Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model.

Sarcopenia burdens the elderly population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are missing. The glucocorticoid prednisone remodels muscle metabolism based on frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone rescued muscle quality in aged 24-month-old mice to levels comparable to young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing PGC1α and its co-factor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose to amino acid biogenesis. We also probed the myocyte-specific Lipin1 as non-redundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes to coordinately rescue energy and mass in sarcopenia.

Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides.

BACKGROUND AND AIMS: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. METHODS: Nt+/+ and Nt-/- mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr-/- mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. RESULTS: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. CONCLUSIONS: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.

Illuminating milling mechanochemistry by tandem real-time fluorescence emission and Raman spectroscopy monitoring.

In pursuit of accessible and interpretable methods for direct and real-time observation of mechanochemical reactions, we demonstrate a tandem spectroscopic method for monitoring of ball-milling transformations combining fluorescence emission and Raman spectroscopy, accompanied by high-level molecular and periodic density-functional theory (DFT) calculations, including periodic time-dependent (TD-DFT) modelling of solid-state fluorescence spectra. This proof-of-principle report presents this readily accessible dual-spectroscopy technique as capable of observing changes to the supramolecular structure of the model pharmaceutical system indometacin during mechanochemical polymorph transformation and cocrystallisation. The observed time-resolved in situ spectroscopic and kinetic data are supported by ex situ X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements. The application of first principles (ab initio) calculations enabled the elucidation of how changes in crystalline environment, that result from mechanochemical reactions, affect vibrational and electronic excited states of molecules. The herein explored interpretation of both real-time and ex situ spectroscopic data through ab initio calculations provides an entry into developing a detailed mechanistic understanding of mechanochemical milling processes and highlights the challenges of using real-time spectroscopy.

Sap and Sun: A Case of Phytophotodermatitis.

We report a case of phytophotodermatitis caused by cow parsnip (Heracleum maximum) exposure affecting a hiker in Colorado. Phytophotodermatitis is a phototoxic skin reaction to UV-A rays after contact with photosensitizing plant substances that presents as a burning, painful rash, often with blisters. Treatment is supportive, including wound hygiene, analgesia, and anti-inflammatories. Avoiding offending plants, protecting the skin from sun, and immediate washing with soap and water after plant contact are the primary means of prevention. We have included a table and photos of plants found in the United States that can cause phytophotodermatitis. Medical providers should include phytophotodermatitis in the differential diagnosis of blistering rashes in patients who have been outdoors with possible exposure to offending plants.

Cerebrospinal Fluid Levels of Lysophosphatidic Acids Can Provide Suitable Biomarkers of Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) has been identified as the signature injury of Operation Iraqi Freedom and Operation Enduring Freedom. Although the incidence of bTBI increased significantly after the introduction of improvised explosive devices, the mechanism of the injury is still uncertain, which is negatively impacting the development of suitable countermeasures. Identification of suitable biomarkers that could aid in the proper diagnosis of and prognosis for both acute and chronic bTBI is essential since bTBI frequently is occult and may not be associated with overtly detectable injuries to the head. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid (CSF) have been reported to increase acutely after non-blast related brain injuries. In the present study, we have evaluated the utility of LPA levels measured in the CSF and plasma of laboratory rats as an acute and chronic biomarker of brain injury resulting from single and tightly coupled repeated blast overpressure exposures. In the CSF, many LPA species increased at acute time-points, returned to normal levels at 1 month, and increased again at 6 months and 1 year post-blast overpressure exposures. In the plasma, several LPA species increased acutely, returned to normal levels by 24 h, and were significantly decreased at 1 year post-blast overpressure exposures. These decreases in LPA species in the plasma were associated with decreased levels of lysophosphatidyl choline, suggesting a defective upstream biosynthetic pathway of LPAs in the plasma. Notably, the changes in LPA levels in the CSF (but not plasma) negatively correlated with neurobehavioral functions in these rats, suggesting that CSF levels of LPAs may provide a suitable biomarker of bTBI that reflects severity of injury.

Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.

Breast cancer cells produce negligible quantities of autotaxin. Instead, previous work indicated that adipocytes in the inflamed adipose tissue adjacent to breast tumors are a major source of autotaxin secretion that drives breast tumor growth, metastasis, and the loss of efficacy for chemotherapy and radiotherapy. To test this hypothesis, we used mice with an adipocyte-specific knock out of autotaxin. The lack of autotaxin secretion from adipocytes failed to decrease the growth of orthotopic E0771 breast tumors in syngeneic C57BL/6 mice and the growth and lung metastasis of spontaneous breast tumors in MMTV-PyMT mice. However, the inhibition of autotaxin with IOA-289 decreased the growth of E0771 tumors, indicating that another source of autotaxin is responsible for tumor growth. Tumor-associated fibroblasts and leukocytes produce the majority of autotoxin transcripts in the E0771 breast tumors, and we hypothesize that they are the main sources of ATX that drive breast tumor growth. Autotaxin inhibition with IOA-289 increased the numbers of CD8α+-T-cells in the tumors. This was accompanied by decreases in the concentrations of CXCL10, CCL2, and CXCL9 in the plasma and LIF, TGFß1, TGFß2, and prolactin in the tumors. Bioinformatics analysis of human breast tumor databases showed that autotaxin (ENPP2) is expressed mainly in endothelial cells and fibroblasts. Autotaxin expression correlated significantly with increases in IL-6 cytokine receptor ligand interactions, signaling by LIF, TGFß, and prolactin. This confirms the relevance of results from autotaxin inhibition in the mouse model. We propose that inhibiting autotaxin activity that is derived from cells presenting breast tumors such as fibroblasts, leukocytes, or endothelial cells changes the tumor micro-environment in such a way as to inhibit tumor growth.

Modelling amorphous materials via a joint solid-state NMR and X-ray absorption spectroscopy and DFT approach: application to alumina.

Understanding a material's electronic structure is crucial to the development of many functional devices from semiconductors to solar cells and Li-ion batteries. A material's properties, including electronic structure, are dependent on the arrangement of its atoms. However, structure determination (the process of uncovering the atomic arrangement), is impeded, both experimentally and computationally, by disorder. The lack of a verifiable atomic model presents a huge challenge when designing functional amorphous materials. Such materials may be characterised through their local atomic environments using, for example, solid-state NMR and XAS. By using these two spectroscopy methods to inform the sampling of configurations from ab initio molecular dynamics we devise and validate an amorphous model, choosing amorphous alumina to illustrate the approach due to its wide range of technological uses. Our model predicts two distinct geometric environments of AlO5 coordination polyhedra and determines the origin of the pre-edge features in the Al K-edge XAS. From our model we construct an average electronic density of states for amorphous alumina, and identify localized states at the conduction band minimum (CBM). We show that the presence of a pre-edge peak in the XAS is a result of transitions from the Al 1s to Al 3s states at the CBM. Deconvoluting this XAS by coordination geometry reveals contributions from both AlO4 and AlO5 geometries at the CBM give rise to the pre-edge, which provides insight into the role of AlO5 in the electronic structure of alumina. This work represents an important advance within the field of solid-state amorphous modelling, providing a method for developing amorphous models through the comparison of experimental and computationally derived spectra, which may then be used to determine the electronic structure of amorphous materials.

Bilirubin Nanoparticle Treatment in Obese Mice Inhibits Hepatic Ceramide Production and Remodels Liver Fat Content.

Studies have indicated that increasing plasma bilirubin levels might be useful for preventing and treating hepatic lipid accumulation that occurs with metabolic diseases such as obesity and diabetes. We have previously demonstrated that mice with hyperbilirubinemia had significantly less lipid accumulation in a diet-induced non-alcoholic fatty liver disease (NAFLD) model. However, bilirubin's effects on individual lipid species are currently unknown. Therefore, we used liquid chromatography-mass spectroscopy (LC-MS) to determine the hepatic lipid composition of obese mice with NAFLD treated with bilirubin nanoparticles or vehicle control. We placed the mice on a high-fat diet (HFD) for 24 weeks and then treated them with bilirubin nanoparticles or vehicle control for 4 weeks while maintaining the HFD. Bilirubin nanoparticles suppressed hepatic fat content overall. After analyzing the lipidomics data, we determined that bilirubin inhibited the accumulation of ceramides in the liver. The bilirubin nanoparticles significantly lowered the hepatic expression of two essential enzymes that regulate ceramide production, Sgpl1 and Degs1. Our results demonstrate that the bilirubin nanoparticles improve hepatic fat content by reducing ceramide production, remodeling the liver fat content, and improving overall metabolic health.

Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease.

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.

Effect of lifestyle-based lipid lowering interventions on the relationship between circulating levels of per-and polyfluoroalkyl substances and serum cholesterol.

Exposure to certain per-and polyfluoroalkyl substances (PFAS) has been shown to be positively associated with total and/or low-density lipoprotein cholesterol. Examining this association in lipid lowering interventions may provide additional evidence linking PFAS to cardiovascular risk. We examined the relationship of 6 PFAS with cholesterol in a 6-month lifestyle-based intervention. We quantitated PFAS in 350 individuals at baseline and post intervention and examined associations of PFAS with cholesterol before and after intervention. Food frequency questionnaires and GIS analyses were used to investigate PFAS hotspots and possible exposure routes. Cholesterol significantly decreased following intervention and in parallel, PFOS, PFOA, PFHxS, and PFHpA significantly decreased. PFOS was positively correlated with total cholesterol only post-intervention. We observed that PFOS was distributed among both non-albumin and albumin lipoprotein fractions pre-intervention, but entirely in albumin fraction post-intervention. Our results indicate that lipid-lowering via lifestyle modification may impact on circulating levels or distribution of PFAS.

Low-Dimensional Metal-Organic Magnets as a Route toward the S = 2 Haldane Phase.

Metal-organic magnets (MOMs), modular magnetic materials where metal atoms are connected by organic linkers, are promising candidates for next-generation quantum technologies. MOMs readily form low-dimensional structures and so are ideal systems to realize physical examples of key quantum models, including the Haldane phase, where a topological excitation gap occurs in integer-spin antiferromagnetic (AFM) chains. Thus, far the Haldane phase has only been identified for S = 1, with S ≥ 2 still unrealized because the larger spin imposes more stringent requirements on the magnetic interactions. Here, we report the structure and magnetic properties of CrCl2(pym) (pym = pyrimidine), a new quasi-1D S = 2 AFM MOM. We show, using X-ray and neutron diffraction, bulk property measurements, density-functional theory calculations, and inelastic neutron spectroscopy (INS), that CrCl2(pym) consists of AFM CrCl2 spin chains (J1 = -1.13(4) meV) which are weakly ferromagnetically coupled through bridging pym (J2 = 0.10(2) meV), with easy-axis anisotropy (D = -0.15(3) meV). We find that, although small compared to J1, these additional interactions are sufficient to prevent observation of the Haldane phase in this material. Nevertheless, the proximity to the Haldane phase together with the modularity of MOMs suggests that layered Cr(II) MOMs are a promising family to search for the elusive S = 2 Haldane phase.

Experimentally Validated Ab Initio Crystal Structure Prediction of Novel Metal-Organic Framework Materials.

First-principles crystal structure prediction (CSP) is the most powerful approach for materials discovery, enabling the prediction and evaluation of properties of new solid phases based only on a diagram of their underlying components. Here, we present the first CSP-based discovery of metal-organic frameworks (MOFs), offering a broader alternative to conventional techniques, which rely on geometry, intuition, and experimental screening. Phase landscapes were calculated for three systems involving flexible Cu(II) nodes, which could adopt a potentially limitless number of network topologies and are not amenable to conventional MOF design. The CSP procedure was validated experimentally through the synthesis of materials whose structures perfectly matched those found among the lowest-energy calculated structures and whose relevant properties, such as combustion energies, could immediately be evaluated from CSP-derived structures.

Tris(1,3-dichloro-2-propyl) phosphate is a metabolism-disrupting chemical in male mice.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant. The primary TDCPP metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), is detectable in the urine of over 90 % of Americans. Epidemiological studies show sex-specific associations between urinary BDCPP levels and metabolic syndrome, which is an established risk factor for type 2 diabetes, heart disease, and stroke. We used a mouse model to determine whether TDCPP exposure disrupts glucose homeostasis. Six-week old male and female C57BL/6J mice were given ad libitum access to diets containing vehicle (0.1 % DMSO) and TDCPP resulting in the following treatment groups: 0 mg/kg/day, 0.02 mg/kg/day, 1 mg/kg/day, or 100 mg/kg/day. After being on the experimental diet for five weeks without interruption, body composition was analyzed, glucose and insulin tolerance tests were performed, and fasting glucose and insulin levels were quantified. TDCPP at 100 mg/kg/day caused male sex-specific adiposity, fasting hyperglycemia, and insulin resistance. TDCPP-induced modulation of nuclear receptor activation was investigated using an in vitro screen to identify potential mechanisms of metabolic disruption. TDCPP activated farnesoid X receptor (FXR) and pregnane X receptor (PXR), and inhibited the androgen receptor (AR). PXR target genes, but not FXR target genes, were upregulated in livers from mice exposed to 100 mg TDCPP/kg/day. Interestingly, PXR target genes were differentially expressed in livers from both males and females. It remains to be determined whether TDCPP-induced metabolic disruption occurs via modulation of nuclear receptor activity. Taken together, these studies build upon the association of TDCPP exposure and metabolic syndrome in humans by identifying sex-specific effects of TDCPP on glucose homeostasis in mice.

Forced Disorder in the Solid Solution Li3P-Li2S: A New Class of Fully Reduced Solid Electrolytes for Lithium Metal Anodes.

All-solid-state batteries based on non-combustible solid electrolytes are promising candidates for safe energy storage systems. In addition, they offer the opportunity to utilize metallic lithium as an anode. However, it has proven to be a challenge to design an electrolyte that combines high ionic conductivity and processability with thermodynamic stability toward lithium. Herein, we report a new highly conducting solid solution that offers a route to overcome these challenges. The Li-P-S ternary was first explored via a combination of high-throughput crystal structure predictions and solid-state synthesis (via ball milling) of the most promising compositions, specifically, phases within the Li3P-Li2S tie line. We systematically characterized the structural properties and Li-ion mobility of the resulting materials by X-ray and neutron diffraction, solid-state nuclear magnetic resonance spectroscopy (relaxometry), and electrochemical impedance spectroscopy. A Li3P-Li2S metastable solid solution was identified, with the phases adopting the fluorite (Li2S) structure with P substituting for S and the extra Li+ ions occupying the octahedral voids and contributing to the ionic transport. The analysis of the experimental data is supported by extensive quantum-chemical calculations of both structural stability, diffusivity, and activation barriers for Li+ transport. The new solid electrolytes show Li-ion conductivities in the range of established materials, while their composition guarantees thermodynamic stability toward lithium metal anodes.

Phase Transformations and Phase Segregation during Potassiation of Sn x P y Anodes.

K-ion batteries (KIBs) have the potential to offer a cheaper alternative to Li-ion batteries (LIBs) using widely abundant materials. Conversion/alloying anodes have high theoretical capacities in KIBs, but it is believed that electrode damage from volume expansion and phase segregation by the accommodation of large K-ions leads to capacity loss during electrochemical cycling. To date, the exact phase transformations that occur during potassiation and depotassiation of conversion/alloying anodes are relatively unexplored. In this work, we synthesize two distinct compositions of tin phosphides, Sn4P3 and SnP3, and compare their conversion/alloying mechanisms with solid-state nuclear magnetic resonance (SSNMR) spectroscopy, powder X-ray diffraction (XRD), and density functional theory (DFT) calculations. Ex situ 31P and 119Sn SSNMR analyses reveal that while both Sn4P3 and SnP3 exhibit phase separation of elemental P and the formation of KSnP-type environments (which are predicted to be stable based on DFT calculations) during potassiation, only Sn4P3 produces metallic Sn as a byproduct. In both anode materials, K reacts with elemental P to form K-rich compounds containing isolated P sites that resemble K3P but K does not alloy with Sn during potassiation of Sn4P3. During charge, K is only fully removed from the K3P-type structures, suggesting that the formation of ternary regions in the anode and phase separation contribute to capacity loss upon reaction of K with tin phosphides.

Association Between Anteromedial Portal Versus Tibial Tunnel Drilling and Meniscal Reoperation Risk Following Anterior Cruciate Ligament Reconstruction: A Cohort Study.

BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) provides functional stability to an injured knee. While multiple techniques can be used to drill the femoral tunnel during ACLR, a single technique has yet to be proven as clinically superior. One marker of postoperative functional stability is subsequent meniscal tears; a lower risk of subsequent meniscal surgery could be expected with improved knee stability. PURPOSE: To determine if there is a meniscal protective effect when using an anteromedial portal (AMP) femoral tunnel drilling technique versus transtibial (TT) drilling. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Data from Kaiser Permanente's ACLR registry were used to identify patients who had a primary isolated ACLR between 2009 and 2018; those with previous surgery in the index knee and meniscal pathology at the time of ACLR were excluded. The exposure of interest was TT (n = 2711) versus AMP (n = 5172) drilling. Multivariable Cox proportional hazard regression was used to evaluate the risk of a subsequent ipsilateral meniscal reoperation with adjustment for age, sex, femoral fixation, and graft choice. We observed a shift in surgeon practice from the TT to AMP over the study time frame; therefore, the relationship between technique and surgeon experience on meniscal reoperation was evaluated using an interaction term in the model. RESULTS: At the 9-year follow-up, the crude cumulative meniscal reoperation probability for AMP procedures was 7.76%, while for TT it was 5.88%. After adjustment for covariates, we observed a higher risk for meniscal reoperation with AMP compared with TT (hazard ratio [HR], 1.53; 95% CI, 1.05-2.23). When stratifying by surgeon experience, this adverse association was observed for patients who had their procedure performed by surgeons with less AMP experience (no previous AMP ACLR: HR, 1.26; 95% CI, 0.84-1.91) while a protective association was observed for patients who had their procedure with more experienced surgeons (40 previous AMP ACLRs: HR, 0.34; 95% CI, 0.13-0.92). CONCLUSION: Drilling the femoral tunnel via the AMP was associated with a higher risk of subsequent meniscal surgery compared with TT drilling. However, when AMP drilling was used by surgeons experienced with the technique, a meniscal protective effect was observed.

Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation.

Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/-) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

Serum concentrations of legacy and emerging per- and polyfluoroalkyl substances in the Anniston Community Health Surveys (ACHS I and ACHS II).

BACKGROUND: Residents of Anniston Alabama were highly exposed to polychlorinated biphenyls (PCBs) due to longstanding manufacturing in the area. The Anniston Community Health Surveys (ACHS I-2005-2007 and II, 2014) have linked these exposures with a variety of deletereous health outcomes. In addition to PCBs, these individuals were likely simultaneously exposed to other persistent organic pollutants including per and polyfluoroalkyl substances (PFAS), which are an emerging class of ubiquitous industrial chemicals that are measurable in the blood of most individuals and have themselves been linked increased risk of some non communicable diseases. METHODS: To characterize PFAS exposures in ACHS I and ACHS II, we measured eight environmentally significant PFAS in serum by UPLC coupled electrospray ionization tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), Perfluorooctanoic acid (PFOA), Perfluorononanoate (PFNA), Perfluorohexane sulfonate (PFHxS), Perfluoroheptanoic acid (PFHpA), Perfluorobutanesulfonic acid (PFBS), Hexafluoropropylene oxide dimer acid (HFPO-DA), and 4:2 Fluorotelomer sulfonic acid (4.2 FTS) were extracted from matched serum samples of individuals who participated in the original ACHS I (2005-2007; n = 297) and the follow up ACHS II (2014; n = 336). Data were collected in negative multiple reaction monitoring (MRM) mode with monitoring of quantitation and qualifier ions for all target PFAS analytes, surrogates and internal standards. VARCLUS procedure was used to create hierarchical clusters between PFAS and other legacy persistent organic pollutants which may share similar exposure routes. RESULTS: Overall, circulating PFAS levels decreased approximately 50% from ACHS I (2005-2007) to ACHS II (2014), but these changes varied by compound. Mean levels of PFOS were >3 times higher in ACHS I subjects than in conpemporaneous NHANES subjects (2005-2006; ACHS I mean: 71.1 ng/ml; NHANES mean: 20.2 ng/mL), and this relationship persisted in ACHS II subjects (2014: ACHS II mean: 34.7 ng/ml; NHANES mean: 5.92 ng/mL). PFNA was also higher in both ACHS I and ACHS II subjects in comparision to NHANES whereas levels of PFOA and PFHxS were lower than in NHANES. Finally, cluster analysis revealed that in ACHS II, most PFAS tracked with polybrominated diphenyl ethers, except PFNA and PFHpA which clustered with industrial PCBs. In ACHS I, PFAS analytes correlated more closely with industrial PCBs and chlorinated pesticides. CONCLUSIONS: Participants in the Anniston Community Health Surveys have higher levels of PFOS and PFNA than the general population with average PFOS levels >3 times contemporaneous NHANES levels. Since PFAS were not known to be manufactured in the area, more work needs to be completed to determine if population demographics, proximity to a military base, or regional manufacturing can explain the elevated levels.