whole grains (for an increment of 30 g/day, adjusted summary hazard ratio 0.87 (95% confidence interval 0.82 to 0.93)) and cereal fibre (for an increment of 10 g/day, 0.75 (0.65 to 0.86)), as well as for moderate intake of total alcohol (for an intake of 12-24 g/day v no consumption, 0.75 (0.67 to 0.83)). Quality of evidence was also high for the association for increased incidence of type 2 diabetes with higher intake of red meat (for an increment of 100 g/day, 1.17 (1.08 to 1.26)), processed meat (for an increment of 50 g/day, 1.37 (1.22 to 1.54)), bacon (per two slices/day, 2.07 (1.40 to 3.05)), and sugar sweetened beverages (for an increase of one serving/day, 1.26 (1.11 to 1.43)). CONCLUSIONS: Overall, the association between dietary factors and type 2 diabetes has been extensively studied, but few of the associations were graded as high quality of evidence. Further factors are likely to be important in type 2 diabetes prevention; thus, more well conducted research, with more detailed assessment of diet, is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018088106

Analysis of motoneuron responses to composite synaptic volleys (computer simulation study)

This paper deals with the analysis of changes in motoneuron (MN) firing evoked by repetitively applied stimuli aimed toward extracting information about the underlying synaptic volleys. Spike trains were obtained from computer simulations based on a threshold-crossing model of tonically firing MN, subjected to stimulation producing postsynaptic potentials (PSPs) of various parameters. These trains were analyzed as experimental results, using the output measures that were previously shown to be most effective for this purpose: peristimulus time histogram, raster plot and peristimulus time intervalgram. The analysis started from the effects of single excitatory and inhibitory PSPs (EPSPs and IPSPs). The conclusions drawn from this analysis allowed the explanation of the results of more complex synaptic volleys, i.e., combinations of EPSPs and IPSPs, and the formulation of directions for decoding the results of human neurophysiological experiments in which the responses of tonically firing MNs to nerve stimulation are analyzed

Genetically Engineered Phages: a Review of Advances over the Last Decade

Summary: Soon after their discovery in the early 20th century, bacteriophages were recognized to have great potential as antimicrobial agents, a potential that has yet to be fully realized. The nascent field of phage therapy was adversely affected by inadequately controlled trials and the discovery of antibiotics. Although the study of phages as anti-infective agents slowed, phages played an important role in the development of molecular biology. In recent years, the increase in multidrug-resistant bacteria has renewed interest in the use of phages as antimicrobial agents. With the wide array of possibilities offered by genetic engineering, these bacterial viruses are being modified to precisely control and detect bacteria and to serve as new sources of antibacterials. In applications that go beyond their antimicrobial activity, phages are also being developed as vehicles for drug delivery and vaccines, as well as for the assembly of new materials. This review highlights advances in techniques used to engineer phages for all of these purposes and discusses existing challenges and opportunities for future work.D.P.P. acknowledges financial support from the Portuguese Foundation for Science and Technology (FCT) through grant SFRH/BD/76440/2011. This work was funded by The Center for Microbiome Informatics and Therapeutics and NSF Expeditions in Computing Program award #1522074 as part of the Living Computing Project. This work was further supported by grants from the Defense Threat Reduction Agency (grants HDTRA1-14-1-0007 and HDTRA1-15-1-0050), the National Institutes of Health (grants 1DP2OD008435,1P50GM098792,1R01EB017755, and 1R21AI12166901), and the U.S. Army Research Laboratory and U.S. Army Research Office, through the Institute for Soldier Nanotechnologies, under contract number W911NF-13-D-0001.S.S.is an FCT investigator (IF/01413/2013). D.P.P., S.S., and J.A. also acknowledge financial support from FCT under the scope of the strategic funding of the UID/ BIO/04469/2013 unit and COMPETE 2020 (grant POCI-01-0145FEDER-006684). T.K.L. is a founder of Sample6 Inc. and Eligo Biosciences, two companies developing phage-based technologies

Searches for Gravitational Waves from Binary Neutron Stars: A Review

A new generation of observatories is looking for gravitational waves. These waves, emitted by highly relativistic systems, will open a new window for ob- servation of the cosmos when they are detected. Among the most promising sources of gravitational waves for these observatories are compact binaries in the final min- utes before coalescence. In this article, we review in brief interferometric searches for gravitational waves emitted by neutron star binaries, including the theory, instru- mentation and methods. No detections have been made to date. However, the best direct observational limits on coalescence rates have been set, and instrumentation and analysis methods continue to be refined toward the ultimate goal of defining the new field of gravitational wave astronomy.Comment: 30 pages, 5 Figures, to appear in "Short-Period Binary Stars: Observations, Analyses, and Results", Ed.s Eugene F. Milone, Denis A. Leahy, David W. Hobil

Entanglement of spin waves among four quantum memories

Quantum networks are composed of quantum nodes that interact coherently by way of quantum channels and open a broad frontier of scientific opportunities. For example, a quantum network can serve as a `web' for connecting quantum processors for computation and communication, as well as a `simulator' for enabling investigations of quantum critical phenomena arising from interactions among the nodes mediated by the channels. The physical realization of quantum networks generically requires dynamical systems capable of generating and storing entangled states among multiple quantum memories, and of efficiently transferring stored entanglement into quantum channels for distribution across the network. While such capabilities have been demonstrated for diverse bipartite systems (i.e., N=2 quantum systems), entangled states with N > 2 have heretofore not been achieved for quantum interconnects that coherently `clock' multipartite entanglement stored in quantum memories to quantum channels. Here, we demonstrate high-fidelity measurement-induced entanglement stored in four atomic memories; user-controlled, coherent transfer of atomic entanglement to four photonic quantum channels; and the characterization of the full quadripartite entanglement by way of quantum uncertainty relations. Our work thereby provides an important tool for the distribution of multipartite entanglement across quantum networks.Comment: 4 figure

Supernumerary, ectopic tooth in the maxillary antrum presenting with recurrent haemoptysis

<p>Abstract</p> <p>Background</p> <p>Ectopic eruption of teeth in non-dental sites is a rare phenomenon and can present in a variety of ways such as chronic or recurrent sinusitis, sepsis, nasolacrimal duct obstruction, headaches, ostiomeatal complex disease and facial numbness. However, presentation of such patients with recurrent haemoptysis has not been described in the literature so far. We have described a case of an ectopic, supernumerary molar tooth in the maxillary antrum in a patient who initially presented with haemoptysis.</p> <p>Case presentation</p> <p>A 45-year-old male presented with a 2-month history of episodic haemoptysis. A pedunculated growth from the inferior nasal turbinate was seen with fibre-optic visualization. Although the patient was empirically started on antibiotic and anti-allergic therapy, there was no improvement after a few weeks and the patient had recurrent episodes of haemoptysis. Fibre-optic visualization was repeated showing bilateral osteomeatal erythema. Computed tomography scan of the paranasal sinuses demonstrated complete opacification of the left maxillary antrum along with a focal area of density comparable to bone. An ectopic, supernumerary molar tooth was found in the left maxillary antrum on endoscopic examination and subsequently removed. In addition, copious purulent discharge was seen. Post-operatively, the patient was treated with a 10-day course of oral amoxicillin-clavulanate. On follow-up, he reported resolution of symptoms.</p> <p>Conclusion</p> <p>Recurrent haemoptysis has not been described as a presentation for a supernumerary, ectopic tooth in literature before. We recommend that in patients with sinusitis-type of opacification of maxillary antrum and whose condition is refractory to conventional medical treatment, consideration should be given to the investigation of possible underlying anomalies as the cause of such symptoms. Presence of foreign bodies and ectopic teeth in paranasal sinuses can be reliably excluded with the use of appropriate radiological imaging and endoscopic examination.</p

Intrinsic gain modulation and adaptive neural coding

In many cases, the computation of a neural system can be reduced to a receptive field, or a set of linear filters, and a thresholding function, or gain curve, which determines the firing probability; this is known as a linear/nonlinear model. In some forms of sensory adaptation, these linear filters and gain curve adjust very rapidly to changes in the variance of a randomly varying driving input. An apparently similar but previously unrelated issue is the observation of gain control by background noise in cortical neurons: the slope of the firing rate vs current (f-I) curve changes with the variance of background random input. Here, we show a direct correspondence between these two observations by relating variance-dependent changes in the gain of f-I curves to characteristics of the changing empirical linear/nonlinear model obtained by sampling. In the case that the underlying system is fixed, we derive relationships relating the change of the gain with respect to both mean and variance with the receptive fields derived from reverse correlation on a white noise stimulus. Using two conductance-based model neurons that display distinct gain modulation properties through a simple change in parameters, we show that coding properties of both these models quantitatively satisfy the predicted relationships. Our results describe how both variance-dependent gain modulation and adaptive neural computation result from intrinsic nonlinearity.Comment: 24 pages, 4 figures, 1 supporting informatio

Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation.

Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation