Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain

The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain

Peripheral nerve injury reduces the excitation-inhibition balance of basolateral amygdala inputs to prelimbic pyramidal neurons projecting to the periaqueductal gray

Cellular and synaptic mechanisms underlying how chronic pain induces maladaptive alterations to local circuits in the medial prefrontal cortex (mPFC), while emerging, remain unresolved. Consistent evidence shows that chronic pain attenuates activity in the prelimbic (PL) cortex, a mPFC subregion. This reduced activity is thought to be driven by increased inhibitory tone within PL circuits. Enhanced input from the basolateral amygdala (BLA) to inhibitory neurons in PL cortex is one well-received mechanism for this circuit change. In mice, we used retrograde labeling, brain slice recordings, and optogenetics to selectively stimulate and record ascending BLA inputs onto PL neurons that send projections to the periaqueductal gray (PAG), which is a midbrain structure that plays a significant role in endogenous analgesia. Activating BLA projections evoked both excitatory and inhibitory currents in cortico-PAG (CP) neurons, as we have shown previously. We measured changes to the ratio of BLA-evoked excitatory to inhibitory currents in the spared nerve injury (SNI) model of neuropathic pain. Our analysis reveals a reduced excitation-inhibition (E/I) ratio of BLA inputs to PL-CP neurons 7 days after SNI. The E/I ratio of BLA inputs to CP neurons in neighboring infralimbic (IL) cortex was unchanged in SNI animals. Collectively, this study reveals that the overall E/I balance of BLA inputs to PL neurons projecting to the PAG is reduced in a robust neuropathic pain model. Overall, our findings provide new mechanistic insight into how nerve injury produces dysfunction in PL circuits connected to structures involved in pain modulation

The evolution of solar flux from 0.1 nm to 160 μm : quantitative estimates for planetary studies

Understanding changes in the solar flux over geologic time is vital for understanding the evolution of planetary atmospheres because it affects atmospheric escape and chemistry, as well as climate. We describe a numerical parameterization for wavelength-dependent changes to the non-attenuated solar flux appropriate for most times and places in the solar system. We combine data from the Sun and solar analogs to estimate enhanced UV and X-ray fluxes for the young Sun and use standard solar models to estimate changing visible and infrared fluxes. The parameterization, a series of multipliers relative to the modern top of the atmosphere flux at Earth, is valid from 0.1 nm through the infrared, and from 0.6 Gyr through 6.7 Gyr, and is extended from the solar zero-age main sequence to 8.0 Gyr subject to additional uncertainties. The parameterization is applied to a representative modern day flux, providing quantitative estimates of the wavelength dependence of solar flux for paleodates relevant to the evolution of atmospheres in the solar system (or around other G-type stars). We validate the code by Monte Carlo analysis of uncertainties in stellar age and flux, and with comparisons to the solar proxies κ1 Cet and EK Dra. The model is applied to the computation of photolysis rates on the Archean Earth.Publisher PDFPeer reviewe

Spectroscopy of Nine Cataclysmic Variable Stars

We present optical spectroscopy of nine cataclysmic binary stars, mostly dwarf novae, obtained primarily to determine orbital periods Porb. The stars and their periods are LX And, 0.1509743(5) d; CZ Aql, 0.2005(6) d; LU Cam, 0.1499686(4) d; GZ Cnc, 0.0881(4) d; V632 Cyg, 0.06377(8) d; V1006 Cyg, 0.09903(9) d; BF Eri, 0.2708804(4) d; BI Ori, 0.1915(5) d; and FO Per, for which Porb is either 0.1467(4) or 0.1719(5) d. Several of the stars proved to be especially interesting. In BF Eri, we detect the absorption spectrum of a secondary star of spectral type K3 +- 1 subclass, which leads to a distance estimate of approximately 1 kpc. However, BF Eri has a large proper motion (100 mas/yr), and we have a preliminary parallax measurement that confirms the large proper motion and yields only an upper limit for the parallax. BF Eri's space velocity is evidently large, and it appears to belong to the halo population. In CZ Aql, the emission lines have strong wings that move with large velocity amplitude, suggesting a magnetically-channeled accretion flow. The orbital period of V1006 Cyg places it squarely within the 2- to 3-hour "gap" in the distribution of cataclysmic binary orbital periods.Comment: 31 pages, 5 postscript and one PNG figure. Accepted for PAS

The Success Story Of First Ever Polymer Flood Field Pilot To Enhance The Recovery Of Heavy Oils On Alaska\u27s North Slope

The primary goal of the first ever polymer flood field pilot at Milne Point is to validate the use of polymers for heavy oil Enhanced Oil Recovery (EOR) on Alaska North Slope (ANS). The specific objectives are systematic evaluation of advanced technology that integrates polymer flooding, low salinity water flooding, horizontal wells, and numerical simulation based on polymer flood performance data. Accordingly, under the co-sponsorship of the US Department of Energy and Hilcorp Alaska LLC the first ever polymer field pilot commenced on August 28, 2018 in the Schrader Bluff heavy oil reservoir at the Milne Point Unit (MPU) on ANS. The pilot started injecting hydrolyzed polyacrylamide (HPAM), at a concentration of 1,750 ppm to achieve a target viscosity of 45 cP, into the two horizontal injectors in the J-pad flood pattern. Since July 2020, HPAM concentration was reduced to 1,200 ppm to control injectivity and optimize polymer utilization. Filter ratio tests conducted on site ensure uniform polymer solution properties. Injectivity is assessed by Hall plots, whereas production is monitored via oil and water rates from the two producers. Water samples are analyzed to determine the produced polymer concentration. Supporting laboratory core floods on polymer retention, injection water salinity, polymer loading, and their combinations on oil recovery, match rock, fluid and test conditions. A calibrated and validated numerical multiphase reservoir model was developed for long-term reservoir performance prediction and for evaluating the project\u27s economic performance in conjunction with an economic model. Concerns related to handling of produced fluids containing polymer are addressed by specialized experiments. As would be expected in a field experiment of this scale, barring some operational and hydration issues, continuous polymer injection has been achieved. As of September 30, 2022, a total of 1.41 million lbs. of polymer or 2.99 million bbls of polymer solution (~18.8% of total pore volume), placed in the pattern serves as an effective indicator of polymer injectivity. During the first half of the pilot period, water cut (WC) drastically reduced in both producers and over the entire duration, the deemed EOR benefit over waterflood was in the range of 700-1,000 bopd, and that too at a low polymer utilization of 1.7 lbs./bbl. Low concentration polymer breakthrough was observed after 26-28 months, which is now stabilized at 600-800 ppm in congruence with the WC. Although as indicated by laboratory experiments, polymer retention in core material is high; ~70% of the injected polymer propagates without any delay, while the remaining 30% tails over several PVs. History matched simulation models consistently forecasts polymer recovery of 1.5-2 times that of waterflood, and when integrated with the economic modeling tool, establish the economic profitability of the first ever polymer flood field pilot. Produced fluid experiments provide operational guidance for treating emulsions and heater-treater operating temperature. Over a duration of ~4.5 years important outstanding technical issues that entail polymer flooding of heavy oils have been resolved, which forms the basis of the success story summarized in the paper. The first ever polymer pilot is deemed as a technical and economic success in significantly improving the heavy oil recovery on ANS. The pilot has provided impetus to not only apply polymer EOR throughout the Milne Point Field, but has paved the way for additional state-funded research targeting even heavier oils on the ANS. The combined success of this work and the future work will contribute to the longevity of the Trans Alaska Pipeline System (TAPS)

Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells

Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines