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

Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis

Combined Toxicity Evaluation of Ochratoxin A and Aflatoxin B1 on Kidney and Liver Injury, Immune Inflammation, and Gut Microbiota Alteration Through Pair-Feeding Pullet Model

Ochratoxin A (OTA) and aflatoxin B1 (AFB1) are often co-contaminated, but their synergistic toxicity in poultry is limitedly described. Furthermore, the traditional ad libitum feeding model may fail to distinguish the specific impact of mycotoxins on the biomarkers and the indirect effect of mildew on the palatability of feed. A pair-feeding model was introduced to investigate the specific effect and the indirect effect of the combined toxicity of OTA and AFB1, which were independent and dependent on feed intake, respectively. A total of 180 one-day-old pullets were randomly divided into 3 groups with 6 replicates, and each replicate contained 10 chicks. The control group (Group A) and the pair-feeding group (Group B) received the basal diet without mycotoxin contamination. Group C was administrated with OTA- and AFB1-contaminated feed (101.41 μg/kg of OTA + 20.10 μg/kg of AFB1). The scale of feeding in Group B matched with the feed intake of Group C. The trial lasted 42 days. Compared with the control group, co-contamination of OTA and AFB1 in feed could adversely affect the growth performance (average daily feed intake (ADFI), body weight (BW), average daily weight gain (ADG), feed conversion ratio (FCR), and shank length (SL)), decrease the relative weight of the spleen (p < 0.01), and increase the relative weight of the kidney (p < 0.01). Moreover, the reduction of feed intake could also adversely affect the growth performance (BW, ADG, and SL), but not as severely as mycotoxins do. Apart from that, OTA and AFB1 also activated the antioxidative and inflammation reactions of chicks, increasing the level of catalase (CAT), reactive oxygen species (ROS), and interleukin-8 (IL-8) while decreasing the level of IL-10 (p < 0.01), which was weakly influenced by the feed intake reduction. In addition, OTA and AFB1 induced histopathological changes and apoptosis in the kidney and liver as well as stimulated the growth of pernicious bacteria to cause toxic effects. There were no histopathological changes and apoptosis in the kidney and liver of the pair-feeding group. The combined toxicity of OTA and AFB1 had more severe effects on pullets than merely reducing feed supply. However, the proper reduction of the feed intake could improve pullets’ physical health by enriching the bacteria Lactobacillus, Phascolarctobacterium, Bacteroides, Parabacteroides, and Barnesiella

HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy

HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy

Conserved and Distinct Modes of CREB/ATF Transcription Factor Regulation by PP2A/B56γ and Genotoxic Stress

Activating transcription factor 1 (ATF1) and the closely related proteins CREB (cyclic AMP resonse element binding protein) and CREM (cyclic AMP response element modulator) constitute a subfamily of bZIP transcription factors that play critical roles in the regulation of cellular growth, metabolism, and survival. Previous studies demonstrated that CREB is phosphorylated on a cluster of conserved Ser residues, including Ser-111 and Ser-121, in response to DNA damage through the coordinated actions of the ataxia-telangiectasia-mutated (ATM) protein kinase and casein kinases 1 and 2 (CK1/2). Here, we show that DNA damage-induced phosphorylation by ATM is a general feature of CREB and ATF1. ATF1 harbors a conserved ATM/CK cluster that is constitutively and stoichiometrically phosphorylated by CK1 and CK2 in asynchronously growing cells. Exposure to DNA damage further induced ATF1 phosphorylation on Ser-51 by ATM in a manner that required prior phosphorylation of the upstream CK residues. Hyperphosphorylated ATF1 showed a 4-fold reduced affinity for CREB-binding protein. We further show that PP2A, in conjunction with its targeting subunit B56γ, antagonized ATM and CK1/2-dependent phosphorylation of CREB and ATF1 in cellulo. Finally, we show that CK sites in CREB are phosphorylated during cellular growth and that phosphorylation of these residues reduces the threshold of DNA damage required for ATM-dependent phosphorylation of the inhibitory Ser-121 residue. These studies define overlapping and distinct modes of CREB and ATF1 regulation by phosphorylation that may ensure concerted changes in gene expression mediated by these factors

A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models

van Lengerich et al. developed a human TREM2 antibody with a transport vehicle (ATV) that improves brain exposure and biodistribution in mouse models. ATV:TREM2 promotes microglial energetic capacity and metabolism via mitochondrial pathways. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Asymptotic behavior of delay difference systems

AbstractThis paper is concerned with a delay difference system where k is a positive integer, and f is a signal transmission function of McCulloch-Pitts type The difference system (*) can be regarded as the discrete analog of the artificial neural network of two neurons with McCulloch-Pitts nonlinearity. Some interesting results are obtained for the asymptotic behavior of the system (*)

On the horizontal-well pumping tests in anisotropic confined aquifers

A method that directly solves the boundary problem of flow to a horizontal-well in an anisotropic confined aquifer is provided. This method solves the point source problem first, and then integrates the point source solution along the horizontal well axis to obtain the horizontal well solution. The short and long time approximations of drawdowns are discussed and are utilized in the semilog analysis of the drawdown. A closed-form analytical solution of geometrical skin effect at the wellbore is derived. Type curves and derivative type curves of horizontal pumping wells are generated using the chow program. This program also calculates the drawdown at any given observation well at any given time. The horizontal-well type curves are different from the vertical-well type curves at early time, reflecting the different nature of flow to a horizontal-well and to a vertical-well. The horizontal-well type curves converge to the vertical-well type curves at late time, showing the similar nature of flow to a horizontal-well and to a vertical-well at late time. The sensitivity of the type curves and derivative type curves on monitoring well location, aquifer anisotropy, horizontal well depth, and horizontal well length is tested. These type curves and derivative type curves can be used in the matching point method for interpreting the pumping test data