Altered distribution of mucosal NK cells during HIV infection.

The human gut mucosa is a major site of human immunodeficiency virus (HIV) infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells have an important role in control of HIV infection, but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here, we show that two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (intraepithelial lymphocytes, IELs) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective killer immunoglobulin-like receptor/human leukocyte antigen genotypes. Both IEL and LP NK cells were significantly expanded in immunological non-responsive patients, who incompletely recovered CD4+ T cells on highly active antiretroviral therapy (HAART). These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T-cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut

PGB pair production at LHC and ILC as a probe of the topcolor-assisted technicolor models

The topcolor-assisted technicolor (TC2) model predicts some light pseudo goldstone bosons (PGBs), which may be accessible at the LHC or ILC. In this work we study the pair productions of the charged or neutral PGBs at the LHC and ILC. For the productions at the LHC we consider the processes proceeding through gluon-gluon fusion and quark-antiquark annihilation, while for the productions at the ILC we consider both the electron-positron collision and the photon-photon collision. We find that in a large part of parameter space the production cross sections at both colliders can be quite large compared with the low standard model backgrounds. Therefore, in future experiments these productions may be detectable and allow for probing TC2 model.Comment: 26 pages, 16 figures. slight changes in the text; notations for curves changed; references adde

Colored Resonant Signals at the LHC: Largest Rate and Simplest Topology

We study the colored resonance production at the LHC in a most general approach. We classify the possible colored resonances based on group theory decomposition, and construct their effective interactions with light partons. The production cross section from annihilation of valence quarks or gluons may be on the order of 400 - 1000 pb at LHC energies for a mass of 1 TeV with nominal couplings, leading to the largest production rates for new physics at the TeV scale, and simplest event topology with dijet final states. We apply the new dijet data from the LHC experiments to put bounds on various possible colored resonant states. The current bounds range from 0.9 to 2.7 TeV. The formulation is readily applicable for future searches including other decay modes.Comment: 29 pages, 9 figures. References updated and additional K-factors include

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Hyperthermia and cardiovascular strain during an extreme heat exposure in young versus older adults

We examined whether older individuals experience greater levels of hyperthermia and cardiovascular strain during an extreme heat exposure compared to young adults. During a 3-hour extreme heat exposure (44°C, 30% relative humidity), we compared body heat storage, core temperature (rectal, visceral) and cardiovascular (heart rate, cardiac output, mean arterial pressure, limb blood flow) responses of young adults (n = 30, 19-28 years) against those of older adults (n = 30, 55-73 years). Direct calorimetry measured whole-body evaporative and dry heat exchange. Body heat storage was calculated as the temporal summation of heat production (indirect calorimetry) and whole-body heat loss (direct calorimetry) over the exposure period. While both groups gained a similar amount of heat in the first hour, the older adults showed an attenuated increase in evaporative heat loss (p < 0.033) in the first 30-min. Thereafter, the older adults were unable to compensate for a greater rate of heat gain (11 ± 1 ; p < 0.05) with a corresponding increase in evaporative heat loss. Older adults stored more heat (358 ± 173 kJ) relative to their younger (202 ± 92 kJ; p < 0.001) counterparts at the end of the exposure leading to greater elevations in rectal (p = 0.043) and visceral (p = 0.05) temperatures, albeit not clinically significant (rise < 0.5°C). Older adults experienced a reduction in calf blood flow (p < 0.01) with heat stress, yet no differences in cardiac output, blood pressure or heart rate. We conclude, in healthy habitually active individuals, despite no clinically observable cardiovascular or temperature changes, older adults experience greater heat gain and decreased limb perfusion in response to 3-hour heat exposure

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

A review of information flow diagrammatic models for product-service systems

A product-service system (PSS) is a combination of products and services to create value for both customers and manufacturers. Modelling a PSS based on function orientation offers a useful way to distinguish system inputs and outputs with regards to how data are consumed and information is used, i.e. information flow. This article presents a review of diagrammatic information flow tools, which are designed to describe a system through its functions. The origin, concept and applications of these tools are investigated, followed by an analysis of information flow modelling with regards to key PSS properties. A case study of selection laser melting technology implemented as PSS will then be used to show the application of information flow modelling for PSS design. A discussion based on the usefulness of the tools in modelling the key elements of PSS and possible future research directions are also presented

LHC Predictions from a Tevatron Anomaly in the Top Quark Forward-Backward Asymmetry

We examine the implications of the recent CDF measurement of the top-quark forward-backward asymmetry, focusing on a scenario with a new color octet vector boson at 1-3 TeV. We study several models, as well as a general effective field theory, and determine the parameter space which provides the best simultaneous fit to the CDF asymmetry, the Tevatron top pair production cross section, and the exclusion regions from LHC dijet resonance and contact interaction searches. Flavor constraints on these models are more subtle and less severe than the literature indicates. We find a large region of allowed parameter space at high axigluon mass and a smaller region at low mass; we match the latter to an SU(3)xSU(3)/SU(3) coset model with a heavy vector-like fermion. Our scenario produces discoverable effects at the LHC with only 1-2 inverse femtobarns of luminosity at 7-8 TeV. Lastly, we point out that a Tevatron measurement of the b-quark forward-backward asymmetry would be very helpful in characterizing the physics underlying the top-quark asymmetry.Comment: 35 pages, 10 figures, 4 table

RG-improved single-particle inclusive cross sections and forward-backward asymmetry in ttˉt\bar t production at hadron colliders

We use techniques from soft-collinear effective theory (SCET) to derive renormalization-group improved predictions for single-particle inclusive (1PI) observables in top-quark pair production at hadron colliders. In particular, we study the top-quark transverse-momentum and rapidity distributions, the forward-backward asymmetry at the Tevatron, and the total cross section at NLO+NNLL order in resummed perturbation theory and at approximate NNLO in fixed order. We also perform a detailed analysis of power corrections to the leading terms in the threshold expansion of the partonic hard-scattering kernels. We conclude that, although the threshold expansion in 1PI kinematics is susceptible to numerically significant power corrections, its predictions for the total cross section are in good agreement with those obtained by integrating the top-pair invariant-mass distribution in pair invariant-mass kinematics, as long as a certain set of subleading terms appearing naturally within the SCET formalism is included.Comment: 55 pages, 14 figures, 6 table