Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Comparison of initial adenosine dose conversion rate for supraventricular tachycardia in the emergency department.

OBJECTIVE: To evaluate the rate of supraventricular tachycardia (SVT) termination between 6 mg and 12 mg initial adenosine doses. METHODS: This multi-center, retrospective cohort study evaluated patients presenting to the emergency department (ED) from January 1, 2020 to June 30, 2022 in SVT and received adenosine. The primary objective of the study is to compare the rate of SVT termination between adenosine 6 mg and 12 mg as documented on a formal electrocardiogram. Secondary endpoints include termination of SVT with subsequent adenosine dose, time to ED disposition, adverse effects, and subgroup analyses of patients with a body mass index greater than or equal to 40 kg/m2 and a history of SVT. RESULTS: Of 213 patients included, a 6 mg initial adenosine dose was administered to 117 patients (54.9 %) and a 12 mg initial adenosine dose was administered to 96 patients (45.1 %). SVT termination following the initial dose of 6 mg or 12 mg was 56.4 % and 79.1 %, respectively (p < 0.001). Among the 46 patients who failed to terminate SVT with an initial 6 mg dose, 33 converted to sinus rhythm with a subsequent adenosine dose in comparison to 1 of the 7 patients receiving an initial dose of 12 mg (71.7 % vs 14.3 %, p = 0.007). Median time to ED disposition, either inpatient admission or discharge, was 209 and 161 min, respectively (p = 0.104). There was no statistical difference in either subgroup analyses. CONCLUSION: A higher rate of SVT termination was observed with an initial adenosine dose of 12 mg in the ED in comparison to the guideline recommended dose of 6 mg. There were no significant differences in adverse effects observed.

The Critical Role of Environmental Synergies in the Creation of Bionanohybrid Microbes.

A wide range of bacteria can synthesize surface-associated nanoparticles (SANs) through exogenous metal ions reacting with sulfide produced via cysteine metabolism, resulting in the emergence of a biological-nanoparticle hybrid (bionanohybrid). The attached nanoparticles may couple to extracellular electron transfer, facilitating de novo photoelectrochemical processes. While SAN-cell coupling in hybrid organisms is opening a range of biotechnological possibilities, observation of bionanohybrids in nature is not commonly reported and their lab-based behavior remains difficult to control. We describe the critical role environmental synergy (microbial growth stage, cell densities, cysteine, and exogenous metal concentrations) plays in controlling the form and occurrence of Escherichia coli and Moorella thermoacetica bionanohybrids. SAN development depends on an appropriate cell density to metal ratio, with too few cells resulting in nanoparticle suppression through cytotoxicity or inhibition of cysteine conversion, and with too many cells diluting the number and size of particles produced. This cell number is governed by the concentration of cysteine present, which acts to protect the cells from metal ion toxicity. Exposing cells to metal and cysteine during the lag phase leads to SAN development, whereas cells in the exponential growth phase predominantly produce dispersed nanoparticles. Applying these principles more broadly, E. coli is shown to biosynthesize composite Bi/Cu sulfide SANs, and Clostridioides difficile can be coaxed into a bionanohybrid lifestyle by fine-tuning the cysteine dosage. Bionanohybrids maintain a remarkable ability for binary fission and sustained growth, opening doors to the production of SANs tailored to specific technological functions. IMPORTANCE Some bacteria can produce nanoscale-sized particles, which remain attached to the surface of the organism. The surface association of these nanoparticles creates a new mode of interaction between the microbe's environment and its internal cellular function, giving rise to a new hybrid lifeform, a biological nanoparticle hybrid (bionanohybrid). These hybrid organisms gain new or enhanced biological functions, and thus their creation opens a wide range of biotechnological possibilities. Despite this potential, the fundamental controls on bionanohybrid formation and occurrence remain poorly constrained. In this study, Escherichia coli K-12, Moorella thermoacetica, and Clostridioides difficile were used to test the combined influences of the growth phase, cell density, cysteine dose, and metal concentration in determining single and composite metal sulfide surface-associated nanoparticle production. The significance of this study is that it defined the critical synergies controlling nanoparticle formation on bacterial cell surfaces, unlocking the potential for bionanohybrid applications in a range of organisms.

Inhibition of Sulfate Reduction and Cell Division by Desulfovibrio desulfuricans Coated in Palladium Metal.

The growth of sulfate-reducing bacteria (SRB) and associated hydrogen sulfide production can be problematic in a range of industries such that inhibition strategies are needed. A range of SRB can reduce metal ions, a strategy that has been utilized for bioremediation, metal recovery, and synthesis of precious metal catalysts. In some instances, the metal remains bound to the cell surface, and the impact of this coating on bacterial cell division and metabolism has not previously been reported. In this study, Desulfovibrio desulfuricans cells (1g dry weight) enabled the reduction of up to 1500 mmol (157.5 g) palladium (Pd) ions, resulting in cells being coated in approximately 1 µm of metal. Thickly coated cells were no longer able to metabolize or divide, ultimately leading to the death of the population. Increasing Pd coating led to prolonged inhibition of sulfate reduction, which ceased completely after cells had been coated with 1200 mmol Pd g-1 dry cells. Less Pd nanoparticle coating permitted cells to carry out sulfate reduction and divide, allowing the population to recover over time as surface-associated Pd diminished. Overcoming inhibition in this way was more rapid using lactate as the electron donor, compared to formate. When using formate as an electron donor, preferential Pd(II) reduction took place in the presence of 100 mM sulfate. The inhibition of important metabolic pathways using a biologically enabled casing in metal highlights a new mechanism for the development of microbial control strategies. IMPORTANCE Microbial reduction of sulfate to hydrogen sulfide is highly undesirable in several industrial settings. Some sulfate-reducing bacteria are also able to transform metal ions in their environment into metal phases that remain attached to their outer cell surface. This study demonstrates the remarkable extent to which Desulfovibrio desulfuricans can be coated with locally generated metal nanoparticles, with individual cells carrying more than 100 times their mass of palladium metal. Moreover, it reveals the effect of metal coating on metabolism and replication for a wide range of metal loadings, with bacteria unable to reduce sulfate to sulfide beyond a specific threshold. These findings present a foundation for a novel means of modulating the activity of sulfate-reducing bacteria.

Ethics Committees: Team Perspectives and Organizational Responses.

Healthcare ethics committees can be valuable resources but are largely underutilized by nurses. The purpose of this project was to review ethics concerns and educational needs of nurses in a large, integrated healthcare delivery system. Seven themes were identified: organizational issues, nonbeneficial care, withdrawing life-sustaining therapies, discharge disposition, challenging patients and families, communication with physicians, and capacity versus competence. A process was then developed to better engage nurses in ethical discussions.

Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies.

Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays. cTnI values typically peaked at 2, 3, 4, or 6 hr after sham dosing and returned to baseline at 22 or 24 hr. In addition, marked increases in heart rate (HR) and blood pressure (BP) occurred in monkeys during the restraint procedures, which likely initiated the cTnI release in these animals. Monkeys that were very well acclimated to the chairing procedures and had vascular access ports for blood sampling did not have marked increases in HRs and BP or increases in cTnI.

BMRF-Net: a software tool for identification of protein interaction subnetworks by a bagging Markov random field-based method.

UNLABELLED: Identification of protein interaction subnetworks is an important step to help us understand complex molecular mechanisms in cancer. In this paper, we develop a BMRF-Net package, implemented in Java and C++, to identify protein interaction subnetworks based on a bagging Markov random field (BMRF) framework. By integrating gene expression data and protein-protein interaction data, this software tool can be used to identify biologically meaningful subnetworks. A user friendly graphic user interface is developed as a Cytoscape plugin for the BMRF-Net software to deal with the input/output interface. The detailed structure of the identified networks can be visualized in Cytoscape conveniently. The BMRF-Net package has been applied to breast cancer data to identify significant subnetworks related to breast cancer recurrence. AVAILABILITY AND IMPLEMENTATION: The BMRF-Net package is available at http://sourceforge.net/projects/bmrfcjava/. The package is tested under Ubuntu 12.04 (64-bit), Java 7, glibc 2.15 and Cytoscape 3.1.0.

Nitric oxide treatment for the control of reverse osmosis membrane biofouling.

Biofouling remains a key challenge for membrane-based water treatment systems. This study investigated the dispersal potential of the nitric oxide (NO) donor compound, PROLI NONOate, on single- and mixed-species biofilms formed by bacteria isolated from industrial membrane bioreactor and reverse osmosis (RO) membranes. The potential of PROLI NONOate to control RO membrane biofouling was also examined. Confocal microscopy revealed that PROLI NONOate exposure induced biofilm dispersal in all but two of the bacteria tested and successfully dispersed mixed-species biofilms. The addition of 40 µM PROLI NONOate at 24-h intervals to a laboratory-scale RO system led to a 92% reduction in the rate of biofouling (pressure rise over a given period) by a bacterial community cultured from an industrial RO membrane. Confocal microscopy and extracellular polymeric substances (EPS) extraction revealed that PROLI NONOate treatment led to a 48% reduction in polysaccharides, a 66% reduction in proteins, and a 29% reduction in microbial cells compared to the untreated control. A reduction in biofilm surface coverage (59% compared to 98%, treated compared to control) and average thickness (20 µm compared to 26 µm, treated compared to control) was also observed. The addition of PROLI NONOate led to a 22% increase in the time required for the RO module to reach its maximum transmembrane pressure (TMP), further indicating that NO treatment delayed fouling. Pyrosequencing analysis revealed that the NO treatment did not significantly alter the microbial community composition of the membrane biofilm. These results present strong evidence for the application of PROLI NONOate for prevention of RO biofouling.

Comparison of two methodologies for calibrating satellite instruments in the visible and near-infrared.

Traditionally, satellite instruments that measure Earth-reflected solar radiation in the visible and near infrared wavelength regions have been calibrated for radiance responsivity in a two-step method. In the first step, the relative spectral response (RSR) of the instrument is determined using a nearly monochromatic light source such as a lamp-illuminated monochromator. These sources do not typically fill the field of view of the instrument nor act as calibrated sources of light. Consequently, they only provide a relative (not absolute) spectral response for the instrument. In the second step, the instrument views a calibrated source of broadband light, such as a lamp-illuminated integrating sphere. The RSR and the sphere's absolute spectral radiance are combined to determine the absolute spectral radiance responsivity (ASR) of the instrument. More recently, a full-aperture absolute calibration approach using widely tunable monochromatic lasers has been developed. Using these sources, the ASR of an instrument can be determined in a single step on a wavelength-by-wavelength basis. From these monochromatic ASRs, the responses of the instrument bands to broadband radiance sources can be calculated directly, eliminating the need for calibrated broadband light sources such as lamp-illuminated integrating spheres. In this work, the traditional broadband source-based calibration of the Suomi National Preparatory Project Visible Infrared Imaging Radiometer Suite sensor is compared with the laser-based calibration of the sensor. Finally, the impact of the new full-aperture laser-based calibration approach on the on-orbit performance of the sensor is considered.

Setting standards for medically-based running analysis.

Setting standards for medically based running analyses is necessary to ensure that runners receive a high-quality service from practitioners. Medical and training history, physical and functional tests, and motion analysis of running at self-selected and faster speeds are key features of a comprehensive analysis. Self-reported history and movement symmetry are critical factors that require follow-up therapy or long-term management. Pain or injury is typically the result of a functional deficit above or below the site along the kinematic chain.

Propylene glycol toxicity in an adolescent secondary to chronic cornstarch ingestion.

Propylene glycol (PG) is a diol (a double alcohol) that is commonly used as a food additive to preserve shelf life and enhance flavors, texture, and appearance. Although PG makes up only a small percentage of cornstarch, ingestion of large doses can cause lactic acidosis leading to hyperosmolarity, high anion gap metabolic acidosis (HAGMA), and a sepsis-like syndrome. A 17-year-old female presented to our emergency department (ED) with chronic chest pain, dyspnea, nausea, and vomiting. Laboratory testing showed an elevated anion gap of 18 mEq/L with no osmolar gap. Toxicology screening was negative. Twelve hours after ED arrival, she admitted to consuming one box of cornstarch daily for the past 6 months. She was admitted to the intensive care unit (ICU) with multisystem organ failure due to propylene glycol toxicity. After empiric treatment with fomepizole and continuous renal replacement therapy, her clinical status gradually improved. This case highlights the importance of obtaining a thorough dietary history in patients with suspected toxicities, especially when laboratory values demonstrate an unexplained HAGMA and/or lactic acidosis. Prompt recognition and therapeutic intervention with fomepizole, a potent inhibitor of alcohol dehydrogenase, is essential in reducing life-threatening sequelae following toxic alcohol ingestions.

Results of aperture area comparisons for exo-atmospheric total solar irradiance measurements.

Exo-atmospheric solar irradiance measurements made by the solar irradiance community since 1978 have incorporated limiting apertures with diameters measured by a number of metrology laboratories using a variety of techniques. Knowledge of the aperture area is a critical component in the conversion of radiant flux measurements to solar irradiance. A National Aeronautics and Space Administration (NASA) Earth Observing System (EOS) sponsored international comparison of aperture area measurements of limiting apertures provided by solar irradiance researchers was performed, the effort being executed by the National Institute of Standards and Technology (NIST) in coordination with the EOS Project Science Office. Apertures that had institutional heritage with historical solar irradiance measurements were measured using the absolute aperture measurement facility at NIST. The measurement technique employed noncontact video microscopy using high-accuracy translation stages. We have quantified the differences between the participating institutions' aperture area measurements and find no evidence to support the hypothesis that preflight aperture area measurements were the root cause of discrepancies in long-term total solar irradiance satellite measurements. Another result is the assessment of uncertainties assigned to methods used by participants. We find that uncertainties assigned to a participant's values may be underestimated.

Optimal dosing regimen of nitric oxide donor compounds for the reduction of Pseudomonas aeruginosa biofilm and isolates from wastewater membranes.

Membrane fouling by bacterial biofilms remains a key challenge for membrane-based water purification systems. Here, the optimal biofilm dispersal potential of three nitric oxide (NO) donor compounds, viz. sodium nitroprusside, 6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine (MAHMA NONOate) and 1-(hydroxy-NNO-azoxy)-L-proline, disodium salt, was investigated using Pseudomonas aeruginosa PAO1 as a model organism. Dispersal was quantitatively assessed by confocal microscopy [bacterial cells and the components of the extracellular polymeric substances (EPS) (polysaccharides and extracellular DNA)] and colony-forming unit counts. The three NO donor compounds had different optimal exposure times and concentrations, with MAHMA NONOate being the optimal NO donor compound. Biofilm dispersal correlated with a reduction in both bacterial cells and EPS. MAHMA NONOate also reduced single species biofilms formed by bacteria isolated from industrial membrane bioreactor and reverse osmosis membranes, as well as in isolates combined to generate mixed species biofilms. The data present strong evidence for the application of these NO donor compounds for prevention of biofouling in an industrial setting.

AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.

Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.

Mechanisms of cannabinoid tolerance.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, ß-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.

OBJECTIVE: The liver is a central regulator of energy metabolism exerting its influence both through intrinsic processing of substrates such as glucose and fatty acid as well as by secreting endocrine factors, known as hepatokines, which influence metabolism in peripheral tissues. Human genome wide association studies indicate that a predicted loss-of-function variant in the Inhibin ßE gene (INHBE), encoding the putative hepatokine Activin E, is associated with reduced abdominal fat mass and cardiometabolic disease risk. However, the regulation of hepatic Activin E and the influence of Activin E on adiposity and metabolic disease are not well understood. Here, we examine the relationship between hepatic Activin E and adipose metabolism, testing the hypothesis that Activin E functions as part of a liver-adipose, inter-organ feedback loop to suppress adipose tissue lipolysis in response to elevated serum fatty acids and hepatic fatty acid exposure. METHODS: The relationship between hepatic Activin E and non-esterified fatty acids (NEFA) released from adipose lipolysis was assessed in vivo using fasted CL 316,243 treated mice and in vitro using Huh7 hepatocytes treated with fatty acids. The influence of Activin E on adipose lipolysis was examined using a combination of Inhbe knockout mice, a mouse model of hepatocyte-specific overexpression of Activin E, and mouse brown adipocytes treated with Activin E enriched media. RESULTS: Increasing hepatocyte NEFA exposure in vivo by inducing adipose lipolysis through fasting or CL 316,243 treatment increased hepatic Inhbe expression. Similarly, incubation of Huh7 human hepatocytes with fatty acids increased expression of INHBE. Genetic ablation of Inhbe in mice increased fasting circulating NEFA and hepatic triglyceride accumulation. Treatment of mouse brown adipocytes with Activin E conditioned media and overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum FFA levels, respectively. The suppressive effects of Activin E on lipolysis were lost in CRISPR-mediated ALK7 deficient cells and ALK7 kinase deficient mice. Disruption of the Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity upon HFD feeding, but caused hepatic steatosis and insulin resistance. CONCLUSIONS: Taken together, our data suggest that Activin E functions as part of a liver-adipose feedback loop, such that in response to increased serum free fatty acids and elevated hepatic triglyceride, Activin E is released from hepatocytes and signals in adipose through ALK7 to suppress lipolysis, thereby reducing free fatty acid efflux to the liver and preventing excessive hepatic lipid accumulation. We find that disrupting this Activin E-ALK7 inter-organ communication network by ablation of Inhbe in mice increases lipolysis and reduces adiposity, but results in elevated hepatic triglyceride and impaired insulin sensitivity. These results highlight the liver-adipose, Activin E-ALK7 signaling axis as a critical regulator of metabolic homeostasis.

On-orbit calibration of SeaWiFS.

Ocean color climate data records (CDRs) require water-leaving radiances with 5% absolute and 1% relative accuracies as input. Because of the amplification of any sensor calibration errors by the atmospheric correction, the 1% relative accuracy requirement translates into a 0.1% long-term radiometric stability requirement for top-of-the-atmosphere (TOA) radiances. The rigorous prelaunch and on-orbit calibration program developed and implemented for Sea-viewing Wide Field-of-view Sensor (SeaWiFS) by the NASA Ocean Biology Processing Group (OBPG) has led to the incorporation of significant changes into the on-orbit calibration methodology over the 13-year lifetime of the instrument. Evolving instrument performance and ongoing algorithm refinement have resulted in updates to approaches for the lunar, solar, and vicarious calibration of SeaWiFS. The uncertainties in the calibrated TOA radiances are addressed in terms of accuracy (biases in the measurements), precision (scatter in the measurements), and stability (repeatability of the measurements). The biases are 2%-3% from lunar calibration and 1%-2% from vicarious calibration. The precision is 0.16% from solar signal-to-noise ratios, 0.13% from lunar residuals, and 0.10% from vicarious gains. The long-term stability of the TOA radiances, derived from the lunar time series, is 0.13%. The stability of the vicariously calibrated TOA radiances, incorporating the uncertainties of the in situ measurements and the atmospheric correction, is 0.30%. This stability of the radiometric calibration of SeaWiFS over its 13-year on-orbit lifetime has allowed the OBPG to produce CDRs from the ocean color data set.

Intermediate Crack Debonding of Externally Bonded FRP Reinforcement-Comparison of Methods.

Many researchers around the world have made extensive efforts to study the phenomenon of fiber-reinforced polymer (FRP) debonding. Based on these efforts, code provisions and various models have been proposed for predicting intermediate crack (IC) debonding failure. The paper presents a comparison of seven selected models: fib bulletin 14 approach, Teng et al. model, Lu model, Seracino et al. model, Said and Wu model, Elsanadedy et al. model and ACI 440. The accuracy of each model was evaluated based on the test results of 58 flexural specimens with IC debonding failures of externally bonded (EB), carbon FRP plates or sheets found in the existing literature. The experimental database was prepared to include a wide range of parameters affecting the issue under consideration. A comparison of the measured and predicted load capacity values was made to evaluate the prediction accuracy of the considered models. The analysis included the limitation of the load capacity estimated based on IC debonding models as well as concrete crushing and FRP rupture types of failure. The results indicate that the latest models proposed for direct implementation in design guidelines-the Said and Wu model and the Elsanadedy et al. model-offer the best accuracy in predicting the load capacity. In contrast, the fib bulletin 14 approach shows a wide dispersion of predictions and a large proportion of highly overestimated results.