Merocytic Dendritic Cells Compose a Conventional Dendritic Cell Subset with Low Metabolic Activity.

Conventional dendritic cells (cDCs) are arguably the most potent APCs that induce the activation of naive T cells in response to pathogens. In addition, at steady-state, cDCs help maintain immune tolerance. Two subsets of cDCs have been extensively characterized, namely cDC1 and cDC2, each contributing differently to immune responses. Recently, another dendritic cell (DC) subset, termed merocytic DCs (mcDCs), was defined. In contrast to both cDC1 and cDC2, mcDCs reverse T cell anergy, properties that could be exploited to potentiate cancer treatments. Yet, whether mcDCs represent an unconventional DC or a cDC subset remains to be defined. In this article, we further characterize mcDCs and find that they bear true characteristics of cDC subsets. Indeed, as for cDCs, mcDCs express the cDC-restricted transcription factor Zbtb46 and display very potent APC activity. In addition, mcDC population dynamics parallels that of cDC1 and cDC2 in both reconstitution kinetic studies and parabiotic mice. We next investigated their relatedness to cDC1 and cDC2 and demonstrate that mcDCs are not dependent on cDC1-related Irf8 and Batf3 transcription factors, are dependent on Irf4, a cDC2-specific transcription factor, and express a unique transcriptomic signature. Finally, we find that cDC1, cDC2, and mcDCs all present with different metabolic phenotypes, in which mcDCs exhibit the lowest glucose uptake activity and mcDC survival is the least affected by glycolysis inhibition. Defining the properties of mcDCs in mice may help identify a functionally equivalent subset in humans leading to the development of innovative cancer immunotherapies.

A proteomic analysis unravels novel CORVET and HOPS proteins involved in Toxoplasma gondii secretory organelles biogenesis.

Apicomplexans use the endolysosomal system for the biogenesis of their secretory organelles, namely, micronemes, rhoptries, and dense granules. In Toxoplasma gondii, our previous in silico search identified the HOPS tethering but not the CORVET complex and demonstrated a role of Vps11 (a common component for both complexes) in its secretory organelle biogenesis. Herein, we performed Vps11-GFP-Trap pull-down assays and identified by proteomic analysis, not only the CORVET-specific subunit Vps8 but also a BEACH domain-containing protein (BDCP) conserved in eukaryotes. We show that knocking-down Vps8 affects targeting of dense granule proteins, transport of rhoptry proteins, and the localization of the cathepsin L protease vacuolar compartment marker. Only a subset of micronemal proteins are affected by the absence of Vps8, shedding light on at least two trafficking pathways involved in microneme maturation. Knocking-down BDCP revealed a restricted and particular role of this protein in rhoptry and vacuolar compartment biogenesis. Moreover, depletion of BDCP or Vps8 abolishes parasite virulence in vivo. This study identified BDCP as a novel CORVET/HOPS-associated protein, playing specific roles and acting in concert during secretory organelle biogenesis, an essential process for host cell infection. Our results open the hypothesis for a role of BDCP in the vesicular trafficking towards lysosome-related organelles in mammals and yeast.

Enhanced representation learning with temporal coding in sparsely spiking neural networks.

Current representation learning methods in Spiking Neural Networks (SNNs) rely on rate-based encoding, resulting in high spike counts, increased energy consumption, and slower information transmission. In contrast, our proposed method, Weight-Temporally Coded Representation Learning (W-TCRL), utilizes temporally coded inputs, leading to lower spike counts and improved efficiency. To address the challenge of extracting representations from a temporal code with low reconstruction error, we introduce a novel Spike-Timing-Dependent Plasticity (STDP) rule. This rule enables stable learning of relative latencies within the synaptic weight distribution and is locally implemented in space and time, making it compatible with neuromorphic processors. We evaluate the performance of W-TCRL on the MNIST and natural image datasets for image reconstruction tasks. Our results demonstrate relative improvements of 53% for MNIST and 75% for natural images in terms of reconstruction error compared to the SNN state of the art. Additionally, our method achieves significantly higher sparsity, up to 900 times greater, when compared to related work. These findings emphasize the efficacy of W-TCRL in leveraging temporal coding for enhanced representation learning in Spiking Neural Networks.

Phosphorylcholine and KR12-Containing Corneal Implants in HSV-1-Infected Rabbit Corneas.

Severe HSV-1 infection can cause blindness due to tissue damage from severe inflammation. Due to the high risk of graft failure in HSV-1-infected individuals, cornea transplantation to restore vision is often contraindicated. We tested the capacity for cell-free biosynthetic implants made from recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) to suppress inflammation and promote tissue regeneration in the damaged corneas. To block viral reactivation, we incorporated silica dioxide nanoparticles releasing KR12, the small bioactive core fragment of LL37, an innate cationic host defense peptide produced by corneal cells. KR12 is more reactive and smaller than LL37, so more KR12 molecules can be incorporated into nanoparticles for delivery. Unlike LL37, which was cytotoxic, KR12 was cell-friendly and showed little cytotoxicity at doses that blocked HSV-1 activity in vitro, instead enabling rapid wound closure in cultures of human epithelial cells. Composite implants released KR12 for up to 3 weeks in vitro. The implant was also tested in vivo on HSV-1-infected rabbit corneas where it was grafted by anterior lamellar keratoplasty. Adding KR12 to RHCIII-MPC did not reduce HSV-1 viral loads or the inflammation resulting in neovascularization. Nevertheless, the composite implants reduced viral spread sufficiently to allow stable corneal epithelium, stroma, and nerve regeneration over a 6-month observation period.

Humoral responses to the measles, mumps and rubella vaccine are impaired in Leigh Syndrome French Canadian patients.

Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry mutations in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell types including the differentiation and function of immune cells. Hence, we postulated that, in addition to neurological and metabolic disorders, LSFC patients may show impaired immune activity. To gain insight into the quality of the immune response in LSFC patients, we examined the response to the measles, mumps and rubella (MMR) vaccine by measuring antibody titers to MMR in the plasma. In a cohort of eight LSFC patients, the response to the MMR vaccine was variable, with some individuals showing antibodies to all three viruses, while others had antibodies to two or fewer viruses. These results suggest that the mutations in the LRPPRC gene present in LSFC patients may affect the immune response to vaccines. Monitoring vaccine response in this fragile population should be considered to ensure full protection against pathogens.

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.

Autonomous Sequence Generation for a Neural Dynamic Robot: Scene Perception, Serial Order, and Object-Oriented Movement.

Neurally inspired robotics already has a long history that includes reactive systems emulating reflexes, neural oscillators to generate movement patterns, and neural networks as trainable filters for high-dimensional sensory information. Neural inspiration has been less successful at the level of cognition. Decision-making, planning, building and using memories, for instance, are more often addressed in terms of computational algorithms than through neural process models. To move neural process models beyond reactive behavior toward cognition, the capacity to autonomously generate sequences of processing steps is critical. We review a potential solution to this problem that is based on strongly recurrent neural networks described as neural dynamic systems. Their stable states perform elementary motor or cognitive functions while coupled to sensory inputs. The state of the neural dynamics transitions to a new motor or cognitive function when a previously stable neural state becomes unstable. Only when a neural robotic system is capable of acting autonomously does it become a useful to a human user. We demonstrate how a neural dynamic architecture that supports autonomous sequence generation can engage in such interaction. A human user presents colored objects to the robot in a particular order, thus defining a serial order of color concepts. The user then exposes the system to a visual scene that contains the colored objects in a new spatial arrangement. The robot autonomously builds a scene representation by sequentially bringing objects into the attentional foreground. Scene memory updates if the scene changes. The robot performs visual search and then reaches for the objects in the instructed serial order. In doing so, the robot generalizes across time and space, is capable of waiting when an element is missing, and updates its action plans online when the scene changes. The entire flow of behavior emerges from a time-continuous neural dynamics without any controlling or supervisory algorithm.