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Oxidized phospholipids (OxPLs) are pro‐inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single‐chain variable fragment (scFv) of the antigen‐binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age‐related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age‐related bone loss. We show here that transgenic expression of E06‐scFv attenuated the age‐associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06‐scFv attenuated the age‐associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA‐seq analysis showed that E06‐scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age‐related bone loss, E06‐scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age‐associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non‐alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06‐scFv in mice. During aging, oxidized phospholipids (OxPL) increase, while IgM natural antibodies, which recognize OxPL, decrease. Transgenic expression of E06‐scFv, an IgM natural antibody fragment that recognizes the phosphocholine (PC) moiety of OxPL, attenuates the age‐related bone loss and increases Wnt10b expression in the bone of aged mice. OxPL contribute to age‐associated bone loss, and neutralization of OxPL is a promising therapeutic target for senile osteoporosis.

Human T-cell leukaemia/lymphoma virus type I (HTLV-I) is a retrovirus that has been identified as the causative agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other illnesses. HTLV-I infects primarily CD4⁺ T cells and the transmission occurs through direct cell-to-cell contact. HAM/TSP patients harbor higher proviral loads in peripheral blood lymphocytes than asymptomatic carriers. Also, HAM/TSP patients exhibit a remarkably high number of circulating HTLV-I-specific CD8⁺ cytotoxic T lymphocytes (CTLs) in the peripheral blood. While CTLs have a protective role by killing the infected cells and lowering the proviral load, a high level of CTLs and their cytotoxicity are believed to be a main cause of the development of HAM/TSP. A mathematical model for HTLV-I infection of CD4⁺ T cells that incorporates the CD8⁺ cytotoxic T-cell (CTL) response is investigated. Our mathematical analysis reveals that the system can stabilize at a carrier steady-state with persistent viral infection but no CTL response, or at a HAM/TSP steady-state at which both the viral infection and CTL response are persistent. We also establish two threshold parameters R ₀ and R ₁, the basic reproduction numbers for viral persistence and for CTL response, respectively. We show that the parameter R ₁ can be used to distinguish asymptomatic carriers from HAM/TSP patients, and as an important control parameter for preventing the development of HAM/TSP.

The scavenger receptor class B member 1 (SCARB1), encoded by Scarb1 , is a cell surface receptor for high density lipoproteins, low density lipoproteins (LDL), oxidized LDL (OxLDL), and phosphocholine-containing oxidized phospholipids (PC-OxPLs). Scarb1 is expressed in multiple cell types, including osteoblasts and macrophages. PC-OxPLs, present on OxLDL and apoptotic cells, adversely affect bone metabolism. Overexpression of E06 IgM – a natural antibody that recognizes PC-OxPLs– increases cancellous and cortical bone at 6 months of age in both sexes and protects against age- and high fat diet- induced bone loss, by increasing bone formation. We have reported that SCARB1 is the most abundant scavenger receptor for OxPLs in osteoblastic cells, and osteoblasts derived from Scarb1 knockout mice ( Scarb1 KO) are protected from the pro-apoptotic and anti-differentiating effects of OxLDL. Skeletal analysis of Scarb1 KO mice produced contradictory results, with some studies reporting elevated bone mass and others reporting low bone mass. To clarify if Scarb1 mediates the negative effects of PC-OxPLs in bone, we deleted it in osteoblast lineage cells using Osx1-Cre transgenic mice. Bone mineral density (BMD) measurements and micro-CT analysis of cancellous and cortical bone at 6 months of age did not reveal any differences between Scarb1 ΔOSX-l mice and their wild-type (WT), Osx1-Cre, or Scarb1 fl/fl littermate controls. We then investigated whether PC-OxPLs could exert their anti-osteogenic effects via activation of SCARB1 in myeloid cells by deleting Scarb1 in LysM-Cre expressing cells. BMD measurements and micro-CT analysis at 6 months of age did not show any differences between Scarb1 ΔLysM mice and their WT, LysM-Cre, or Scarb1 fl/fl controls. Based on this evidence, we conclude that the adverse skeletal effects of PC-OxPLs in adult mice are not mediated by Scarb1 expressed in osteoblast lineage cells or myeloid cells.

Infantile hemangiomas (IHs) are the most common benign tumors in early childhood. They show a distinctive mechanism of tumor growth in which a rapid proliferative phase is followed by a regression phase (involution). Propranolol is an approved treatment for IHs, but its mechanism of action remains unclear. We integrated and harmonized microRNA and mRNA transcriptome data from newly generated microarray data on IHs with publicly available data on toxicological transcriptomics from propranolol exposure, and with microRNA data from IHs and propranolol exposure. We identified subsets of putative biomarkers for proliferation and involution as well as a small set of putative biomarkers for propranolol’s mechanism of action for IHs, namely EPAS1 , LASP1 , SLC25A23 , MYO1B , and ALDH1A1 . Based on our integrative data approach and confirmatory experiments, we concluded that hypoxia in IHs is regulated by EPAS1 (HIF-2α) instead of HIF-1α, and also that propranolol-induced apoptosis in endothelial cells may occur via mitochondrial stress.

The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER) and metabolic (PPARα, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARα expression prior to obesity development.

The protective effect of estrogens against cortical bone loss is mediated via direct actions on mesenchymal cells, but functional evidence for the mediators of these effects has only recently begun to emerge. We report that the matrix metalloproteinase 13 (MMP13) is the highest up-regulated gene in mesenchymal cells from mice lacking the estrogen receptor alpha (ERα). In sham-operated female mice with conditional Mmp13 deletion in Prrx1 expressing cells ( Mmp13 ΔPrrx1 ), the femur and tibia length was lower as compared to control littermates ( Mmp13f. /f ). Additionally, in the sham-operated female Mmp13 ΔPrrx1 mice cortical thickness and trabecular bone volume in the femur and tibia were higher and osteoclast number at the endocortical surfaces was lower, whereas bone formation rate was unaffected. Notably, the decrease of cortical thickness caused by ovariectomy (OVX) in the femur and tibia of Mmp13f. /f mice was attenuated in the Mmp13 ΔPrrx1 mice; but the decrease of trabecular bone caused by OVX was not affected. These results reveal that mesenchymal cell–derived MMP13 may regulate osteoclast number and/or activity, bone resorption, and bone mass. And increased production of mesenchymal cell-derived factors may be important mediators of the adverse effect of estrogen deficiency on cortical, but not trabecular, bone.

The scavenger receptor class B member 1 (SR-B1 or Scarb1) is a cell surface receptor for high density lipoproteins. It also binds oxidized low density lipoproteins and phosphocholine-containing oxidized phospholipids (PC-OxPL), which adversely affect bone homeostasis. Overexpression of a single chain form of the antigen-binding domain of E06 IgM–a natural antibody that recognizes PC-OxPL–increases trabecular and cortical bone mass in female and male mice by stimulating bone formation. We have previously reported that Scarb1 is the most abundant scavenger receptor for PC-OxPL in calvaria-derived osteoblastic cells. Additionally, bone marrow- and calvaria-derived osteoblasts from Scarb1 knockout mice (Scarb1 KO) are protected from the pro-apoptotic and anti-differentiating effects of OxPL. Previous skeletal analysis of Scarb1 KO mice has produced contradictory results, with some studies reporting elevated bone mass but another study reporting low bone mass. To clarify the role of Scarb1 in osteoblasts, we deleted Scarb1 specifically in cells of the osteoblast lineage using Osx1-Cre transgenic mice. We observed no difference in bone mineral density measured by DXA in either female or male Osx1-Cre;Scarb1 fl/fl mice compared to wild type (WT), Osx1-Cre, or Scarb1 fl/fl littermate controls. Additionally, microCT analysis of 6-month-old females and 7-month-old males did not detect any difference in trabecular or cortical bone mass between genotypes. These results indicate that expression of Scarb1 in cells of the osteoblast lineage does not play an important role in bone homeostasis and, therefore, it is not essential for the effects of PC-OxPL on these cells.

Background SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread. Case presentation A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary. Conclusions This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors.

Soy infant formula which is fed to over half a million infants per year contains isoflavones such as genistein, which have been shown to be estrogenic at high concentrations. The developing testis is sensitive to estrogens, raising concern that the use of soy formulas may result in male reproductive toxicity. In the current study, male White-Dutch Landrace piglets received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/kg/d) (M + E2) or supplemented with genistein (84 mg/L of diet; (M + G) from postnatal day 2 until day 21. E2 treatment reduced testis weight (p < 0.05) as percentage of body weight, significantly suppressed serum androgen concentrations, increased tubule area, Germ cell and Sertoli cell numbers (p < 0.05) relative to those of Sow or Milk groups. Soy formula had no such effects relative to Sow or Milk groups. mRNAseq revealed 103 differentially expressed genes in the M + E2 group compared to the Milk group related to endocrine/metabolic disorders. However, little overlap was observed between the other treatment groups. These data suggest soy formula is not estrogenic in the male neonatal piglet and that soy formula does not significantly alter male reproductive development.

Evaluating whether common algorithmic fairness-improving approaches can improve low-birth-weight predictive model performance can provide important implications for population health management and health equity. This study aimed to evaluate alternative approaches for improving algorithmic fairness for low-birth-weight predictive models. Retrospective, cross-sectional study of birth certificates linked with medical insurance claims. Birth certificates (n = 191,943; 2014-2022) were linked with insurance claims (2013-2021) from the Arkansas All-Payer Claims Database to assess alternative approaches for algorithmic fairness in predictive models for low birth weight (< 2500 g). We fit an original model and compared 6 fairness-improving approaches using elastic net models trained and tested with 70/30 balanced random split samples and 10-fold cross validation. The original model had lower accuracy (percent predicted correctly) in predicting low birth weight among Black, Native Hawaiian/Other Pacific Islander, Asian, and unknown racial/ethnic populations relative to White individuals. For Black individuals, accuracy increased with all 6 fairness-improving approaches relative to the original model; however, sensitivity (true-positives correctly predicted as low birth weight) significantly declined, as much as 31% (from 0.824 to 0.565), in 5 of 6 approaches. When developing and implementing decision-making algorithms, it is critical that model performance metrics align with management goals for the predictive tool. In our study, fairness-improving models improved accuracy and area under the curve scores for Black individuals but decreased sensitivity and negative predictive value, suggesting that the original model, although unfair, was not improved. Implementation of unfair models for allocating preventive services could perpetuate racial/ethnic inequities by failing to identify individuals most at risk for a low-birth-weight delivery.