IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion.

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B.

Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling.

Targeting the interleukin-6 (IL-6)/glycoprotein 130 (GP130) signaling pathway holds significant promise for cancer therapy given its essential role in the survival and progression of various cancer types. We have identified that bazedoxifene (BZA), a Food and Drug Administration (FDA)-approved drug used for the prevention of postmenopausal osteoporosis, when combined with conjugated estrogens in Duavee, also has a novel function as an inhibitor of IL-6/GP130 interaction. BZA is currently under investigation for its potential anticancer therapeutic function through the inhibition of the IL-6/GP130 pathway.

"Necessary evil": the difficulties of establishing programmatic culture in the transfer portal era.

The implementation of the transfer portal and eased transfer restrictions has drastically impacted the migration of college football players. While such athlete autonomy aligns with sweeping organizational policy adopted, and mandated, by the National Collegiate Athletic Association (NCAA), the absence of barriers preventing the mobility of players may have a resultant effect on the development of sustained organizational culture. Through interviews with direct stakeholders currently coaching football at the Football Bowl Subdivision (FBS) level, the findings of this study reveal that while the transfer portal is commonly utilized to achieve short-term success, building a roster composed predominantly of transfer players was perceived as unsustainable in the desired cultivation of meaningful organizational culture.

Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.

Background: Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood.

Methods: Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery.

Correction: Ziemssen et al. Immune Response to Initial and Booster SARS-CoV-2 mRNA Vaccination in Patients Treated with Siponimod-Final Analysis of a Nonrandomized Controlled Clinical Trial (AMA-VACC). 2023, , 1374.

The authors would like to make the following corrections to this published paper [...

[Ofatumumab in the treatment of multiple sclerosis - A summary of preclinical and clinical data].

Background:   B-cell targeted therapies are highly effective in multiple sclerosis (MS). Most of these therapies are administered intravenously at long intervals. Ofatumumab, an anti-CD20 antibody that is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure, became available for the treatment of MS in 2021.

[Immunological foundations of neurological diseases].

Background: Neurodegenerative diseases represent an increasing challenge in ageing societies, as only limited treatment options are currently available.

Objective: New research methods and interdisciplinary interaction of different disciplines have changed the way neurological disorders are viewed and paved the way for the comparatively new field of neuroimmunology, which was established in the early 1980s. Starting from neurological autoimmune diseases, such as multiple sclerosis, knowledge about the involvement of immunological processes in other contexts, such as stroke or traumatic brain injury, has been significantly expanded in recent years.

Volume loss during muscle reinnervation surgery is correlated with reduced CMAP amplitude but not reduced force output in a rat hindlimb model.

Muscle reinnervation (MR) surgery offers rehabilitative benefits to amputees by taking severely damaged nerves and providing them with new denervated muscle targets (DMTs). However, the influence of physical changes to muscle tissue during MR surgery on long-term functional outcomes remains understudied. Our rat hindlimb model of MR surgery utilizes vascularized, directly neurotized DMTs made from the lateral gastrocnemius (LG), which we employed to assess the impact of muscle tissue size on reinnervation outcomes, specifically pairing the DMT with the transected peroneal nerve.

Metabolic dysfunction and the development of physical frailty: an aging war of attrition.

The World Health Organization recently declared 2021-2030 the decade of healthy aging. Such emphasis on healthy aging requires an understanding of the biologic challenges aging populations face. Physical frailty is a syndrome of vulnerability that puts a subset of older adults at high risk for adverse health outcomes including functional and cognitive decline, falls, hospitalization, and mortality.

Neutralizing antibody titers over 12 months after SARS-CoV-2 mRNA vaccine booster in patients with relapsing multiple sclerosis continuously treated with ofatumumab.

Booster vaccinations against SARS-CoV-2 are recommended 6-12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed.

Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27.

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFβ and IL-27 signaling along with isolated platelets and cultured macrophages.

Immune Response to Initial and Booster SARS-CoV-2 mRNA Vaccination in Patients Treated with Siponimod-Final Analysis of a Nonrandomized Controlled Clinical Trial (AMA-VACC).

Background: Evidence on SARS-CoV-2 mRNA vaccination under siponimod treatment is rare.

Methods: AMA-VACC is a prospective, open-label clinical study on SARS-CoV-2 mRNA vaccination during ongoing siponimod treatment (cohort 1), during siponimod interruption (cohort 2), or during treatment with other disease-modifying therapies or without therapy (cohort 3). SARS-CoV-2-specific antibodies and T-cell reactivity were measured six months after the initial vaccination and one month after the booster.

Ubiquitination and cell-autonomous immunity.

Cell-autonomous immunity is the first line of defense by which cells recognize and contribute to eliminating invasive pathogens. It is composed of immune signaling networks that sense microbial pathogens, promote pathogen restriction, and stimulate their elimination, including host cell death. Ubiquitination is a pivotal orchestrator of these pathways, by changing the activity of signal transducers and effector proteins in an efficient way.

Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline: Insights From an Inducible Humanized IL-6 Knock-In Mouse Model.

Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter.

Results on SARS-CoV-2 mRNA Vaccine Booster from an Open-Label Multicenter Study in Ofatumumab-Treated Participants with Relapsing Multiple Sclerosis.

Background: Few data exist on how ofatumumab treatment impacts SARS-CoV-2 booster vaccination response.

Methods: KYRIOS is an ongoing prospective open-label multicenter study on the response to initial and booster SARS-CoV-2 mRNA vaccination before or during ofatumumab treatment in relapsing MS patients. The results on the initial vaccination cohort have been published previously.

Modulation of cellular transcriptome and proteome composition by azidohomoalanine-implications on click chemistry-based secretome analysis.

The analysis of the secretome provides important information on proteins defining intercellular communication and the recruitment and behavior of cells in specific tissues. Especially in the context of tumors, secretome data can support decisions for diagnosis and therapy. The mass spectrometry-based analysis of cell-conditioned media is widely used for the unbiased characterization of cancer secretomes in vitro.

Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern.

Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites.

The Role of LFA-1 for the Differentiation and Function of Regulatory T Cells-Lessons Learned from Different Transgenic Mouse Models.

Regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Treg dysfunction results in diverse inflammatory and autoimmune diseases with life-threatening consequences. β-integrins (CD11a-d/CD18) play important roles in the migration of leukocytes into inflamed tissues and cell signaling.

NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation.

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αβ thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1.

Identifying patients at high risk for multidrug-resistant organisms after hospitalization abroad.

Objectives: We quantified the percentage of multidrug-resistant organism (MDRO) carriers among repatriated patients. We identified factors associated with MDRO carriage, and we evaluated the yield of MDRO detection per screened body site.

Design: Retrospective cohort study.

IL-17A-producing CD8 T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8 T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC.