Advanced progress of vestibular compensation in vestibular neural networks.

Vestibular compensation is the natural process of recovery that occurs with acute peripheral vestibular lesion. Here, we summarize the current understanding of the mechanisms underlying vestibular compensation, focusing on the role of the medial vestibular nucleus (MVN), the central hub of the vestibular system, and its associated neural networks. The disruption of neural activity balance between the bilateral MVNs underlies the vestibular symptoms after unilateral vestibular damage, and this balance disruption can be partially reversed by the mutual inhibitory projections between the bilateral MVNs, and their top-down regulation by other brain regions via different neurotransmitters. However, the detailed mechanism of how MVN is involved in vestibular compensation and regulated remains largely unknown. A deeper understanding of the vestibular neural network and the neurotransmitter systems involved in vestibular compensation holds promise for improving treatment outcomes and developing more effective interventions for vestibular disorders.

Inhibition of MAT2A Impairs Skeletal Muscle Repair Function.

The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53-Fas-mediated apoptosis.

In vivo mapping of the mouse Galnt3-specific O-glycoproteome.

The UDP-N-acetylgalactosamine polypeptide:N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes initiates O-linked glycosylation by catalyzing the addition of the first GalNAc sugar to serine or threonine on proteins destined to be membrane-bound or secreted. Defects in individual isoforms of the GalNAc-T family can lead to certain congenital disorders of glycosylation (CDG). The polypeptide N-acetylgalactosaminyltransferase 3 (GALNT)3-CDG, is caused by mutations in GALNT3, resulting in hyperphosphatemic familial tumoral calcinosis due to impaired glycosylation of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) within osteocytes of the bone. Patients with hyperphosphatemia present altered bone density, abnormal tooth structure, and calcified masses throughout the body. It is therefore important to identify all potential substrates of GalNAc-T3 throughout the body to understand the complex disease phenotypes. Here, we compared the Galnt3-/- mouse model, which partially phenocopies GALNT3-CDG, with WT mice and used a multicomponent approach using chemoenzymatic conditions, a product-dependent method constructed using EThcD triggered scans in a mass spectrometry workflow, quantitative O-glycoproteomics, and global proteomics to identify 663 Galnt3-specific O-glycosites from 269 glycoproteins across multiple tissues. Consistent with the mouse and human phenotypes, functional networks of glycoproteins that contain GalNAc-T3-specific O-glycosites involved in skeletal morphology, mineral level maintenance, and hemostasis were identified. This library of in vivo GalNAc-T3-specific substrate proteins and O-glycosites will serve as a valuable resource to understand the functional implications of O-glycosylation and to unravel the underlying causes of complex human GALNT3-CDG phenotypes.

Molecular profile of vestibular compensation in the medial vestibular nucleus after unilateral labyrinthectomy.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.

[Interaction Effects of Vegetation and Soil Factors on Microbial Communities in Alpine Steppe Under Degradation].

To clarify the regulating effect of vegetation and soil factors on microbial communities in the alpine steppe under degradation on the Qinghai-Xizang Plateau, the alpine steppe in the Sanjiangyuan area of the Qinghai-Tibet Plateau was chosen. We analyzed the differences in vegetation and soil factors in different stages of degradation （non-degradation, moderate degradation, and severe degradation） and detected the variations in microbial community characteristics in the alpine steppe under different degradation stages using high-throughput sequencing technology. Eventually, redundancy analysis （RDA） and multiple regression matrixes （MRM） based on the similarity or dissimilarity matrix were used to identify key environmental factors regulating microbial （bacterial and fungal） community changes under degradation. The results showed that the degradation of the alpine steppe significantly changed the community coverage, height, biomass, and important value of graminae； significantly reduced the contents of soil organic matter, total nitrogen, total phosphorus, and silt； and increased the soil bulk density and sand content. Degradation did not change the composition of bacteria and fungi, but their composition proportions changed and also resulted in the loss of microbial richness （Chao1 index and Richness index） but did not significantly change the microbial diversity （Shannon index）. With the occurrence of degradation, the vegetation characteristics, soil physicochemical properties, and microbial diversity showed a consistent change trend. Combined with the characteristics of the network topology changes （the number of nodes and clustering coefficient significantly decreased）, it was found that degradation of the alpine steppe led to the decline of interspecies interactions, decentralization of network, and homogenization of microorganisms, but the cooperation relations among the species were maintained （positive correlation connections accounted for more than 90% in all degradation stages）. Under the alpine steppe degradation, the vegetation-soil interaction had the greatest effect on soil bacterial community, whereas soil physicochemical properties had the greatest influence on soil fungal community. Specifically, vegetation community height, biomass, and soil bulk density were the mutual factors regulating soil microorganisms, whereas the vegetation Simpson index, important value of graminae, soil total phosphorus, total potassium, and silt content were the unique factors affecting the soil bacterial community, and soil pH and total nitrogen content were the particular factors affecting the soil fungal community.

Testing the amount of nicotinamide mononucleotide and urolithin A as compared to the label claim.

Healthy Longevity Medicine aims to optimize health by targeting aging processes across the lifespan. Addressing accelerated aging involves adaptation of lifestyle and the use of geroprotective drugs and supplements, including nutritional supplements and bioactive compounds. The Food and Drug Administration, under the Dietary Supplement Health and Education Act, categorizes bioactive compounds and medicinal products as dietary supplements. While numerous companies sell ingredients that can be deemed geroprotectors, there's limited oversight in their quality control. Governmental safety authorities only verify the presence of prohibited compounds, not the accuracy of ingredients listed on labels.Here, Nicotinamide mononucleotide and Urolithin A supplements, easily accessible online or in pharmacies, were tested for their active ingredient content. Results showed a significant deviation from the labeled amounts, ranging from + 28.6% to -100%. This indicates a considerable disparity in the quality of geroprotective supplements.To address this variability, collaboration between and within societies representing healthcare professionals, industry and regulatory bodies is imperative to ensure the quality of geroprotective supplements.

Characteristics of the phyllosphere microbial community and its relationship with major aroma precursors during the tobacco maturation process.

Numerous bacteria, fungi and other microorganisms in the tobacco phyllosphere interstellar area participate in the physiological metabolism of plants by interacting with the host. However, there is currently little research on the characteristics of tobacco phyllosphere microbial communities, and the correlation between tobacco phyllosphere microbial communities and phyllosphere factor indicators is still unknown. Therefore, high-throughput sequencing technology based on the 16S rRNA/ITS1 gene was used to explore the diversity and composition characteristics of tobacco phyllosphere bacterial and fungal communities from different maturation processes, and to identify marker genera that distinguish phyllosphere microbial communities. In this study, the correlations between tobacco phyllosphere bacterial and fungal communities and the precursors of major aroma compounds were explored. The results showed that as the tobacco plants matured, the density of glandular trichomes on the tobacco leaves gradually decreased. The surface physicochemical properties of tobacco leaves also undergo significant changes. In addition, the overall bacterial alpha diversity in the tobacco phyllosphere area increased with maturation, while the overall fungal alpha diversity decreased. The beta diversity of bacteria and fungi in the tobacco phyllosphere area also showed significant differences. Specifically, with later top pruning time, the relative abundances of Acidisoma, Ralstonia, Bradyrhizobium, Alternaria and Talaromyces gradually increased, while the relative abundances of Pseudomonas, Filobassidium, and Tausonia gradually decreased. In the bacterial community, Acidisoma, Ralstonia, Bradyrhizobium, and Alternaria were significantly positively correlated with tobacco aroma precursors, with significant negative correlations with tobacco phyllosphere trichome morphology, while Pseudomonas showed the opposite pattern; In the fungal community, Filobasidium and Tausonia were significantly negatively correlated with tobacco aroma precursors, and significantly positively correlated with tobacco phyllosphere trichome morphology, while Alternaria showed the opposite pattern. In conclusion, the microbiota (bacteria and fungi) and aroma precursors of the tobacco phyllosphere change significantly as tobacco matures. The presence of Acidisoma, Ralstonia, Bradyrhizobium and Alternaria in the phyllosphere microbiota of tobacco may be related to the aroma precursors of tobacco.

Lercanidipine's Antioxidative Effect Prevents Noise-Induced Hearing Loss.

Noise-induced hearing loss (NIHL) is a prevalent form of adult hearing impairment, characterized by oxidative damage to auditory sensory hair cells. Although certain dihydropyridines, the L-type calcium channel blockers, exhibit protective properties against such damage, the ability of third-generation dihydropryidines like lercanidipine to mitigate NIHL remains unclear.We utilized glucose oxidase (GO)-treated OC1 cell lines and cochlear explants to evaluate the protective influence of lercanidipine on hair cells. To further investigate its effectiveness, we exposed noise-stimulated mice in vivo and analyzed their hearing thresholds. Additionally, we assessed the antioxidative capabilities of lercanidipine by examining oxidation-related enzyme expression and levels of oxidative stress markers, including 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE). Our findings demonstrate that lercanidipine significantly reduces the adverse impacts of GO on both OC-1 cell viability (0.3 to 2.5 µM) and outer hair cell (OHC) survival in basal turn cochlear explants (7 µM). These results are associated with increased mRNA expression of antioxidant enzyme genes (HO-1, SOD1/2, and Txnrd1), along with decreased expression of oxidase genes (COX-2, iNOS). Crucially, lercanidipine administration prior to, and following, noise exposure effectively ameliorates NIHL, as evidenced by lowered hearing thresholds and preserved OHC populations in the basal turn, 14 days post-noise stimulation at 110 dB SPL. Moreover, our observations indicate that lercanidipine's antioxidative action persists even three days after simultaneous drug and noise treatments, based on 3-nitrotyrosine and 4-hydroxynonenal immunostaining in the basal turn. Based on these findings, we propose that lercanidipine has the capacity to alleviate NIHL and safeguard OHC survival in the basal turn, potentially via its antioxidative mechanism. These results suggest that lercanidipine holds promise as a clinically viable option for preventing NIHL in affected individuals.

Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition.

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system.

Vestibular dysfunction leads to cognitive impairments: State of knowledge in the field and clinical perspectives (Review).

The vestibular system may have a critical role in the integration of sensory information and the maintenance of cognitive function. A dysfunction in the vestibular system has a significant impact on quality of life. Recent research has provided evidence of a connection between vestibular information and cognitive functions, such as spatial memory, navigation and attention. Although the exact mechanisms linking the vestibular system to cognition remain elusive, researchers have identified various pathways. Vestibular dysfunction may lead to the degeneration of cortical vestibular network regions and adversely affect synaptic plasticity and neurogenesis in the hippocampus, ultimately contributing to neuronal atrophy and cell death, resulting in memory and visuospatial deficits. Furthermore, the extent of cognitive impairment varies depending on the specific type of vestibular disease. In the present study, the current literature was reviewed, potential causal relationships between vestibular dysfunction and cognitive performance were discussed and directions for future research were proposed.

mGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus.

AIMS: To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed. RESULTS: mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL. CONCLUSION: mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.

Handelin alleviates cachexia- and aging-induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation.

BACKGROUND: Handelin is a bioactive compound from Chrysanthemum indicum L. that improves motor function and muscle integrity during aging in Caenorhabditis elegans. This study aimed to further evaluate the protective effects and molecular mechanisms of handelin in a mouse muscle atrophy model induced by cachexia and aging. METHODS: A tumour necrosis factor (TNF)-α-induced atrophy model was used to examine handelin activity in cultured C2C12 myotubes in vitro. Lipopolysaccharide (LPS)-treated 8-week-old model mice and 23-month-old (aged) mice were used to examine the therapeutic effects of handelin on cachexia- and aging-induced muscle atrophy, respectively, in vivo. Protein and mRNA expressions were analysed by Western blotting, ELISA and quantitative PCR, respectively. Skeletal muscle mass was measured by histological analysis. RESULTS: Handelin treatment resulted in an upregulation of protein levels of early (MyoD and myogenin) and late (myosin heavy chain, MyHC) differentiation markers in C2C12 myotubes (P < 0.05), and enhanced mitochondrial respiratory (P < 0.05). In TNF-α-induced myotube atrophy model, handelin maintained MyHC protein levels, increased insulin-like growth factor (Igf1) mRNA expression and phosphorylated protein kinase B protein levels (P < 0.05). Handelin also reduced atrogin-1 expression, inhibited nuclear factor-κB activation and reduced mRNA levels of interleukin (Il)6, Il1b and chemokine ligand 1 (Cxcl1) (P < 0.05). In LPS-treated mice, handelin increased body weight (P < 0.05), the weight (P < 0.01) and cross-sectional area (CSA) of the soleus muscle (P < 0.0001) and improved motor function (P < 0.05). In aged mice, handelin slightly increased the weight of the tibialis anterior muscle (P = 0.06) and CSA of the tibialis anterior and gastrocnemius muscles (P < 0.0001). In the tibialis anterior muscle of aged mice, handelin upregulated mRNA levels of Igf1 (P < 0.01), anti-inflammatory cytokine Il10 (P < 0.01), mitochondrial biogenesis genes (P < 0.05) and antioxidant-related enzymes (P < 0.05) and strengthened Sod and Cat enzyme activity (P < 0.05). Handelin also reduced lipid peroxidation and protein carbonylation, downregulated mRNA levels of Fbxo32, Mstn, Cxcl1, Il1b and Tnf (P < 0.05), and decreased IL-1ß levels in serum (P < 0.05). Knockdown of Hsp70 or using an Hsp70 inhibitor abolished the ameliorating effects of handelin on myotube atrophy. CONCLUSIONS: Handelin ameliorated cachexia- and aging-induced skeletal muscle atrophy in vitro and in vivo, by maintaining homeostasis of protein synthesis and degradation, possibly by inhibiting inflammation. Handelin is a potentially promising drug candidate for the treatment of muscle wasting.

Tuning the Catalytic Activity of Covalent Metal-Organic Frameworks for CO2 Cycloaddition Reactions.

The development of efficient, recyclable and low-cost heterogeneous catalysts for conversion of carbon dioxide (CO2 ) into epoxides is highly desired, yet remain a challenge. Herein, we have prepared three two-dimensional (2D) copper(I) cyclic trinuclear units (Cu(I)-CTUs) based covalent metal-organic frameworks (CMOFs), namely JNM-13, JNM-14, and JNM-15, via a one-pot reaction by combination of coordination and dynamic covalent chemistry. Among them, JNM-15 contained the highest density of copper catalytic sites, and exhibited the highest capacity for adsorption of CO2 . More interestingly, JNM-15 delivered the highest catalytic activity for cycloaddition of CO2 to epoxides with good yields (up to 99 %), good substrate compatibility (11 examples) and reusability (four catalytic cycles) under mild condition.

The Effects of Unilateral Labyrinthectomy on Monoamine Neurotransmitters in the Medial Vestibular Nucleus of Rats.

BACKGROUND: This study aimed to investigate the effects of unilateral labyrinthectomy (UL) on monoamine neurotransmitters in the medial vestibular nucleus (MVN) of rats. METHODS: Adult Sprague-Dawley rats were utilized for the vestibular impaired animal model through UL. The success of the model establishment and the recovery process were evaluated using vestibular behavioral tests, including spontaneous nystagmus, postural asymmetry, and balance beam test. Additionally, the expression levels of c-Fos protein in the MVN were assessed by immunofluorescence. Furthermore, changes in the expression levels of monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), and histamine in the MVN, were analyzed using high-performance liquid chromatography (HPLC) at different time points after UL (4 h, 8 h, 1 day, 2 days, 4 days, and 7 days). RESULTS: Compared to the sham control group, the UL group exhibited the most pronounced vestibular impairment symptoms at 4 h post-UL, which significantly decreased at 4 days and almost fully recovered by 7 days. Immunofluorescence results showed a notable upregulation of c-Fos expression in the MVN subsequent to the UL-4 h, serving as a reliable indicator of heightened neuronal activity. In comparison with the sham group, HPLC analysis showed that the levels of 5-HT and NE in the ipsilesional MVN of the UL group were significantly elevated within 4 days after UL, and peaked on 1 day and 2 days, respectively. DA showed an increasing trend at different time points up to 7 days post-UL, while histamine levels significantly increased only at 1 day post-UL. CONCLUSIONS: UL-induced dynamic changes in monoamine neurotransmitters during the early compensation period in the rat MVN may be associated with the regulation of the central vestibular compensation mechanism by the MVN.

Dispelling Mist That Obscures Positional Vertigo in Vestibular Migraine.

(1) Background: Patients with vestibular migraine (VM) often present with positional vertigo. A portion of these patients have features of benign paroxysmal positional vertigo (BPPV). It is a challenge to rapidly identify the BPPV component of VM associated with positional vertigo. (2) Methods: Retrospective data collected from 60 VM and 47 VM + BPPV patients were used to build a diagnostic model, and then prospective data from 47 patients were used for the external validation. All patients had VM manifesting as positional vertigo, with or without accompanying BPPV. The clinical manifestations and the results of vestibular function tests were comprehensively analyzed using logistic regression. (3) Results: The univariate and multivariate analyses showed that the age, symptom duration, tinnitus, ear fullness, nausea, head shaking nystagmus, the direction of the Dix-Hallpike and roll tests, and horizontal gain could help differentiate between the two groups. A nomogram and an online calculator were generated. The C-index was 0.870. The diagnostic model showed good discriminative power and calibration performance during internal and external validation. (4) Conclusions: This study provided a new perspective for diagnosing VM with positional vertigo by identifying the BPPV component and, for the first time, offers a prediction model integrating multiple predictors.

Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.

The family of GalNAc-Ts (GalNAcpolypeptide:N-Acetylgalactosaminyl transferases) catalyzes the first committed step in the synthesis of O-glycans, which is an abundant and biologically important protein modification. Abnormalities in the activity of individual GalNAc-Ts can result in congenital disorders of O-glycosylation (CDG) and influence a broad array of biological functions. How site-specific O-glycans regulate biology is unclear. Compiling in vivo O-glycosites would be an invaluable step in determining the function of site-specific O-glycans. We integrated chemical and enzymatic conditions that cleave O-glycosites, a higher-energy dissociation product ions-triggered electron-transfer/higher-energy collision dissociation mass spectrometry (MS) workflow and software to study nine mouse tissues and whole blood. We identified 2,154 O-glycosites from 595 glycoproteins. The O-glycosites and glycoproteins displayed consensus motifs and shared functions as classified by Gene Ontology terms. Limited overlap of O-glycosites was observed with protein O-GlcNAcylation and phosphorylation sites. Quantitative glycoproteomics and proteomics revealed a tissue-specific regulation of O-glycosites that the differential expression of Galnt isoenzymes in tissues partly contributes to. We examined the Galnt2-null mouse model, which phenocopies congenital disorder of glycosylation involving GALNT2 and revealed a network of glycoproteins that lack GalNAc-T2-specific O-glycans. The known direct and indirect functions of these glycoproteins appear consistent with the complex metabolic phenotypes observed in the Galnt2-null animals. Through this study and interrogation of databases and the literature, we have compiled an atlas of experimentally identified mouse O-glycosites consisting of 2,925 O-glycosites from 758 glycoproteins.

Study on the Effect of Pain Programmed Care Based on the Concept of Prehabilitation on the Recovery of Joint Function and WHOQOL-BREF Score in Elderly Patients after Total Hip Arthroplasty.

Objective: To assess the impact of pain-programmed care, utilizing the concept of prehabilitation, on the postoperative recovery of joint function and WHOQOL-BREF score in elderly patients following total hip arthroplasty. Methods: Ninety cases of elderly patients with total hip arthroplasty admitted to our hospital from January to December 2022 were selected as the observation sample, and the 90 elderly patients with total hip arthroplasty were divided into 45 control groups and 45 control groups by random number table method. The pain assessment, functional exercise compliance, hip joint function and quality of life of the two groups were compared after the intervention. Results: The nursing intervention led to a significant reduction in pain scores and improvement in quality of life for elderly patients undergoing total hip joint replacement. The observation group showed a greater reduction in resting pain scores (6.20 ± 0.63 vs. 3.78 ± 0.67, P < .05) and activity pain scores (8.78 ± 0.64 vs. 4.89 ± 0.68, P < .05) compared to the control group. Additionally, the observation group demonstrated significant improvements in physiology (55.73 ± 2.14 vs. 71.87 ± 21.59, P < .05), psychology (55.71 ± 2.13 vs. 72.60 ± 2.20, P < .05), social relations (55.73 ± 2.13 vs. 71.96 ± 1.57, P < .05), and environmental effect (55.60 ± 2.15 vs. 68.62 ± 1.51, P < .05) after care, whereas the control group exhibited lesser improvements in these areas (physiology: 55.60 ± 2.24 vs. 64.53±2.02, P < .05; psychology: 55.60 ± 2.22 vs. 66.33±1.99, P < .05; social relations: 55.82 ± 2.09 vs. 67.84 ± 1.73, P < .05; environmental effect: 55.89 ± 2.18 vs. 62.09 ± 51.49, P < .05). These findings demonstrate the significant impact of nursing intervention on pain reduction and improved quality of life for elderly patients undergoing total hip joint replacement. Conclusion: Pain programmed care based on the concept of prehabilitation for elderly patients undergoing total hip arthroplasty has a significant positive impact on pain control, compliance with functional exercise, recovery of hip function, and improvement of quality of life. These findings highlight the benefits of implementing pain management strategies and rehabilitation programs in the field of total hip arthroplasty and elderly care.

Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model.

The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

Differential Modulation of Cerebellar Flocculus Unipolar Brush Cells during Vestibular Compensation.

Vestibular compensation is a natural behavioral recovery process following unilateral vestibular injury. Understanding the mechanism can considerably enhance vestibular disorder therapy and advance the adult central nervous system functional plasticity study after injury. The cerebellum, particularly the flocculonodular lobe, tightly modulates the vestibular nucleus, the center for vestibular compensation; however, it is still unclear if the flocculus on both sides is involved in vestibular compensation. Here we report that the unipolar brush cells (UBCs) in the flocculus are modulated by unilateral labyrinthectomy (UL). UBCs are excitatory interneurons targeting granule cells to provide feedforward innervation to the Purkinje cells, the primary output neurons in the cerebellum. According to the upregulated or downregulated response to the mossy fiber glutamatergic input, UBC can be classified into ON and OFF forms of UBCs. Furthermore, we discovered that the expression of marker genes of ON and OFF UBCs, mGluR1α and calretinin, was increased and decreased, respectively, only in ipsilateral flocculus 4-8 h after UL. According to further immunostaining studies, the number of ON and OFF UBCs was not altered during UL, demonstrating that the shift in marker gene expression level in the flocculus was not caused by the transformation of cell types between UBCs and non-UBCs. These findings imply the importance of ipsilateral flocculus UBCs in the acute response of UL, and ON and OFF UBCs may be involved in vestibular compensation in opposite directions.

Dynamic expression of mucins and the genes controlling mucin-type O-glycosylation within the mouse respiratory system.

The COVID-19 global pandemic has underscored the need to understand how viruses and other pathogens are able to infect and replicate within the respiratory system. Recent studies have highlighted the role of highly O-glycosylated mucins in the protection of the respiratory system as well as how mucin-type O-glycosylation may be able to modify viral infectivity. Therefore, we set out to identify the specific genes controlling mucin-type O-glycosylation throughout the mouse respiratory system as well as determine how their expression and the expression of respiratory mucins is influenced by infection or injury. Here, we show that certain mucins and members of the Galnt family are abundantly expressed in specific respiratory tissues/cells and demonstrate unique patterns of O-glycosylation across diverse respiratory tissues. Moreover, we find that the expression of certain Galnts and mucins is altered during lung infection and injury in experimental mice challenged with infectious agents, toxins, and allergens. Finally, we examine gene expression changes of Galnts and mucins in a mouse model of SARS-CoV-2 infection. Our work provides foundational knowledge regarding the specific expression of Galnt enzyme family members and mucins throughout the respiratory system, and how their expression is altered upon lung infection and injury.