Showing papers by "Mayo Clinic published in 2022"

TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Abstract: Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord 1 . A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing 2–4 . Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies 5,6 , but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A . Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS ( UNC13A genetic variants), and loss of TDP-43 function.

Generation time of the alpha and delta SARS-CoV-2 variants: an epidemiological analysis

Abstract: BackgroundIn May, 2021, the delta (B.1.617.2) SARS-CoV-2 variant became dominant in the UK, superseded by the omicron (B.1.1.529) variant in December, 2021. The delta variant is associated with increased transmissibility compared with the alpha variant, which was the dominant variant in the UK between December, 2020, and May, 2021. To understand transmission and the effectiveness of interventions, we aimed to investigate whether the delta variant generation time (the interval between infections in infector–infectee pairs) is shorter—ie, transmissions are happening more quickly—than that of the alpha variant.MethodsIn this epidemiological analysis, we analysed transmission data from an ongoing UK Health Security Agency (UKHSA) prospective household study. Households were recruited to the study after an index case had a positive PCR test and genomic sequencing was used to determine the variant responsible. By fitting a mathematical transmission model to the data, we estimated the intrinsic generation time (which assumes a constant supply of susceptible individuals throughout infection) and the household generation time (which reflects realised transmission in the study households, accounting for susceptible depletion) for the alpha and delta variants.FindingsBetween February and August, 2021, 227 households consisting of 559 participants were recruited to the UKHSA study. The alpha variant was detected or assumed to be responsible for infections in 131 households (243 infections in 334 participants) recruited in February–May, and the delta variant in 96 households (174 infections in 225 participants) in May–August. The mean intrinsic generation time was shorter for the delta variant (4·7 days, 95% credible interval [CI] 4·1–5·6) than the alpha variant (5·5 days, 4·7–6·5), with 92% posterior probability. The mean household generation time was 28% (95% CI 0–48%) shorter for the delta variant (3·2 days, 95% CI 2·5–4·2) than the alpha variant (4·5 days, 3·7–5·4), with 97·5% posterior probability.InterpretationThe delta variant transmits more quickly in households than the alpha variant, which can be attributed to faster depletion of susceptible individuals in households and a possible decrease in the intrinsic generation time. Interventions such as contact tracing, testing, and isolation might be less effective if transmission of the virus occurs quickly.FundingNational Institute for Health Research, UK Health Security Agency, Engineering and Physical Sciences Research Council, and UK Research and Innovation. In May, 2021, the delta (B.1.617.2) SARS-CoV-2 variant became dominant in the UK, superseded by the omicron (B.1.1.529) variant in December, 2021. The delta variant is associated with increased transmissibility compared with the alpha variant, which was the dominant variant in the UK between December, 2020, and May, 2021. To understand transmission and the effectiveness of interventions, we aimed to investigate whether the delta variant generation time (the interval between infections in infector–infectee pairs) is shorter—ie, transmissions are happening more quickly—than that of the alpha variant. In this epidemiological analysis, we analysed transmission data from an ongoing UK Health Security Agency (UKHSA) prospective household study. Households were recruited to the study after an index case had a positive PCR test and genomic sequencing was used to determine the variant responsible. By fitting a mathematical transmission model to the data, we estimated the intrinsic generation time (which assumes a constant supply of susceptible individuals throughout infection) and the household generation time (which reflects realised transmission in the study households, accounting for susceptible depletion) for the alpha and delta variants. Between February and August, 2021, 227 households consisting of 559 participants were recruited to the UKHSA study. The alpha variant was detected or assumed to be responsible for infections in 131 households (243 infections in 334 participants) recruited in February–May, and the delta variant in 96 households (174 infections in 225 participants) in May–August. The mean intrinsic generation time was shorter for the delta variant (4·7 days, 95% credible interval [CI] 4·1–5·6) than the alpha variant (5·5 days, 4·7–6·5), with 92% posterior probability. The mean household generation time was 28% (95% CI 0–48%) shorter for the delta variant (3·2 days, 95% CI 2·5–4·2) than the alpha variant (4·5 days, 3·7–5·4), with 97·5% posterior probability. The delta variant transmits more quickly in households than the alpha variant, which can be attributed to faster depletion of susceptible individuals in households and a possible decrease in the intrinsic generation time. Interventions such as contact tracing, testing, and isolation might be less effective if transmission of the virus occurs quickly.

A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

Abstract: Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

The Female-Predominant Persistent Immune Dysregulation of the Post-COVID Syndrome

Abstract: To describe the clinical data from the first 108 patients seen in the Mayo Clinic post-COVID-19 care clinic (PCOCC).After Institutional Review Board approval, we reviewed the charts of the first 108 patients seen between January 19, 2021, and April 29, 2021, in the PCOCC and abstracted from the electronic medical record into a standardized database to facilitate analysis. Patients were grouped into phenotypes by expert review.Most of the patients seen in our clinic were female (75%; 81/108), and the median age at presentation was 46 years (interquartile range, 37 to 55 years). All had post-acute sequelae of SARS-CoV-2 infection, with 6 clinical phenotypes being identified: fatigue predominant (n=69), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women, and the dyspnea-predominant phenotype was more common in men. Interleukin 6 (IL-6) was elevated in 61% of patients (69% of women; P=.0046), which was more common than elevation in C-reactive protein and erythrocyte sedimentation rate, identified in 17% and 20% of cases, respectively.In our PCOCC, we observed several distinct clinical phenotypes. Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection.

Ultra-stable all-solid-state sodium metal batteries enabled by perfluoropolyether-based electrolytes

Abstract: Rechargeable batteries paired with sodium metal anodes are considered to be one of the most promising high-energy and low-cost energy-storage systems. However, the use of highly reactive sodium metal and the formation of sodium dendrites during battery operation have caused safety concerns, especially when highly flammable liquid electrolytes are used. Here we design and develop solvent-free solid polymer electrolytes (SPEs) based on a perfluoropolyether-terminated polyethylene oxide (PEO)-based block copolymer for safe and stable all-solid-state sodium metal batteries. Compared with traditional PEO SPEs, our results suggest that block copolymer design allows for the formation of self-assembled nanostructures leading to high storage modulus at elevated temperatures with the PEO domains providing transport channels even at high salt concentration (ethylene oxide/sodium = 8/2). Moreover, it is demonstrated that the incorporation of perfluoropolyether segments enhances the Na+ transference number of the electrolyte to 0.46 at 80 °C and enables a stable solid electrolyte interface. The new SPE exhibits highly stable symmetric cell-cycling performance at high current density (0.5 mA cm−2 and 1.0 mAh cm−2, up to 1,000 h). Finally, the assembled all-solid-state sodium metal batteries demonstrate outstanding capacity retention, long-term charge/discharge stability (Coulombic efficiency, 99.91%; >900 cycles with Na3V2(PO4)3 cathode) and good capability with high loading NaFePO4 cathode (>1 mAh cm−2). Rechargeable batteries with sodium metal anodes are promising as energy-storage systems despite safety concerns related to reactivity and dendrite formation. Solvent-free perfluoropolyether-based electrolytes are now reported for safe and stable all-solid-state sodium metal batteries.

The 2018–2020 Multi‐Year Drought Sets a New Benchmark in Europe

Abstract: During the period 2018–2020, Europe experienced a series of hot and dry weather conditions with significant socioeconomic and environmental consequences. Yet, the extremity of these multi-year dry conditions is not recognized. Here, we provide a comprehensive spatio-temporal assessment of the drought hazard over Europe by benchmarking past exceptional events during the period from 1766 to 2020. We identified the 2018–2020 drought event as a new benchmark having an unprecedented intensity that persisted for more than 2 years, exhibiting a mean areal coverage of 35.6% and an average duration of 12.2 months. What makes this event truly exceptional compared with past events is its near-surface air temperature anomaly reaching +2.8 K, which constitutes a further evidence that the ongoing global warming is exacerbating present drought events. Furthermore, future events based on climate model simulations Coupled Model Intercomparison Project v5 suggest that Europe should be prepared for events of comparable intensity as the 2018–2020 event but with durations longer than any of those experienced in the last 250 years. Our study thus emphasizes the urgent need for adaption and mitigation strategies to cope with such multi-year drought events across Europe.

Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations

Abstract: Frontotemporal dementia comprises a group of clinical syndromes that are characterised by progressive changes in behaviour, executive function, or language. The term frontotemporal lobar degeneration encompasses the neurodegenerative diseases that give rise to these clinical syndromes and involve proteinopathies associated with frontotemporal network dysfunction. Improvements in clinical, genetic, and molecular characterisation have provided new insights into frontotemporal dementia and frontotemporal lobar degeneration, with a much broader range of signs and symptoms at presentation than has been previously considered. Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition. Advances in plasma and CSF biomarkers, and innovations in structural and functional imaging, will prove useful for future clinical trials in people with frontotemporal dementia.

Comparing national greenhouse gas budgets reported in UNFCCC inventories against atmospheric inversions

Abstract: Abstract. In support of the global stocktake of the Paris Agreement on climate change, this study presents a comprehensive framework to process the results of an ensemble of atmospheric inversions in order to make their net ecosystem exchange (NEE) carbon dioxide (CO2) flux suitable for evaluating national greenhouse gas inventories (NGHGIs) submitted by countries to the United Nations Framework Convention on Climate Change (UNFCCC). From inversions we also deduced anthropogenic methane (CH4) emissions regrouped into fossil and agriculture and waste emissions, as well as anthropogenic nitrous oxide (N2O) emissions. To compare inversion results with national reports, we compiled a new global harmonized database of emissions and removals from periodical UNFCCC inventories by Annex I countries, and from sporadic and less detailed emissions reports by non-Annex I countries, given by national communications and biennial update reports. No gap filling was applied. The method to reconcile inversions with inventories is applied to selected large countries covering ∼90 % of the global land carbon uptake for CO2 and top emitters of CH4 and N2O. Our method uses results from an ensemble of global inversions produced by the Global Carbon Project for the three greenhouse gases, with ancillary data. We examine the role of CO2 fluxes caused by lateral transfer processes from rivers and from trade in crop and wood products and the role of carbon uptake in unmanaged lands, both not accounted for by NGHGIs. Here we show that, despite a large spread across the inversions, the median of available inversion models points to a larger terrestrial carbon sink than inventories over temperate countries or groups of countries of the Northern Hemisphere like Russia, Canada and the European Union. For CH4, we find good consistency between the inversions assimilating only data from the global in situ network and those using satellite CH4 retrievals and a tendency for inversions to diagnose higher CH4 emission estimates than reported by NGHGIs. In particular, oil- and gas-extracting countries in central Asia and the Persian Gulf region tend to systematically report lower emissions compared to those estimated by inversions. For N2O, inversions tend to produce higher anthropogenic emissions than inventories for tropical countries, even when attempting to consider only managed land emissions. In the inventories of many non-Annex I countries, this can be tentatively attributed to a lack of reporting indirect N2O emissions from atmospheric deposition and from leaching to rivers, to the existence of natural sources intertwined with managed lands, or to an underestimation of N2O emission factors for direct agricultural soil emissions. Inversions provide insights into seasonal and interannual greenhouse gas fluxes anomalies, e.g., during extreme events such as drought or abnormal fire episodes, whereas inventory methods are established to estimate trends and multi-annual changes. As a much denser sampling of atmospheric CO2 and CH4 concentrations by different satellites coordinated into a global constellation is expected in the coming years, the methodology proposed here to compare inversion results with inventory reports (e.g., NGHGIs) could be applied regularly for monitoring the effectiveness of mitigation policy and progress by countries to meet the objective of their pledges. The dataset constructed by this study is publicly available at https://doi.org/10.5281/zenodo.5089799 (Deng et al., 2021).

Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

Abstract: Significance Statement Hematopoietic stem cell transplant (HSCT) is a treatment for certain hematologic malignancies and immune disorders. A complication of HSCT is membranous nephropathy (MN), which results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The antigen in most cases of HSCT-associated MN is not known. Laser microdissection and mass spectrometry identified a novel protein, protocadherin FAT1 (FAT1), in HSCT-associated MN. Kidney biopsy specimens showed granular staining for FAT1 along the GBM in HSCT-associated MN. Antibodies to FAT1 were detected in serum and in kidney biopsy tissue in HSCT-associated MN, but not in controls. FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents the majority of MN associated with HSCT. Background Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. Methods We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'. Results MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN. Conclusions FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT. Visual Abstract Export

Nintedanib in Patients With Autoimmune Disease–Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the <scp>INBUILD</scp> Trial

Abstract: Objective To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease–related interstitial lung diseases (ILDs) with a progressive phenotype. Methods The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease–related ILDs. Results Among 170 patients with autoimmune disease–related ILDs, the rate of decline in FVC over 52 weeks was −75.9 ml/year with nintedanib versus −178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. Conclusion In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease–related ILDs, with AEs that were manageable for most patients.

Autoimmune/Paraneoplastic Encephalitis Antibody Biomarkers: Frequency, Age, and Sex Associations

Abstract: To determine the frequency of detection and the age and sex associations of autoimmune/paraneoplastic encephalitis antibody biomarkers (AE-Abs).There were 42,032 patients tested in the Mayo Clinic Neuroimmunology Laboratory between January 2018 and December 2019 for AE-Abs in serum or cerebrospinal fluid (CSF), including NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, CASPR2-IgG, LGI1-IgG, GAD65-IgG, CRMP5-IgG, amphiphysin-IgG, PCA1/2/Tr-IgGs, ANNA1/2/3-IgGs, GFAP-IgG, mGluR1-IgG, DPPX-IgG, and MOG-IgG1. Results were examined to determine frequency of antibody positivity. Age and sex associations were examined by multivariable logistic regression.Adult serum analysis (22,472 patients; 56% female) revealed that 814 (3.6%) were positive: NMDA-R-IgG (24.6%) > GAD65-IgG (21.5%) > LGI1-IgG (20.5%) > others. Of children (5649; 50% female), 251 (4.4%) were positive: NMDA-R-IgG (53.1%) > MOG-IgG1 (32%) > GAD65-IgG (7.1%) > others. Adult CSF analysis (18,745 patients; 54% female) revealed that 796 (4.2%) were positive: NMDA-R-IgG (39.7%) > GAD65-IgG (28.5%) > LGI1-IgG (11.4%) > others. Of children (5136; 50% female), 282 (5.5%) were positive: NMDA-R-IgG (88.1%) > GAD65-IgG (8.7%) > others. Age younger than 20 years was associated with NMDA-R-IgG and MOG-IgG1 (odds ratio [OR], 8.11 and 7.84, respectively; P<.001). Age older than 65 years was associated with GABAB-R-IgG, LGI1-IgG, CASPR2-IgG, and ANNA1-IgG (OR, 7.33, 14.98, 3.67, and 14.53; P<.001). Women accounted for 60% of NMDA-R-IgG (CSF) and 78% of GAD65-IgG (CSF and serum) cohorts (OR, 1.32 [P=.002] and 2.23 [P<.001], respectively). Men accounted for 62% of the LGI1-IgG cohort (OR, 1.87; P<.001). Age and sex interacted for NMDA-R-IgG, particularly in female patients younger than 20 years (OR, 7.72; P<.001).The most frequent AE-Abs detected were NMDA-R-IgG, GAD65-IgG, LGI1-IgG, and MOG-IgG1. Age and sex associations may suggest paraneoplastic, or aging influences on neurologic autoimmunity.

Effect of grain size and volume fraction of eutectic structure on mechanical properties and corrosion behavior of as-cast Zn–Mg binary alloys

Abstract: In this work, the effects of Mg content on the microstructure evolution, mechanical properties, and corrosion behavior of as-cast Zn-xMg (x = 0.1, 0.3, 0.5, 1.0, 1.5, and 3.0, wt.%) binary alloys were investigated. The microstructure of as-cast alloys is composed of α-Zn matrix and a ternary eutectic phase (α-Zn + Mg2Zn11+MgZn2). With the increase of Mg content, the average grain size of the alloys decreases from 104 μm to 11 μm while the volume fraction of eutectic structure increases from 3% to 84%, resulting in the improvement of tensile strength. In vitro immersion tests demonstrate that the corrosion rate decreases to a minimum value of 0.086 mm y−1 as Mg content increases from 0.1 to 0.3, followed by an increasing trend with the further increase of Mg content. The variation of corrosion rate with Mg content originates from the competition between the positive effect of grain refinement and the negative effective of eutectic volume fraction increment. Zn-0.3 Mg alloy has the optimal corrosion resistance because of the dominant role of grain refinement induced corrosion resistance enhancement. In addition, the corrosion mechanism varies from localized pitting to a more uniform corrosion as Mg content rises.