Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury.

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

Characterization and epidemiologic analysis of mycoplasmal pneumonia of sheep in Qinghai Province.

Mycoplasmal pneumonia in sheep and goats usually result covert but huge economic losses in the sheep and goat industry. The disease is prevalent in various countries in Africa and Asia. Clinical manifestations in affected animals include anorexia, fever, and respiratory symptoms such as dyspnea, polypnea, cough, and nasal discharge. Due to similarities with other respiratory infections, accurate diagnosis can be challenging, and isolating the causative organism is often problematic. However, the utilization of molecular techniques, such as PCR, allows for rapid and specific identification of pathogens. Thus, a goat infection model with Mycoplasma was established and the pathogen was tested using PCR. The results indicated that this approach could be effectively utilized for the rapid detection of mycoplasma in clinical settings. Additionally, the prevalence of contagious pleuropneumonia of sheep in Qinghai Province was further investigated through PCR analysis. A total of 340 nasal swabs were collected from 17 sheep farms in Qinghai province. Among these samples, 84 tested positive for Mycoplasma mycoides subsp. capri (Mmc) and 148 tested positive for Mycoplasma ovipneumoniae (Movi), resulting in positive rates of 24.71% and 43.53% respectively. Furthermore, our investigation revealed positive PCR results for nasal swabs, trachea, and lung samples obtained from sheep exhibiting symptoms suggestive of mycoplasma infection. Moreover, three distinct strains were isolated from these positive samples. Additionally, the inflammatory cytokines of peripheral blood mononuclear cells (PBMCs) were assessed using RT-PCR. The findings demonstrated a high susceptibility of sheep to Movi in Qinghai province, with infected sheep displaying an inflammatory response. Consequently, the outcomes of this study will furnish valuable epidemiological insights for the effective prevention and control of this disease within Qinghai Province.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. In male mice, we note that HFHC triggered increases in amyloid beta, an observation not seen in female mice. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains.

The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer's disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

Genetic analysis of the causal relationship between gut microbiota and intervertebral disc degeneration: a two-sample Mendelian randomized study.

PURPOSE: Several recent studies have reported a possible association between gut microbiota and intervertebral disc degeneration; however, no studies have shown a causal relationship between gut microbiota and disc degeneration. This study was dedicated to investigate the causal relationship between the gut microbiota and intervertebral disc degeneration and the presence of potentially bacterial traits using two-sample Mendelian randomization. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of the gut microbiota from the largest available genome-wide association study meta-analysis conducted by the MiBioGen consortium. Summary statistics of intervertebral disc degeneration were obtained from the FinnGen consortium R8 release data. Five basic methods and MR-PRESSO were used to examine causal associations. The results of the study were used to examine the causal association between gut microbiota and intervertebral disc degeneration. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. RESULTS: By using Mendelian randomization analysis, 10 bacterial traits potentially associated with intervertebral disc degeneration were identified: genus Eubacterium coprostanoligenes group, genus Lachnoclostridium, unknown genus id.2755, genus Marvinbryantia, genus Ruminococcaceae UCG003, family Rhodospirillaceae, unknown genus id.959, order Rhodospirillales, genus Lachnospiraceae NK4A136 grou, genus Eubacterium brachy group. CONCLUSION: This Mendelian Randomization study found a causal effect between 10 gut microbiota and intervertebral disc degeneration, and we summarize the possible mechanisms of action in the context of existing studies. However, additional research is essential to fully understand the contribution of genetic factors to the dynamics of gut microbiota and its impact on disc degeneration.

ORFV entry into host cells via clathrin-mediated endocytosis and macropinocytosis.

Orf virus (ORFV), also known as infectious pustular virus, leads to an acute contagious zoonotic infectious disease. ORFV can directly contact and infect epithelial cells of skin and mucosa, causing damage to tissue cells. So far, the pathway of ORFV entry into cells is unclear. Therefore, finding the internalization pathway of ORFV will help to elucidate the cellular and molecular mechanisms of ORFV infection and invasion, which in turn will provide a certain reference for the prevention and treatment of ORFV. In the present study, chemical inhibitors were used to analyze the mechanism of ORFV entry into target cells. The results showed that the inhibitor of clathrin-mediated endocytosis could inhibit ORFV entry into cells. However, the inhibitor of caveolae-mediated endocytosis cannot inhibit ORFV entry into cells. In addition, inhibition of macropinocytosis pathway also significantly reduced ORFV internalization. Furthermore, the inhibitors of acidification and dynamin also prevented ORFV entry. However, results demonstrated that inhibitors inhibited ORFV entry but did not inhibit ORFV binding. Notably, extracellular trypsin promoted ORFV entry into cells directly, even when the endocytic pathway was inhibited. In conclusion, ORFV enters into its target cells by clathrin-mediated endocytosis and macropinocytosis, while caveolae-dependent endocytosis has little effects on this process. In addition, the entry into target cells by ORFV required an acid environment and the effect of dynamin. Meanwhile, we emphasize that broad-spectrum antiviral inhibitors and extracellular enzyme inhibitors are likely to be effective strategies for the prevention and treatment of ORFV infection.

PAI-1 regulates AT2-mediated re-alveolarization and ion permeability.

BACKGROUND: Acute lung injury is characterized by overwhelmingly elevated PAI-1 in both lung edema fluid and the circulating system. The role of increased PAI-1, encoded by Serpine1 gene, in the regeneration of injured lung epithelium has not been understood completely. This study aimed to investigate the role of Serpine1 in the regulation of alveolar type 2 epithelial cell (AT2) fate in a humanized mouse line carrying diseased mutants (Serpine1Tg). METHODS: Wild-type (wt) and Serpine1Tg AT2 cells were either cultured as monolayers or 3D alveolospheres. Colony-forming assay and total surface area of organoids were analyzed. AT1 and AT2 cells in organoids were counted by immunohistochemistry and fluorescence-activated cell sorting (FACS). To test the potential effects of elevated PAI-1 on the permeability in the epithelial monolayers, we digitized the biophysical properties of polarized AT2 monolayers grown at the air-liquid interface. RESULTS: A significant reduction in total AT2 cells harvested in Serpine1Tg mice was observed compared with wt controls. AT2 cells harvested from Serpine1Tg mice reduced significantly over the wt controls. Spheroids formed by Serpine1Tg AT2 cells were lesser than wt control. Similarly, the corresponding surface area, a readout of re-alveolarization of injured epithelium, was markedly reduced in Serpine1Tg organoids. FACS analysis revealed a significant suppression in the number of AT2 cells, in particular, the CD44+ subpopulation, in Serpine1Tg organoids. A lesser ratio of AT1:AT2 cells in Serpine1Tg organoids was observed compared with wt cultures. There was a significant increase in transepithelial resistance but not amiloride inhibition. CONCLUSIONS: Our study suggests elevated PAI-1 in injured lungs downregulates alveolar epithelial regeneration by reducing the AT2 self-renewal, particularly in the CD44+ cells.

A comparative study on efficacy of modified endoscopic minimally invasive treatment and traditional open surgery for primary carpal tunnel syndrome.

BACKGROUND AND OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common type of median nerve entrapment neuropathy. This study aims to comparatively assess the effectiveness and clinical efficacy of modified transforaminal endoscopic minimally invasive incision of transverse carpal ligament against traditional open incision of transverse carpal ligament in the treatment of CTS. METHOD: The clinical data of 35 patients (57 wrists) with primary CTS treated in Shanxi Bethune Hospital, China, were retrospectively analyzed. The patients were divided into observation group (21 cases, 33 wrists) and control group (14 cases, 24 wrists), respectively, who underwent modified endoscopic minimally invasive incision of transverse carpal ligament and traditional open incision of transverse carpal ligament release. The Boston Carpal Tunnel Questionnaire (BCTQ) was assessed at for points: before the operation; 2 weeks; 1 month; and 3 months after operation. The BCTQ scores of the two groups were compared on all four points. The incidence of intraoperative and postoperative complication was used as the evaluation index. The study variables were comparatively assessed before and postoperation and also between the groups. RESULTS: The BCTQ scores at 2 weeks, 1 month and 3 months after the operation were significantly lower than preoperative BCTQ scores (P < 0.005) for both the groups. There was no significant difference in BCTQ scores between the two groups at the four assessment points (P > 0.005). The scar size and wound healing time were significantly better with modified transforaminal endoscopic minimally invasive transverse carpal ligament incision. CONCLUSION: The clinical effects of both modified transforaminal minimally invasive incision of transverse carpal ligament and traditional open incision of transverse carpal ligament are significant, while the treatment efficacy of modified transforaminal minimally invasive transverse carpal ligament incision is better in terms of operation time, wound size, postoperative scar size and incision healing time.

Effect of SARS-CoV-2 infection on seizure, anxiety, and depression in 107 patients with epilepsy.

OBJECTIVE: To study the effects of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) on epileptic seizures, anxiety, and depression in patients with epilepsy. METHODS: Based on the inclusion and exclusion criteria, an ambispective cohort study was hereby conducted on patients with epilepsy infected with SARS-CoV-2 who visited the outpatient and ward of the Department of Neurology of Xinyang Central Hospital from December 2022 (when the domestic epidemic prevention and control policy was lifted) to February 2023. A face-to-face questionnaire survey involving factors including basic information, vaccination with inactivated COVID-19 vaccines, number of seizures within 2 months before and after SARS-CoV-2 infection, and scores of anxiety and depression was carried out. RESULTS: A total of 107 patients with epilepsy satisfying the inclusion and exclusion criteria completed the follow-up after 2 months. It was found that enrolled patients maintained the original dose of antiepileptic drugs, but the frequency of seizures after COVID-19 infection could not be controlled. After infection with SARS-CoV-2, the frequency of seizures in patients with epilepsy in 2 months increased compared with that before infection (P < 0.05). Meanwhile, compared with the vaccinated group, the high-frequency seizure rate of epilepsy in the unvaccinated group was higher. (P < 0.05), and the anxiety and depression scores of patients with epilepsy were worse than those before they were infected (P < 0.05). CONCLUSION: Being infected with SARS-CoV-2 can increase the number of seizures and aggravate the degree of anxiety and depression in patients with epilepsy. The inactivated vaccine is protective, and the inactivated SARS-CoV-2 vaccine can reduce the rate of high-frequency seizures.

Research advances and trends in the surgical treatment of carpal tunnel syndrome from 2003 to 2022: A CiteSpace-based bibliometric analysis.

Background: Carpal Tunnel Syndrome (CTS) is one of the most common peripheral neuropathies. The typical symptoms are tingling and numbness in the median nerve distribution of the hand. Current treatment for CTS includes general conservative treatment and surgical treatment. Surgical treatment plays a crucial role in the management of CTS, but little bibliometric analysis has been conducted on it. Therefore, this study aimed to map the literature co-citation network using CiteSpace (6.1 R4) software. Research frontiers and trends were identified by retrieving subject headings with significant changing word frequency trends, which can be used to predict future research advances in the surgical treatment of CTS. Methods: Publications on the surgical treatment of CTS in the Web of Science database were collected between 2003 and 2022. CiteSpace software was applied to visualize and analyze publications, countries, institutions, journals, authors, references, and keywords. Results: A total of 336 articles were collected, with the USA being the major publishing power in all countries/regions. JOURNAL OF HAND SURGERY AMERICAN VOLUME was the journal with the most published and co-cited articles. Based on keyword and reference co-citation analysis, keywords such as CTS, surgery, release, median nerve, and diagnosis were the focus of the study. Conclusion: The results of this bibliometric study provide clinical research advances and trends in the surgical treatment of patients with CTS over the past 20 years, which may help researchers to identify hot topics and explore new directions for future research in the field.

Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

PAI-1 regulates AT2-mediated re-alveolarization and ion permeability.

Background Acute lung injury is characterized by overwhelmingly elevated PAI-1 in both lung edema fluid and the circulating system. The role of increased PAI-1, encoded by Serpine1 gene, in the regeneration of injured lung epithelium has not been understood completely. This study aimed to investigate the role of Serpine1 in the regulation of alveolar type 2 epithelial cell (AT2) fate in a humanized mouse line carrying diseased mutants (Serpine1Tg). Methods Wild type (wt) and Serpine1Tg AT2 cells were either cultured as monolayers or 3D alveolospheres. Colony forming assay and total surface area of organoids were analyzed. AT1 and AT2 cells in organoids were counted by immunohistochemistry and fluorescence-activated cell sorting (FACS). To test the potential effects of elevated PAI-1 on the permeability in the epithelial monolayers, we digitized the biophysical properties of polarized AT2 monolayers grown at the air-liquid interface. Results A significant reduction in total AT2 cells harvested in Serpine1Tg mice was observed compared with wt controls. AT2 cells harvested from Serpine1Tg mice reduced significantly over the wt controls. Spheroids formed by Serpine1Tg AT2 cells were lesser than wt control. Similarly, the corresponding surface area, a readout of realveolarization of injured epithelium, was markedly reduced in Serpine1Tg organoids. FACS analysis revealed a significant suppression in the number of AT2 cells, in particular, the CD44+ subpopulation, in Serpine1Tg organoids. A lesser ratio of AT1:AT2 cells in Serpine1Tg organoids was observed compared with wt cultures. There was a significant increase in transepithelial resistance but not amiloride inhibition. Conclusions Our study suggests elevated PAI-1 in injured lungs downregulates alveolar epithelial regeneration by reducing the AT2 self-renewal, particularly in the CD44+ cells.

Intestinal Microbial Diversity of Free-Range and Captive Yak in Qinghai Province.

BACKGROUND: The gut microbiome is a large and complex organic assemblage with subtle and close relationships with the host. This symbiotic mechanism is important for the health and adaptability of the host to the environment. Compared with other ruminants, there are few studies on yak intestinal microbes. The study of the gut microbiota of the yak will help us better understand the correlation between the microbiota and the environmental adaptability of the host. In this study, we adapted 16S rDNA sequencing technology to investigate the diversity and composition of the intestinal microbial community in free-range yaks and captive yaks living on the Qinghai-Tibet Plateau (QTP). RESULTS: Sequencing results showed that the intestinal microbial community diversity was significantly different between free-range yaks and captive yaks. Firmicutes and Bacteroidetes were the dominant bacteria in both free-range and captive yaks. However, there were differences between the microbes of the two analyzed feeding styles in different classification levels. Compared with the captive type, free-range yaks had a higher abundance of Ruminococcaceae, Eubacteriaceae, Desulfovibrionaceae, Elusimicrobium, and Oscillibacter, while the abundance of Succinivibrionaceae, Clostridiales, Lachnospiraceae, Prevotellaceae, Roseburia, and Barnesiella was relatively low. The feeding method may be the key factor for the formation of intestinal flora differences in yaks, while altitude did not significantly affect Qinghai yak. CONCLUSIONS: In this study, we used 16S rDNA sequencing technology to investigate the composition of intestinal flora in free-range and captive yaks living on the QTP. The exploration of dietary factors can provide a theoretical basis for scientifically and rationally breeding yaks and provides a new direction for the development of prebiotics and microecological agents.

Comparison of percutaneous endoscopic and open posterior lumbar interbody fusion for the treatment of single-segmental lumbar degenerative diseases.

BACKGROUND: Endoscopic lumbar interbody fusion has become an emerging technique. Some researchers have reported the technique of percutaneous endoscopic transforaminal lumbar interbody fusion. We propose percutaneous endoscopic posterior lumbar interbody fusion (PE-PLIF) as an alternative approach. The purpose of this study was to assess the clinical efficacy of PE-PLIF by comparing percutaneous endoscopic and open posterior lumbar interbody fusion (PLIF). METHODS: Thirty patients were enrolled in each group. Demographic data, perioperative data, and radiological parameters were collected prospectively. The clinical outcomes were evaluated by visual analog scale (VAS) and Oswestry Disability Index (ODI) scores. RESULTS: The background data were comparable between the two groups. The mean operation time was longer in the PE-PLIF group. The PE-PLIF group showed benefits in less blood loss and shorter hospital stay. VAS and ODI scores significantly improved in both groups. However, the VAS score of low-back pain was lower in the PE-PLIF group. The satisfaction rate was 96.7% in both groups. The radiological outcomes were similar in both groups. In the PE-PLIF group, the fusion rate was 93.3%, and the cage subsidence rate was 6.7%; in the open PLIF group, the fusion and cage subsidence rates were 96.7% and 16.7%. There were minor complications in one patient in the PE-PLIF group and two in the open PLIF group. CONCLUSIONS: The current study revealed that PE-PLIF is safe and effective compared with open PLIF. In addition, this minimally invasive technique may enhance postoperative recovery by reducing tissue damage and blood loss.

The Role of Autophagy in Lamellar Body Formation and Surfactant Production in Type 2 Alveolar Epithelial Cells.

The lamellar body (LB), a concentric structure loaded with surfactant proteins and phospholipids, is an organelle specific to type 2 alveolar epithelial cells (AT2). However, the origin of LBs has not been fully elucidated. We have previously reported that autophagy regulates Weibel-Palade bodies (WPBs) formation, and here we demonstrated that autophagy is involved in LB maturation, another lysosome-related organelle. We found that during development, LBs were transformed from autophagic vacuoles containing cytoplasmic contents such as glycogen. Fusion between LBs and autophagosomes was observed in wild-type neonate mice. Moreover, the markers of autophagic activity, microtubule-associated protein 1 light chain 3B (LC3B), largely co-localized on the limiting membrane of the LB. Both autophagy-related gene 7 (Atg7) global knockout and conditional Atg7 knockdown in AT2 cells in mice led to defects in LB maturation and surfactant protein B production. Additionally, changes in autophagic activity altered LB formation and surfactant protein B production. Taken together, these results suggest that autophagy plays a critical role in the regulation of LB formation during development and the maintenance of LB homeostasis during adulthood.

Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system.

Introduction: Progranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations. Methods: First, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT). Results: Male PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner. Discussion: Our data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.

Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology.

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. METHODS: We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)-an inhibitor of nuclear factor kappa B (NFκB)-to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. RESULTS: High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. CONCLUSIONS: This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice.

Vitamin D suppresses bleomycin-induced pulmonary fibrosis by targeting the local renin-angiotensin system in the lung.

Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-ß and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-ß induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-ß and angiotensin II synergistically induced TGF-ß, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.

Endoscopic Lumbar Interbody Fusion and Minimally Invasive Transforaminal Lumbar Interbody Fusion for the Treatment of Lumbar Degenerative Diseases: A Systematic Review and Meta-Analysis.

OBJECTIVE: To compare clinical efficacy and safety of endoscopic lumbar interbody fusion (Endo-LIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in treatment of lumbar degenerative diseases. METHODS: A literature search was performed using PubMed, Embase, Web of Science, and Cochrane Library databases. Studies published up to November 15, 2020, that compared Endo-LIF with MIS-TLIF for treating lumbar degenerative diseases were retrieved. Data were extracted according to predefined clinical outcome measures. Primary outcomes were preoperative and postoperative visual analog scale for leg and back pain and Oswestry Disability Index scores. Secondary outcomes were operative time and intraoperative blood loss; length of hospitalization; and complication, reoperation, and fusion rates. Data analysis was conducted with statistical software. RESULTS: The meta-analysis included 6 studies comprising 480 patients. Results of the merged analysis revealed similar complication, reoperation, and fusion rates and preoperative and postoperative visual analog scale for leg and back pain and Oswestry Disability Index scores (P > 0.05) for Endo-LIF and MIS-TLIF. Nevertheless, with the exception of longer operative time (P < 0.05), Endo-LIF compared favorably with MIS-TLIF, with less intraoperative blood loss, shorter hospital stay (P < 0.05), and better long-term functional outcome. CONCLUSIONS: Based on the evidence provided by this study, there is no significant difference in clinical efficacy and safety between Endo-LIF and MIS-TLIF in the treatment of lumbar degenerative diseases. Although Endo-LIF has a longer operative time, it has the advantages of less tissue trauma and rapid recovery after operation.