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Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.

Abstract Osteoarthritis (OA) represents a significant global health burden without a known disease modifying agent thereby necessitating pursuit of innovative therapeutic approaches. The infrapatellar fat pad (IFP) serves as a reservoir of mesenchymal stem/stromal cells (MSC), and with adjacent synovium plays key roles in joint disease affecting local inflammatory responses. Therapeutically, IFP-MSC have garnered attention for their potential in OA treatment due to their immunomodulatory and regenerative properties. However, optimizing their therapeutic efficacy necessitates a comprehensive understanding of how growth medium and inflammatory/hormonal priming influence their behavior. In this study, we isolated and expanded IFP-MSC in three different growth media: DMEM + 10% fetal bovine serum (FBS), DMEM + 10% human platelet lysate (HPL), and xeno-/serum-free synthetic (XFSF) medium. Subsequently, cells were induced with an inflammatory/fibrotic cocktail (TIC) with or without oxytocin (OXT). We evaluated various parameters including growth kinetics, phenotype, immunomodulatory capacity, gene expression, and macrophage polarization capacity. Our results revealed significant differences in the behavior of MSC cultured in different media. IFP-MSC cultured in HPL and XFSF exhibited superior growth kinetics and colony-forming abilities compared to those cultured in FBS. Furthermore, both HPL and XFSF media enhanced the expression of MSC markers (> 90%) and potentiated their immunomodulatory properties. Notably, XFSF-conditioned IFP-MSC demonstrated the highest attenuation of peripheral blood mononuclear cell (PBMC) proliferation, indicating their robust immunosuppressive capacity. Additionally, TIC priming further augmented the immunomodulatory functionality of MSC, with IFP-MSC exhibiting enhanced suppression of PBMC proliferation upon TIC priming. Of particular interest, gene expression analysis revealed distinct patterns in TIC + OXT induced MSC compared to TIC only induced, with upregulation of genes associated with immunomodulatory and regenerative functions. Furthermore, TIC + OXT priming promoted M2 polarization in macrophages, suggesting a potential therapeutic strategy for immune-mediated inflammatory joint conditions including OA. Our findings highlight the critical influence of growth medium and inflammatory/hormonal priming on MSC behavior and therapeutic potential. XFSF and HPL media offer promising alternatives to FBS, enhancing MSC growth and immunomodulatory properties. Moreover, TIC + OXT priming represents a novel approach to augment MSC immunomodulation and promote M2 polarization, providing insights into potential therapeutic strategies for OA and other immune-mediated inflammatory conditions.

Abstract A significant challenge in measurements of neutrino oscillations is reconstructing the incoming neutrino energies. While modern fully-active tracking calorimeters such as liquid argon time projection chambers in principle allow the measurement of all final state particles above some detection threshold, undetected neutrons remain a considerable source of missing energy with little to no data constraining their production rates and kinematics. We present the first demonstration of tagging neutrino-induced neutrons in liquid argon time projection chambers using secondary protons emitted from neutron-argon interactions in the MicroBooNE detector. We describe the method developed to identify neutrino-induced neutrons and demonstrate its performance using neutrons produced in muon-neutrino charged current interactions. The method is validated using a small subset of MicroBooNE’s total dataset. The selection yields a sample with $$60\%$$ 60 % of selected tracks corresponding to neutron-induced secondary protons. At this purity, the integrated efficiency is 8.4% for neutrons that produce a detectable proton.

Abstract Aliphatics prevail in asteroids, comets, meteorites and other bodies in our solar system. They are also found in the interstellar and circumstellar media both in gas-phase and in dust grains. Among aliphatics, linear alkanes (n-CnH2n+2) are known to survive in carbonaceous chondrites in hundreds to thousands of parts per billion, encompassing sequences from CH4 to n-C31H64. Despite being systematically detected, the mechanism responsible for their formation in meteorites has yet to be identified. Based on advanced laboratory astrochemistry simulations, we propose a gas-phase synthesis mechanism for n-alkanes starting from carbon and hydrogen under conditions of temperature and pressure that mimic those found in carbon-rich circumstellar envelopes. We characterize the analogs generated in a customized sputter gas aggregation source using a combination of atomically precise scanning tunneling microscopy, non-contact atomic force microscopy and ex-situ gas chromatography-mass spectrometry. Within the formed carbon nanostructures, we identify the presence of n-alkanes with sizes ranging from n-C8H18 to n-C32H66. Ab-initio calculations of formation free energies, kinetic barriers, and kinetic chemical network modelling lead us to propose a gas-phase growth mechanism for the formation of large n-alkanes based on methyl-methylene addition (MMA). In this process, methylene serves as both a reagent and a catalyst for carbon chain growth. Our study provides evidence of an aliphatic gas-phase synthesis mechanism around evolved stars and provides a potential explanation for its presence in interstellar dust and meteorites.

IntroductionPatients with incurable illnesses often experience existential distress, profoundly impacting their well-being. Current medical approaches have limitations in addressing these burdens. Psilocybin, a promising psychedelic compound, may offer therapeutic benefits. This pilot survey study aimed to investigate the attitudes and openness toward psilocybin-assisted psychotherapy (PAT) among patients with incurable illnesses. The objective is to assess patients’ attitudes toward PAT and identify potential barriers and concerns, including exploring the association between beliefs in psilocybin’s therapeutic benefits and interest in receiving this treatment.MethodsThe survey study was conducted at the Tampa General Hospital Palliative Care Outpatient office in the United States. Participants were 32 English-fluent patients, aged 18 or older, with incurable illnesses. The survey included demographic questions, a validated tool to measure existential distress, and questions about knowledge and concerns regarding psilocybin. Attitudes toward PAT and interest in its future use were assessed using Likert scale responses.ResultsAmong the 31 analyzed participants, 51.6% expressed interest in future psilocybin treatment, while 32.3% did not indicate interest. Belief in the psilocybin’s therapeutic benefits for stress and anxiety significantly correlated with interest in use. Concerns included risk of psychosis, lack of trained providers, and potential for exploitation. No demographic factors were associated with interest or levels of distress.ConclusionsThis pilot study provides insights into the attitudes and concerns toward PAT among patients with incurable illnesses. Over half of participants expressed interest. However, concerns regarding its use were identified, with patients’ concern for the risk of exploitation associated with PAT as an especially novel concern documented in this patient population. This highlighted the need for further education of risks and benefits or PAT by trained clinicians and rigorous training of clinicians with the establishment of safeguards against exploitation. Further research is necessary to explore the potential benefits of PAT and related non-psilocybin psychedelic compounds in addressing existential distress among patients with incurable illnesses.

Abstract The factors influencing the incidence of COVID‐19, including the impact of the vaccination programs, have been studied in the literature. Most studies focus on one or two factors, without considering their interactions, which is not enough to assess a vaccination program in a statistically robust manner. We examine the impact of the U.S. vaccination program on the SARS‐CoV‐2 positivity rate while simultaneously considering a large number of factors involved in the spread of the virus and the feedbacks among them. We consider the effects of the following sets of factors: socioeconomic factors, public policy factors, environmental factors, and non‐observable factors. A time series Error Correction Model (ECM) was used to estimate the impact of the vaccination program at the national level on the positivity rate. Additionally, state‐level ECMs with panel data were combined with machine learning techniques to assess the impact of the program and identify relevant factors to build the best‐fitting models. We find that the vaccination program reduced the virus positivity rate. However, the program was partially undermined by a feedback loop in which increased vaccination led to increased mobility. Although some external factors reduced the positivity rate, the emergence of new variants increased the positivity rate. The positivity rate was associated with several forces acting simultaneously in opposite directions such as the number of vaccine doses administered and mobility. The existence of complex interactions, between the factors studied, implies that there is a need to combine different public policies to strengthen the impact of the vaccination program.

The International Cocoa Organization recognized Colombian cocoa as ''fine aroma,'' but in recent years, clone CCN 51 has grown in popularity, widely due to its high yield. The Tolima department is the fourth producer of cacao in Colombia, but there is a lack of knowledge of the chemical properties of regional cocoa genotypes. The aim of this study was to evaluate the morphological, antioxidant activity, total polyphenol content and the methylxanthines ratio of four regional genotypes (UTLP02, UTVE01, UTGC01 and UTLM02) of Theobroma cacao L. from Tolima, Colombia. The universal clone of CCN51 was used as control. The highest values for the qualitative descriptors were obtained by the variants UTVE01 and CCN51 with FRAP and TPC ranging from 44.51 ± 0.90 to 106.77 ± 5.21 mg GAE/g and 27.13 ± 0.14 to 52.12 ± 4.71 mmol TE/g respectively. The genotypes with the highest values for FRAP and TPC were UTGC01 and CCN51. According to the methylxanthine ratio, UTVE01 was classified as Criollo, while UTLM02, UTGC01 and UTLP02, CCN51 are Trinitario and Forastero, respectively. Although CCN51 is considered a remarkable material in terms of productivity, the genotypes evaluated present good yields and interesting values of TPC and antioxidant activity, making them promising trees in local breeding programs.

Abstract Background Obesity and adipose tissue expansion is characterized by a chronic state of systemic inflammation that contributes to disease. The neuropeptide, oxytocin, working through its receptor has been shown to attenuate inflammation in sepsis, wound healing, and cardiovascular disease. The current study examined the effects of chronic oxytocin infusions on adipose tissue inflammation in a murine model of obesity, the leptin receptor-deficient (db/db) mouse. Methods The effect of obesity on oxytocin receptor protein and mRNA expression in adipose tissue was evaluated by Western blotting and real-time polymerase chain reaction. Mice were implanted with osmotic minipumps filled with oxytocin or vehicle for 8 weeks. At study endpoint adipose tissue inflammation was assessed by measurement of cytokine and adipokine mRNA tissue levels, adipocyte size and macrophage infiltration via histopathology, and plasma levels of adiponectin and serum amyloid A as markers of systemic inflammation. Results The expression of adipose tissue oxytocin receptor was increased in obese db/db mice compared to lean controls. In adipose tissue oxytocin infusion reduced adipocyte size, macrophage infiltration, IL-6 and TNFα mRNA expression, and increased the expression of the anti-inflammatory adipokine, adiponectin. In plasma, oxytocin infusion reduced the level of serum amyloid A, a marker of systemic inflammation, and increased circulating adiponectin. Conclusions In an animal model of obesity and diabetes chronic oxytocin treatment led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which may play a role in disease progression.

Abstract Background Chronic spinal cord injury (SCI) increases morbidity and mortality associated with cardiometabolic diseases, secondary to increases in central adiposity, hyperlipidaemia and impaired glucose tolerance. While upper-body Moderate Intensity Continuous Training (MICT) improves cardiorespiratory fitness, its effects on cardiometabolic component risks in adults with SCI appear relatively modest. The aim of this study is to assess the acute effects of Continuous Resistance Training (CRT), High Intensity Interval Training (HIIT), MICT and rest (CON) on fasting and postprandial systemic biomarkers and substrate utilisation. Methods Eleven healthy, chronic SCI (> 1 year, ASIA A-C) men will be recruited. Following preliminary testing, each will complete four experimental conditions, where they will report to the laboratory following an ~ 10-h overnight fast. A venous blood sample will be drawn and expired gases collected to estimate resting metabolic rate (RMR). In order to ensure an isocaloric exercise challenge, each will complete CRT first, with the remaining three conditions presented in randomised order: (1) CRT, ~ 45 min of resistance manoeuvres (weight lifting) interspersed with low-resistance, high-speed arm-crank exercise; (2) CON, seated rest; (3) MICT, ~ 45 min constant arm-crank exercise at a resistance equivalent to 30–40% peak power output (PPO) and; (4) HIIT, ~ 35 min arm-crank exercise with the resistance alternating every 2 min between 10% PPO and 70% PPO. After each ~ 45-min condition, participants will ingest a 2510-kJ liquid test meal (35% fat, 50% carbohydrate, 15% protein). Venous blood and expired gas samples will be collected at the end of exercise and at regular intervals for 120 min post meal. Discussion This study should establish the acute effects of different forms of exercise on fasting and postprandial responses in chronic SCI male patients. Measures of glucose clearance, insulin sensitivity, lipid and inflammatory biomarker concentrations will be assessed and changes in whole-body substrate oxidation estimated from expired gases. Trial registration ClinicalTrials.gov, ID: NCT03545867. Retrospectively registered on 1 June 2018.

Abstract Background Diabetes mellitus is associated with an increased risk in diabetic cardiomyopathy (DCM) that is distinctly not attributed to co-morbidities with other vasculature diseases. To date, while dysregulation of calcium handling is a key hallmark in cardiomyopathy, studies have been inconsistent in the types of alterations involved. In this study human cardiomyocytes were exposed to an environmental nutritional perturbation of high glucose, fatty acids, and l-carnitine to model DCM and iTRAQ-coupled LC–MS/MS proteomic analysis was used to capture proteins affected by the perturbation. The proteins captured were then compared to proteins currently annotated in the cardiovascular disease (CVD) gene ontology (GO) database to identify proteins not previously described as being related to CVD. Subsequently, GO analysis for calcium regulating proteins and endoplasmic/sarcoplasmic reticulum (ER/SR) associated proteins was carried out. Results Here, we identified CCDC47 (calumin) as a unique calcium regulating protein altered in our in vitro nutritional perturbation model. The cellular and functional role of CCDC47 was then assessed in rat cardiomyocytes. In rat H9C2 myocytes, overexpression of CCDC47 resulted in increase in ionomycin-induced calcium release and reuptake. Of interest, in a diet-induced obese (DIO) rat model of DCM, CCDC47 mRNA expression was increased in the atrium and ventricle of the heart, but CCDC47 protein expression was significantly increased only in the atrium of DIO rats compared to lean control rats. Notably, no changes in ANP, BNP, or β-MHC were observed between DIO rats and lean control rats. Conclusions Together, our in vitro and in vivo studies demonstrate that CCDC47 is a unique calcium regulating protein that is associated with early onset hypertrophic cardiomyopathy.

Abstract Background Inhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. In the present report, the specific isoform Hsp90ab1, was identified as playing a major role in regulating insulin signaling and glucose metabolism. Methods In a diet-induced obese (DIO) mouse model of diabetes, expression of various Hsp90 isoforms in skeletal tissue was examined. Subsequent experiments characterized the role of Hsp90ab1 isoform in glucose metabolism and insulin signaling in primary human skeletal muscle myoblasts (HSMM) and a DIO mouse model. Results In DIO mice Hsp90ab1 mRNA was upregulated in skeletal muscle compared to lean mice and knockdown using anti-sense oligonucleotide (ASO) resulted in reduced expression in skeletal muscle that was associated with improved glucose tolerance, reduced fed glucose and fed insulin levels compared to DIO mice that were treated with a negative control oligonucleotide. In addition, knockdown of HSP90ab1 in DIO mice was associated with reduced pyruvate dehydrogenase kinase-4 mRNA and phosphorylation of the muscle pyruvate dehydrogenase complex (at serine 232, 293 and 300), but increased phosphofructokinase 1, glycogen synthase 1 and long-chain specific acyl-CoA dehydrogenase mRNA. In HSMM, siRNA knockdown of Hsp90ab1 induced an increase in substrate metabolism, mitochondrial respiration capacity, and insulin sensitivity, providing further evidence for the role of Hsp90ab1 in metabolism. Conclusions The data support a novel role for Hsp90ab1 in arbitrating skeletal muscle plasticity via modulation of substrate utilization including glucose and fatty acids in normal and disease conditions. Hsp90ab1 represents a novel target for potential treatment of metabolic disease including diabetes.