CPT2 mediated fatty acid oxidation is dispensable for humoral immunity.

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids and fatty acids. While several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. Here, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte specific deletion of CPT2. Stable 13C isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2 deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and antibody production upon either thymus-dependent or -independent antigen challenges. Together, our findings indicate that CPT2 mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

Diagnostic Performance of 18F-FDG Positron Emission Tomography/Computed Tomography and Blood Test Parameters for Pulmonary Inflammatory Pseudotumor.

PURPOSE: Pulmonary inflammatory pseudotumor (PIP) is an inflammatory proliferative tumor-like lesion that frequently exhibits hypermetabolism on 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging (PET/CT) and is readily misdiagnosed as a malignant tumor. The purpose of this study was to identify PIP by combining PET/computed tomography metabolic and blood test characteristics with machine learning. PATIENTS AND METHODS: We recruited 27 patients with PIP and 28 patients with lung cancer (LC). The PET metabolic and blood test parameters were collected, and the differences between the groups were evaluated. In addition, we combined the support vector machine (SVM) classifier with the indicators that differed between the groups to classify PIP and LC. RESULTS: For PET metabolic parameters, our findings showed that, as compared with the LC group, maximal standardized uptake value (P< 0.001, t = -4.780), Mean standardized uptake value SUVmean, P< 0.001, t = -4.946), and SD40% (P< 0.001, t = -4.893) were considerably reduced in the PIP group, whereas CV40% (P= 0.004, t = 3.012) was significantly greater. For blood test parameters, the total white blood cell count (P< 0.001, t= 6.457) and absolute neutrophil count (P< 0.001, t= 6.992) were substantially higher in the PIP group than in the LC group. Furthermore, the performance of SVM trained solely on PET metabolic parameters (mean area under the curve [AUC] = 0.84) was comparable to that of SVM trained solely on blood test parameters (mean AUC = 0.86). Surprisingly, utilizing the combined parameters increased SVM performance significantly (mean AUC = 0.98). CONCLUSION: PET metabolic and blood test parameters differed significantly between the PIP and LC groups, and the SVM paradigm using these significantly different features has the potential to be used to classify PIP and LC, which has important clinical implications.

Rag-GTPase-TFEB/TFE3 axis controls B cell mitochondrial fitness and humoral immunity independent of mTORC1.

During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 axis as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Self-concept mediates the relationships between childhood traumatic experiences and adolescent depression in both clinical and community samples.

BACKGROUND: Childhood trauma is a pivotal risk factor for adolescent depression. While the association between childhood trauma and depression is well-established, the mediating role of self-concept has not been acknowledged. Specifically, limited attention has been paid to how childhood maltreatment impacts adolescent depression through physical and social self-concept, both in clinical and community samples. This study aims to investigate how distinct and cumulative childhood trauma affects adolescent depression, as well as the potential mediating role of self-concept in their relationships. METHODS: We recruited 227 depressed adolescents (dataset 1, 45 males, age = 15.34 ± 1.96) and 574 community adolescents (dataset 2, 107 males, age = 16.79 ± 0.65). Each participant was assessed on five subtypes of childhood trauma severity, cumulative trauma index, physical and social self-concept, and depression. Mediation models were tested separately in the clinical and community samples. RESULTS: Clinically depressed adolescents experienced a higher level of trauma severity, a greater number of trauma subtypes, and had lower levels of physical and social self-concept compared to community adolescents. Analyses on childhood trauma severity and cumulative trauma index jointly indicated that physical and social self-concept played mediation roles in the relationships between childhood trauma experiences and depression. Moreover, the mediating effects of self-concept were stronger in depressed adolescents when compared to community samples. CONCLUSIONS: Our findings suggest that physical and social self-concept play mediating roles in the pathway linking childhood trauma and adolescent depression, particularly in clinically depressed individuals.

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 pathway as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Downregulation of HMGB1 carried by macrophage-derived extracellular vesicles delays atherosclerotic plaque formation through Caspase-11-dependent macrophage pyroptosis.

BACKGROUND: Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS: In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1). ApoE-/- mice were used to construct an AS mouse model by a high-fat diet, followed by injection of macrophage-EV/siHMGB1 to assess the in vivo effect of macrophage-EV/siHMGB1 on AS mice. RAW264.7 cells were subjected to ox-LDL, LPS or macrophage-EV/siHMGB1 for analyzing the in vitro effect of macrophage-EV/siHMGB1 on macrophage pyrophosis and inflammation. RESULTS: In silico analysis found that HMGB1 was closely related to the development of AS. Macrophage-EV/siHMGB could inhibit the release of HMGB1 from macrophages to outside cells, and the reduced HMGB1 release could inhibit foam cell formation. Besides, macrophage-EV/siHMGB also inhibited the LPS-induced Caspase-11 activation, thus inhibiting macrophage pyroptosis and preventing atherosclerotic plaque formation. CONCLUSION: Our results proved that macrophage-EV/siHMGB could inhibit foam cell formation and suppress macrophage pyroptosis, finally preventing atherosclerotic plaque formation in AS mice.

Multiple Early Biomarkers to Predict Cognitive Decline in Dementia-Free Older Adults.

INTRODUCTION: Baseline olfactory impairment, poor performance on cognitive test, and medial temporal lobe atrophy are considered biomarkers for predicting future cognitive decline in dementia-free older adults. However, the combined effect of these predictors has not been fully investigated. METHODS: A group of 110 participants without dementia were continuously recruited into this study, and underwent olfactory, cognitive tests and MRI scanning at baseline and 5-year follow-up. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). Participants were divided into the cognitive decliners and non-decliners. RESULTS: Among 87 participants who completed the 5-year follow-up, cognitive decline was present in 32 cases and 55 remained stable. Compared with non-decliners, cognitive decliners presented lower scores on both the UPSIT and the Montreal Cognitive Assessment (MoCA), and smaller hippocampal volume at baseline (all P < .001). The logistic regression analysis revealed that lower scores on UPSIT and MoCA, and smaller hippocampal volume were strongly associated with subsequent cognitive decline, respectively (all P < .001). For the prediction of cognitive decline, lower score on UPSIT performed the sensitivity of 63.6% and specificity of 81.2%, lower score on MoCA with the sensitivity of 74.5% and specificity of 65.6%, smaller hippocampal volume with the sensitivity of 70.9% and specificity of 78.1%, respectively. Combining three predictors resulted in the sensitivity of 83.6% and specificity of 93.7%. CONCLUSIONS: The combination of olfactory test, cognitive test with structural MRI may enhance the predictive ability for future cognitive decline for dementia-free older adults.

PP2A catalytic subunit alpha is critically required for CD8+ T cell homeostasis and anti-bacterial responses.

While the functions of tyrosine phosphatases in T cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T cell homeostasis and effector functions. Our results demonstrate that T cell intrinsic PP2A Cα is critically required for CD8+ T cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T cell anti-bacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8+ T cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore the defective anti-bacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8+ T cell homeostasis and effector functions.

Automatic synthesis of 18F-AV-45 and its clinical application in Alzheimer's disease.

OBJECTIVE: To investigate the automatic synthesis of ß-amyloid (Aß) positron emission tomography (PET) imaging agent (E) -4- (2- (6- (2- (2-18F fluoroethoxy) ethoxy) ethoxy) pyridine-3-yl) vinyl) - N-methylaniline (18F-AV-45) for the diagnosis of Alzheimer's disease (AD) and its clinical application in AD patients. MATERIALS AND METHODS: Fluorine-18-AV-45 was synthesized with AV-105 as the precursor, and the factors affecting the synthesis efficiency, such as the amount of precursor, nucleophilic reaction temperature were studied. At the same time, 18F-AV-45 PET/computed tomography (CT) brain scanning was performed in 15 patients with dementia to determine whether AD was the cause of the dementia. RESULTS: After optimizing the parameters, it was discovered that the highest synthesis efficiency was achieved with a AV-105 dosage of 2mg, a reaction temperature of 130oC, and 1mL of DMSO. The radiochemical yield (RCP) was greater than 98, and the uncorrected synthesis efficiency was about 31.0%±2.8%. Ten of the 15 patients with dementia showed positive Aß protein deposition, and the main deposition site of the imaging agent was the gray matter area of the brain, which was consistent with AD diagnosis, while the other 5 patients showed negative Aß protein deposition, suggesting non-AD dementia. CONCLUSION: ß-amyloid protein 18F-AV-45 imaging agent can be easily and quickly prepared by the All in One radiochemical synthesis module. Our preliminary results offer hope that it can effectively detect ß-amyloid deposition in the brain of AD patients in order to determine the etiology of dementia.

A novel necroptosis signature for predicting survival in lung adenocarcinoma.

BACKGROUND: To explore the necroptosis-related genes (NRGs) signature and its predictive values in lung adenocarcinoma (LUAD). METHODS: The training cohort consisted of tumor samples from The Cancer Genome Atlas, and the validation set comprised data from the Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were applied to identify the prognostic NRG signature as an independent molecular indicator. Correlation analysis was used for the association assessment between the NRG signature and immune checkpoint molecules. RESULTS: NRGs involved in necroptosis and immune NOD-like receptor signaling. The NRG signature based on eight NRGs can divide tumors into high-risk and low-risk groups, which was significantly associated with worse survival. Multivariate Cox regression analysis showed that this NRG signature remained an independent prognostic indicator. Stratification analyses demonstrated that this NRG signature was still effective for predicting survival in each stratum of age, gender, and tumor stage. The ROC curve showed a good predictive ability using the NRG signature in the validation cohort (AUC = 0.81). The NRG signature was related to immune checkpoint molecules PD - 1, PD-L1, and PD-L2. CONCLUSIONS: The NRG signature could be a novel predictor of the prognosis and may become a potential therapeutic target in LUAD.

The performance and applied value of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a rare inert B lymphocyte lymphoma and the role of FDG PET/CT imaging in WM has not been well established. This study aimed to evaluate the metabolic status of WM by 18F-FDG PET/CT imaging. We retrospectively analyzed 20 patients who underwent pretherapy 18F-FDG PET-CT scan. All patients were diagnosed by bone marrow aspiration, laboratory examination and clinical symptoms. Bone marrow involvement was identified with 18F-FDG PET/CT imaging in 16 of 20, and the mean SUVmax of bone marrow was 4.06±0.85, Lymph nodes were involved in 8 of 20 patients, and the mean SUVmax of Lymph nodes was 4.07±1.27. Liver and spleen were involved in one case respectively, with SUVmax being 3.6 and 3.3. 1 case of extramedullary infiltration and 1 case of lymphomatous transformation. 18F-FDG PET/CT imaging not only could reveal the metabolic status of lymph nodes, liver, spleen and bone marrow in WM patients, but also evaluate the status of tumor burden which helps to formulate personalized treatment plans.

Charge Self-Regulation of Metallic Heterostructure Ni2 P@Co9 S8 for Alkaline Water Electrolysis with Ultralow Overpotential at Large Current Density.

Designing cost-effective alkaline water-splitting electrocatalysts is essential for large-scale hydrogen production. However, nonprecious catalysts face challenges in achieving high activity and durability at a large current density. An effective strategy for designing high-performance electrocatalysts is regulating the active electronic states near the Fermi-level, which can improve the intrinsic activity and increase the number of active sites. As a proof-of-concept, it proposes a one-step self-assembly approach to fabricate a novel metallic heterostructure based on nickel phosphide and cobalt sulfide (Ni2 P@Co9 S8 ) composite. The charge transfer between active Ni sites of Ni2 P and Co─Co bonds of Co9 S8 efficiently enhances the active electronic states of Ni sites, and consequently, Ni2 P@Co9 S8 exhibits remarkably low overpotentials of 188 and 253 mV to reach the current density of 100 mA cm-2 for the hydrogen evolution reaction and oxygen evolution reaction, respectively. This leads to the Ni2 P@Co9 S8 incorporated water electrolyzer possessing an ultralow cell voltage of 1.66 V@100 mA cm-2 with ≈100% retention over 100 h, surpassing the commercial Pt/C║RuO2 catalyst (1.9 V@100 mA cm-2 ). This work provides a promising methodology to boost the activity of overall water splitting with ultralow overpotentials at large current density by shedding light on the charge self-regulation of metallic heterostructure.

Consistent effects of the genetics of happiness across the lifespan and ancestries in multiple cohorts.

Happiness is a fundamental human affective trait, but its biological basis is not well understood. Using a novel approach, we construct LDpred-inf polygenic scores of a general happiness measure in 2 cohorts: the Adolescent Brain Cognitive Development (ABCD) cohort (N = 15,924, age range 9.23-11.8 years), the Add Health cohort (N = 9129, age range 24.5-34.7) to determine associations with several well-being and happiness measures. Additionally, we investigated associations between genetic scores for happiness and brain structure in ABCD (N = 9626, age range (8.9-11) and UK Biobank (N = 16,957, age range 45-83). We detected significant (p.FDR < 0.05) associations between higher genetic scores vs. several well-being measures (best r2 = 0.019) in children of multiple ancestries in ABCD and small yet significant correlations with a happiness measure in European participants in Add Health (r2 = 0.004). Additionally, we show significant associations between lower genetic scores for happiness with smaller structural brain phenotypes in a white British subsample of UK Biobank and a white sub-sample group of ABCD. We demonstrate that the genetic basis for general happiness level appears to have a consistent effect on happiness and wellbeing measures throughout the lifespan, across multiple ancestral backgrounds, and multiple brain structures.

Prognostic value of secretory autophagosomes in patients with acute respiratory distress syndrome.

BACKGROUND: Growing evidence supports that extracellular vesicles (EVs) in blood plasma and other body fluids may function as biomarkers for disease. We previously found that secretory autophagosomes (SAPs), a kind of EV, could exacerbate lung injury in mice. However, the clinical value of SAPs in acute respiratory distress syndrome (ARDS), the most severe form of lung injury, remains unknown. Our study investigated the prognostic value of secretory autophagosomes in ARDS. METHODS: ARDS patients (n = 46) and controls (n = 8) were included in a prospective monocentric study. Bronchoalveolar lavage fluid (BALF) samples were collected from ARDS patients on the first day (Day 1) or the third day (Day 3) of enrollment and were collected from controls on Day 1. Gradient centrifugation was performed to isolate EVs. The size and concentration of EVs were characterized by nanoparticle tracking analysis (NTA). SAPs in EVs were characterized by flow cytometry, transmission electron microscopy, and western blot analysis, and the proportion of SAPs in EVs (PSV) was measured by flow cytometry. The association of SAPs with 28-day mortality was assessed. RESULTS: On Days 1 and 3, the proportion of SAPs (SAPs%) in BALF was higher in patients with ARDS than in controls. On Day 3, the SAPs% was significantly higher in nonsurvivors than in survivors. In particular, a high SAPs% was associated with poor overall survival in ARDS patients. Furthermore, the combination of SAPs% and SOFA obtained a higher predictive value of ARDS outcome than PSV or SOFA alone. CONCLUSION: SAPs% in BALF is elevated in patients with ARDS and is associated with the risk of death in ARDS, suggesting that SAPs% may be a novel prognostic biomarker in ARDS.

Revisiting Assessment of Computational Methods for Hi-C Data Analysis.

The performances of algorithms for Hi-C data preprocessing, the identification of topologically associating domains, and the detection of chromatin interactions and promoter-enhancer interactions have been mostly evaluated using semi-quantitative or synthetic data approaches, without utilizing the most recent methods, since 2017. In this study, we comprehensively evaluated 24 popular state-of-the-art methods for the complete end-to-end pipeline of Hi-C data analysis, using manually curated or experimentally validated benchmark datasets, including a CRISPR dataset for promoter-enhancer interaction validation. Our results indicate that, although no single method exhibited superior performance in all situations, HiC-Pro, DomainCaller, and Fit-Hi-C2 showed relatively balanced performances of most evaluation metrics for preprocessing, topologically associating domain identification, and chromatin interaction/promoter-enhancer interaction detection, respectively. The comprehensive comparison presented in this manuscript provides a reference for researchers to choose Hi-C analysis tools that best suit their needs.

Novel mono- and multivalent N-acetylneuraminic acid glycoclusters as potential broad-spectrum entry inhibitors for influenza and coronavirus infection.

N-acetylneuraminic acid (Neu5Ac) is a glycan receptor of viruses spread in many eukaryotic cells. The present work aimed to design, synthesis and biological evaluation of a panel of Neu5Ac derivatives based on a cyclodextrin (CD) scaffold for targeting influenza and coronavirus membrane proteins. The multivalent Neu5Ac glycoclusters efficiently inhibited chicken erythrocyte agglutination induced by intact influenza virus in a Neu5Ac density-dependent fashion. Compared with inhibition by Neu5Ac, the multivalent inhibitor with 21 Neu5Ac residues on the primary face of the ß-CD scaffold afforded 1788-fold higher binding affinity inhibition for influenza virus hemagglutinin with a dissociation constant (KD) of 3.87 × 10-7 M. It showed moderate binding affinity to influenza virus neuraminidase, but with only about one-thirtieth the potency of that with the HA protein. It also exhibited strong binding affinity to the spike protein of three human coronaviruses (severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2), with KD values in the low micromolar range, which is about 10-time weaker than that of HA. Therefore, these multivalent sialylated CD derivatives have possible therapeutic application as broad-spectrum antiviral entry inhibitors for many viruses by targeting the Neu5Ac of host cells.

A Compact Piezo-Inertia Actuator Utilizing the Double-Rocker Flexure Hinge Mechanism.

With a simple structure and control method, the piezo-inertia actuator is a preferred embodiment in the field of microprecision industry. However, most of the previously reported actuators are unable to achieve a high speed, high resolution, and low deviation between positive and reverse velocities at the same time. To achieve a high speed, high resolution, and low deviation, in this paper we present a compact piezo-inertia actuator with a double rocker-type flexure hinge mechanism. The structure and operating principle are discussed in detail. To study the load capacity, voltage characteristics, and frequency characteristics of the actuator, we made a prototype and conducted a series of experiment. The results indicate good linearity in both positive and negative output displacements. The maximum positive and negative velocities are about 10.63 mm/s and 10.12 mm/s, respectively, and the corresponding speed deviation is 4.9%. The positive and negative positioning resolutions are 42.5 nm and 52.5 nm, respectively. In addition, the maximum output force is 220 g. These results show that the designed actuator has a minor speed deviation and good output characteristics.

Crosstalk between Interleukin-1 Receptor-Like 1 and Transforming Growth Factor-ß Receptor Signaling Promotes Renal Fibrosis

IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-ß (TGF-ß)­induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias ST2), the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33­ or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-ß receptor (TGF-ßR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-ßR signaling or suppressing ST2 expression impeded Smad2 and Smad3 phosphorylation, thereby reducing ECM production, suggesting that IL-33­induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induced a proximate interaction between ST2 and TGF-ßRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this study identified a novel and essential role for IL-33 in promoting TGF-ß signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

Subjective and objective sleep and circadian parameters as predictors of depression-related outcomes: A machine learning approach in UK Biobank.

BACKGROUND: Sleep and circadian disruption are associated with depression onset and severity, but it is unclear which features (e.g., sleep duration, chronotype) are important and whether they can identify individuals showing poorer outcomes. METHODS: Within a subset of the UK Biobank with actigraphy and mental health data (n = 64,353), penalised regression identified the most useful of 51 sleep/rest-activity predictors of depression-related outcomes; including case-control (Major Depression (MD) vs. controls; postnatal depression vs. controls) and within-case comparisons (severe vs. moderate MD; early vs. later onset, atypical vs. typical symptoms; comorbid anxiety; suicidality). Best models (of lasso, ridge, and elastic net) were selected based on Area Under the Curve (AUC). RESULTS: For MD vs. controls (n(MD) = 24,229; n(control) = 40,124), lasso AUC was 0.68, 95 % confidence interval (CI) 0.67-0.69. Discrimination was reasonable for atypical vs. typical symptoms (n(atypical) = 958; n(typical) = 18,722; ridge: AUC 0.74, 95 % CI 0.71-0.77) but poor for remaining models (AUCs 0.59-0.67). Key predictors across most models included: difficulty getting up, insomnia symptoms, snoring, actigraphy-measured daytime inactivity and lower morning activity (~8 am). In a distinct subset (n = 310,718), the number of these factors shown was associated with all depression outcomes. LIMITATIONS: Analyses were cross-sectional and in middle-/older aged adults: comparison with longitudinal investigations and younger cohorts is necessary. DISCUSSION: Sleep and circadian measures alone provided poor to moderate discrimination of depression outcomes, but several characteristics were identified that may be clinically useful. Future work should assess these features alongside broader sociodemographic, lifestyle and genetic features.