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Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

Environmental heat stress triggers a series of compensatory mechanisms in sheep that are dependent on their genetic regulation of thermotolerance. Our objective was to identify genes and regulatory pathways associated with thermotolerance in ewes exposed to heat stress. We performed next-generation RNA sequencing on blood collected from 16 pregnant ewes, which were grouped as tolerant and non-tolerant to heat stress according to a physiological indicator. Additional samples were collected to measure complete blood count. A total of 358 differentially expressed genes were identified after applying selection criteria. Gene expression analysis detected 46 GO terms and 52 KEGG functional pathways. The top-three signaling pathways were p53, RIG-I-like receptor and FoxO, which suggested gene participation in biological processes such as apoptosis, cell signaling and immune response to external stressors. Network analysis revealed ATM, ISG15, IRF7, MDM4, DHX58 and TGFβR1 as over-expressed genes with high regulatory potential. A co-expression network involving the immune-related genes ISG15, IRF7 and DXH58 was detected in lymphocytes and monocytes, which was consistent with hematological findings. In conclusion, transcriptomic analysis revealed a non-viral immune mechanism involving apoptosis, which is induced by external stressors and appears to play an important role in the molecular regulation of heat stress tolerance in ewes.

Placental insufficiency (PI) induced intrauterine growth restriction (IUGR) increases the risk of mortality and morbidity in both newborns and adults. PI causes a progressive, chronic, and severe decline in the maternal-fetal nutrient transport starting in mid-gestation, which results in fetal hypoxemia and hypoglycemia. Unfortunately, the decline in nutrient availability occurs concurrently with critical myogenic windows in fetal development establishing the proper complement of skeletal muscle mass in utero. Thus, IUGR fetuses are also afflicted with sarcopenia that persists into adulthood and predisposes offspring to metabolic diseases. Recent evidence indicates that the metabolic capacity of the skeletal muscle of IUGR fetuses is lowered in response to low nutrient availability. IUGR skeletal muscle adaptations to low nutrient availability includes lower protein synthesis rates as well as lower fractional glucose oxidation and amino acid oxidation rates.In the current studies, we test the hypothesis that mitochondria isolated from IUGR fetal sheep skeletal muscle have defects in both nutrient oxidation and energy production. Previous findings have linked hypoglycemia and hypoxemia to lower glucose oxidation rates in the IUGR fetus. It was postulated that pyruvate oxidation was hindered in IUGR skeletal muscle mitochondria due to the inhibition pyruvate dehydrogenase (PDH), the first step in pyruvate metabolism. However, we show PDH activity is 67% higher in IUGR skeletal muscle. Moreover, the abundance of Mitochondrial Pyruvate Carrier 2 (MPC2), the primary mitochondrial pyruvate transporter, as well as the abundances of rate-limiting Tricarboxylic Acid Cycle (TCA) enzymes, isocitrate dehydrogenase and oxoglutarate dehydrogenase, are lower in IUGR mitochondria compared to controls (P<0.05). The lower abundances of enzymes involved in substrate oxidation in IUGR fetuses are accompanied by a 47% lower complex-I mediated oxygen consumption rate (OCR) and 18% lower Complex I activity, both of which indicate impaired electron transport chain (ETC) function. Reduced pyruvate oxidation in IUGR fetal skeletal muscle is the result of concomitant decreases in pyruvate transport, TCA cycle function, and ETC function.Fetal adaptations to nutrient restriction program metabolic dysfunction in postnatal skeletal muscle in IUGR individuals. We hypothesized that mitochondria isolated from myotubes which are differentiated from 30-day old IUGR lamb satellite cells have a 44% lower complex-I mediated OCR compared to controls. The lower OCR in IUGR myotube mitochondria is associated with lower abundances of ETC Complex III and IV subunit abundances. Although the mitochondrial metabolic changes observed in IUGR myotubes differ from the metabolic changes observed in IUGR fetal skeletal muscle mitochondria, these results show the persistence of skeletal muscle mitochondrial dysfunction in IUGR individuals from birth into postnatal life.

Human glioblastoma is a devastating, difficult to treat disease with a poor prognosis. Contemporary chemotherapy regiments are systemically damaging and non-specific. Therefore, the development of targeted therapy is critical for the treatment of glioblastoma. In our current study, the efficacy of the small, novel molecule, AKS7, was characterized, in vitro, against the human glioblastoma cell line, U87-MG. Our investigation, which utilized next generation sequencing and molecular wet-lab techniques, demonstrates that AKS7-treated U87 cells are growth-arrested, normalized, and show profound morphological changes. Both a 48-hour post-treatment cell cycle analysis and bioinformatics analysis reveal that AKS7-treated cells are arrested in the G2/M phase of the cell cycle. AKS7-treated U87 cells also resulted in an astrocytic or neuronal phenotype, as well as possible transdifferentiation into endothelial-like cells. The astrocytic, star-like phenotype is characterized by a large, flat cell body with multiple projections while the neuronal phenotype is characterized by a small, round cell body with two long projections on either end. Our investigation focused on the astrocytic phenotype due to the origin of U87, which is an astrocytoma. Analysis of the next generation transcriptomic sequencing data of AKS7-treated U87 cells showed upregulated response in synapse genes and differentiation markers along with upregulated inflammatory product production. Additionally, it was found that AKS7 induces extreme vacuolization at high concentrations. The vacuoles are of intracellular origin, yet their production and origin remain an enigma. Our investigation also showed that AKS7 chelates iron (III), localizes within mitochondria, and interferes with mitochondrial function. AKS7-treated cells show an increase in mitochondrial ?? as well as an increase in ATP production followed by cell death characterized by massive vacuolization. The implications of normalization and differentiation of astrocytoma necessitates future studies conducted on the mechanism of action of AKS7. AKS7-induced cell cycle arrest and differentiation in U87 cells makes AKS7 a promising candidate for the treatment of glioblastoma.

We have performed a high-resolution 4–13 μm spectral survey of the hot molecular gas associated with the massive protostars AFGL 2591 and AFGL 2136. Here we present the results of the analysis of the ν 2 band of H2O, detected with the Echelon Cross Echelle Spectrograph on board the Stratospheric Observatory for Infrared Astronomy between wavelengths of 5 and 8 μm. All lines are seen in absorption. Rotation diagrams indicate that the gas is optically thick and lines are observed to saturate at 40% and 15% relative to the continuum for AFGL 2136 and AFGL 2591, respectively. We applied two curve of growth analyses to derive the physical conditions, one assuming a foreground origin and one a circumstellar disk origin. We find temperatures of 400–600 K. A foreground origin would require the presence of externally heated clumps that are smaller than the continuum source. The disk analysis is based on stellar atmosphere theory, which takes into consideration the temperature gradient in the disk. We discuss the challenges with each model, taking into consideration the properties of other species detected in the spectral survey, and conclude that further modeling efforts are required to establish whether the absorption has a disk or foreground origin. The main challenge to the foreground model is that molecules are expected to be observed in emission. The main challenges to the disk model are the midplane heating mechanism and the presence of narrow absorption lines shifted from the systemic velocity.

We present in this paper mid-infrared (5–8 μm) spectroscopy toward the massive young binary W3 IRS 5, using the Echelon Cross Echelle Spectrograph (EXES) spectrometer in high-resolution mode (R ∼ 50,000) from the NASA Stratospheric Observatory for Infrared Astronomy (SOFIA). Many (∼180) ν 2 = 1–0 and (∼90) ν 2 = 2–1 absorption rovibrational transitions are identified. Two hot components over 500 K and one warm component of 190 K are identified through Gaussian fittings and rotation diagram analysis. Each component is linked to a CO component identified in the IRTF/iSHELL observations (R = 88,100) through their kinematic and temperature characteristics. Revealed by the large scatter in the rotation diagram, opacity effects are important, and we adopt two curve-of-growth analyses, resulting in column densities of ∼1019 cm−2. In one analysis, the model assumes a foreground slab. The other assumes a circumstellar disk with an outward-decreasing temperature in the vertical direction. The disk model is favored because fewer geometry constraints are needed, although this model faces challenges as the internal heating source is unknown. We discuss the chemical abundances along the line of sight based on the CO-to-H2O connection. In the hot gas, all oxygen not locked in CO resides in water. In the cold gas, we observe a substantial shortfall of oxygen and suggest that the potential carrier could be organics in solid ice.

The dusty interstellar medium (ISM) of the Milky Way is distributed in a complex, cloudy structure. It is fundamental to the radiation balance within the Milky Way, provides a reaction surface to form complex molecules, and is the feedstock for future generations of stars and planets. The life cycle of interstellar dust is not completely understood, and neither are its structure nor composition. The abundance, composition, and structure of dust in the diffuse ISM can be determined by combining infrared, optical, and ultraviolet spectroscopy. JWST enables measurement of the faint absorption of ISM dust grains against bright stars at kiloparsec distances across the infrared spectrum. Here we present an overview of the project “Webb Investigation of Silicates, Carbons, and Ices” (WISCI) along with interpretation of two targets, GSC 08152-02121 and CPD-59 5831. Observations of 12 WISCI target stars were taken by JWST, the Hubble Space Telescope, Himalayan Chandra Telescope, and the Very Large Telescope. We use these to characterize the targets’ spectral types and calculate their line-of-sight extinction parameters, AV and RV. We find absorption in the JWST spectra of GSC 08152-02121 and CPD-59 5831 associated with carbonaceous dust around 3.4 and 6.2 μm and amorphous silicates at 9.7 μm. In GSC 08152-02121, we also find indications of absorption by trapped water around 3 μm. This first look from WISCI demonstrates the line-of-sight variability within the sample, and the program’s potential to identify and correlate features across ultraviolet to mid-infrared wavelengths.

Abstract Frailty, the state of increased vulnerability to physical stressors as a result of progressive and sustained degeneration in multiple physiological systems, is common in those with chronic kidney disease (CKD). In fact, the prevalence of frailty in the older adult population is reported to be 11%, whereas the prevalence of frailty has been reported to be greater than 60% in dialysis-dependent CKD patients. Frailty is independently linked with adverse clinical outcomes in all stages of CKD and has been repeatedly shown to be associated with an increased risk of mortality and hospitalization. In recent years there have been efforts to create an operationalized definition of frailty to aid its diagnosis and to categorize its severity. Two principal concepts are described, namely the Fried Phenotype Model of Physical Frailty and the Cumulative Deficit Model of Frailty. There is no agreement on which frailty assessment approach is superior, therefore, for the time being, emphasis should be placed on any efforts to identify frailty. Recognizing frailty should prompt a holistic assessment of the patient to address risk factors that may exacerbate its progression and to ensure that the patient has appropriate psychological and social support. Adequate nutritional intake is essential and individualized exercise programmes should be offered. The acknowledgement of frailty should prompt discussions that explore the future care wishes of these vulnerable patients. With further study, nephrologists may be able to use frailty assessments to inform discussions with patients about the initiation of renal replacement therapy.

The Gulf of Maine has recently experienced its warmest 5-year period (2015–2020) in the instrumental record. This warming was associated with a decline in the signature subarctic zooplankton species, Calanus finmarchicus. The temperature changes have also led to impacts on commercial species such as Atlantic cod (Gadus morhua) and American lobster (Homarus americanus) and protected species including Atlantic puffins (Fratercula arctica) and northern right whales (Eubalaena glacialis). The recent period also saw a decline in Atlantic herring (Clupea harengus) recruitment and an increase in novel harmful algal species, although these have not been attributed to the recent warming. Here, we use an ensemble of numerical ocean models to characterize expected ocean conditions in the middle of this century. Under the high CO2 emissions scenario (RCP8.5), the average temperature in the Gulf of Maine is expected to increase 1.1°C to 2.4°C relative to the 1976–2005 average. Surface salinity is expected to decrease, leading to enhanced water column stratification. These physical changes are likely to lead to additional declines in subarctic species including C. finmarchicus, American lobster, and Atlantic cod and an increase in temperate species. The ecosystem changes have already impacted human communities through altered delivery of ecosystem services derived from the marine environment. Continued warming is expected to lead to a loss of heritage, changes in culture, and the necessity for adaptation.