Exhausted CD4⁺ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4⁺ T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4⁺ T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4⁺ T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4+ T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4⁺ T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4⁺ T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4⁺ T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4⁺ T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4⁺ T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4⁺ T cells during malaria infection and other chronic conditions

An investigation into the prevalence of dog bites to primary school children in Trinidad

<p>Abstract</p> <p>Background</p> <p>To estimate the prevalence of dog bites to primary school children between the ages of 8–12 years using a semi-structured interview process. With the increase in the pet population and popularity of dangerous breeds of dog and a high stray dog population combined with a dearth of information on the risk of dog attacks to children in Trinidad, a semi-structured interview process was used to determine risk factors associated with dog attacks.</p> <p>Methods</p> <p>A questionnaire survey of 1109 primary school children between the ages of 8–12 years was conducted in Trinidad from November 2002 to September 2003. The survey was conducted to determine the risk factors such as age, gender, size of dog and relationship of dog and victim, in dog bite incidents. The chi-square statistic and odds ratios were used to estimate risk factors for a bite incident.</p> <p>Results</p> <p>Twenty-eight percent of children were bitten at least once by a dog. Gender (male) and owning a dog were statistically significant risk factors (p = 0.003 and 0.008 respectively, χ²<it>df</it>, 95% confidence). Most attacks occurred outside of the home (58.0%) followed by the victims' home (42.0%) and were by a dog known but not owned (54.6%) by the victim. Many victims (33.0%) were bitten without having any interaction with the dog and the majority (61.9%) of victims did not receive professional medical assistance. Overall, the lower leg or foot was most often injured (39.3%).</p> <p>Conclusion</p> <p>A public educational campaign is needed on responsible pet ownership. In addition, children must be taught effective ways of avoiding attacks or reducing injury in the event of a dog attack. The Dangerous dogs Act 2000 must be proclaimed in parliament by the Government of Trinidad and Tobago to exert more pressure on pet owners to safeguard the public from the menace of dog attacks.</p

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt

Larvicidal effects of Chinaberry (Melia azederach) powder on Anopheles arabiensis in Ethiopia

<p>Abstract</p> <p>Background</p> <p>Synthetic insecticides are employed in the widely-used currently favored malaria control techniques involving indoor residual spraying and treated bednets. These methods have repeatedly proven to be highly effective at reducing malaria incidence and prevalence. However, rapidly emerging mosquito resistance to the chemicals and logistical problems in transporting supplies to remote locations threaten the long-term sustainability of these techniques. Chinaberry (<it>Melia azederach</it>) extracts have been shown to be effective growth-inhibiting larvicides against several insects. Because several active chemicals in the trees' seeds have insecticidal properties, the emergence of resistance is unlikely. Here, we investigate the feasibility of Chinaberry as a locally available, low-cost sustainable insecticide that can aid in controlling malaria. Chinaberry fruits were collected from Asendabo, Ethiopia. The seeds were removed from the fruits, dried and crushed into a powder. From developmental habitats in the same village, <it>Anopheles arabiensis </it>larvae were collected and placed into laboratory containers. Chinaberry seed powder was added to the larval containers at three treatment levels: 5 g m^-2, 10 g m^-2and 20 g m^-2, with 100 individual larvae in each treatment level and a control. The containers were monitored daily and larvae, pupae and adult mosquitoes were counted. This experimental procedure was replicated three times.</p> <p>Results</p> <p>Chinaberry seed powder caused an inhibition of emergence of 93% at the 5 g m^-2treatment level, and 100% inhibition of emergence at the two higher treatment levels. The Chinaberry had a highly statistically significant larvicidal effect at all treatment levels (χ²= 184, 184, and 155 for 5 g m^-2, 10 g m^-2and 20 g m^-2, respectively; p < 0.0001 in all cases). In addition, estimates suggest that sufficient Chinaberry seed exists in Asendabo to treat developmental habitat for the duration of the rainy season and support a field trial.</p> <p>Conclusions</p> <p>Chinaberry seed is a very potent growth-inhibiting larvicide against the major African malaria vector <it>An. arabiensis</it>. The seed could provide a sustainable additional malaria vector control tool that can be used where the tree is abundant and where <it>An. arabiensis </it>is a dominant vector. Based on these results, a future village-scale field trial using the technique is warranted.</p

Higher-order multipole amplitudes in charmonium radiative transitions

Using 24 million $\psi' \equiv \psi(2S)$ decays in CLEO-c, we have searched for higher multipole admixtures in electric-dipole-dominated radiative transitions in charmonia. We find good agreement between our data and theoretical predictions for magnetic quadrupole (M2) amplitudes in the transitions $\psi' \to \gamma \chi_{c1,2}$ and $\chi_{c1,2} \to \gamma J/\psi$, in striking contrast to some previous measurements. Let $b_2^J$ and $a_2^J$ denote the normalized M2 amplitudes in the respective aforementioned decays, where the superscript $J$ refers to the angular momentum of the $\chi_{cJ}$. By performing unbinned maximum likelihood fits to full five-parameter angular distributions, we determine the ratios $a_2^{J=1}/a_2^{J=2} = 0.67^{+0.19}_{-0.13}$ and $a_2^{J=1}/b_2^{J=1} = -2.27^{+0.57}_{-0.99}$, where the theoretical predictions are independent of the charmed quark magnetic moment and are $a_2^{J=1}/a_2^{J=2} = 0.676 \pm 0.071$ and $a_2^{J=1}/b_2^{J=1} = -2.27 \pm 0.16$.Comment: 32 pages, 7 figures, acceptance updat

Dalitz Plot Analysis of Ds to K+K-pi+

We perform a Dalitz plot analysis of the decay Ds to K+K-pi+ with the CLEO-c data set of 586/pb of e+e- collisions accumulated at sqrt(s) = 4.17 GeV. This corresponds to about 0.57 million D_s+D_s(*)- pairs from which we select 14400 candidates with a background of roughly 15%. In contrast to previous measurements we find good agreement with our data only by including an additional f_0(1370)pi+ contribution. We measure the magnitude, phase, and fit fraction of K*(892) K+, phi(1020)pi+, K0*(1430)K+, f_0(980)pi+, f_0(1710)pi+, and f_0(1370)pi+ contributions and limit the possible contributions of other KK and Kpi resonances that could appear in this decay.Comment: 21 Pages,available through http://www.lns.cornell.edu/public/CLNS/, submitted to PR

Search for D0 to p e- and D0 to pbar e+

Using data recorded by CLEO-c detector at CESR, we search for simultaneous baryon and lepton number violating decays of the D^0 meson, specifically, D^0 --> p-bar e^+, D^0-bar --> p-bar e^+, D^0 --> p e^- and D^0-bar --> p e^-. We set the following branching fraction upper limits: D^0 --> p-bar e^+ (D^0-bar --> p-bar e^+) p e^- (D^0-bar --> p e^-) < 1.2 * 10^{-5}, both at 90% confidence level.Comment: 10 pages, available through http://www.lns.cornell.edu/public/CLNS/, submitted to PRD. Comments: changed abstract, added reference for section 1, vertical axis in Fig.5 changed (starts from 1.5 rather than 2.0), fixed typo

Charmonium decays to gamma pi0, gamma eta, and gamma eta'

Using data acquired with the CLEO-c detector at the CESR e+e- collider, we measure branching fractions for J/psi, psi(2S), and psi(3770) decays to gamma pi0, gamma eta, and gamma eta'. Defining R_n = B[ psi(nS)-->gamma eta ]/B[ psi(nS)-->gamma eta' ], we obtain R_1 = (21.1 +- 0.9)% and, unexpectedly, an order of magnitude smaller limit, R_2 < 1.8% at 90% C.L. We also use J/psi-->gamma eta' events to determine branching fractions of improved precision for the five most copious eta' decay modes.Comment: 14 pages, available through http://www.lns.cornell.edu/public/CLNS/, published in Physical Review

Precision Measurement of B(D+ -> mu+ nu) and the Pseudoscalar Decay Constant fD+

We measure the branching ratio of the purely leptonic decay of the D+ meson with unprecedented precision as B(D+ -> mu+ nu) = (3.82 +/- 0.32 +/- 0.09)x10^(-4), using 818/pb of data taken on the psi(3770) resonance with the CLEO-c detector at the CESR collider. We use this determination to derive a value for the pseudoscalar decay constant fD+, combining with measurements of the D+ lifetime and assuming |Vcd| = |Vus|. We find fD+ = (205.8 +/- 8.5 +/- 2.5) MeV. The decay rate asymmetry [B(D+ -> mu+ nu)-B(D- -> mu- nu)]/[B(D+ -> mu+ nu)+B(D- -> mu- nu)] = 0.08 +/- 0.08, consistent with no CP violation. We also set 90% confidence level upper limits on B(D+ -> tau+ nu) < 1.2x10^(-3) and B(D+ -> e+ nu) < 8.8x10^(-6).Comment: 24 pages, 11 figures and 6 tables, v2 replaced some figure vertical axis scales, v3 corrections from PRD revie

Precision Measurement of the Mass of the h_c(1P1) State of Charmonium

A precision measurement of the mass of the h_c(1P1) state of charmonium has been made using a sample of 24.5 million psi(2S) events produced in e+e- annihilation at CESR. The reaction used was psi(2S) -> pi0 h_c, pi0 -> gamma gamma, h_c -> gamma eta_c, and the reaction products were detected in the CLEO-c detector. Data have been analyzed both for the inclusive reaction and for the exclusive reactions in which eta_c decays are reconstructed in fifteen hadronic decay channels. Consistent results are obtained in the two analyses. The averaged results of the present measurements are M(h_c)=3525.28+-0.19 (stat)+-0.12(syst) MeV, and B(psi(2S) -> pi0 h_c)xB(h_c -> gamma eta_c)= (4.19+-0.32+-0.45)x10^-4. Using the 3PJ centroid mass, Delta M_hf(1P)= - M(h_c) = +0.02+-0.19+-0.13 MeV.Comment: 9 pages, available through http://www.lns.cornell.edu/public/CLNS/, submitted to PR