Klotho controls the brain-immune system interface in the choroid plexus.

Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis

Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice.

A152T-variant human tau (hTau-A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau-A152T or wild-type hTau (hTau-WT), we find age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau-A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau-A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau-A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau-A152T and amyloid-β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors

Bis[μ-2-(2-benzoyl­hydrazinylidenemeth­yl)-6-methoxy­phenolato][2-(2-benzoyl­hydrazinylidenemeth­yl)-6-methoxy­phenolato]dimanganese(II) perchlorate methanol solvate

In the title complex, [Mn2(C15H13N2O3)3]ClO4·CH3OH, the two MnII ions are bridged by two phenolate O atoms from two ligands, forming an Mn2O2 quadrangle. Each MnII ion has a distorted octa­hedral coordination geometry. One MnII ion is coordinated by two N atoms and four O atoms from two ligands, and the other is coordinated by one N atom and five O atoms from three ligands. A dimer is formed by inter­molecular N—H⋯O hydrogen bonds. The dimers, perchlorate anions and methanol solvent mol­ecules are further connected into a chain along [01] through N—H⋯O and O—H⋯O hydrogen bonds

DOMAIN: MilDly COnservative Model-BAsed OfflINe Reinforcement Learning

Model-based reinforcement learning (RL), which learns environment model from offline dataset and generates more out-of-distribution model data, has become an effective approach to the problem of distribution shift in offline RL. Due to the gap between the learned and actual environment, conservatism should be incorporated into the algorithm to balance accurate offline data and imprecise model data. The conservatism of current algorithms mostly relies on model uncertainty estimation. However, uncertainty estimation is unreliable and leads to poor performance in certain scenarios, and the previous methods ignore differences between the model data, which brings great conservatism. Therefore, this paper proposes a milDly cOnservative Model-bAsed offlINe RL algorithm (DOMAIN) without estimating model uncertainty to address the above issues. DOMAIN introduces adaptive sampling distribution of model samples, which can adaptively adjust the model data penalty. In this paper, we theoretically demonstrate that the Q value learned by the DOMAIN outside the region is a lower bound of the true Q value, the DOMAIN is less conservative than previous model-based offline RL algorithms and has the guarantee of security policy improvement. The results of extensive experiments show that DOMAIN outperforms prior RL algorithms on the D4RL dataset benchmark, and achieves better performance than other RL algorithms on tasks that require generalization.Comment: 13 pages, 6 figure

Amyloid-beta/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer’s Disease

Alzheimer\u27s disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn.Weshowed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded wholecell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit

CROP: Conservative Reward for Model-based Offline Policy Optimization

Offline reinforcement learning (RL) aims to optimize policy using collected data without online interactions. Model-based approaches are particularly appealing for addressing offline RL challenges due to their capability to mitigate the limitations of offline data through data generation using models. Prior research has demonstrated that introducing conservatism into the model or Q-function during policy optimization can effectively alleviate the prevalent distribution drift problem in offline RL. However, the investigation into the impacts of conservatism in reward estimation is still lacking. This paper proposes a novel model-based offline RL algorithm, Conservative Reward for model-based Offline Policy optimization (CROP), which conservatively estimates the reward in model training. To achieve a conservative reward estimation, CROP simultaneously minimizes the estimation error and the reward of random actions. Theoretical analysis shows that this conservative reward mechanism leads to a conservative policy evaluation and helps mitigate distribution drift. Experiments on D4RL benchmarks showcase that the performance of CROP is comparable to the state-of-the-art baselines. Notably, CROP establishes an innovative connection between offline and online RL, highlighting that offline RL problems can be tackled by adopting online RL techniques to the empirical Markov decision process trained with a conservative reward. The source code is available with https://github.com/G0K0URURI/CROP.git

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments

Salmonella Outer Protein B Suppresses Colitis Development via Protecting Cell From Necroptosis

Salmonella effectors translocated into epithelial cells contribute to the pathogenesis of infection. They mediate epithelial cell invasion and subsequent intracellular replication. However, their functions in vivo have not been well-identified. In this study, we uncovered a role for Salmonella outer protein B (SopB) in modulating necroptosis to facilitate bacteria escape epithelial cell and spread to systemic sites through a Salmonella-induced colitis model. Mice infected with SopB deleted strain ΔsopB displayed increased severity to colitis, reduced mucin expression and increased bacterial translocation. In vitro study, we found there was an increased goblet cell necroptosis following ΔsopB infection. Consistently, mice infected with ΔsopB had a strong upregulation of mixed lineage kinase domain-like (MLKL) phosphorylation. Deletion of MLKL rescued severity of tissue inflammatory, improved mucin2 expression and abolished the increased bacterial translocation in mice infected with ΔsopB. Intriguingly, the expression of sopB in LS174T cells was downregulated. The temporally regulated SopB expression potentially switched the role from epithelial cell invasion to bacterial transmission. Collectively, these results indicated a role for SopB in modulating the onset of necroptosis to increased bacteria pathogenesis and translocated to systemic sites

A huge-amplitude white-light superflare on a L0 brown dwarf discovered by GWAC survey

White-light superflares from ultra cool stars are thought to be resulted from magnetic reconnection, but the magnetic dynamics in a fully convective star is not clear yet. In this paper, we report a stellar superflare detected with the Ground Wide Angle Camera (GWAC), along with rapid follow-ups with the F60A, Xinglong 2.16m and LCOGT telescopes. The effective temperature of the counterpart is estimated to be $2200\pm50$K by the BT-Settl model, corresponding to a spectral type of L0. The $R-$band light curve can be modeled as a sum of three exponential decay components, where the impulsive component contributes a fraction of 23\% of the total energy, while the gradual and the shallower decay phases emit 42\% and 35\% of the total energy, respectively. The strong and variable Balmer narrow emission lines indicate the large amplitude flare is resulted from magnetic activity. The bolometric energy released is about $6.4\times10^{33}$ ergs, equivalent to an energy release in a duration of 143.7 hours at its quiescent level. The amplitude of $\Delta R=-8.6$mag ( or $\Delta V=-11.2$ mag), placing it one of the highest amplitudes of any ultra cool star recorded with excellent temporal resolution. We argue that a stellar flare with such rapidly decaying and huge amplitude at distances greater than 1 kpc may be false positive in searching for counterparts of catastrophic events such as gravitational wave events or gamma-ray bursts, which are valuable in time-domain astronomy and should be given more attention.Comment: 9 pages, 5 figures, 1 table, MNRAS accepte