Timing of immune escape linked to success or failure of vaccination

Successful vaccination against HIV should limit viral replication sufficiently to prevent the emergence of viral immune escape mutations. Broadly directed immunity is likely to be required to limit opportunities for immune escape variants to flourish. We studied the emergence of an SIV Gag cytotoxic T cell immune escape variant in pigtail macaques expressing the Mane-A*10 MHC I allele using a quantitative RT-PCR to measure viral loads of escape and wild type variants. Animals receiving whole Gag expressing vaccines completely controlled an SIV_mac251 challenge, had broader CTL responses and exhibited minimal CTL escape. In contrast, animals vaccinated with only a single CTL epitope and challenged with the same SIV_mac251 stock had high levels of viral replication and rapid CTL escape. Unvaccinated naïve animals exhibited a slower emergence of immune escape variants. Thus narrowly directed vaccination against a single epitope resulted in rapid immune escape and viral levels equivalent to that of naïve unvaccinated animals. These results emphasize the importance of inducing broadly directed HIV-specific immunity that effectively quashes early viral replication and limits the generation of immune escape variants. This has important implications for the selection of HIV vaccines for expanded human trials.

Fault tolerance force for redundant manipulators

Fault tolerant manipulators maintain their trajectory even if their joint/s fails. Assuming that the manipulator is fault tolerant on its trajectory, fault tolerant compliance manipulators provide required force at their end-effector even when a joint fails. To achieve this, the contributions of the faulty joints for the force of the end-effector are required to be mapped into the proper compensating joint torques of the healthy joints to maintain the force. This paper addresses the optimal mapping to minimize the force jump due to a fault, which is the maximum effort to maintain the force when a fault occurs. The paper studies the locked joint fault/s of the redundant manipulators and it relates the force jump at the end-effector to the faults within the joints. Adding on a previous study to maintain the trajectory, in here the objective is to providing fault tolerant force at the end-effector of the redundant manipulators. This optimal mapping with minimum force jump is presented using matrix perturbation model. And the force jump is calculated through this model for single and multiple joints fault. The proposed optimal mapping is used in different fault scenarios for a 5-DOF manipulator; also it is deployed to compensate the force at the end-effector for the 5-DOF manipulator through simulation study and the results are presented.

Optimal actuator fault tolerance for static nonlinear systems based on minimum output velocity jump

Fault tolerance for a class of non linear systems is addressed based on the velocity of their output variables. This paper presents a mapping to minimize the possible jump of the velocity of the output, due to the actuator failure. The failure of the actuator is assumed as actuator lock. The mapping is derived and it provides the proper input commands for the healthy actuators of the system to tolerate the effect of the faulty actuator on the output of the system. The introduced mapping works as an optimal input reconfiguration for fault recovery, which provides a minimum velocity jump suitable for static nonlinear systems. The proposed mapping is validated through different case studies and a complementary simulation. In the case studies and the simulation, the mapping provides the commands to compensate the effect of different faults within the joints of a robotic manipulator. The new commands and the compare between the velocity of the output variables for the health and faulty system are presented.

Fault tolerance operation of cooperative manipulators

Autonomous or teleoperation of critical tasks in space applications require fault tolerant robotic manipulators. These manipulators are able to maintain their tasks even if a joint fails. If it is presumed that the manipulator is fault tolerant on its trajectory, then the next step is to provide a fault tolerant force at the end-effector of the manipulator. The problem of cooperative fault tolerant force is addressed in this paper within the operation of two manipulators. The cooperative manipulators are used to compensate the force jump which occurs on the force of the end-effector of one manipulator due to a joint failure. To achieve fault tolerant operation, the contribution of the faulty joint for the force of the end-effector of the faulty manipulator is required to be optimally mapped into the torque of the faulty and healthy manipulators. The optimal joint torque reconfigurations of both manipulators for compensating this force jump are illustrated. The proposed frameworks are deployed for two cooperative PUMA560 manipulators. The results of the case studies validate the fault tolerant cooperation strategies.

Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria

Cerebral malaria is a severe complication of malaria. Sequestration of parasitized RBCs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. In this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ECM). We show that a rapid increase in parasite biomass is strongly associated with the induction of ECM, mediated by IFN-γ and lymphotoxin α, whereas TNF and IL-10 limit this process. Crucially, we discovered that host CD4+ and CD8+ T cells promote parasite accumulation in vital organs, including the brain. Modulation of CD4+ T cell responses by helminth coinfection amplified CD4+ T cell-mediated parasite sequestration, whereas vaccination could generate CD4+ T cells that reduced parasite biomass and prevented ECM. These findings provide novel insights into immune-mediated mechanisms of ECM pathogenesis and highlight the potential of T cells to both prevent and promote infectious diseases.

Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity

Background : We sought to determine whether skeletal muscle oxidative capacity, fiber type proportions, and fiber size, capillary density or muscle mass might explain the impaired exercise tolerance in chronic heart failure (CHF). Previous studies are equivocal regarding the maladaptations that occur in the skeletal muscle of patients with CHF and their role in the observed exercise intolerance.

Methods and results : Total body O₂ uptake (VO_2peak) was determined in 14 CHF patients and 8 healthy sedentary similar-age controls. Muscle samples were analyzed for mitochondrial adenosine triphosphate (ATP) production rate (MAPR), oxidative and glycolytic enzyme activity, fiber size and type, and capillary density. CHF patients demonstrated a lower VO_2peak (15.1±1.1 versus 28.1±2.3 mL·kg⁻¹·min⁻¹, P<.001) and capillary to fiber ratio (1.09±0.05 versus 1.40±0.04; P<.001) when compared with controls. However, there was no difference in capillary density (capillaries per square millimeter) across any of the fiber types. Measurements of MAPR and oxidative enzyme activity suggested no difference in muscle oxidative capacity between the groups.

Conclusions : Neither reductions in muscle oxidative capacity nor capillary density appear to be the cause of exercise limitation in this cohort of patients. Therefore, we hypothesize that the low VO_2peak observed in CHF patients may be the result of fiber atrophy and possibly impaired activation of oxidative phosphorylation.

Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin–angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11–12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

A hybrid approach for fault tolerance in robotics

This paper studies the difference between the human behaviours for fault tolerance with a pseudo inverse reconfiguration approach for fault tolerance of robotic arms. If this difference is well understood then it can be used to introduce a hybrid approach for fault tolerant motion of robotic arms. The proposed approach is expected to combine human fault-tolerance dexterity and advantages of a model based fault tolerance. The main aim is to add human dexterity for fault tolerance of robotic arms.

Multiple actuator fault tolerance for static nonlinear systems based on minimum velocity jump

Static nonlinear systems are common when the model of the kinematics of mechanical or civil structures is analyzed for instance kinematics of robotic manipulators. This paper addresses the maximum effort toward fault tolerance for any number of the locked actuators failures in static nonlinear systems. It optimally reconfigures the inputs via a mapping that maximally accommodates the failures. The mapping maps the failures to an extra action of healthy actuators that results to a minimum jump for the velocity of the output variables. Then from this mapping, the minimum jump of the velocity of the output is calculated. The conditions for a zero velocity jump of the output variables are discussed. This shows that, when the conditions of fault tolerance are maintained, the proposed framework is capable of fault recovery not only at fault instances but also at the whole output trajectory. The proposed mapping is validated by three case studies.

Heat tolerance, behavioural temperature selection and temperature-dependent respiration in larval Octopus huttoni

This study reports temperature effects on paralarvae from a benthic octopus species, Octopus huttoni, found throughout New Zealand and temperate Australia. We quantified the thermal tolerance, thermal preference and temperature-dependent respiration rates in 1-5 days old paralarvae. Thermal stress (1°C increase h^-1) and thermal selection (~10-24°C vertical gradient) experiments were conducted with paralarvae reared for 4 days at 16°C. In addition, measurement of oxygen consumption at 10, 15, 20 and 25°C was made for paralarvae aged 1, 4 and 5 days using microrespirometry. Onset of spasms, rigour (CT_max) and mortality (upper lethal limit) occurred for 50% of experimental animals at, respectively, 26.0±0.2°C, 27.8±0.2°C and 31.4±0.1°C. The upper, 23.1±0.2°C, and lower, 15.0±1.7°C, temperatures actively avoided by paralarvae correspond with the temperature range over which normal behaviours were observed in the thermal stress experiments. Over the temperature range of 10°C-25°C, respiration rates, standardized for an individual larva, increased with age, from 54.0 to 165.2nmol larvae^-1h^-1 in one-day old larvae to 40.1-99.4nmol h^-1 at five days. Older larvae showed a lesser response to increased temperature: the effect of increasing temperature from 20 to 25°C (Q₁₀) on 5 days old larvae (Q₁₀=1.35) was lower when compared with the 1 day old larvae (Q₁₀=1.68). The lower Q₁₀ in older larvae may reflect age-related changes in metabolic processes or a greater scope of older larvae to respond to thermal stress such as by reducing activity. Collectively, our data indicate that temperatures >25°C may be a critical temperature. Further studies on the population-level variation in thermal tolerance in this species are warranted to predict how continued increases in ocean temperature will limit O. huttoni at early larval stages across the range of this species.

The central nucleus of the amygdala ; a conduit for modulation of HPA axis responses to an immune challenge?

Physical stressors such as infection, inflammation and tissue injury elicit activation of the hypofhalamic-pituitary-adrenal (HPA) axis. This response has significant implications for both immune and central nervous system function. Investigations in rats into the neural substrates responsible for HPA axis activation to an immune challenge have predominantly utilized an experimental paradigm involving the acute administration of the pro-inflammatory cytokine interleukin-1 β (IL-1β). It is well recognized that medial parvocellular corticotrophin-releasing factor cells of the paraventricular nucleus (mPVN CRF) are critical in generating HPA axis responses to an immune challenge but little is known about how peripheral immune signals can activate and/or modulate the mPVN CRF cells. Studies that have examined the afferent control of the mPVN CRF cell response to systemic IL-1β have centred largely on the inputs from brainstem catecholamine cells. However, other regulatory neuronal populations also merit attention and one such region is a component of the limbic system, the central nucleus of the amygdala (CeA). A large number of CeA cells are recruited following systemic IL-lβ administration and there is a significant body of work indicating that the CeA can influence HPA axis function. However, the contribution of the CeA to HPA axis responses to an immune challenge is only just beginning to be addressed. This review examines three aspects of HPA axis control by systemic IL-lβ; (i) whether the CeA has a role in generating HPA axis responses to systemic IL-1 β, (ii) the identity of the neural connections between the CeA and mPVN CRF cells that might be important to HPA axis responses and (iii) the mechanisms by which systemic IL-lβ triggers the recruitment of CeA cells.

A critical role for the parabrachial nucleus in generating central nervous system responses elicited by a systemic immune challenge

Using Fos immunolabelling as a marker of neuronal activation, we investigated the role of the parabrachial nucleus in generating central neuronal responses to the systemic administration of the proinflammatory cytokine interleukin-1β (1 μg/kg, i.a.). Relative to intact animals, parabrachial nucleus lesions significantly reduced the number of Fos-positive cells observed in the central amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the ventrolateral medulla (VLM) after systemic interleukin-1β. In a subsequent experiment in which animals received parabrachial-directed deposits of a retrograde tracer, it was found that many neurons located in the nucleus tractus solitarius (NTS) and the VLM neurons were both retrogradely labelled and Fos-positive after interleukin-1β administration. These results suggest that the parabrachial nucleus plays a critical role in interleukin-1β-induced Fos expression in CeA, BNST and VLM neurons and that neurons of the NTS and VLM may serve to trigger or at least influence changes in parabrachial nucleus activity that follows systemic interleukin-1β administration.