Genetic dissection of NK cell responses

The association of Natural Killer (NK) cell deficiencies with disease susceptibility has established a central role for NK cells in host defence. In this context, genetic approaches have been pivotal in elucidating and characterizing the molecular mechanisms underlying NK cell function. To this end, homozygosity mapping and linkage analysis in humans have identified mutations that impact NK cell function and cause life-threatening diseases. However, several critical restrictions accompany genetic studies in humans. Studying NK cell pathophysiology in a mouse model has therefore proven a useful tool. The relevance of the mouse model is underscored by the similarities that exist between cell-structure-sensing receptors and the downstream signaling that leads to NK cell activation. In this review, we provide an overview of how human and mouse quantitative trait locis (QTLs) have facilitated the identification of genes that modulate NK cell development, recognition, and killing of target cells

NK Cell Receptor/H2-Dk–Dependent Host Resistance to Viral Infection Is Quantitatively Modulated by H2q Inhibitory Signals

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2k, we generated double congenic mice between MA/My and BALB.K mice and an F2 cross between FVB/N (H-2q) and BALB.K (H2k) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2k in conjunction with Cmv3MA/My or Cmv3FVB were resistant to MCMV infection. Subsequently, an F3 cross was carried out between transgenic FVB/H2-Dk and MHC-I deficient mice in which only the progeny expressing Cmv3FVB and a single H2-Dk class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell–dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2q alleles influence the expression level of H2q molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2q alleles. Our results support a model in which H-2q molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-Dk on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell–mediated control of viral load

Coupled effect of loading frequency and amplitude on the fatigue behavior of advanced sheet molding compound (A-SMC)

This paper presents the experimental results of tension-tension stress-controlled fatigue tests performed on advanced sheet molding compound (A-SMC). It aims at analyzing the effect of fiber orientation, loading amplitude, and frequency on the fatigue response and the related temperature evolution due to the self-heating phenomenon. Two types of A-SMC have been analyzed: randomly oriented (RO) and highly oriented (HO). The coupled effect of the loading amplitude and the frequency has been studied. It has been shown that the couple frequency-amplitude affects the nature of the fatigue overall response which can be governed by the damage mechanisms accumulation (mechanical fatigue) and/or by the self-heating (induced thermal fatigue). For fatigue loading at 100 Hz, self-heating has been observed and yielded to a temperature rise up to 70 C. The latter causes a decrease of the storage modulus related to the b-transition of the vinylester. It has been demonstrated that the self-heating produced a material softening and decreased the fatigue life. SEM observations revealed that the samples tested at 100 Hz, exhibit smooth debonding surfaces due to the induced thermal softening of the matrix whereas more brittle fracture of the matrix surrounding fibers is observed during the fatigue tests achieved at 10 Hz

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo

Neural network-based predictive control system for energy optimization in sports facilities: a case study

Given the increased global energy demand and its associated environmental impacts, the management and optimization of sports facilities is becoming imperative as they are characterized by high energy demand and occupancy profiles. In this work, the theory of model predictive control ȋMPCȌ is combined with neural networks for temperature setpoint selection to achieve energy and performance optimization of sports facilities. It is demonstrated using the building information model ȋBIMȌ of a sports hall in the sports complex of Qatar University. MPC systems are powerful as they allow integrated dynamic optimization that accounts for the future system behavior in the decision-making process, while neural networks are advantageous for their ability to represent complex interdependencies with high accuracy. The proposed approach was able to achieve a total energy savings of around ͵͵Ψ. Considerations about the network performance, MPC settings tuning, and optimization sub-optimality or failure are essential during the design and implementation phases of the proposed system

Building energy management systems for sports facilities in the Gulf region: a focus on impacts and considerations

Sports tourism in the Gulf region started to flourish where several international sports events were secured for the next decade. This reflects on the number of sports facilities, their energy consumption, and CO2 emissions mainly due to the indoor and outdoor air conditioning requirements. This paper aims to emphasize the significance of energy management in sports facilities especially for hot climatic regions. It presents a review of the works for optimizing building management systems’ (BMSs) operation, anomaly diagnosis, and mitigation. It indicates their application scarcity for sports facilities compared to other types of buildings, and for the regions with hot and humid weather conditions compared to amiable and cold ones, in addition to the considerations for optimizing BMSs of sports facilities based on their type and regional location. An overview is presented of the impacts related to the security and the reliable operation of the BMSs of sports facilities given the advancements in the deployed technologie

Distinct MHC class I–dependent NK cell–activating receptors control cytomegalovirus infection in different mouse strains

MCMV-infected cells are recognized by multiple MHC class I–restricted Ly49-activating receptors in genetically distinct mouse strains

Bisphosphoglycerate mutase deficiency protects against cerebral malaria and severe malaria-induced anemia

The replication cycle and pathogenesis of the Plasmodium malarial parasite involves rapid expansion in red blood cells (RBCs), and variants of certain RBC-specific proteins protect against malaria in humans. In RBCs, bisphosphoglycerate mutase (BPGM) acts as a key allosteric regulator of hemoglobin/oxyhemoglobin. We demonstrate here that a loss-of-function mutation in the murine Bpgm (BpgmL166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in BpgmL166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of BpgmL166P involves a dual mechanism that enhances the host’s stress erythroid response to Plasmodium-driven RBC loss and simultaneously alters the intracellular milieu of the RBCs, including increased oxyhemoglobin and reduced energy metabolism, reducing Plasmodium maturation, and replication. Overall, our study highlights the importance of BPGM as a regulator of hemoglobin/oxyhemoglobin in malaria pathogenesis and suggests a new potential malaria therapeutic target