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The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes
Get PDFProtein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs
Linking higher amyloid beta 1-38 (Aβ(1-38)) levels to reduced Alzheimer's disease progression risk
Get PDFINTRODUCTION: The beneficial effects of amyloid beta 1-38, or Aβ(1-38), on Alzheimer's disease (AD) progression in humans in vivo remain controversial. We investigated AD patients' cerebrospinal fluid (CSF) Aβ(1-38) and AD progression. METHODS: Cognitive function and diagnostic change were assessed annually for 3 years in 177 Aβ-positive participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia from the German Center for Neurodegenerative Diseases (DZNE) longitudinal cognitive impairment and dementia study (DELCODE) cohort using the Mini-Mental State Examination (MMSE), Preclinical Alzheimer's Cognitive Composite (PACC), Clinical Dementia Rating (CDR), and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Mixed linear and Cox regression analyses were conducted. CSF was collected at baseline. RESULTS: Higher Aβ(1-38) levels were associated with slower PACC (p = 0.001) and slower CDR Sum of Boxes (CDR-SB) (p = 0.002) but not MMSE decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed an association of Aβ(1-38) with slower PACC decline (p = 0.005), but not with CDR-SB or MMSE decline. In addition, higher Aβ(1-38) baseline levels were associated with a reduced dementia conversion risk. DISCUSSION: Further research is needed to understand the role of Aβ(1-38) in AD and its potential for future therapeutic strategies
Identification of TTLL8, POTEE, and PKMYT1 as immunogenic cancer-associated antigens and potential immunotherapy targets in ovarian cancer
Get PDFMost high-grade serous ovarian cancers (OC) do not respond to current immunotherapies. To identify potential new actionable tumor antigens in OC, we performed immunopeptidomics on a human OC cell line expressing the HLA-A02:01 haplotype, which is commonly expressed across many racial and ethnic groups. From this dataset, we identified TTLL8, POTEE, and PKMYT1 peptides as candidate tumor antigens with low expression in normal tissues and upregulated expression in OC. Using tissue microarrays, we assessed the protein expression of TTLL8 and POTEE and their association with patient outcomes in a large cohort of OC patients. TTLL8 was found to be expressed in 56.7% of OC and was associated with a worse overall prognosis. POTEE was expressed in 97.2% of OC patients and had no significant association with survival. In patient TILs, increases in cytokine production and tetramer-positive populations identified antigen-specific CD8 T cell responses, which were dependent on antigen presentation by HLA class I. Antigen-specific T cells triggered cancer cell killing of antigen-pulsed OC cells. These findings suggest that TTLL8, POTEE, and PKMYT1 are potential targets for the development of antigen-targeted immunotherapy in OC
Sex differences in the relationship of socioeconomic position with cardiovascular disease, cardiovascular risk factors and estimated cardiovascular disease risk: results of the German National Cohort
Get PDFBACKGROUND: Using data from the largest German cohort study, we aimed to investigate sex differences in the relationship of socioeconomic position (SEP) with cardiovascular disease (CVD), CVD risk factors, and estimated CVD risk. METHODS AND RESULTS: A total of 204 780 (50.5% women) participants from the baseline examination of the population‐based NAKO (German National Cohort) were included. Logistic, multinomial, and linear regression models were used to estimate sex‐specific odds ratios (ORs) and β coefficients with 95% CIs of CVD, CVD risk factors, and very high‐risk score (Systemic Coronary Risk Estimation‐2) for CVD associated with SEP. Women-to-men ratios of ORs (RORs) with 95% CIs were estimated. In women compared with men, low versus high SEP (educational attainment and relative income) was more strongly associated with myocardial infarction, hypertension, obesity, overweight, elevated blood pressure, antihypertensive medication, and current alcohol consumption, but less strongly with current and former smoking. In women with the lowest versus highest educational level, the OR for a very high 10‐year CVD risk was 3.61 (95% CI, 2.88–4.53) compared with 1.72 (95% CI, 1.51–1.96) in men. The women‐to‐men ROR was 2.33 (95% CI, 1.78–3.05). For the comparison of low versus high relative income, the odds of having a very high 10‐year CVD risk was 2.55 (95% CI, 2.04–3.18) in women and 2.25 (95% CI, 2.08–2.42) in men (women‐to‐men ROR, 1.31 [95% CI, 1.05–1.63]). CONCLUSIONS: In women and men, there was an inverse relationship between indicators of SEP and the likelihood of having several CVD risk factors and a very high 10‐year CVD risk. This association was stronger in women, suggesting that CVD risk is more strongly influenced by SEP in women compared with men
The concept of neuroglia - the state of the art circa 1900
Get PDFGlial cells were first defined by Rudolf Virchow in 1856. About 40 years later, glial research had developed into a field distinct from the mainstream study of neurons as the central elements governing brain function. By that time, substantial knowledge about the properties of glial cells had accumulated, exemplified by five important publications by four distinguished investigators: Gustav Retzius, Michael von Lenhossek, Carl Weigert, and Hans Held. These treatises broadly summarized what was known about glial cells, comparing findings from leeches to humans. Practically speaking, these articles represent the foundation of our current knowledge. All five contributions were published in German, which at the time was one of the dominant languages for scientific exchange. This article summarizes and comments on their findings and thus provides insight into what was known about glial cells at that time. More importantly, in the Supporting Information, we provide English translations and original scans of these five publications, making them accessible to an international readership
TIFA renders intestinal epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice
Get PDFIntestinal immune homeostasis relies on intestinal epithelial cells (IECs), which provide an efficient barrier, and warrant a state of tolerance between the microbiome and the mucosal immune system. Thus, proper epithelial microbial sensing and handling of microbes is key to preventing excessive immunity, such as seen in patients with inflammatory bowel disease (IBD). To date, the molecular underpinnings of these processes remain incompletely understood. This study identifies TIFA as a driver of intestinal inflammation and an epithelial signaling hub between the microbiome and mucosal immune cells. TIFA was constitutively expressed in crypt epithelial cells and was highly induced in the intestine of mice and IBD patients with intestinal inflammation. We further identified IL-22 signaling via STAT3 as key mechanism driving TIFA expression in IECs. At the molecular level, we demonstrate that TIFA expression is essential for IEC responsiveness to the bacterial metabolite ADP-heptose. Most importantly, ADP-heptose-induced TIFA signaling orchestrates an inflammatory cellular response in the epithelium, with NF-(κ)B and inflammasome activation, and high levels of chemokine production. Finally, mice lacking TIFA were protected from intestinal inflammation when subjected to a model of experimental colitis. In conclusion, our study implicates that targeting TIFA may be a strategy for future IBD therapy
Deuterated oxazines are bright near-infrared fluorophores for mitochondrial imaging and single molecule spectroscopy
Get PDFBright near-infrared fluorophores are in demand for microscopy. We showcase a deuterated oxazine being 23% brighter vs. ATTO700. With a longer lifetime of 1.85 nanoseconds, we find the best-in-class SulfoOxazine700-d10 to stain mitochondria for confocal microscopy, and demonstrate unaffected diffusion properties in single molecule fluorescence correlation spectroscopy
Multicenter longitudinal quality assessment of MS-based proteomics in plasma and serum
Get PDFAdvancing MS-based proteomics toward clinical applications evolves around developing standardized start-to-finish and fit-for-purpose workflows for clinical specimens. Steps along the method design involve the determination and optimization of several bioanalytical parameters such as selectivity, sensitivity, accuracy, and precision. In a joint effort, eight proteomics laboratories belonging to the MSCoreSys initiative including the CLINSPECT-M, MSTARS, DIASyM, and SMART-CARE consortia performed a longitudinal round-robin study to assess the analysis performance of plasma and serum as clinically relevant samples. A variety of LC-MS/MS setups including mass spectrometer models from ThermoFisher and Bruker as well as LC systems from ThermoFisher, Evosep, and Waters Corporation were used in this study. As key performance indicators, sensitivity, precision, and reproducibility were monitored over time. Protein identifications range between 300 and 400 IDs across different state-of-the-art MS instruments, with timsTOF Pro, Orbitrap Exploris 480, and Q Exactive HF-X being among the top performers. Overall, 71 proteins are reproducibly detectable in all setups in both serum and plasma samples, and 22 of these proteins are FDA-approved biomarkers, which are reproducibly quantified (CV < 20% with label-free quantification). In total, the round-robin study highlights a promising baseline for bringing MS-based measurements of serum and plasma samples closer to clinical utility
Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma
No full textThe bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis
Outer retina micro-inflammation is driven by T cell responses prior to retinal degeneration in early age-related macular degeneration
Get PDFINTRODUCTION: Age-related macular degeneration (AMD) is a leading cause of blindness with limited treatment options. Dysfunction of the retinal pigment epithelium (RPE) is a unifying salient feature of the pathology and a primary end-point damage leading to complications such as geographic atrophy (GA), which represents the most common end-stage of AMD. METHODS: Human and murine ocular tissues were used for histological examinations. Furthermore, flow cytometry and gene expression analysis were used on ocular and splenic tissues of Cx3cr1(GFP/GFP) and C57BL/6J mice at 8 and 12 months of age to characterize the dynamics of local and systemic T cell populations. RESULTS: We show the presence of memory T cells such as CD45RO(+) cells in the choroid and retina of patients with AMD with a peak of abundance in early stages of AMD. As further evidence for the contribution of the adaptive immune system to GA we identified an increased frequency of CD44(+) CD69(+) KLRG1(+) T cells and para-inflammation of the retina in a mouse model that mimics features of GA. Importantly, the activation of T cells found at early AMD-like stages prior to degeneration possessed long-lasting cytotoxic properties and adopted typical features of senescent immune cells. T cells were intimately associated with the RPE, suggesting transmigration and participating in local micro-inflammation. DISCUSSION: Our data support that activation and accumulation of memory T cells can be considered as a hallmark of early AMD, and that adaptive immunosenescence likely to contribute to the chronic inflammation associated with RPE damage and the progression to large lesions as seen in GA