Changes In Signatures Research Articles

How long does carbon stay in a near-pristine central Amazon forest? An empirical estimate with radiocarbon

Abstract. Amazon forests play a significant role in the global C cycle by assimilating large amounts of CO2 through photosynthesis and by storing C largely as biomass and soil organic matter. To evaluate the net budget of C in the Amazon, we must also consider the amplitude and timing of losses of C back to the atmosphere through respiration and biomass burning. One useful timescale metric that integrates such information in terrestrial ecosystems is the transit time of C, defined as the time elapsed between C entering and leaving the ecosystem; the transit time is equivalent to the age of C exiting the ecosystem, which occurs mostly through respiration. We estimated the mean transit time of C for a central Amazon forest based on the C age during ecosystem respiration (ER), taking advantage of the large variations in CO2 in the atmosphere below the forest canopy to estimate the radiocarbon signature of mean ER (Δ14CER) using Keeling and Miller–Tans mixing models. We collected air samples to evaluate changes in the isotopic signature of the main ER sources by estimating the δ13CER. We collected air samples in vertical profiles in October 2019 and December 2021 at the Amazon Tall Tower Observatory (ATTO) in the central Amazon. Air samples were collected in a diel cycle from two heights below the canopy (4 and 24 m above ground level (a.g.l.)). Afternoon above-canopy samples (79 and 321 m a.g.l.) were collected as the background. For the campaign of October 2019, the mean Δ14CER ranged from 24 ‰ to 41 ‰ with both Keeling and Miller–Tans methods. In December 2021, mean Δ14CER ranged from 53 ‰ to 102 ‰. The δ13CER showed a smaller variation, being −27.8 ‰ ± 0.3 ‰ in October 2019 and −29.0 ‰ ± 0.5 ‰ in December 2021. The Δ14CER estimates were compared with the record of atmospheric radiocarbon from the bomb period, providing estimates of mean transit time of 6 ± 2 years for 2019 and 18 ± 4 years for 2021. In contrast to steady-state carbon balance models that predict constant mean transit times, these results suggest an important level of variation in mean transit times. We discuss these results in the context of previous model-based estimates of mean transit time for tropical forests and the Amazon region. In addition, we discuss previous studies that indicate that approximately 70 % of assimilated carbon is respired as autotrophic respiration in the central Amazon. Our results suggest that newly fixed carbon in this terra firme tropical forest is respired within 1 to 2 decades, implying that only a fraction of assimilated C can act as a sink for decades or longer.

Listening to the Formation of Polymorphs in a Ball Mill.

In this contribution, we apply our newly developed ball-milling operando platform, which combines Raman spectroscopy and thermal (IR) imaging, as well as acoustic and high-speed optical video recordings, to the synthesis and transformation of citric acid-isonicotinamide (1:2) cocrystal polymorphs in transparent PMMA jars. Particularly, we demonstrate how Raman, temperature, acoustic, and video data are complementary and enable detection and connection of chemical and physical events happening during ball-milling in a time-resolved manner. Importantly, we show that the formation of the three cocrystal polymorphs can be detected through acoustic analyses solely. Even more impressively, the meticulous analyses of the sound data allowed subtle polymorphic transitions to be perceived in operando mode when the Raman spectroscopy was not conclusive enough. Such changes in sound signatures are greatly linked to the beads' motions in the milling jar. A new data analysis methodology of acoustic recordings is proposed through a combination of energetic and statistical approaches that simplifies the data analyses for potential users. The interpretation of the detected sound signals was further validated thanks to the high-speed videos recorded in synchronization with all other operando techniques. Finally, we broaden this acoustic methodology to opaque stainless-steel jars, showing the relevance of the acoustic analysis method for following polymorphic transformations of cocrystals, as well as pure substances, in any type of milling jar.

Reverberation Mapping of Two Variable Active Galactic Nuclei: Probing the Distinct Characteristics of the Inner and Outer Broad-line Regions

Abstract Current reverberation mapping (RM) studies primarily focus on single emission lines, particularly the Hβ line, which may not fully reveal the geometry and kinematic properties of the broad-line region (BLR). To overcome this limitation, we have conducted multiline RM observations on two highly variable active galactic nuclei (AGNs), KUG 1141+371 and UGC 3374, using the Lijiang 2.4 m telescope. Our goal was to investigate the detailed structures of different regions within the BLR. We measured the time lags of multiple broad emission lines (Hα, Hβ, Hγ, He i, and He ii) and found clear evidence of radial ionization stratification in the BLRs of both AGNs. Velocity-resolved RM analysis revealed distinct geometry and kinematics between the inner and outer regions of the BLRs. Assuming that the velocity-resolved lags reflect the kinematics of the BLR, our observations indicate that: (1) in KUG 1141+371, the inner BLR exhibits outflow signatures, while the outer region is consistent with virialized motion; and (2) in UGC 3374, the inner region displays virial motion, while the outer region shows inflow. Furthermore, we detected “breathing” behavior in the outer BLR regions of both AGNs, while the inner BLR regions show “anti-breathing,” which may be linked to intrinsic BLR properties. We discuss these findings in the context of various BLR formation models, highlighting the importance of long-term, multiline RM campaigns in understanding of BLR structure and evolution. Additionally, our results suggest that the observed stratification in BLR geometry and kinematics may contribute to the scatter in black hole mass estimates and the rapid changes in velocity-resolved RM signatures reported in recent studies.

Transcriptomic Profiling and Tumor Microenvironment Classification Reveal Unique and Dynamic Immune Biology in HIV-Associated Kaposi Sarcoma.

Kaposi Sarcoma (KS) is a vascular tumor originating from endothelial cells and is associated with human herpesvirus 8 (KSHV) infection. It disproportionately affects populations facing health disparities. Although antiretroviral therapy (ART) has improved KS control in people with HIV (PWH), treatment options for advanced KS remain limited. This study investigates the tumor microenvironment (TME) of KS through whole-transcriptomic profiling, analyzing changes over time and differences based on HIV status. The TME was categorized into four subtypes: immune-enriched (IE), non-fibrotic, immune-enriched/fibrotic (IE/F), fibrotic (F) and immune-depleted (D). Nine KS patients (four HIV-negative and five HIV-positive) were enrolled in the study. Longitudinally collected KS samples from three patients (one HIV-negative and two HIV-positive) allowed for the investigation of dynamic TME changes within individual patients. The immune cellular composition was determined using deconvolution and compared to a cohort of non-KS patients. Our findings revealed that all KS samples, regardless of HIV status, were enriched in endothelial cells. Compared to non-KS tissues, the KS samples contained a higher percentage of NK and CD8+ T cells. HIV-negative KS samples displayed the IE and IE/F TME subtypes, while HIV-positive samples exhibited IE, IE/F, and F subtypes. Over the course of the disease, a decrease in angiogenic signatures was observed in two HIV-positive KS patients. Notably, HIV-negative KS samples showed alterations in NK cell-mediated immunity and cytotoxic response pathways, whereas HIV-positive samples exhibited changes in growth regulation and protein kinase activity pathways at the time of initial diagnosis. The gene expression of immune checkpoints, including CD274 (PD-L1) and PDCD1LC2 (PD-L2), was comparable between HIV-positive and HIV-negative KS samples at diagnosis. Furthermore, sequencing identified a shared TCRβ chain in all patients analyzed, indicating a T-cell immune response to a common antigen. This study demonstrates unique transcriptomic features and TME subtypes in KS that differ based on HIV status. Additionally, it illustrates longitudinal dynamic changes in the gene signatures and TME subtypes in individual patients. The identification of a shared TCRβ chain suggests that immune T cells in KS patients may target a common antigen. Future studies should further explore the immune microenvironment and unique T cell clonotypes, which could pave the way for the development of novel therapeutic strategies for KS patients.

Convergent and divergent immune aberrations in COVID-19, post-COVID-19-interstitial lung disease, and idiopathic pulmonary fibrosis.

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14+HLA-DRlowCD163+ monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF.NEW & NOTEWORTHY Changes in the 50-gene signature, reflective of increase in CD14+HLA-DRlowCD163+ monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DRlow monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.

Harnessing Raman spectroscopy and multimodal imaging of cartilage for osteoarthritis diagnosis

Osteoarthritis (OA) is a complex disease of cartilage characterised by joint pain, functional limitation, and reduced quality of life with affected joint movement leading to pain and limited mobility. Current methods to diagnose OA are predominantly limited to X-ray, MRI and invasive joint fluid analysis, all of which lack chemical or molecular specificity and are limited to detection of the disease at later stages. A rapid minimally invasive and non-destructive approach to disease diagnosis is a critical unmet need. Label-free techniques such as Raman Spectroscopy (RS), Coherent anti-Stokes Raman scattering (CARS), Second Harmonic Generation (SHG) and Two Photon Fluorescence (TPF) are increasingly being used to characterise cartilage tissue. However, current studies are based on whole tissue analysis and do not consider the different and structurally distinct layers in cartilage. In this work, we use Raman spectroscopy to obtain signatures from the superficial (top) and deep (bottom) layer of healthy and osteoarthritic cartilage samples from 64 patients (19 control and 45 OA). Spectra were acquired both in the ‘fingerprint’ region from 700 to 1720 cm− 1 and high-frequency stretching region from 2500 to 3300 cm− 1. Principal component and linear discriminant analysis was used to identify the peaks that contributed significantly to classification accuracy of the different samples. The most pronounced differences were observed at the proline (855 cm− 1 and 921 cm− 1) and hydroxyproline (877 cm− 1 and 938 cm− 1), sulphated glycosaminoglycan (sGAG) (1064 cm− 1 and 1380 cm− 1) frequencies for both control and OA as well as the 1245 cm− 1 and 1272 cm− 1, 1320 cm− 1 and 1345 cm− 1, 1451 cm− 1 collagen modes were altered in OA samples, consistent with expected collagen structural changes. Classification accuracy based on Raman fingerprint spectral analysis of superficial and deep layer cartilage for controls was found to be 97% and 93% on using individual/all spectra and, 100% and 95% on using mean spectra per patient, respectively. OA diseased cartilage was classified with an accuracy of 88% and 84% for individual/all spectra, and 96% and 95% for mean spectra per patient based on analysis of the superficial and the deep layers, respectively. Raman spectra from the C-H stretching region (2500–3300 cm− 1) resulted in high classification accuracy for identification of different layers and OA diseased cartilage but low accuracy for controls. Differential changes in superficial and deep layer cartilage signatures were observed with age (under 60 and over 60 years), in contrast, less significant differences were observed with gender. Prominent chemical changes in the different layers of cartilage were preliminarily imaged using CARS, SHG and TPF. Cell clustering was observed in OA together with differences in pericellular matrix and collagen structure in the superficial and the deep layers correlating with the Raman spectral analysis. The current study demonstrates the potential of Raman Spectroscopy and multimodal imaging to interrogate cartilage tissue and provides insight into the chemical and structural composition of its different layers with significant implications for OA diagnosis for an increasing aging demographic.

RNA Sequencing Revealed a Weak Response of Gingival Fibroblasts Exposed to Hyaluronic Acid.

Hyaluronic acid was proposed to support soft tissue recession surgery and guided tissue regeneration. The molecular mechanisms through which hyaluronic acid modulates the response of connective tissue cells remain elusive. To elucidate the impact of hyaluronic acid on the connective tissue cells, we used bulk RNA sequencing to determine the changes in the genetic signature of gingival fibroblasts exposed to 1.6% cross-linked hyaluronic acid and 0.2% natural hyaluronic acid. Transcriptome-wide changes were modest. Even when implementing a minimum of 1.5 log2 fold-change and a significance threshold of 1.0 -log10, only a dozenth of genes were differentially expressed. Upregulated genes were PLK3, SLC16A6, IL6, HBEGF, DGKE, DUSP4, PTGS2, FOXC2, ATAD2B, NFATC2, and downregulated genes were MMP24 and PLXNA2. RT-PCR analysis supported the impact of hyaluronic acid on increasing the expression of a selected gene panel. The findings from bulk RNA sequencing suggest that gingival fibroblasts experience weak changes in their transcriptome when exposed to hyaluronic acid.

Ambient ultraviolet-B exposure brings quantum changes in phenotypic and molecular signatures of the embryo of a high-altitude fish, Tor putitora.

Effects of environmentally relevant ultraviolet B (UVB) light on the embryonic development of a high-altitude dwelling endangered fish, Tor putitora (golden mahseer), were investigated for the first time. For that, three sets of embryos (in triplicates) were exposed to various ambient UVB light doses (1, 2 and 3 W/m2, corresponding to 3.6, 7.2 and 10.8kJ/m2/day) for 1h at two different embryonic stages (1 hpf-hours post fertilization and 32 hpf). Another set of embryos was exposed to visible light for the same duration and served as the light control (LC), and the last set was kept under ideal dark conditions for incubation (the dark control, DC). The results showed that the higher levels of UVB light (> 2 W/m2) decreased the hatching rate and survival of embryos and hatchlings, extended the hatching window or hatching time and caused embryonic and hatching deformities. The qPCR analysis revealed upregulation of genes such as nf-kb2, il-1β, tnfα, tlr5, nrf2, bcl2, caspase9, p53, ddb2, mmp13a, mc1r and hsp70 in a dose-dependent manner upon UVB exposure. Overall, the high ambient level of UVB exposure (3 W/m2, equivalent to 10.8kJ/m2/day) in golden mahseer embryos proved to be lethal or sub-lethal, which were mediated by (or related to) immunological changes, oxidative stress, apoptosis, DNA damage and aberrant development. Further, harmful effects of UVB were found to be stage-dependent and were more significant at 32 hpf. The study is the first preliminary report, at the molecular level, on the impact of environmentally occurring UVB on the embryonic development of an endangered fish species, the golden mahseer.

Machine Learning Model Discriminate Ischemic Heart Disease Using Breathome Analysis.

Background: Ischemic heart disease (IHD) impacts the quality of life and is the most frequently reported cause of morbidity and mortality globally. Aims: To assess the changes in the exhaled volatile organic compounds (VOCs) in patients with vs. without ischemic heart disease (IHD) confirmed by stress computed tomography myocardial perfusion (CTP) imaging. Objectives: IHD early diagnosis and management remain underestimated due to the poor diagnostic and therapeutic strategies including the primary prevention methods. Materials and Methods: A single center observational study included 80 participants. The participants were aged ≥ 40 years and given an informed written consent to participate in the study and publish any associated figures. Both groups, G1 (n = 31) with and G2 (n = 49) without post stress-induced myocardial perfusion defect, passed cardiologist consultation, anthropometric measurements, blood pressure and pulse rate measurements, echocardiography, real time breathing at rest into PTR-TOF-MS-1000, cardio-ankle vascular index, bicycle ergometry, and immediately after performing bicycle ergometry repeating the breathing analysis into the PTR-TOF-MS-1000, and after three minutes from the end of the second breath, repeat the breath into the PTR-TOF-MS-1000, then performing CTP. LASSO regression with nested cross-validation was used to find the association between the exhaled VOCs and existence of myocardial perfusion defect. Statistical processing performed with R programming language v4.2 and Python v.3.10 [^R], STATISTICA program v.12, and IBM SPSS v.28. Results: The VOCs specificity 77.6% [95% confidence interval (CI); 0.666; 0.889], sensitivity 83.9% [95% CI; 0.692; 0.964], and diagnostic accuracy; area under the curve (AUC) 83.8% [95% CI; 0.73655857; 0.91493173]. Whereas the AUC of the bicycle ergometry 50.7% [95% CI; 0.388; 0.625], specificity 53.1% [95% CI; 0.392; 0.673], and sensitivity 48.4% [95% CI; 0.306; 0.657]. Conclusions: The VOCs analysis appear to discriminate individuals with vs. without IHD using machine learning models. Other: The exhaled breath analysis reflects the myocardiocytes metabolomic signature and related intercellular homeostasis changes and regulation perturbances. Exhaled breath analysis poses a promise result to improve the diagnostic accuracy of the physical stress tests using machine learning models.

Charge State Tuning and Photochemical Stability of Au25(SR)18 Nanoclusters

The photolysis of the gold nanoclusters Au25(SR)18z (z = 1‐, 0 and 1+, R=C2H4Ph and C12H25) NCs in halogenated solvents such as dichloromethane leads to changes in the charged states of the Au25(SR)18z observed using UV‐Visible and 1H NMR spectroscopic techniques. Matrix assisted laser desorption mass spectrometry results proved that during charge transformation, from anion to neutral and eventually cation forms, the size of nanoclusters remains intact. Electrochemistry of Au25(SR)18 has enabled us to monitor changes by cyclic voltammetry, indicating decay in the redox peak current upon irradiation. In the absence of light and/or in a non‐halogenated solvent, e.g., tetrahydrofuran, no substantial change in the photophysical signatures of Au25 nanoclusters was observed. These observations highlight (i) the importance on selecting appropriate solvent(s) in the synthesis and photochemical studies of atomically precise metal nanoclusters and (ii) possibility of using photochemistry in halogenated solvents to synthesize different charge state of atomically precise metal nanoclusters. Thus, we envision that other monodispersed molecule‐like nanoclusters, with various size and charges can be achieved via this photosynthetic protocol under controlled conditions, e.g., solvent, light, and photolysis duration.

FC24 Zasocitinib (TAK-279), an oral, allosteric, highly selective TYK2 inhibitor, modulates disease-central cytokine pathways that define clinical response in patients with moderate-to-severe plaque psoriasis

Abstract Zasocitinib (TAK-279) demonstrated promising efficacy and was generally well tolerated in a completed Phase 2b study (NCT04999839) in patients with moderate-to-severe plaque psoriasis, with the primary endpoint [75% improvement in psoriasis area and severity (PASI75)] achieved at doses ≥5 mg vs. placebo at Week 12. In an exploratory analysis of this study, associations between zasocitinib treatment, psoriasis/tyrosine kinase 2 (TYK2) biomarkers, and clinical/histological response were investigated. Lesional/non-lesional serum samples and skin biopsies were obtained with consent at Day 1 (pre-dose) and Weeks 4 and 12 from patients receiving zasocitinib (2, 5, 15, and 30 mg) or placebo orally once daily. RT-qPCR, RNA-seq and immunohistochemistry were used to assess changes in lesion keratinocyte proliferation (KRT16 expression), psoriasis/TYK2 biomarkers and lesion gene signatures, and their associations with clinical (PASI75) and histological (plaque resolution) response. Serum samples from 252 patients and biopsy samples from 63 patients were analysed. At Week 12, most clinical responders (n = 21/24, 88%) experienced reductions in KRT16 expression of >87% vs. baseline lesion levels. Pooled analysis showed that, in most histological responders (n = 18/25, 72%), interleukin (IL)17A and IL17F expression reduced by >80% vs. baseline lesion levels. Reductions in lesional type I interferon, IL-12 and IL-23 pathway gene expression were observed at zasocitinib 15 and 30 mg doses compared with baseline levels (P < 0.05). Dose- and time-dependent reductions in serum IL-17A, IL-17C and IL-17F were observed in all zasocitinib groups vs. placebo. In the 15 and 30 mg groups (n = 23), expression of key psoriasis/TYK2 biomarkers (e.g. DEFB4A, IL36G, IL23A) reverted to non-lesional levels at Week 12. Among evaluable PASI90 responders at Week 12 (n = 12), 48/50 of the top upregulated genes in lesions reverted to non-lesional expression levels. In all dose groups, patients had reduced lesional epidermal thickness, CD3+ T-cell counts and CD11c+ myeloid dendritic cell counts with zasocitinib vs. baseline. Zasocitinib treatment did not result in clinically meaningful longitudinal changes in laboratory parameters associated with Janus kinase inhibition. Zasocitinib modulated psoriasis/TYK2 biomarkers were associated with clinical and histological response in patients with moderate-to-severe plaque psoriasis.

Analysis of periodic temporal changes in the spectral signature of IR sources by modeling of spectral artifacts in FTIR systems

Analysis of periodic temporal changes in the spectral signature of IR sources by modeling of spectral artifacts in FTIR systems

Candida albicans cells exhibit media specific proteomic profiles during induction of filamentation

Candida albicans is an opportunist pathogen responsible for a broad spectrum of infections, from superficial mycosis to the systemic disease candidiasis. C. albicans has various morphological forms, including unicellular budding yeasts, filamentous pseudohyphae and true hyphae, and the ability to switch from yeast to hyphal forms is a key survival mechanism underlying the adaptation of the pathogen to the microenvironments encountered within the host. Filamentation is regulated by multiple signalling pathways and its induction in different growth media in vitro has often led to conflicting results. In this study, we performed quantitative proteomic analyses to compare the response of C. albicans yeast cells grown in YNB minimal medium to those of cells grown in four media widely used in the literature to induce the yeast-to-hyphae transition: YNB-Serum, YNB-N-acetylglucosamine (YNB-NAG), Lee medium and rich Spider medium. We show that each growth medium induces a unique pattern of response in C. albicans cells, and that some conditions trigger an original and specific adaptive metabolic response, showing significant differences in the intracellular content of the various filamentous forms. Moreover, this comparison of proteomic profiles indicates that the medium used can modify the thiol-dependent redox status of the cells, particularly in YNB-Serum and Lee medium and, to a lesser extent, in Spider medium, confirming the role of oxidative stress in the filamentation process. Overall, our data indicate that some of the media routinely used to induce hyphae cause significant changes in proteomic signature that should be taken account more carefully when exploring the hyphal transition in this pathogen.

Lipid signature changes of women with gestational diabetes mellitus in response to puerperal exclusive breastfeeding.

We here investigated whether lactation during puerperium could help to reverse the diabetogenic effect of gestation and further explored the lipid profiling changes upon breastfeeding. Thirty-five women diagnosed with GDM were recruited, and fasting plasma samples were collected at ~6 weeks postpartum. Maternal metabolic parameters were determined, and an untargeted lipidomic analysis was performed. The relationship between underlying lipidomic responses and lactation was explored. Improved glucose homeostasis and insulin sensitivity were observed in GDM women who adopted breastfeeding during the puerperium. Further lipidomics analysis revealed prominent correlations between lipid constitution changes and breastfeeding in women with GDM. A total of 766 lipid species were identified, 33 of which were found to be significantly altered in response to lactation. Significant associations between dysregulated lipids and maternal metabolic parameters were also shown. Subsequently, we identified a panel of three lipids that were strongly associated with breastfeeding, from which we constructed a predictive model with higher discriminating power. We generally revealed that lactation during puerperium appears to have favorable effects on diabetogenic risk factors for GDM women. We also discovered that lipidomic changes related to lactation could elucidate the mother's recovery from GDM pregnancy.

IL-1β promotes glutamate excitotoxicity: indications for the link between inflammatory and synaptic vesicle cycle in Ménière's disease.

Ménière's disease (MD) is a complex inner ear disorder characterized by a range of symptoms, with its pathogenesis linked to immune-related mechanisms. Our previous research demonstrated that IL-1β maturation and release can trigger cell pyroptosis, exacerbating the severity of the endolymphatic hydrops in a mouse model; however, the specific mechanism through which IL-1β influences MD symptoms remains unclear. This study conducted on patients with MD examined changes in protein signatures in the vestibular end organs (VO) and endolymphatic sac (ES) using mass spectrometry. Gene ontology and protein pathway analyses showed that differentially expressed proteins in the ES are closely related to adhesion, whereas those in the VO are related to synapse processes. Additionally, the study found elevated expression of Glutaminase (GLS) in the VO of MD patients compared to controls. Further investigations revealed that IL-1β increased glutamate levels by upregulating GLS expression in HEI-OC1 cells. Treatment with a GLS inhibitor or an IL-1β receptor antagonist alleviated auditory-vestibular dysfunction and reduced glutamate levels in mice with endolymphatic hydrops. These findings collectively suggest that imbalanced neurotransmitter release and immune responses contribute to the pathology of MD, potentially explaining the hearing loss and vertigo associated with the disease and offering new avenues for therapeutic interventions.

Multi-strain probiotic administration decreases necrotizing enterocolitis severity and alters the epigenetic profile in mice.

Probiotic administration may decrease the incidence of necrotizing enterocolitis (NEC) through mechanisms that are largely unknown. We investigated the effects of probiotics on intestinal epigenetics and assessed their effects on intestinal inflammation and motility using both ileum-predominant and combined ileo-colitis mouse NEC models. C57BL/6 J mice were gavage-fed a multi-strain probiotic from postnatal days 3-11, consisting of B. infantis, B. lactis, and S. thermophilus. From p8, mice were exposed to ileo-colitis NEC involving formula containing NEC bacteria and 0.5% DSS. DNA methylation was measured using the Infinium Methylation Assay. Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Probiotic colonization was measured in probiotic-fed mice by qPCR. Probiotic administration caused significant changes in the small intestine's epigenetic signature, a reduction in NEC severity, and improved intestinal motility. The effects of probiotics were more pronounced in the ileo-colitis NEC model. These findings shed light on the role of probiotics in two clinically relevant models of NEC, add additional insights into their underlying mechanism of action, and reveal unanticipated epigenetic modifications to the intestinal mucosa after their use. These findings shed light on the role of multi-strain probiotics in two clinically relevant animal models of NEC, and add additional insights into their underlying mechanism of action This study provides a new, clinically relevant model for the study of NEC including administration of 0.5% DSS, to include ileal dominant and ileo-colonic dominant phenotypes of the disease. These results reveal that clinically relevant strains of probiotic bacteria can exert epigenetic effects on the small intestine in mice, and can attenuate the epigenetic changes induced by NEC.

Deucravacitinib in Plaque Psoriasis: Laboratory Parameters Through 4 Years of Treatment in the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious versus placebo and apremilast and was well tolerated in the global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) parent trials. At Week 52, patients could enroll in the ongoing POETYK long-term extension (LTE) (NCT04036435) trial and receive open-label deucravacitinib. Changes in blood laboratory parameters known to be associated with Janus kinase (JAK) 1,2,3 inhibitors were evaluated through 4 years of deucravacitinib treatment. Methods: Changes from baseline in lipid (cholesterol, triglycerides), chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, creatine phosphokinase [CPK]), and hematology (hemoglobin, lymphocytes, neutrophils, platelets) parameters in the blood known to be affected by JAK1,2,3 inhibitors in clinical trials were evaluated through Week 208 (4 years; data cutoff, November 1, 2023). Treatment discontinuations due to laboratory abnormalities were assessed. Results: A total of 1519 patients received ≥1 deucravacitinib dose (total exposure, 4392.8 person-years); 1203 (79.2%) had ≥52 weeks and 542 (35.7%) had ≥208 weeks of continuous deucravacitinib exposure (median, 185 weeks). No trends or clinically meaningful mean changes from baseline were observed in any of the above laboratory parameters. In total, 3 patients discontinued treatment due to increased CPK, and 1 patient each discontinued due to lymphopenia, abnormal hepatic function, increased ALT, and increased AST. Discontinuations due to triglyceride elevations were not observed. Conclusion: In PSO-1/PSO-2/LTE, no trends or clinically meaningful mean changes from baseline were observed in lipid, chemistry, or hematology parameters, in contrast to signature changes (eg, increased cholesterol, creatinine, serum transaminases, CPK, cytopenias) observed with JAK1,2,3 inhibitors. Discontinuations due to laboratory abnormalities noted above were rare (n=7 events) through 4 years of deucravacitinib treatment. Results suggest deucravacitinib treatment does not warrant routine laboratory testing for all patients, in contrast with the requirements for JAK1,2,3 inhibitors, reflecting its selectivity for TYK2.

Calcium isotope evidence for the formation of early condensates in the Solar System from unmixed reservoirs with distinct nucleosynthetic origins

Calcium-aluminum rich inclusions (CAIs) are the oldest condensates in the Solar System. Previous studies have revealed that moderately heavy and trace element isotope anomalies (e.g., Ti, Sr, Mo, and Nd) in CAIs record large nucleosynthetic isotope variations compared to bulk meteorites. Calcium is a major element in CAIs that has six stable isotopes with multiple nucleosynthetic origins. As such, Ca isotopes in CAIs have been an important target of isotopic analysis since the 1970s. However, the Ca isotope compositions of CAIs measured by previous-generation mass spectrometers are less precise than recent isotopic data of heavy elements, which complicates their direct comparisons. Obtaining high-precision Ca isotopic data provides a stronger link between CAI-formation processes from nebular gas and the origin of their source materials.In this study, we report high-precision Ca isotopic compositions of CAIs, amoeboid olivine aggregates, and an Al-rich chondrule from Vigarano-type carbonaceous chondrites. The obtained µ43Ca and µ48Ca values range from +5.8 ± 1.4 to +40.2 ± 5.2 and +181.2 ± 44.8 to +743.1 ± 8.3 ppm, respectively (µXCa represents the mass bias corrected relative deviation in the XCa/44Ca ratio of the sample from a standard material in parts per million). The improved precision of our measurements reveals that the Ca isotopic compositions of CAIs vary over a narrower range than previously thought. Our precise data also show that µ43Ca and µ48Ca values in CAIs are anti-correlated, which cannot be explained by analytical artifacts such as matrix effects. Additionally, the µ43Ca and µ48Ca values of CAIs increase and decrease, respectively, with increasing Ca abundances of the inclusions. These observations suggest the presence of two distinct gaseous reservoirs from which CAIs condensed, one of which was more enriched in 43Ca but depleted in 48Ca, while the other reservoir was more depleted in 43Ca but enriched in 48Ca. Given the distinct nucleosynthetic sources of 43Ca and 48Ca, this change in isotopic signature is best understood if the two reservoirs inherited material derived from distinct nucleosynthetic sites. As such, our results suggest the presence of more than two compositionally distinct gas reservoirs for Ca isotopes in the early Solar System. If correct, this suggests that the infalling material contributing to the CAI-forming reservoirs was not fully mixed.

PINK1/Parkin-Mediated Mitophagy Ameliorates Mitochondrial Dysfunction in Lacrimal Gland Acinar Cells During Aging.

Aging alters the function of the lacrimal gland and disrupts the balance of the microenvironment on the ocular surface, eventually leading to aqueous-tear-deficient dry eye. Mitophagy has been reported to play an important role in aging, but the underlying mechanism remains unclear. The young (6 weeks) and middle-aged (12months) male C57BL/6J mice were used in this study, and mitophagy agonist rapamycin and inhibitor Mdivi-1 were used in in vivo experiments. Hematoxylin and eosin, Masson, Oil Red O, and reactive oxygen species (ROS) staining were used to detect histological changes and lipids in lacrimal gland. Changes in the expression of proteins were identified by Western blotting of lacrimal gland lysates. Transmission electron microscopy and immunofluorescence staining were used to assess mitophagy. The single-cell RNA sequencing (scRNA-seq) and bioinformatics analyses were used to detect transcription signature changes during aging. In this study, we discovered that aging increased oxidative stress, which increased apoptosis, and generated ROS in acinar epithelial cells. Furthermore, activation of PINK1/Parkin-mediated mitophagy by rapamycin reduced lacrimal gland ROS concentrations and prevented aging-induced apoptosis of acinar cells, thereby causing histological alterations, microstructural degradation, and increasing tear secretion associated with ROS accumulation. By contrast, Mdivi-1 aggregates mitochondrial function and thereafter leads to lacrimal gland function impairment by inhibiting mitochondrial fission and giving rise to mitophagy. Overall, our findings suggested that aging could impair mitochondrial function of acinar cells, and age-related alterations may be treated with therapeutic approaches that enhance mitophagy while maintaining mitochondrial function.

Fecal and Sputum Microbiota and Treatment Response in Patients with Mycobacterium abscessus Pulmonary Disease.

The microbiota is a potential source of biomarkers for clinical outcomes in chronic respiratory conditions, but its role in Mycobacterium abscessus pulmonary disease (PD) remains unexplored. We aimed to identify microbial signatures in fecal and sputum microbiotas associated with treatment response in patients with M. abscessus PD. We conducted a cohort study prospectively enrolling patients undergoing antibiotic treatment for M. abscessus PD. Fecal and sputum samples were collected before, and 2 weeks and 6 months after, treatment initiation. 16S rRNA amplicon sequencing approach was used to characterize the microbiotas. After categorizing patients as early treatment responders and non-responders based on sputum culture results at 2 weeks, we elucidated the differences in their diversity and composition of microbiotas. Among 32 patients enrolled, 27 patients (median 66 years, 85.2% women, 48.1% with subspecies abscessus) were included for microbiota analysis. Fifteen patients (55.6%) achieved negative conversion at 2 weeks, which was maintained in 14 (93.3%) after 6 months. Alpha-diversity of the fecal microbiota after 2 weeks of treatment decreased significantly in responders, but not in non-responders (P=0.029). Increased abundance of Eubacterium hallii group in baseline fecal microbiota was indicative of unresponsiveness to antibiotics, whereas an increase in Enterococcus in fecal microbiota at week 2 was linked with favorable response. Increased abundance of Burkholderia-Caballeronia-Paraburkholderia and Porphyromonas in baseline, and decreased abundance of Rothia in week 2 sputum microbiota were also associated with good treatment response. In M. abscessus PD, changes in microbial diversity and compositional signatures vary with treatment response.