ABSTRACT
Wild ungulates play crucial roles in maintaining the structure and function of local ecosystems. The alpine musk deer (Moschus chrysogaste), white-lipped deer (Przewalskium albirostris), and red serow (Capricornis rubidus) are widely distributed throughout the Nyenchen Tanglha Mountains of Tibet. However, research on the mechanisms underlying their coexistence in the same habitat remains lacking. This study aimed to investigate the mechanisms underlying the coexistence of these species based on their dietary preferences through DNA barcoding using the fecal samples of these animals collected from the study area. These species consume a wide variety of food types. Alpine musk deer, white-lipped deer, and red serow consume plants belonging to 74 families and 114 genera, 62 families and 122 genera, and 63 families and 113 genera, respectively. Furthermore, significant differences were observed in the nutritional ecological niche among these species, primarily manifested in the differentiation of food types and selection of food at the genus level. Owing to differences in social behavior, body size, and habitat selection, these three species further expand their differentiation in resource selection, thereby making more efficient use of environmental resources. Our findings indicate these factors are the primary reasons for the stable coexistence of these species.
ABSTRACT
Musk secreted by the musk glands in male forest musk deer (FMD; Moschus berezovskii) is highly valued for its pharmaceutical and perfumery applications. However, the regulatory mechanisms underlying musk secretion are not well understood. This study aimed to investigate the genes and transcription factors involved in musk secretion across different periods and ages. We analyzed the musk glands of adult male FMD during the non-secretory and secretory periods, as well as juvenile and adult male FMD during the secretory period, using single-cell multiome ATAC+gene expression technique. Our analysis identified 13 cell types, including acinar cells of Types 1 and 2. Chromatin accessibility analysis and gene expression data confirmed that the genes Map3k2, Hsd17b12, and Jun are critical for musk secretion. Additionally, EHF, NR4A2, and FOXO1 proteins play crucial regulatory roles. Weighted gene co-expression network analysis (WGCNA) highlighted the importance of GnRH signaling pathway in musk secretion. Gene set enrichment analysis (GSEA) showed that the steroid hormone biosynthesis pathway is notably enriched in acinar cells. Furthermore, intercellular communication appears to influence both the initiation and maintenance of musk secretion. These findings provide valuable insights into the molecular pathways of musk secretion in FMD, offering potential avenues for increasing musk production and developing treatment for inflammation and tumors.
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INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction. MG patients may present de novo with primary otolaryngology complaints, including swallowing dysfunction. This study describes a range of unique presentations and rare diagnostic serologies, which have not previously been fully described. METHODS: A retrospective review was performed of all patients presenting with primary symptom of dysphagia and subsequently diagnosed with MG. Data collected included demographics, clinical presentation, swallow studies, serology, imaging, treatment, and response. RESULTS: Five patients met the inclusion criteria. Four endorsed dysphagia as primary complaint and one endorsed dysphagia and dysphonia. All patients underwent in-office swallow evaluations that showed vallecular or pyriform sinus residue. Three patients completed modified barium swallow studies that showed pharyngeal weakness and epiglottic dysfunction in all, and upper esophageal sphincter dysfunction in two. One patient with additional symptom of dyspnea was admitted and found to be in myasthenic crisis. Upon serologic evaluation, three patients were positive for acetylcholine receptor (AChR) antibodies only, one for muscle-specific-kinase (MuSK) antibodies only, and one for low density lipoprotein receptor-related protein 4 (LRP4) antibodies only. All patients received neurology evaluation and were treated with steroids, pyridostigmine, plasma exchange, or rituximab. In three patients with over 1 year follow-up, symptoms were significantly improved or resolved. CONCLUSION: MG is an important differential diagnosis in patients with unexplained pharyngeal dysphagia. While workup can include AChR antibody screening, in seronegative patients with persistent symptoms, additional testing for MuSK and LRP4 may lead to diagnosis and effective treatment. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2024.
ABSTRACT
Myasthenia gravis (MG) is characterized by muscle weakness and fatigability. The presence of autoantibodies against the acetylcholine receptors (AChR) at the neuromuscular junction, which impairs neuromuscular transmission, is the hallmark of the disease. However, a minority of patients have antibodies against muscle-specific tyrosine kinase (MuSK), which is referred to as MuSK myasthenia gravis (MuSK-MG). We present the case of a 56-year-old female patient presenting with progressive dysphagia, slurred speech, and fatigable ptosis. She had a positive icepack test and a positive repetitive nerve stimulation test (RNST). Her AchR antibodies were negative, and the MuSK antibodies were positive. Her clinical response to pyridostigmine was unsatisfactory, but she had a good recovery with rituximab. Even though MuSK-MG is rare, it is an important diagnostic consideration, particularly in patients presenting with atypical symptoms or lacking AChR antibodies and in patients who have a poor response to conventional treatment. Acetylcholinesterase inhibitors, corticosteroids, immunosuppressants, and newer biologic agents targeting B cells are some of the treatments.
ABSTRACT
Musk is an important animal product, but the musk secretion mechanism of forest musk deer (Moschus berezovskii) is still unclear. The musk synthesis process in forest musk deer is extremely complex, and many raw materials are directly or indirectly derived from forest musk deer blood. In this study, metabolomics was used to analyze the blood of forest musk deer in secretory and non-secretory phases for the first time, aim at explaining the secretion mechanism from the perspective of blood metabolism. We found that P450-related, choline-related, axonal regeneration and other pathways and related metabolites were significantly enriched during the musk secretion of forest musk deer. These pathways and metabolites related to P450 and choline in blood may have important implications for the mechanism of musk secretion in forest musk deer, because blood components were closely related to musk components and could provide raw materials for musk synthesis in musk gland cells.
Subject(s)
Deer , Fatty Acids, Monounsaturated , Metabolome , Animals , Deer/blood , Deer/metabolism , Fatty Acids, Monounsaturated/blood , Fatty Acids, Monounsaturated/metabolism , Metabolomics/methods , ForestsABSTRACT
Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.
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Neuromuscular signal transmission is affected in various diseases including myasthenia gravis, congenital myasthenic syndromes, and sarcopenia. We used an ATF2-luciferase system to monitor the phosphorylation of MuSK in HEK293 cells introduced with MUSK and LRP4 cDNAs to find novel chemical compounds that enhanced agrin-mediated acetylcholine receptor (AChR) clustering. Four compounds with similar chemical structures carrying benzene rings and heterocyclic rings increased the luciferase activities 8- to 30-folds, and two of them showed continuously graded dose dependence. The effects were higher than that of disulfiram, a clinically available aldehyde dehydrogenase inhibitor, which we identified to be the most competent preapproved drug to enhance ATF2-luciferase activity in the same assay system. In C2C12 myotubes, all the compounds increased the area, intensity, length, and number of AChR clusters. Three of the four compounds increased the phosphorylation of MuSK, but not of Dok7, JNK. ERK, or p38. Monitoring cell toxicity using the neurite elongation of NSC34 neuronal cells as a surrogate marker showed that all the compounds had no effects on the neurite elongation up to 1 µM. Extensive docking simulation and binding structure prediction of the four compounds with all available human proteins using AutoDock Vina and DiffDock showed that the four compounds were unlikely to directly bind to MuSK or Dok7, and the exact target remained unknown. The identified compounds are expected to serve as a seed to develop a novel therapeutic agent to treat defective NMJ signal transmission.
Subject(s)
Muscle Fibers, Skeletal , Receptors, Nicotinic , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Animals , Mice , Cell Line , Humans , Activating Transcription Factor 2/genetics , Activating Transcription Factor 2/metabolism , Genes, Reporter , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cholinergic/genetics , Receptors, Cholinergic/metabolism , Multigene Family , Signal Transduction/drug effects , Muscle Proteins/genetics , Muscle Proteins/metabolism , Neurites , Bungarotoxins/pharmacology , Benzene/pharmacology , Heterocyclic Compounds/pharmacology , Molecular Docking SimulationABSTRACT
Myasthenia gravis with positive MuSK antibody often involves the bulbar muscles and is usually refractory to acetylcholinesterase inhibitors. For MuSK-MG patients who experience acute exacerbations and do not respond to conventional treatments, there is an urgent need to find more suitable treatment options. With the advent of biologic agents, efgartigimod has shown promising results in the treatment of MG. We report a 65-year-old MuSK-MG patient who presented with impaired eye movements initially, and the symptoms rapidly worsened within a week, affecting the limbs and neck muscles, and had difficulties in chewing and swallowing. Lymphoplasmapheresis did not achieve satisfactory results, but after a cycle of efgartigimod treatment, the patient's symptoms gradually improved and remained in a good clinical state for several months.
Subject(s)
Myasthenia Gravis , Receptors, Cholinergic , Humans , Myasthenia Gravis/drug therapy , Aged , Receptors, Cholinergic/immunology , Treatment Outcome , Receptor Protein-Tyrosine Kinases/immunology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Autoantibodies/immunology , Autoantibodies/blood , Male , FemaleABSTRACT
Cryptosporidium spp. are protozoa commonly found in domestic and wild animals. Limited information is available on Cryptosporidium in deer worldwide. In this study, 201 fecal samples were collected from Alpine musk deer on three farms in Gansu Province, China. Detection and subtyping of Cryptosporidium were performed by PCR and sequence analysis of the SSU rRNA and gp60 genes. The prevalence of Cryptosporidium infection in Alpine musk deer was 3.9% (8/201), with infection rates of 1.0% (1/100), 2.8% (1/36), and 9.2% (6/65) in three different farms. All positive samples for Cryptosporidium were from adult deer. Two Cryptosporidium species were identified, including C. parvum (n = 2) and C. xiaoi (n = 6). The C. parvum isolates were subtyped as IIdA15G1, while the C. xiaoi isolates were subtyped as XXIIIa (n = 2) and XXIIIg (n = 4). The IIdA15G1 subtype of C. parvum was found for the first time in deer. These results provide important insights into the identity and human infectious potential of Cryptosporidium in farmed Alpine musk deer.
Subject(s)
Cryptosporidiosis , Cryptosporidium , Deer , Feces , Animals , Deer/parasitology , Cryptosporidiosis/parasitology , Cryptosporidiosis/epidemiology , Cryptosporidium/genetics , Cryptosporidium/isolation & purification , Cryptosporidium/classification , China/epidemiology , Feces/parasitology , Prevalence , DNA, Protozoan/genetics , Phylogeny , Polymerase Chain Reaction , Sequence Analysis, DNA , Genotype , DNA, Ribosomal/genetics , DNA, Ribosomal/chemistryABSTRACT
Background: Forest musk deer (FMD, Moschus Berezovskii) is a critically endangered species world-widely, the death of which can be caused by pulmonary disease in the farm. Pulmonary fibrosis (PF) was a huge threat to the health and survival of captive FMD. MicroRNAs (miRNAs) and messenger RNAs (mRNAs) have been involved in the regulation of immune genes and disease development. However, the regulatory profiles of mRNAs and miRNAs involved in immune regulation of FMD are unclear. Methods: In this study, mRNA-seq and miRNA-seq in blood were performed to constructed coexpression regulatory networks between PF and healthy groups of FMD. The hub immune- and apoptosis-related genes in the PF blood of FMD were explored through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Further, protein-protein interaction (PPI) network of immune-associated and apoptosis-associated key signaling pathways were constructed based on mRNA-miRNA in the PF blood of the FMD. Immune hub DEGs and immune hub DEmiRNAs were selected for experimental verification using RT-qPCR. Results: A total of 2744 differentially expressed genes (DEGs) and 356 differentially expressed miRNAs (DEmiRNAs) were identified in the PF blood group compared to the healthy blood group. Among them, 42 DEmiRNAs were negatively correlated with 20 immune DEGs from a total of 57 correlations. The DEGs were significantly associated with pathways related to CD molecules, immune disease, immune system, cytokine receptors, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, cytokine-cytokine receptor interaction, intestinal immune network for IgA production, and NOD-like receptor signaling pathway. There were 240 immune-related DEGs, in which 186 immune-related DEGs were up-regulated and 54 immune-related DEGs were down-regulated. In the protein-protein interaction (PPI) analysis of immune-related signaling pathway, TYK2, TLR2, TLR4, IL18, CSF1, CXCL13, LCK, ITGB2, PIK3CB, HCK, CD40, CD86, CCL3, CCR7, IL2RA, TLR3, and IL4R were identified as the hub immune genes. The mRNA-miRNA coregulation analysis showed that let-7d, miR-324-3p, miR-760, miR-185, miR-149, miR-149-5p, and miR-1842-5p are key miRNAs that target DEGs involved in immune disease, immune system and immunoregulation. Conclusion: The development and occurrence of PF were significantly influenced by the immune-related and apoptosis-related genes present in PF blood. mRNAs and miRNAs associated with the development and occurrence of PF in the FMD.
Subject(s)
Deer , Gene Expression Profiling , Gene Regulatory Networks , MicroRNAs , Pulmonary Fibrosis , RNA, Messenger , Transcriptome , Animals , MicroRNAs/genetics , Deer/genetics , Deer/immunology , RNA, Messenger/genetics , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/immunology , Protein Interaction Maps , Gene Expression Regulation , Computational Biology/methodsABSTRACT
BACKGROUND: The forest musk deer, a rare fauna species found in China, is famous for its musk secretion which is used in selected Traditional Chinese medicines. However, over-hunting has led to musk deer becoming an endangered species, and their survival is also greatly challenged by various high incidence and high mortality respiratory and intestinal diseases such as septic pneumonia and enteritis. Accumulating evidence has demonstrated that Akkermannia muciniphila (AKK) is a promising probiotic, and we wondered whether AKK could be used as a food additive in animal breeding programmes to help prevent intestinal diseases. METHODS: We isolated one AKK strain from musk deer feces (AKK-D) using an improved enrichment medium combined with real-time PCR. After confirmation by 16S rRNA gene sequencing, a series of in vitro tests was conducted to evaluate the probiotic effects of AKK-D by assessing its reproductive capability, simulated gastrointestinal fluid tolerance, acid and bile salt resistance, self-aggregation ability, hydrophobicity, antibiotic sensitivity, hemolysis, harmful metabolite production, biofilm formation ability, and bacterial adhesion to gastrointestinal mucosa. RESULTS: The AKK-D strain has a probiotic function similar to that of the standard strain in humans (AKK-H). An in vivo study found that AKK-D significantly ameliorated symptoms in the enterotoxigenic Escherichia coli (ETEC)-induced murine diarrhea model. AKK-D improved organ damage, inhibited inflammatory responses, and improved intestinal barrier permeability. Additionally, AKK-D promoted the reconstitution and maintenance of the homeostasis of gut microflora, as indicated by the fact that AKK-D-treated mice showed a decrease in Bacteroidetes and an increase in the proportion of other beneficial bacteria like Muribaculaceae, Muribaculum, and unclassified f_Lachnospiaceae compared with the diarrhea model mice. CONCLUSION: Taken together, our data show that this novel AKK-D strain might be a potential probiotic for use in musk deer breeding, although further extensive systematic research is still needed.
ABSTRACT
Here, we presented 6 patients who were admitted to our institution and diagnosed as myasthenia gravis (MG) with tongue muscle atrophy. All these 6 patients developed symptoms of bulbar muscle weakness in acetylcholine receptor antibodies positive MG (AChR-MG) (3/6), muscle-specific receptor tyrosine kinase antibodies positive MG (MuSK-MG) (1/6), and sero-negative MG (2/6). Most of patients had "triple-furrowed" tongue except for patient 2 with irregular atrophy of tongue muscle. Tongue muscle atrophy occurs in patients with MuSK-MG, AChR-MG, and sero-negative MG. Atrophied tongue muscles of five patients with MG were reversible after immunotherapy.
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Patients occasionally present with reports of ocular exposure to fluids from rattlesnakes, claiming or suspecting the substance to be venom. This study set out to evaluate and characterize reported cases of suspected venom-induced ophthalmia in humans. A retrospective review of rattlesnake exposures reported to the Arizona Poison and Drug Information Center over a 24-year period was conducted for ocular exposures. Recorded information included patient demographics, clinical course, laboratory results, and treatments. Documentation regarding interactions between patients and snakes was reviewed by Arizona Poison and Drug Information Center herpetologists to evaluate what substance was expelled from the snake resulting in ocular exposure. Our review of rattlesnake encounters found a total of 26 ocular exposure cases. Patient demographics were largely intentional interactions and involved the male sex. Symptoms ranged from asymptomatic to minor effects with 46.2% managed from home and treated with fluid irrigation. A review of cases by herpetologists concluded the exposure patients commonly experienced was to snake musk. Kinematics of venom expulsion by rattlesnakes conclude the venom gland must be compressed, fangs erected to ≥60o, and fang sheath compressed against the roof of the mouth for venom expulsion. Evidence suggests the chance of venom "spitting" by rattlesnakes is close to zero. Rattlesnakes are documented to forcefully expel airborne malodorous "musk" defensively. An important distinction to remember is musk has a foul odor and is usually colorless, while venom is comparatively odorless and yellow. Rattlesnake venom-induced ophthalmia is a rare event as venom expulsion requires the kinematics of feeding or defensive bites. If the rattlesnake is not in the process of biting or otherwise contacting some other object with its mouth, it is more biologically plausible patients are being exposed to snake musk as a deterrent. Whether it's venom or musk, topical exposure to the eyes should prompt immediate irrigation.
Subject(s)
Crotalid Venoms , Crotalus , Snake Bites , Animals , Arizona , Humans , Male , Retrospective Studies , Female , Crotalid Venoms/toxicity , Adult , Middle Aged , Adolescent , Aged , Child , Eye/drug effects , Young Adult , Poison Control CentersABSTRACT
BACKGROUND: Myasthenia gravis (MG) with MuSK antibodies (MuSK-MG) represents a distinct subtype with different responses to treatments compared to patients with AChR antibodies, especially in terms of tolerance to acetylcholinesterase inhibitors (AChEI). However, AChEI are often used as first line symptomatic treatment in MuSK-MG, despite reports that they are poorly tolerated, seldom effective or even deleterious. METHODS: We analyzed demographic, clinical and therapeutic responses and side-effects in the large cohort of 202 MuSK-MG patients cared for at the MG Clinic of Azienda Ospedaliero-Universitaria Pisana. RESULTS: 165 patients had received AChEI at first evaluation. Only 7/165 patients (4.2%) reported an initial clinical benefit. Conversely, 76.9% of patients reported at least one side effect, most commonly neuromuscular hyperexcitability (68.4%), gastrointestinal (53.9%) and neurovegetative (35.8%) disturbances. 56 (33.9%) patients reported a concomitant worsening of muscle weakness and twelve patients (7.3%) suffered a cholinergic crisis. According to these patients, the severity of cholinergic side effects was greater at higher doses of AChEI, but side effects occurred regardless of the dose administered and ceased once the drug was discontinued. CONCLUSIONS: This is the largest population of MuSK-MG patients reported for perceived responsiveness and tolerance to AChEI treatment. Our obervations strongly suggest avoiding this treatment in MuSK-MG.
Subject(s)
Autoantibodies , Cholinesterase Inhibitors , Myasthenia Gravis , Receptor Protein-Tyrosine Kinases , Receptors, Cholinergic , Humans , Myasthenia Gravis/drug therapy , Myasthenia Gravis/immunology , Cholinesterase Inhibitors/therapeutic use , Male , Female , Middle Aged , Receptors, Cholinergic/immunology , Adult , Receptor Protein-Tyrosine Kinases/immunology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Aged , Autoantibodies/blood , Young Adult , Adolescent , Aged, 80 and over , Treatment Outcome , Cohort StudiesABSTRACT
Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.
Subject(s)
Autoantibodies , Immunoglobulin G , Myasthenia Gravis , Receptor Protein-Tyrosine Kinases , Receptors, Cholinergic , Humans , Myasthenia Gravis/immunology , Myasthenia Gravis/blood , Myasthenia Gravis/diagnosis , Male , Middle Aged , Female , Adult , Aged , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Retrospective Studies , Young Adult , Adolescent , Autoantibodies/blood , Autoantibodies/immunology , Aged, 80 and over , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Severity of Illness Index , ChildABSTRACT
The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PRF/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.
Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , Disease Models, Animal , Neuromuscular Junction , Receptor Protein-Tyrosine Kinases , Animals , Neuromuscular Junction/metabolism , Neuromuscular Junction/drug effects , Mice , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/drug therapy , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Humans , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Longevity/drug effects , Motor Neurons/metabolism , Motor Neurons/drug effects , Agrin/metabolism , Agrin/genetics , Mice, Transgenic , Antibodies/pharmacology , Receptors, Cholinergic/metabolism , Receptors, Cholinergic/genetics , LDL-Receptor Related Proteins/metabolism , LDL-Receptor Related Proteins/geneticsABSTRACT
Galaxolide (HHCB) and tonalide (AHTN) are dominant musks added to personal care products. However, the accumulate and trophic transfer of SMs through the marine food chain are unclear. In this study, organisms were collected from three bays in Bohai Sea to investigate the bioaccumulation, trophic transfer, and health risk of SMs. The HHCB and AHTN concentrations in the muscles range from 2.75 to 365.40 µg/g lw and 1.04-4.94 µg/g lw, respectively. The median HHCB concentrations in muscles were the highest in Bohai Bay, followed by Laizhou Bay and Liaodong Bay, consistent with the HHCB concentrations in sediments. The different fish tissues from Bohai Bay were analyzed, and the HHCB and AHTN concentrations followed the heart > liver > gill > muscles. The trophic magnification factors (TMF) were lower than 1 and the health risk assessment showed no adverse health effects. The results provide insights into the bioaccumulation and trophic transfer behavior of SMs in marine environments.
Subject(s)
Environmental Monitoring , Fishes , Food Chain , Water Pollutants, Chemical , Risk Assessment , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/metabolism , Animals , Fishes/metabolism , China , Bioaccumulation , Benzopyrans , Fatty Acids, Monounsaturated/analysis , Fatty Acids, Monounsaturated/metabolism , Tetrahydronaphthalenes/analysis , BaysABSTRACT
In multiple instance learning (MIL), a bag represents a sample that has a set of instances, each of which is described by a vector of explanatory variables, but the entire bag only has one label/response. Though many methods for MIL have been developed to date, few have paid attention to interpretability of models and results. The proposed Bayesian regression model stands on two levels of hierarchy, which transparently show how explanatory variables explain and instances contribute to bag responses. Moreover, two selection problems are simultaneously addressed; the instance selection to find out the instances in each bag responsible for the bag response, and the variable selection to search for the important covariates. To explore a joint discrete space of indicator variables created for selection of both explanatory variables and instances, the shotgun stochastic search algorithm is modified to fit in the MIL context. Also, the proposed model offers a natural and rigorous way to quantify uncertainty in coefficient estimation and outcome prediction, which many modern MIL applications call for. The simulation study shows the proposed regression model can select variables and instances with high performance (AUC greater than 0.86), thus predicting responses well. The proposed method is applied to the musk data for prediction of binding strengths (labels) between molecules (bags) with different conformations (instances) and target receptors. It outperforms all existing methods, and can identify variables relevant in modeling responses.
ABSTRACT
Musk secreted by male forest musk deer (Moschus berezovskii) musk glands is an invaluable component of medicine and perfume. Musk secretion depends on musk gland maturation; however, the mechanism of its development remains elusive. Herein, using single cell multiome ATAC + gene expression coupled with several bioinformatic analyses, a dynamic transcriptional cell atlas of musk gland development was revealed, and key genes and transcription factors affecting its development were determined. Twelve cell types, including two different types of acinar cells (Clusters 0 and 10) were identified. Single-nucleus RNA and single-nucleus ATAC sequencing analyses revealed that seven core target genes associated with musk secretion (Hsd17b2, Acacb, Lss, Vapa, Aldh16a1, Aldh7a1, and Sqle) were regulated by 12 core transcription factors (FOXO1, CUX2, RORA, RUNX1, KLF6, MGA, NFIC, FOXO3, ETV5, NR3C1, HSF4, and MITF) during the development of Cluster 0 acinar cells. Kyoto Encyclopedia of Genes and Genomes enrichment showed significant changes in the pathways associated with musk secretion during acinar cell development. Gene set variation analysis also revealed that certain pathways associated with musk secretion were enriched in 6-year-old acinar cells. A gene co-expression network was constructed during acinar cell development to provide a precise understanding of the connections between transcription factors, genes, and pathways. Finally, intercellular communication analysis showed that intercellular communication is involved in musk gland development. This study provides crucial insights into the changes and key factors underlying musk gland development, which serve as valuable resources for studying musk secretion mechanisms and promoting the protection of this endangered species.
Subject(s)
Deer , Transcriptome , Animals , Deer/genetics , Male , Fatty Acids, Monounsaturated/metabolism , Chromatin/metabolismABSTRACT
Chinese forest musk deer (FMD), an endangered species, have exhibited low reproductive rates even in captivity due to stress conditions. Investigation revealed the presence of di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, in the serum and skin of captive FMDs. Feeding FMDs with maslinic acid (MA) has been observed to alleviate the stress response and improve reproductive rates, although the precise molecular mechanisms remain unclear. Therefore, this study aims to investigate the molecular mechanisms underlying the alleviation of DEHP-induced oxidative stress and cell apoptosis in primary peritubular myoid cells (PMCs) through MA intake. Primary PMCs were isolated and exposed to DEHP in vitro. The results demonstrated that DEHP significantly suppressed antioxidant levels and promoted cell apoptosis in primary PMCs. Moreover, interfering with the expression of PRDX6 was found to induce excessive reactive oxygen species (ROS) production and cell apoptosis in primary PMCs. Supplementation with MA significantly upregulated the expression of PRDX6, thereby attenuating DEHP-induced oxidative stress and cell apoptosis in primary PMCs. These findings provide a theoretical foundation for mitigating stress levels and enhancing reproductive capacity of in captive FMDs.