[Analysis of the Jumping Characteristics and Influencing Factors of Ozone Pollution in Beijing].

Based on environmental monitoring data and meteorological observation data from 2016 to 2022 in Beijing, combined with backward trajectory clustering and potential source area contribution analysis, the characteristics, meteorological impacts, and potential source areas of ozone (O3) pollution were analyzed. The results showed that there was a total of 41 O3 pollution processes with jumping characteristics in Beijing from 2016 to 2022, with an average of 5.9 times a year. The occurrence time was concentrated in May to July, and the day of the jump (OJD2) was higher than the day before the jump (OJD1). The average value of ρ(O3-8h) was 78.3% higher, and the peak concentration was 78.9% higher. The high O3 concentration zone in the OJD2 region exhibited a characteristic of advancing from south to north. The main reasons for the occurrence of jumped O3 pollution in Beijing could be summarized as local accumulation caused by unfavorable meteorological conditions and regional transmission impact. The occurrence of jump-type ozone pollution was characterized by an increase in southerly wind frequency, temperature rise, pressure decrease, and precipitation decrease. The increase in southerly wind frequency provided conditions for the transport of O3 and its precursors, and rapid photochemical reactions occurred under local high temperatures, with less superimposed precipitation, comprehensively pushing up the ozone concentration level of OJD2. Six air mass transporting pathways were identified through clustering analysis; the air mass from the direction north of OJD2 decreased by 11.2%, whereas the air mass from the south and east directions increased by 6.7% and 4.4%, respectively, with the air masses mainly transmitting over short distances. The ozone concentration corresponding to the south and east directions was relatively high, making a significant contribution to Beijing's pollution. The analysis of potential source areas revealed that the main potential source areas of OJD2 ozone pollution were the central, southern, and eastern parts of Beijing-Tianjin-Hebei, which contributed 82.6% to the pollution trajectory. There was a significant contribution of regional transport during jump-type ozone pollution, and it is necessary to strengthen joint prevention and control in the Beijing-Tianjin-Hebei Region.

Attenuation of Alzheimer's brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model. METHODS: 5XFAD mice, an early onset ß-amyloid (Aß)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1-34 (50 µg/Kg), 5 days/week, starting at 2-month old (MO) for 2-3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aß and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope. RESULTS: A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aß-associated brain pathologies, including Aß and Aß deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice. CONCLUSIONS: These results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34's therapeutic potential for patients with not only osteoporosis but also AD.

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals.

Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation of Lrp4, a gene required for NMJ formation; inducible knockout of Lrp4 in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.

Muscular Swedish mutant APP-to-Brain axis in the development of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. Notably, patients with AD often suffer from severe sarcopenia. However, their direct link and relationship remain poorly understood. Here, we generated a mouse line, TgAPPsweHSA, by crossing LSL (LoxP-STOP-LoxP)-APPswe with HSA-Cre mice, which express APPswe (Swedish mutant APP) selectively in skeletal muscles. Examining phenotypes in TgAPPsweHSA mice showed not only sarcopenia-like deficit, but also AD-relevant hippocampal inflammation, impairments in adult hippocampal neurogenesis and blood brain barrier (BBB), and depression-like behaviors. Further studies suggest that APPswe expression in skeletal muscles induces senescence and expressions of senescence-associated secretory phenotypes (SASPs), which include inflammatory cytokines and chemokines; but decreases growth factors, such as PDGF-BB and BDNF. These changes likely contribute to the systemic and hippocampal inflammation, deficits in neurogenesis and BBB, and depression-like behaviors, revealing a link of sarcopenia with AD, and uncovering an axis of muscular APPswe to brain in AD development.

Osteoblastic Swedish mutant APP expedites brain deficits by inducing endoplasmic reticulum stress-driven senescence.

Patients with Alzheimer's disease (AD) often have osteoporosis or osteopenia. However, their direct link and relationship remain largely unclear. Previous studies have detected osteoporotic deficits in young adult Tg2576 and TgAPPsweOCN mice, which express APPswe (Swedish mutant) ubiquitously and selectively in osteoblast (OB)-lineage cells. This raises the question, whether osteoblastic APPswe contributes to AD development. Here, we provide evidence that TgAPPsweOCN mice also exhibit AD-relevant brain pathologies and behavior phenotypes. Some brain pathologies include age-dependent and regional-selective increases in glial activation and pro-inflammatory cytokines, which are accompanied by behavioral phenotypes such as anxiety, depression, and altered learning and memory. Further cellular studies suggest that APPswe, but not APPwt or APPlon (London mutant), in OB-lineage cells induces endoplasmic reticulum-stress driven senescence, driving systemic and cortex inflammation as well as behavioral changes in 6-month-old TgAPPsweOCN mice. These results therefore reveal an unrecognized function of osteoblastic APPswe to brain axis in AD development.

Parkinson's in the bone.

Patients with Parkinson's disease (PD) exhibit systemic deficits, including arthritis and osteoporosis-like symptoms. However, the questions, how the deficits in periphery organs or tissues occur in PD patients, and what are the relationship (s) of the periphery tissue deficits with the brain pathology (e.g., dopamine neuron loss), are at the beginning stage to be investigated. Notice that both PD and osteoporosis are the products of a complex interaction of genetic and environmental risk factors. Genetic mutations in numerous genes have been identified in patients either with recessive or autosomal dominant PD. Most of these PD risk genes are ubiquitously expressed; and many of them are involved in regulation of bone metabolism. Here, we review the functions of the PD risk genes in regulating bone remodeling and homeostasis. The knowledge gaps in our understanding of the bone-to-brain axis in PD development are also outlined.

Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis.

BACKGROUND AND OBJECTIVE: To determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms. METHODS: Immunoglobulin (Ig) was purified from a patient with myasthenia gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified. RESULTS: Patient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the ß3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4-MuSK interaction. DISCUSSION: Anti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4-MuSK interaction.

Hepcidin contributes to Swedish mutant APP-induced osteoclastogenesis and trabecular bone loss.

Patients with Alzheimer's disease (AD) often have lower bone mass than healthy individuals. However, the mechanisms underlying this change remain elusive. Previously, we found that Tg2576 mice, an AD animal model that ubiquitously expresses Swedish mutant amyloid precursor protein (APPswe), shows osteoporotic changes, reduced bone formation, and increased bone resorption. To understand how bone deficits develop in Tg2576 mice, we used a multiplex antibody array to screen for serum proteins that are altered in Tg2576 mice and identified hepcidin, a master regulator of iron homeostasis. We further investigated hepcidin's function in bone homeostasis and found that hepcidin levels were increased not only in the serum but also in the liver, muscle, and osteoblast (OB) lineage cells in Tg2576 mice at both the mRNA and protein levels. We then generated mice selectively expressing hepcidin in hepatocytes or OB lineage cells, which showed trabecular bone loss and increased osteoclast (OC)-mediated bone resorption. Further cell studies suggested that hepcidin increased OC precursor proliferation and differentiation by downregulating ferroportin (FPN) expression and increasing intracellular iron levels. In OB lineage cells, APPswe enhanced hepcidin expression by inducing ER stress and increasing OC formation, in part through hepcidin. Together, these results suggest that increased hepcidin expression in hepatocytes and OB lineage cells in Tg2576 mice contributes to enhanced osteoclastogenesis and trabecular bone loss, identifying the hepcidin-FPN-iron axis as a potential therapeutic target to prevent AD-associated bone loss.

Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response.

Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate-aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.

Linking cortical astrocytic neogenin deficiency to the development of Moyamoya disease-like vasculopathy.

Moyamoya-like vasculopathy, the "puff of smoke"-like small vessels in the brain, is initially identified in patients with Moyamoya disease (MMD), a rare cerebrovascular disease, and later found in patients with various types of neurological conditions, including Down syndrome, Stroke, and vascular dementia. It is thus of interest to understand how this vasculopathy is developed. Here, we provided evidence for cortical astrocytic neogenin (NEO1) deficiency to be a risk factor for its development. NEO1, a member of deleted in colorectal cancer (DCC) family netrin receptors, was reduced in brain samples of patients with MMD. Astrocytic Neo1-loss resulted in an increase of small blood vessels (BVs) selectively in the cortex. These BVs were dysfunctional, with leaky blood-brain barrier (BBB), thin arteries, and accelerated hyperplasia in veins and capillaries, resembled to the features of moyamoya-like vasculopathy. Additionally, we found that both MMD patient and Neo1 mutant mice exhibited altered gene expression in their cortex in proteins critical for not only angiogenesis [e.g., an increase in vascular endothelial growth factor (VEGFa)], but also axon guidance (e.g., netrin family proteins) and inflammation. In aggregates, these results suggest a critical role of astrocytic NEO1-loss in the development of Moyamoya-like vasculopathy, providing a mouse model for investigating mechanisms of Moyamoya-like vasculopathy.

Critical Roles of Embryonic Born Dorsal Dentate Granule Neurons for Activity-Dependent Increases in BDNF, Adult Hippocampal Neurogenesis, and Antianxiety-like Behaviors.

BACKGROUND: Dentate gyrus (DG), a "gate" that controls information flow into the hippocampus, plays important roles in regulating both cognitive (e.g., spatial learning and memory) and mood behaviors. Deficits in DG neurons contribute to the pathogenesis of not only neurological, but also psychiatric, disorders, such as anxiety disorder. Whereas DG's function in spatial learning and memory has been extensively investigated, its role in regulating anxiety remains elusive. METHODS: Using c-Fos to mark DG neuron activation, we identified a group of embryonic born dorsal DG (dDG) neurons, which were activated by anxiogenic stimuli and specifically express osteocalcin (Ocn)-Cre. We further investigated their functions in regulating anxiety and the underlying mechanisms by using a combination of chemogenetic, electrophysiological, and RNA-sequencing methods. RESULTS: The Ocn-Cre+ dDG neurons were highly active in response to anxiogenic environment but had lower excitability and fewer presynaptic inputs than those of Ocn-Cre- or adult born dDG neurons. Activating Ocn-Cre+ dDG neurons suppressed anxiety-like behaviors and increased adult DG neurogenesis, whereas ablating or chronically inhibiting Ocn-Cre+ dDG neurons exacerbated anxiety-like behaviors, impaired adult DG neurogenesis, and abolished activity (e.g., voluntary wheel running)-induced anxiolytic effect and adult DG neurogenesis. RNA-sequencing screening for factors induced by activation of Ocn-Cre+ dDG neurons identified BDNF, which was required for Ocn-Cre+ dDG neurons mediated antianxiety-like behaviors and adult DG neurogenesis. CONCLUSIONS: These results demonstrate critical functions of Ocn-Cre+ dDG neurons in suppressing anxiety-like behaviors but promoting adult DG neurogenesis, and both functions are likely through activation of BDNF.

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development.

Myosin X (Myo X) transports cargos to the tips of filopodia for cell adhesion, migration, and neuronal axon guidance. Deleted in Colorectal Cancer (DCC) is one of the Myo X cargos that is essential for Netrin-1-regulated axon pathfinding. The function of Myo X in axon development in vivo and the underlying mechanisms remain elusive. Here, we provide evidence for the role of Myo X in Netrin-1-DCC-regulated axon development in developing mouse neocortex. The knockout (KO) or knockdown (KD) of Myo X in cortical neurons of embryonic mouse brain impairs axon initiation and contralateral branching/targeting. Similar axon deficits are detected in Netrin-1-KO or DCC-KD cortical neurons. Further proteomic analysis of Myo X binding proteins identifies KIF13B (a kinesin family motor protein). The Myo X interaction with KIF13B is induced by Netrin-1. Netrin-1 promotes anterograde transportation of Myo X into axons in a KIF13B-dependent manner. KIF13B-KD cortical neurons exhibit similar axon deficits. Together, these results reveal Myo X-KIF13B as a critical pathway for Netrin-1-promoted axon initiation and branching/targeting.SIGNIFICANCE STATEMENT Netrin-1 increases Myosin X (Myo X) interaction with KIF13B, and thus promotes axonal delivery of Myo X and axon initiation and contralateral branching in developing cerebral neurons, revealing unrecognized functions and mechanisms underlying Netrin-1 regulation of axon development.

Linking skeletal muscle aging with osteoporosis by lamin A/C deficiency.

The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-ß-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells.

Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional "myosin tail homology 4-band 4.1, ezrin, radixin, moesin" (MyTH4-FERM) domain containing myosin, is implicated in regulating osteoclast (OC) adhesion, podosome positioning, and differentiation in vitro. However, evidence is lacking for Myo10 in vivo function. Here we show that mice with Myo10 loss of function, Myo10m/m , exhibit osteoporotic deficits, which are likely due to the increased OC genesis and bone resorption because bone formation is unchanged. Similar deficits are detected in OC-selective Myo10 conditional knockout (cko) mice, indicating a cell autonomous function of Myo10. Further mechanistic studies suggest that Unc-5 Netrin receptor B (Unc5b) protein levels, in particular its cell surface level, are higher in the mutant OCs, but lower in RAW264.7 cells or HEK293 cells expressing Myo10. Suppressing Unc5b expression in bone marrow macrophages (BMMs) from Myo10m/m mice by infection with lentivirus of Unc5b shRNA markedly impaired RANKL-induced OC genesis. Netrin-1, a ligand of Unc5b, increased RANKL-induced OC formation in BMMs from both wild-type and Myo10m/m mice. Taken together, these results suggest that Myo10 plays a negative role in OC formation, likely by inhibiting Unc5b cell-surface targeting, and suppressing Netrin-1 promoted OC genesis. © 2019 American Society for Bone and Mineral Research.

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress.

Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer's disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP's role in promoting bone formation. Mice that knocked out App gene (APP-/-) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP-/- OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.

Neogenin in Amygdala for Neuronal Activity and Information Processing.

Fear learning and memory are vital for livings to survive, dysfunctions in which have been implicated in various neuropsychiatric disorders. Appropriate neuronal activation in amygdala is critical for fear memory. However, the underlying regulatory mechanisms are not well understood. Here we report that Neogenin, a DCC (deleted in colorectal cancer) family receptor, which plays important roles in axon navigation and adult neurogenesis, is enriched in excitatory neurons in BLA (Basolateral amygdala). Fear memory is impaired in male Neogenin mutant mice. The number of cFos+ neurons in response to tone-cued fear training was reduced in mutant mice, indicating aberrant neuronal activation in the absence of Neogenin. Electrophysiological studies show that Neogenin mutation reduced the cortical afferent input to BLA pyramidal neurons and compromised both induction and maintenance of Long-Term Potentiation evoked by stimulating cortical afferent, suggesting a role of Neogenin in synaptic plasticity. Concomitantly, there was a reduction in spine density and in frequency of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents, suggesting a role of Neogenin in forming excitatory synapses. Finally, ablating Neogenin in the BLA in adult male mice impaired fear memory likely by reducing mEPSC frequency in BLA excitatory neurons. These results reveal an unrecognized function of Neogenin in amygdala for information processing by promoting and maintaining neurotransmission and synaptic plasticity and provide insight into molecular mechanisms of neuronal activation in amygdala.SIGNIFICANCE STATEMENT Appropriate neuronal activation in amygdala is critical for information processing. However, the underlying regulatory mechanisms are not well understood. Neogenin is known to regulate axon navigation and adult neurogenesis. Here we show that it is critical for neurotransmission and synaptic plasticity in the amygdala and thus fear memory by using a combination of genetic, electrophysiological, behavioral techniques. Our studies identify a novel function of Neogenin and provide insight into molecular mechanisms of neuronal activation in amygdala for fear processing.

Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4.

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice.SIGNIFICANCE STATEMENT This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.

[Variation of O3 Concentration in Different Regions of Beijing from 2006-2015].

O3 continuous monitoring data for the Dingling, Guanyuan, Liulihe, and Qianmen sites from 2006-2015 were analyzed to investigate concentration levels, variation trends, temporal variations, and relationships with precursors and meteorological factors. The results showed that the ten year average concentrations of O3 at the Dingling site were the highest at 65.2 µg·m-3, followed by concentrations at Liulihe (53.4 µg·m-3), Guanyuan (49.6 µg·m-3) and Qianmen (40.4 µg·m-3). The O3 concentrations at Dingling showed a decreasing trend[0.5 µg·(m3·a)-1], while O3 concentrations at Guanyuan[0.9 µg·(m3·a)-1], Liulihe[0.3 µg·(m3·a)-1], and Qianmen[0.3 µg·(m3·a)-1] showed an increasing trend. The highest monthly average concentrations appeared during June and August, and the highest frequency occurred in July (17 times) with average concentrations of 99.8 µg·m-3. The lowest monthly average concentrations appeared during November and February, and the highest frequency occurred in January (14 times) with an average concentration of 16.6 µg·m-3. Notably, the time for the peak concentrations of O3 appeared earlier in the day in recent years. The peak concentrations of O3 appeared at 15:00-16:00 during 2013-2015, which was 1-2 hours earlier than previous years. The heavy air pollution of O3 occurred on 11 days at the Dingling site in 2015, which was ten days more than in 2013, indicating O3 pollution in the downwind suburban regions of Beijing in summer became more and more serious. The concentrations of O3 and NO2 at Dingling showed a positive correlation, while the concentrations of O3 and NO2 at the other sites showed a negative correlation, indicating O3 formation in Dingling was sensitive to NO2 chemistry, while O3 formation at the other sites was sensitive to VOC chemistry. The concentrations of O3 showed a positive correlation with temperature and negative correlations with humidity and surface pressure. Temperature had the greatest influence on O3 concentration, followed by surface pressure and humidity. For cases when daily maximum temperature exceeded 30℃ and relative humidity was between 30% and 70%, the probability of the O3 daily maximum 8 h concentration exceeding 200 µg·m-3 was high, indicating the air quality level reached levels for light pollution and moderate pollution.

YAP promotes osteogenesis and suppresses adipogenic differentiation by regulating ß-catenin signaling.

YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with ß-catenin and is necessary for maintenance of nuclear ß-catenin level and Wnt/ß-catenin signaling. Expression of ß-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-ß-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.