Similar Signatures Research Articles

T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia

AbstractAcquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis of T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human peripheral blood mononuclear cells, we first established a model that recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (CLL) (PGA-1, CII, and Mec-1), but not from other B-cell malignancies, altered the T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to oxidative phosphorylation (OXPHOS). Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening the activation, which could be restored by the blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after the in vivo reduction of the leukemic burden with combination therapy (venetoclax and obinutuzumab), restoring T-cell function. In conclusion, we uncovered a pseudohypoxic program connected with T-cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.

BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.

Voluminous Paleoproterozoic plutonic belt of the Bacajá domain in Amazon Craton: Petrology, geotectonic setting and Pb–Pb zircon evaporation ages

To the north of the well-known Archean Carajás Metallogenetic Province, the Bacajá Domain abounds voluminous Rhyacian plutonic bodies predominate largely over remnants of Siderian and Neoarchean crust. The Rhyacian granitoids of the Bacajá Domain present a wide lithological variety and a geological evolution marked by syntectonic emplacement, which printed strongly elongated geometries to the bodies, according to a WNW regional orientation. The Rhyacian granitoids form three distinct units. The Bacajaí intrusive suite comprises 2112 ± 8 Ma metaquartz diorites, tonalites, granodiorites and monzogranites of calc-alkaline signature. Sm–Nd isotopic analyses of these rocks yielded a TDM age of 2310 Ma and an εNd value of +0.56. The Arapari intrusive suite is composed of quartz diorites, tonalites, granodiorites and monzogranites of calc-alkaline signature. A preliminary Pb–Pb zircon dating pointed an age of 2072 Ma to the Arapari intrusive suite. Nd isotopes yielded TDM ages varying from 2100 to 2170 Ma and positive εNd (+2.11 to +3.04). Both Bacajaí and Arapari intrusive suites have similar chemical signatures suggesting continental magmatic arc environment. The origin of Bacajaí and Arapari magmas could be explained by partial melting of mantle and crustal sources. The João Jorge intrusive suite encloses high-K calc-alkaline quartz diorites, monzogranites, syenogranites, alkali feldspar granites, shoshonitic alkali feldspar syenites and monzonites. The alkali feldspar syenites have Pb–Pb zircon age of 2076 Ma, TDM age of 2210 Ma and positive εNd value (+1.51). Spatial relationship between shoshonitic bodies and strike-slip shear zones or geological contacts seems to reflect the influence of crustal anisotropies on mantle-derived magmas ascending. Partial melting of metassomatized mantle after extraction of granite melts could explain the origin of syenites and monzonites. The three granitoid unities show rhythmic layering defined by alternation of quartz-feldspathic and ferromagnesian-enriched levels. Regionally penetrative steep-dipping magmatic foliation was formed in the presence of both crystals and melt, under conditions of increasing deformation and decreasing temperatures. The Bacajaí metagranitoids underwent locally thermal effects of hornblende hornfels facies caused by the later granitoid suites. These hornfelsed granitoids may present granoblastic textures, overgrown muscovite, reddish biotite and clinopyroxene. Late WNW strike-slip ductile zones and brittle faults crosscut some of the plutons, closing the ancient geological evolution of the Bacajá Domain.

Relation Between Oceanic Plate Structure, Patterns of Interplate Locking and Microseismicity in the 1922 Atacama Seismic Gap

AbstractWe deployed a dense geodetic and seismological network in the Atacama seismic gap in Chile. We derive a microseismicity catalog of >30,000 events, time series from 70 GNSS stations, and utilize a transdimensional Bayesian inversion to estimate interplate locking. We identify two highly locked regions of different sizes whose geometries appear to control seismicity patterns. Interface seismicity concentrates beneath the coastline, just downdip of the highest locking. A region with lower locking (27.5°S–27.7°S) coincides with higher seismicity levels, a high number of repeating earthquakes and events extending toward the trench. This area is situated where the Copiapó Ridge is subducted and has shown previous indications of both seismic and aseismic slip, including an earthquake sequence in 2020. While these findings suggest that the structure of the downgoing oceanic plate prescribes patterns of interplate locking and seismicity, we note that the Taltal Ridge further north lacks a similar signature.

Assessment of salinity and heat impacts on natural organic matter composition in bentonite for used nuclear fuel storage

Bentonite clay (MX-80, Wyoming, USA) is a proposed sealing material for the safe and long-term management of Canada's used nuclear fuel in a deep geological repository (DGR). Due to the physiochemical properties of bentonite, this buffer layer can limit radionuclide mobilization, and minimize air and water circulation, and hence suppress microbial activity near the used fuel container. However, natural organic matter (NOM) in mined Wyoming-type bentonite (MX-80) may serve as microbial substrates and cause further corrosion to the used fuel container. In the proposed DGR, bentonite will be exposed to high salinity due to saline groundwater and heat released from radioactive decay of radionuclide inventory of the used nuclear fuel. There is limited knowledge about how NOM quantity and quality in MX-80 may change after being exposed to the anticipated levels of salinity and heat in a DGR, especially at the molecular-level. To explore this, organic carbon contents and NOM composition (both soluble- and solid-phase) in MX-80 after exposure to different saline (NaCl) solutions (1 M, 2 M, 3 M, 4 M and 5 M) with and without heat exposure (90 °C) were analyzed. Dissolved organic carbon (DOC) solubility decreased with increasing salinity but these differences were not statistically significant when compared to the control (P < 0.05). DOC solubilization was not significantly altered with heat (P < 0.05). Dissolved organic matter (DOM) composition was analyzed with solution-state 1H nuclear magnetic resonance (NMR) and ultraviolet–visible (UV–Vis) spectroscopy. The NMR results indicated that DOM samples with varied salinities and heat exposure had similar chemical signatures. The results from UV–Vis analysis revealed a small decrease in less unsaturated components in DOM with NaCl solution compared to deionized water. The chemistry of solid-phase NOM that remained in MX-80 after DOM isolation was similar and suggests an insensitivity to either heat and/or salinity. The solubilized DOC contributes less than 1% to the total organic carbon in MX-80, thus, the anticipated level of salinity and heat in a DGR is unlikely to enhance NOM solubilization and change NOM chemistry in the bentonite markedly. As the bentonite in this study was only exposed to the heat and salinity in a short-term experiment, further studies examining NOM composition and reactivity under long-term saline and heat conditions are recommended.

Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia

The COVID-19 pandemic continues to be a health crisis with major unmet medical needs. The early responses from airway epithelial cells, the first target of the virus regulating the progression toward severe disease, are not fully understood. Primary human air-liquid interface cultures representing the broncho-alveolar epithelia were used to study the kinetics and dynamics of SARS-CoV-2 variants infection. The infection measured by nucleoprotein expression, was a late event appearing between day 4-6 post infection for Wuhan-like virus. Other variants demonstrated increasingly accelerated timelines of infection. All variants triggered similar transcriptional signatures, an "early" inflammatory/immune signature preceding a "late" type I/III IFN, but differences in the quality and kinetics were found, consistent with the timing of nucleoprotein expression. Response to virus was spatially organized: CSF3 expression in basal cells and CCL20 in apical cells. Thus, SARS-CoV-2 virus triggers specific responses modulated over time to engage different arms of immune response.

Spatial immunophenotypes orchestrate prognosis in triple-negative breast cancer with Miller-Payne grade 4 following neoadjuvant chemotherapy

Some triple-negative breast cancer (TNBC) patients evaluated as Miller-Payne 4 with ypN0 after neoadjuvant chemotherapy (NACT) who have better prognoses should avoid escalation of therapy. We aim to identify these patients by evaluating pretherapeutic spatial distributions of immunophenotypes. Our retrospective study in patients with TNBC assessed as Miller-Payne grade 4/5 with ypN0 showed that Miller-Payne 4 with ypN0 group had poorer 5-year disease-free survival (DFS, 63.8% vs. 83.0%, p = 0.003) and the 5-year overall survival (OS, 71.0% vs. 85.5%, p = 0.007) than Miller-Payne 5 with ypN0 group. High TILs were significantly associated with better DFS and OS in patients with Miller-Payne 4 and ypN0 (both p = 0.016). Spatially, detected by multiplexed ion beam imaging by the time of flight combined with proteomics, tumors assessed as Miller-Payne 4 and ypN0 with good prognosis exhibited an inflamed phenotype, with dominant CD8+ T cells on tumor center, few scattered CD68+ myeloid-derived cells far away from T cells, and deposit of increased activated molecules of lymphocyte. While those with poor prognoses presented excluded phenotypes, with few CD8+ T cells restricted to invasive margins and a high density of CD14+CD68+CD11c+ myeloid cells. A good classifier model based on 29 spatial immunophenotypes was established by the random forest algorithm (AUC = 0.975), for identifying patients with Miller-Payne 4 and ypN0 who had favorable prognoses. We also observed similar signatures in patients with Miller-Payne 5 and ypN0. Taken together, spatial immunophenotypes may assess the prognosis in TNBC patients with Miller-Payne 4 and ypN0 after NACT.

National-scale imperviousness mapping and detection of urban land changes

With high land take for urbanization a serious concern, the European Union and Member States have set quantitative targets for limiting land take in Europe. Consistent and reliable information on land take is crucial for measuring progress in achieving these targets. In the big data era, Earth observation data offers opportunities to regularly and consistently monitor land use change dynamics on a national scale. However, often-used methods such as image classification do not solve the mixed pixels problem common to urban areas with high heterogeneity. Moreover, the urban land use changes detected by these methods are often affected by random noise caused by non-relevant changes in atmospheric conditions, sun angle, vegetation phenology, etc. Therefore, the resulting products are often judged as being of insufficient quality for operational application.In this study, we present an approach to measuring annual land take using imperviousness mapping and change detection. Based on the Google Earth cloud computing platform, we first applied a data mining approach on annual Sentinel-2 image scenes to extract temporal and spectral information at Germany wide scale. Then spectral unmixing algorithm was used to estimate sub-pixel fractions of imperviousness. We end by using imperviousness changes to detect newly built surfaces. The change detection products were validated using high-resolution historical aerial photos and images. The results achieved an accuracy of 87% for detecting new built-up and 98% for detecting changes. The difference between the two numbers is caused by the areas with changes on the surface but not for urban use.We found that the integration of temporal information improves the performance of spectral unmixing than using spectral information alone, because it can better distinguish imperviousness from other land covers with similar spectral signatures but different temporal characteristics. We also found that, due to the sub-pixel analysis approach, spectral-unmixing-derived imperviousness is sensitive to urban features even with a size of just a few pixels. Moreover, the imperviousness layer represents urban land with a continuous index, meaning that random noise, represented as a low-range change of fractions, can be filtered out. Our study demonstrated that remote sensing products can be tailored to fulfil the needs of specific applications supporting sustainable land-use policy. This opens up more possibilities for the diverse and growing user communities of urban land change products.

NETosis promotes chronic inflammation and fibrosis in systemic lupus erythematosus and COVID-19

Pulmonary fibrosis, a serious complication of systemic lupus erythematosus (SLE) and coronavirus disease 2019 (COVID-19), leads to irreversible lung damage. However, the underlying mechanism of this condition remains unclear. In this study, we revealed the landscape of transcriptional changes in lung biopsies from individuals with SLE, COVID-19-induced pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF) using histopathology and RNA sequencing, respectively. Despite the diverse etiologies of these diseases, lung expression of matrix metalloproteinase genes in these diseases showed similar patterns. Particularly, the differentially expressed genes were significantly enriched in the pathway of neutrophil extracellular trap formation, showing similar enrichment signature between SLE and COVID-19. The abundance of Neutrophil extracellular traps (NETs) was much higher in the lungs of individuals with SLE and COVID-19 compared to those with IPF. In-depth transcriptome analyses revealed that NETs formation pathway promotes epithelial-mesenchymal transition (EMT). Furthermore, stimulation with NETs significantly up-regulated α-SMA, Twist, Snail protein expression, while decreasing the expression of E-cadherin protein in vitro. This indicates that NETosis promotes EMT in lung epithelial cells. Given drugs that are efficacious in degrading damaged NETs or inhibiting NETs production, we identified a few drug targets that were aberrantly expressed in both SLE and COVID-19. Among these targets, the JAK2 inhibitor Tofacitinib could effectively disrupted the process of NETs and reversed NET-induced EMT in lung epithelial cells. These findings support that the NETs/EMT axis, activated by SLE and COVID-19, contributes to the progression of pulmonary fibrosis. Our study also highlights that JAK2 as a potential target for the treatment of fibrosis in these diseases.

Trace element redistributions during metamorphism of E-chondrites: Implications for reduced bodies and the Earth

We report on new trace element analyses of enstatite chondrites (ECs) to clarify their behavior during the metamorphism. During the transition from a type 3 to a type 5 or higher, silicates lose a large portion of their trace elements to sulfides. Our procedure allows us to obtain trace element abundances of the silicate fraction of an EC quite easily. The element patterns of these fractions (especially REE patterns) are quite different for EH and EL chondrites, and are furthermore dependent on the metamorphic grade. This procedure can be usefull to classify meteorites, in particular when the sulfides are altered. Applied to anomalous ECs, it allows direct recognition of the EH affinity of QUE 94204, and suggests that Zakłodzie, NWA 4301, and NWA 4799 derive from the same EH-like body of previously unsampled composition.We have used the concentrations obtained on the silicate fractions of the most metamorphosed chondrites to discuss the chemical characteristics of the primitive mantles of reduced bodies of EH or EL affinity (i.e., after core segregation). Our data indicate that these mantles are very depleted in refractory lithophile elements (RLEs), particularly in rare earth elements (REEs), and notably show significant positive anomalies in Sr, Zr, Hf, and Ti. These estimates imply that the cores contain most of the REEs, U and Th of these bodies. Interestingly, the inferred primitive mantles of these reduced bodies contrast with that of the Earth. If the Earth accreted essentially from ECs, one would expect similar signatures to be preserved, which is not the case. This mismatch can be explained either by a later homogenization of the bulk silicate Earth, or alternatively, that the materials that were accreted were isotopically similar to ECs, but mineralogically different (i.e., oldhamite-free).

Functional connectome fingerprinting and stability in multiple sclerosis.

Functional connectome fingerprinting can identify individuals based on their functional connectome. Previous studies relied mostly on short intervals between fMRI acquisitions. This cohort study aimed to determine the stability of connectome-based identification and their underlying signatures in patients with multiple sclerosis and healthy individuals with long follow-up intervals. We acquired resting-state fMRI in 70 patients with multiple sclerosis and 273 healthy individuals with long follow-up times (up to 4 and 9 years, respectively). Using functional connectome fingerprinting, we examined the stability of the connectome and additionally investigated which regions, connections and networks supported individual identification. Finally, we predicted cognitive and behavioural outcome based on functional connectivity. Multiple sclerosis patients showed connectome stability and identification accuracies similar to healthy individuals, with longer time delays between imaging sessions being associated with accuracies dropping from 89% to 76%. Lesion load, brain atrophy or cognitive impairment did not affect identification accuracies within the range of disease severity studied. Connections from the fronto-parietal and default mode network were consistently most distinctive, i.e., informative of identity. The functional connectivity also allowed the prediction of individual cognitive performances. Our results demonstrate that discriminatory signatures in the functional connectome are stable over extended periods of time in multiple sclerosis, resulting in similar identification accuracies and distinctive long-lasting functional connectome fingerprinting signatures in patients and healthy individuals.

Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma

Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity.

Patients with dermatomyositis shared partially similar transcriptome signature with COVID-19 infection

Dermatomyositis (DM) is an autoimmune disease that primarily affects the skin and skeletal muscle. Virus infection and type I interferon-related signaling pathways play an important role in the pathogenesis of dermatomyositis. In this study, we found that the skin of patients with DM and the skin of patients with COVID-19 have similar transcriptional profiles, and identified key genes involved in dermatomyositis based on bioinformatics analysis. These hub-genes might be served as potential biomarkers for the early diagnosis and therapy of DM, including MX1, ISG15, IFIT3, IFIT1, RSAD2, IFIT2, IFI6, XAF1, IRF9, MX2.

An oceanic core complex preserved in the Squanga Lake ophiolite, northern Atlin terrane, Yukon

The Squanga Lake ophiolite of southern Yukon exhibits a non-Penrose pseudostratigraphy with mantle tectonites separated from upper crustal rocks by an extensional detachment zone (Squanga Lake detachment zone, SLDZ), compatible with formation in an oceanic core complex. Spinel, orthopyroxene and clinopyroxene mineral compositions indicate dynamic re-crystallisation during exhumation of ophiolitic mantle rocks. The rocks and structures of the SLDZ also preserve evidence of exhumation: 1) clasts of primitive olivine-cumulates in the SLDZ mélange represent excised lower oceanic crust; 2) structures in the SLDZ indicate ductile to brittle conditions; 3) temperatures along the SLDZ span from upper- to lower-amphibolite facies conditions. We obtained 248.77 ± 0.22, 248.53 ± 0.41, and 248.84 ± 2.09 Ma U-Pb zircon ages from upper crustal gabbro, a gabbro fragment within the SLDZ mélange and a dyke within the SLDZ implying syn-kinematic magmatism. Calc-silicate alteration associated with cross-cutting diabase dykes yielded a UPb titanite age of 247 ± 10.5 Ma. All igneous rocks show similar geochemical signatures with ubiquitous subduction input. Our data indicate that Squanga Lake ophiolite preserves an oceanic core complex, formed in a back-arc basin environment.

BCR-ABL promotes hematopoietic stem and progenitor cell formation in embryonic stem cells

Generating hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) has been a long-lasting quest in the field of hematopoiesis. Previous studies suggested that enforced expression of BCR-ABL, the unique oncogenic driver of chronic myelogeneous leukemia (CML), in embryonic stem cells (ESCs)-derived hematopoietic cells is sufficient to confer long-term in vivo repopulating potential. To precisely uncover the molecular events regulated by the tyrosine kinase activity of BCR-ABL1 (p210) during the course of hematopoietic differentiation, we engineered a Tet-ON inducible system to modulate its expression in murine ESCs (mESCs). We showed in unique site-directed knock-in ESC model that BCR-ABL expression tightly regulated by doxycycline (dox) controls the formation and the maintenance of immature hematopoietic progenitors. Interestingly, these progenitors can be expanded in vitro for several passages in the presence of dox. Our analysis of cell surface markers and transcriptome compared with wild-type fetal and adult HSCs unraveled a similar molecular signature. Long-term culture initiating cell (LTC-IC) assay confirmed their self-renewal capacities albeit with a differentiation bias toward erythroid and myeloid cells. Collectively, our novel Tet-ON system represents a unique in vitro model to shed lights on ESC-derived hematopoiesis, CML initiation, and maintenance.

Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis.

Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.

Consensus Techniques for Unsupervised Binary Change Detection Using Multi-Scale Segmentation Detectors for Land Cover Vegetation Images

Change detection in very-high-spatial-resolution (VHR) remote sensing images is a very challenging area with applicability in many problems ranging from damage assessment to land management and environmental monitoring. In this study, we investigated the change detection problem associated with analysing the vegetation corresponding to crops and natural ecosystems over VHR multispectral and hyperspectral images obtained by sensors onboard drones or satellites. The challenge of applying change detection methods to these images is the similar spectral signatures of the vegetation elements in the image. To solve this issue, a consensus multi-scale binary change detection technique based on the extraction of object-based features was developed. With the objective of capturing changes at different granularity levels taking advantage of the high spatial resolution of the VHR images and, as the segmentation operation is not well defined, we propose to use several detectors based on different segmentation algorithms, each applied at different scales. As the changes in vegetation also present high variability depending on capture conditions such as illumination, the use of the CVA-SAM applied at the segment level instead of at the pixel level is also proposed. The results revealed the effectiveness of the proposed approach for identifying changes over land cover vegetation images with different types of changes and different spatial and spectral resolutions.

OXALATE-DEGRADING ACTIVITY IN FECAL MICROBIOTA IS ASSOCIATED WITH OBESITY AND CARDIOVASCULAR EVENTS IN END-STAGE KIDNEY DISEASE PATIENTS

Objective: In contrast to the general population, the obesity paradox observed in end-stage kidney disease (ESKD) patients is associated with a better CVD prognosis. Considering the similar signature of the gut microbiota in oxalate metabolism, obesity, and CVD, we hypothesized that altered oxalate-degrading activity (ODA) in the fecal microbiota, rather than obesity per se, might influence the development of CVD in ESKD patients. Design and method: A total of 32 ESKD patients aged 52.5 (40-62) years were enrolled in this retrospective observational cohort pilot study. CVD events were defined as any new-onset disease of the heart and associated blood vessels during the 3-year follow-up period after completion of evaluation. The fecal total ODA, defined as the total ability of the different strains of oxalate-degrading bacteria to metabolize oxalate, was determined by redoximetric titration with KMnO4; results were expressed as % oxalate degradation per 0.01 g of feces. Data analysis and all graphs were generated using MedCalc software. Results: Total fecal ODA ranged from -16 to 24%/0.01 g feces and was inversely correlated with BMI (Fig. 1). During the 3-year follow-up period, 5/7 (71.4%) obese patients, 2/11 (18.2%) overweight patients, and 2/14 (14.3%) normal-weight patients experienced CVD (⇙2 = 8.4, p = 0.01). The ROC analysis showed that a negative total fecal ODA (&lt;-1%/0.01 g feces) was the most appropriate cut-off point for predicting CVD events in ESKD patients, with a sensitivity of 77.8% and a specificity of 74% (Fig. 2). In univariate Cox regression analysis, both obesity (HR 8.2, 95% CI 1.2; 18.1) and negative fecal total ODA (HR 9.4, 95% CI 2.3; 19.4) were associated with CVD events. In the multivariate model of Cox regression analysis adjusted for age, dialysis vintage, diabetes, and dyslipidemia, negative total fecal ODA, but not obesity, was associated with CVD events in our cohort (Fig. 3). Conclusions: Our findings provide preliminary evidence that a decrease in fecal total ODA is associated with obesity and the development of CVD in ESKD patients. Further studies are needed to determine altered fecal total ODA as a risk factor for the development of CVD in ESKD patients.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

Basal Plane Dislocation Slip Band Characterization and Epitaxial Propagation in 4H SiC

Correlation of X-ray topography and production line defect inspection tools has demonstrated the capability of in-line tools to differentiate between geometrically comparable basal plane slip bands (BPSB) and bar stacking faults (BSF) on 4H SiC wafers. BPSBs were found to propagate through epitaxial growth at high rates and with similar photoluminescence signatures to post-epitaxy BSFs. Molten KOH etching post-epitaxy provided evidence of distinguishing features between BPSBs and BSFs, suggesting that the defects were indeed correctly identified by in-line defect inspection tools pre-epitaxy.