Potential Application of Tregitopes as Immunomodulating Agents in Multiple Sclerosis

The induction of immunologic tolerance is an important clinical goal in autoimmunity. CD4+ regulatory T (Treg) cells, defined by the expression of the transcription factor forkhead box P3 (FoxP3), play a central role in the control of autoimmune responses. Quantitative and qualitative defects of Tregs have been postulated to contribute to failed immune regulation in multiple sclerosis (MS) and other autoimmune diseases. This paper highlights the potential uses of T regulatory cell epitopes (Tregitopes), natural Treg epitopes found to be contained in human immunoglobulins, as immunomodulating agents in MS. Tregitopes expand Treg cells and induce “adaptive Tregs” resulting in immunosuppression and, therefore, are being considered as a potential therapy for autoimmune diseases. We will compare Tregitopes versus intravenous immunoglobulin (IVIg) in the treatment of EAE with emphasis on the potential applications of Tregitope for the treatment of MS

Global Fluctuation Spectra in Big Crunch/Big Bang String Vacua

We study Big Crunch/Big Bang cosmologies that correspond to exact world-sheet superconformal field theories of type II strings. The string theory spacetime contains a Big Crunch and a Big Bang cosmology, as well as additional ``whisker'' asymptotic and intermediate regions. Within the context of free string theory, we compute, unambiguously, the scalar fluctuation spectrum in all regions of spacetime. Generically, the Big Crunch fluctuation spectrum is altered while passing through the bounce singularity. The change in the spectrum is characterized by a function $\Delta$, which is momentum and time-dependent. We compute $\Delta$ explicitly and demonstrate that it arises from the whisker regions. The whiskers are also shown to lead to ``entanglement'' entropy in the Big Bang region. Finally, in the Milne orbifold limit of our superconformal vacua, we show that $\Delta\to 1$ and, hence, the fluctuation spectrum is unaltered by the Big Crunch/Big Bang singularity. We comment on, but do not attempt to resolve, subtleties related to gravitational backreaction and light winding modes when interactions are taken into account.Comment: 68 pages, 1 figure; typos correcte

Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the parasite clearance curve , has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation. METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound\u27s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication. RESULTS: These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal. CONCLUSIONS: Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites

A toy model for the AdS/CFT correspondence

We study the large N gauged quantum mechanics for a single Hermitian matrix in the Harmonic oscillator potential well as a toy model for the AdS/CFT correspondence. We argue that the dual geometry should be a string in two dimensions with a curvature of stringy size. Even though the dual geometry is not weakly curved, one can still gain knowledge of the system from a detailed study of the open-closed string duality. We give a mapping between the basis of states made of traces (closed strings) and the eigenvalues of the matrix (D-brane picture) in terms of Schur polynomials. We connect this model with the study of giant gravitons in AdS_5 x S^5. We show that the two giant gravitons that expand along AdS_5 and S^5 can be interpreted in the matrix model as taking an eigenvalue from the Fermi sea and exciting it very much, or as making a hole in the Fermi sea respectively. This is similar to recent studies of the c=1 string. This connection gives new insight on how to perform calculations for giant gravitons.Comment: 19 pages JHEP, 4 figures. v2: comments added, typos fixed, additional refs. v3: The paper has been largely revised, to make the relation as a limit of N=4 SYM clear, also some proofs have been written in full rather than sketched. This updated version reflects the changes that were made in the published versio

Local non-Gaussianity from rapidly varying sound speeds

We study the effect of non-trivial sound speeds on local-type non-Gaussianity during multiple-field inflation. To this end, we consider a model of multiple-field DBI and use the deltaN formalism to track the super-horizon evolution of perturbations. By adopting a sum separable Hubble parameter we derive analytic expressions for the relevant quantities in the two-field case, valid beyond slow variation. We find that non-trivial sound speeds can, in principle, curve the trajectory in such a way that significant local-type non-Gaussianity is produced. Deviations from slow variation, such as rapidly varying sound speeds, enhance this effect. To illustrate our results we consider two-field inflation in the tip regions of two warped throats and find large local-type non-Gaussianity produced towards the end of the inflationary process.Comment: 30 pages, 7 figures; typos corrected, references added, accepted for publication in JCA

Evolution of fNL to the adiabatic limit

We study inflationary perturbations in multiple-field models, for which zeta typically evolves until all isocurvature modes decay--the "adiabatic limit". We use numerical methods to explore the sensitivity of the nonlinear parameter fNL to the process by which this limit is achieved, finding an appreciable dependence on model-specific data such as the time at which slow-roll breaks down or the timescale of reheating. In models with a sum-separable potential where the isocurvature modes decay before the end of the slow-roll phase we give an analytic criterion for the asymptotic value of fNL to be large. Other examples can be constructed using a waterfall field to terminate inflation while fNL is transiently large, caused by descent from a ridge or convergence into a valley. We show that these two types of evolution are distinguished by the sign of the bispectrum, and give approximate expressions for the peak fNL.Comment: v1: 25 pages, plus Appendix and bibliography, 6 figures. v2: minor edits to match published version in JCA

Inflation Dynamics and Reheating

We review the theory of inflation with single and multiple fields paying particular attention to the dynamics of adiabatic and entropy/isocurvature perturbations which provide the primary means of testing inflationary models. We review the theory and phenomenology of reheating and preheating after inflation providing a unified discussion of both the gravitational and nongravitational features of multi-field inflation. In addition we cover inflation in theories with extra dimensions and models such as the curvaton scenario and modulated reheating which provide alternative ways of generating large-scale density perturbations. Finally we discuss the interesting observational implications that can result from adiabatic-isocurvature correlations and non-Gaussianity.Comment: 51 pages, latex, 16 figures, version to appear in Reviews of Modern Physic

Long term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: a modelling study

BACKGROUND: Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity.METHODS AND FINDINGS: We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus.CONCLUSIONS: Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality.</p

The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence

<p>Abstract</p> <p>Background</p> <p>Over-expression of <it>HER2 </it>in a subset of breast cancers (<it>HER2</it>+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of <it>HER2</it>+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients.</p> <p>Methods</p> <p>A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in <it>HER2</it>+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in <it>HER2</it>+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI).</p> <p>Results</p> <p>TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 <it>HER2</it>+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 <it>HER2</it>+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts.</p> <p>Conclusions</p> <p>Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in <it>HER2+ </it>breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with <it>HER2 </it>targeted therapy.</p