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Investigating the geometry of the tangent bundle (TM, π,M) over a smooth manifold M is one of the most significant fields of modern differential geometry and has remarkable applications in various problems specifically in the theory of physical fields. This significance provides a constructive setting for the development of novel notions and geometric structures such as systems of second order differential equations (SODE), metric structures, semisprays and nonlinear connections. Accordingly analysis of above mentioned concepts can be considered as a powerful tool for the thorough investigation of the geometric properties of a tangent bundle. This paper is devoted to exhaustive geometric analysis of totally geodesic SODE submanifolds. Investigating the induced SODE structure on submanifolds is our main objective in this paper. Indeed, it is demonstrated that the metric which is obtained from the metrizability of a given semispray, plays a fundamental role in inducing SODE structure on submanifolds. Particularly, a necessary and sufficient condition for an SODE submanifold to be totally geodesic is presented. [ABSTRACT FROM AUTHOR]

The geometry of a system of second order differential equations is the geometry of a semispray, which is a globally defined vector field on TM. The metric compatibility of a given semispray is of special importance. In this paper, the metric associated with the semispray S is applied in order to study some types of foliations on the tangent bundle which are compatible with SODE structure. Indeed, sufficient conditions for the metric associated with the semispray S are obtained to extend to a bundle-like metric for the lifted foliation on TM. Thus, the lifted foliation converts to a Riemanian foliation on the tangent space which is adapted to the SODE structure. Particularly, the metric compatibility property of the semispray S is applied in order to induce SODE structure on transversals. Finally, some equivalent conditions are presented for the transversals to be totally geodesic. [ABSTRACT FROM AUTHOR]

Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in FHP in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted- P  = 2.5 × 10 -3 ) and is enriched in CCL3 hi /CCL4 hi and S100A hi classical monocytes (adjusted- P  < 2.2 × 10 -16 ). Trajectory analyses demonstrate that S100A hi classical monocytes differentiate into SPP1 hi lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZM hi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. Conclusions: Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZM hi cytotoxic CD4 +  and CD8 +  T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100A hi and CCL3 hi /CCL4 hi classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Glioma is a highly lethal brain cancer in humans. Despite advancements in treatment, the prognosis for patients remains unfavorable. Epigenetic factors, along with their interactions and non-coding RNAs (ncRNAs), are crucial in glioma cells' development and aggressive characteristics. MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that modulate the expression of various genes by binding to target mRNA molecules. They play a critical role in regulating essential biological mechanisms such as cell proliferation and differentiation, cell cycle, and apoptosis. MiR-146a/miR-146b is a significant and prevalent miRNA whose expression alterations are linked to various pathological changes in cancer cells, as well as the modulation of several cellular signaling pathways, including NF-κB, TGF-β, PI3K/Akt, and Notch-1. Scientists may identify novel targets in clinical settings by studying the complicated link between Mir-146a/mir-146b, drug resistance, molecular pathways, and pharmacological intervention in gliomas. Additionally, its interactions with other ncRNAs, such as circular RNA and long non-coding RNA, contribute to the pathogenesis of glioma. As well as miR-146 holds potential as both a diagnostic and therapeutic biomarker for patients with this condition. In the current review, we investigate the significance of miRNAs in the context of glioma, with a particular focus on the critical role of Mir-146a/mir-146b in glioma tumors. Additionally, we examined the clinical relevance of this miRNA, highlighting its potential implications for diagnosis and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Sepsis is a syndrome that occurs following an infection and marked by severe inflammatory responses, and if not treated in time, it can lead to multi-organ failure syndrome and death. This study examines the effects of a novel combination therapy using azithromycin and mesenchymal stem cell-derived extracellular vesicles (EVs) on a cecal ligation and puncture (CLP) model of sepsis., Methods: Human Wharton's jelly-mesenchymal stem cells were cultured, characterized, and used to extract EVs. The CLP sepsis model was induced in mice, followed by treatments: saline, AZM, EVs, and combination therapy (A+E). Clinical sepsis scores were recorded 24 h post-treatment. Serum, peritoneal fluid, and organ tissues (kidney, liver, lung) were collected and analyzed for biochemical parameters (AST ALT, and creatinine), inflammatory markers, bacterial load, and histopathological changes., Results: The A+E combined treatment improved the clinical scores of septic mice. The administration of A+E reduced bacterial loads in the peritoneum of septic mice, contributing to effective control of infection. Inflammatory markers of neutrophils-to-lymphocytes ratio (NLR) and TNF-α serum levels were significantly lower in the combinational therapy group, indicating significant anti-inflammatory effect of this combination. Additionally, combination of AZM and EVs alleviated organ damage mainly within liver, kidneys and lungs. Based on histopathological assessments and biochemical parameters, there was diminished tissue damage as well as reduced inflammation, which is correlated with improved functions of these vital organs., Conclusion: The combined use of azithromycin and EVs offers a promising therapeutic approach for sepsis by effectively controlling infection and modulating the inflammatory response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA)., Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor., Methods: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease., Measurements and Main Results: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis., Conclusions: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Rationale: Changes in peripheral blood cell populations have been observed, but not detailed, at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing. Flow cytometry was used for validation. Protein concentrations of regulatory T cells (Tregs) and monocyte chemoattractants were measured in plasma and lung homogenates from patients with IPF and control subjects. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched control subjects yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in patients with progressive and stable IPF compared with control subjects (32.1%, 25.2%, and 17.9%, respectively; P  < 0.05). Total lymphocytes were decreased in patients with IPF versus control subjects and in progressive versus stable IPF (52.6% vs. 62.6%, P  = 0.035). Tregs were increased in progressive versus stable IPF (1.8% vs. 1.1% of all PBMCs, P  = 0.007), although not different than controls, and may be associated with decreased survival ( P  = 0.009 in Kaplan-Meier analysis; and P  = 0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of patients with IPF. The fraction of Tregs out of all T cells was also increased in two cohorts of lung single-cell RNA sequencing. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Background: Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7's special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment., Methods: The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response., Results: The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124&#95;1127dupTGCC is the most common variant; three patients had this variant., Conclusion: We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients., (© 2024. The Author(s).)

Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated CMKLR1 expression as a transient signature of monocyte-derived macrophages (MDMφ) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMφ as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1-targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high CMKLR1 expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases.