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This paper investigates the origin of the γ -ray emission from MGRO J1908+06 in the GeV–TeV energy band. By analyzing the data collected by the Fermi Large Area Telescope, the Very Energetic Radiation Imaging Telescope Array System, and High Altitude Water Cherenkov, with the addition of spectral data previously reported by LHAASO, a multiwavelength study of the morphological and spectral features of MGRO J1908+06 provides insight into the origin of the γ -ray emission. The mechanism behind the bright TeV emission is studied by constraining the magnetic field strength, the source age, and the distance through detailed broadband modeling. Both spectral shape and energy-dependent morphology support the scenario that inverse Compton emission of an evolved pulsar wind nebula associated with PSR J1907+0602 is responsible for the MGRO J1908+06 γ -ray emission with a best-fit true age of T = 22 ± 9 kyr and a magnetic field of B = 5.4 ± 0.8 μ G, assuming the distance to the pulsar d _PSR = 3.2 kpc.

In 2017 February, the blazar OJ 287 underwent a period of intense multiwavelength activity. It reached a new historic peak in the soft X-ray (0.3–10 keV) band, as measured by the Swift X-ray Telescope. This event coincides with a very-high-energy (VHE) γ -ray outburst that led VERITAS to detect emission above 100 GeV, with a detection significance of 10 σ (from 2016 December 9 to 2017 March 31). The time-averaged VHE γ -ray spectrum was consistent with a soft power law (Γ = −3.81 ± 0.26) and an integral flux corresponding to ∼2.4% that of the Crab Nebula above the same energy. Contemporaneous data from multiple instruments across the electromagnetic spectrum reveal a complex flaring behavior, primarily in the soft X-ray and VHE bands. To investigate the possible origin of such an event, our study focuses on three distinct activity states: before, during, and after the 2017 February peak. The spectral energy distributions during these periods suggest the presence of at least two nonthermal emission zones, with the more compact one responsible for the observed flare. Broadband modeling results and observations of a new radio knot in the jet of OJ 287 in 2017 are consistent with a flare originating from a strong recollimation shock outside the radio core.

G106.3+2.7, commonly considered to be a composite supernova remnant (SNR), is characterized by a boomerang-shaped pulsar wind nebula (PWN) and two distinct (“head” and “tail”) regions in the radio band. A discovery of very-high-energy gamma-ray emission ( E _γ > 100 GeV) followed by the recent detection of ultrahigh-energy gamma-ray emission ( E _γ > 100 TeV) from the tail region suggests that G106.3+2.7 is a PeVatron candidate. We present a comprehensive multiwavelength study of the Boomerang PWN (100″ around PSR J2229+6114) using archival radio and Chandra data obtained two decades ago, a new NuSTAR X-ray observation from 2020, and upper limits on gamma-ray fluxes obtained by Fermi-LAT and VERITAS observatories. The NuSTAR observation allowed us to detect a 51.67 ms spin period from the pulsar PSR J2229+6114 and the PWN emission characterized by a power-law model with Γ = 1.52 ± 0.06 up to 20 keV. Contrary to the previous radio study by Kothes et al., we prefer a much lower PWN B -field ( B ∼ 3 μ G) and larger distance ( d ∼ 8 kpc) based on (1) the nonvarying X-ray flux over the last two decades, (2) the energy-dependent X-ray size of the PWN resulting from synchrotron burn-off, and (3) the multiwavelength spectral energy distribution (SED) data. Our SED model suggests that the PWN is currently re-expanding after being compressed by the SNR reverse shock ∼1000 yr ago. In this case, the head region should be formed by GeV–TeV electrons injected earlier by the pulsar propagating into the low-density environment.

We report on multiwavelength target-of-opportunity observations of the blazar PKS 0735+178, located 2.°2 away from the best-fit position of the IceCube neutrino event IceCube-211208A detected on 2021 December 8. The source was in a high-flux state in the optical, ultraviolet, X-ray, and GeV γ -ray bands around the time of the neutrino event, exhibiting daily variability in the soft X-ray flux. The X-ray data from Swift-XRT and NuSTAR characterize the transition between the low-energy and high-energy components of the broadband spectral energy distribution (SED), and the γ -ray data from Fermi-LAT, VERITAS, and H.E.S.S. require a spectral cutoff near 100 GeV. Both the X-ray and γ -ray measurements provide strong constraints on the leptonic and hadronic models. We analytically explore a synchrotron self-Compton model, an external Compton model, and a lepto-hadronic model. Models that are entirely based on internal photon fields face serious difficulties in matching the observed SED. The existence of an external photon field in the source would instead explain the observed γ -ray spectral cutoff in both the leptonic and lepto-hadronic models and allow a proton jet power that marginally agrees with the Eddington limit in the lepto-hadronic model. We show a numerical lepto-hadronic model with external target photons that reproduces the observed SED and is reasonably consistent with the neutrino event despite requiring a high jet power.

The Breakthrough Listen Initiative is conducting a program using multiple telescopes around the world to search for “technosignatures”: artificial transmitters of extraterrestrial origin from beyond our solar system. The Very Energetic Radiation Imaging Telescope Array System (VERITAS) Collaboration joined this program in 2018 and provides the capability to search for one particular technosignature: optical pulses of a few nanoseconds in duration detectable over interstellar distances. We report here on the analysis and results of dedicated VERITAS observations of Breakthrough Listen targets conducted in 2019 and 2020 and of archival VERITAS data collected since 2012. Thirty hours of dedicated observations of 136 targets and 249 archival observations of 140 targets were analyzed and did not reveal any signals consistent with a technosignature. The results are used to place limits on the fraction of stars hosting transmitting civilizations. We also discuss the minimum pulse sensitivity of our observations and present VERITAS observations of CALIOP: a space-based pulsed laser on board the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations. The detection of these pulses with VERITAS, using the analysis techniques developed for our technosignature search, allows a test of our analysis efficiency and serves as an important proof of principle.

We report the detection of very high energy gamma-ray emission from the blazar S3 1227+25 (VER J1230+253) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS). VERITAS observations of the source were triggered by the detection of a hard-spectrum GeV flare on 2015 May 15 with the Fermi-Large Area Telescope (LAT). A combined 5 hr VERITAS exposure on May 16 and 18 resulted in a strong 13 σ detection with a differential photon spectral index, Γ = 3.8 ± 0.4, and a flux level at 9% of the Crab Nebula above 120 GeV. This also triggered target-of-opportunity observations with Swift, optical photometry, polarimetry, and radio measurements, also presented in this work, in addition to the VERITAS and Fermi-LAT data. A temporal analysis of the gamma-ray flux during this period finds evidence of a shortest variability timescale of τ _obs = 6.2 ± 0.9 hr, indicating emission from compact regions within the jet, and the combined gamma-ray spectrum shows no strong evidence of a spectral cutoff. An investigation into correlations between the multiwavelength observations found evidence of optical and gamma-ray correlations, suggesting a single-zone model of emission. Finally, the multiwavelength spectral energy distribution is well described by a simple one-zone leptonic synchrotron self-Compton radiation model.

This study investigated the relationships amongst personality traits and attitudes of 311 dairy stockpeople and the milk yield they obtained. A questionnaire pack consisting of a big-five measure of personality (which includes the traits of extraversion, agreeableness, conscientiousness, emotional stability and intellect), a four-factor attitude questionnaire and associated demographic and production questions was posted out to Northern Ireland dairy farmers. Pearson correlations were used to assess the relationship between personality and attitudes and partial correlations were calculated between milk yield and these psychometric measures. The personality traits of agreeableness and conscientiousness were most strongly correlated to positive attitudes towards working with dairy cows. None of the stockpeople’s personality traits were significantly correlated with the milk yield they obtained. Three of the attitude scales, however, were significantly correlated with milk yield; milk yield was related to higher levels of empathy and job satisfaction and lower levels of negative beliefs. These findings, along with previous research, suggest stockperson attitudes may be important in relation to dairy cow welfare and production.

Although most field and modeling studies of river corridor exchange have been conducted at scales ranging from tens to hundreds of meters, results of these studies are used to predict their ecological and hydrological influences at the scale of river networks. Further complicating prediction, exchanges are expected to vary with hydrologic forcing and the local geomorphic setting. While we desire predictive power, we lack a complete spatiotemporal relationship relating discharge to the variation in geologic setting and hydrologic forcing that is expected across a river basin. Indeed, the conceptual model of Wondzell (2011) predicts systematic variation in river corridor exchange as a function of (1) variation in baseflow over time at a fixed location, (2) variation in discharge with location in the river network, and (3) local geomorphic setting. To test this conceptual model we conducted more than 60 solute tracer studies including a synoptic campaign in the 5th-order river network of the H. J. Andrews Experimental Forest (Oregon, USA) and replicate-in-time experiments in four watersheds. We interpret the data using a series of metrics describing river corridor exchange and solute transport, testing for consistent direction and magnitude of relationships relating these metrics to discharge and local geomorphic setting. We confirmed systematic decrease in river corridor exchange space through the river networks, from headwaters to the larger main stem. However, we did not find systematic variation with changes in discharge through time or with local geomorphic setting. While interpretation of our results is complicated by problems with the analytical methods, the results are sufficiently robust for us to conclude that space-for-time and time-for-space substitutions are not appropriate in our study system. Finally, we suggest two strategies that will improve the interpretability of tracer test results and help the hyporheic community develop robust datasets that will enable comparisons across multiple sites and/or discharge conditions.

A comprehensive set of measurements and calculated metrics describing physical, chemical, and biological conditions in the river corridor is presented. These data were collected in a catchment-wide, synoptic campaign in the H. J. Andrews Experimental Forest (Cascade Mountains, Oregon, USA) in summer 2016 during low-discharge conditions. Extensive characterization of 62 sites including surface water, hyporheic water, and streambed sediment was conducted spanning 1st- through 5th-order reaches in the river network. The objective of the sample design and data acquisition was to generate a novel data set to support scaling of river corridor processes across varying flows and morphologic forms present in a river network. The data are available at https://doi.org/10.4211/hs.f4484e0703f743c696c2e1f209abb842 (Ward, 2019).

Despite growing interest in resilience, there is still significant scope for increasing its conceptual clarity and practical relevance in socio-hydrological contexts: specifically, questions of how socio-hydrological systems respond to and cope with perturbations and how these connect to resilience remain unanswered. In this opinion paper, we propose a novel conceptual framework for understanding and assessing resilience in coupled socio-hydrological contexts, and encourage debate on the inter-connections between socio-hydrology and resilience. Taking a systems perspective, we argue that resilience is a set of systematic properties with three dimensions: absorptive, adaptive, and transformative, and contend that socio-hydrological systems can be viewed as various forms of human–water couplings, reflecting different aspects of these interactions. We propose a framework consisting of two parts. The first part addresses the identity of socio-hydrological resilience, answering questions such as resilience of what in relation to what. We identify three existing framings of resilience for different types of human–water systems and subsystems, which have been used in different fields: (1) the water subsystem, highlighting hydrological resilience to anthropogenic hazards; (2) the human subsystem, foregrounding social resilience to hydrological hazards; and (3) the coupled human–water system, exhibiting socio-hydrological resilience. We argue that these three system types and resiliences afford new insights into the clarification and evaluation of different water management challenges. The first two types address hydrological and social states, while the third type emphasises the feedbacks and interactions between human and water components within complex systems subject to internal or external disturbances. In the second part, we focus on resilience management and develop the notion of the resilience canvas, a novel heuristic device to identify possible pathways and to facilitate the design of bespoke strategies for enhancing resilience in the socio-hydrological context. The resilience canvas is constructed by combining absorptive and adaptive capacities as two axes. At the corners of the resulting two-dimensional space are four quadrants which we conceptualise as representing resilient, vulnerable, susceptible, and resistant system states. To address projected change-induced uncertainties, we recommend that efforts now be focused on shifting socio-hydrological systems from resistant towards resilient status. In sum, the novel framework proposed here clarifies the ambiguity inherent in socio-hydrological resilience, and provides a viable basis for further theoretical and practical development.

Hantaan virus (HTNV) and Puumala virus (PUUV) are pathogenic hantaviruses found in Asia and Europe, respectively. DNA vaccines targeting the envelope glycoproteins of these viruses have been constructed and found to elicit neutralizing antibodies when delivered to humans by various technologies including intramuscular electroporation. Here, we report findings from a Phase 2a clinical trial of a combined HTNV/PUUV DNA vaccine delivered at varying doses and administration schedules using the Ichor Medical Systems TriGrid intramuscular electroporation delivery technology. The study was designed to characterize the effects of DNA vaccine dose and number of administrations on the frequency and magnitude of immunological response. Subjects (n = 120) were divided into four cohorts. Cohorts 1 and 2 received a dose of 2 mg of DNA (1 mg per plasmid), and cohorts 3 and 4 received a dose of 1 mg of DNA (0.5 mg per plasmid) each vaccination. Each of the four cohorts received a series of four administrations (days 0, 28, 56 and 168). For cohorts 1 and 3, the DNA vaccine candidate was delivered at each of the four administrations. For cohorts 2 and 4, in order to maintain blinding, subjects received the DNA vaccine on days 0, 56 and 168, but on day 28 received only the phosphate buffered saline vehicle rather the DNA vaccine. Sera were collected on days 0, 28, 56, 84, 140, 168, 196, 252 and 365 and evaluated for the presence of neutralizing antibodies by PUUV and HTNV pseudovirion neutralization assays (PsVNAs). Day 84 was also evaluated by a plaque reduction neutralization test (PRNT). Overall the PsVNA50 geometric mean titers (GMTs) and seropositivity rates among cohorts were similar. Cohort 3 exhibited the highest frequency of subjects that became seropositive to both PUUV and HTNV after vaccination, the highest peak GMT against both viruses, and the highest median titers against both viruses.

Abstract Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.

Myocarditis is an infrequent complication of influenza infection that is most often diagnosed clinically in the setting of confirmed influenza infection and elevated cardiac enzymes. Pericarditis can also occur in cases of influenza myocarditis and may require pericardiocentesis for tamponade. Patients with fulminant myocarditis have cardiogenic shock; however, echocardiographic findings may be subtle, showing a preserved ejection fraction and diffuse left ventricular wall thickening (compared to baseline) due to inflammatory edema. Recognizing these echocardiographic findings in the appropriate clinical setting facilitates the early recognition of fulminant myocarditis. Therefore, we report a case of fulminant influenza A myocarditis in healthy 37-year-old women complicated by transient left ventricular wall thickening and tamponade, highlighting the importance of early diagnosis and supportive management for a successful outcome.

Abstract Carbonaceous chondrites (CCs) contain the earliest preserved Solar System material, and objects containing this material are targets of numerous sample return missions. Both laboratory and remote sensing data have shown that this material can be highly porous, but the origin and nature of this porosity is currently not well understood. Because the majority of porosity within CCs is submicron to micron in size, previous lab efforts have been restricted by the limited observational scale required to examine this porosity with currently available techniques. Here we present results from a newly developed technique that allows submicron porosity to be examined in 3D within a 12 mm3 volume of CM Murchison. We use X-ray computed tomography combined with the highly attenuating noble gas xenon to characterize porosity well below the spatial resolution of the data (3.01 µm/voxel). This method not only allows examination of submicron porosity within a significantly larger volume than previously possible but also reveals the full three-dimensional porosity structure and pore connectivity. Our data reveal that some fine-grained rims (FGRs) surrounding chondrules have a complex 3D porosity structure, suggesting formation of the FGRs via dust aggregates or variable secondary processing around the rim after accretion.

Abstract Background Manual analysis of cross-sectional area, fiber-type distribution, and total and centralized nuclei in skeletal muscle cross sections is tedious and time consuming, necessitating an accurate, automated method of analysis. While several excellent programs are available, our analyses of skeletal muscle disease models suggest the need for additional features and flexibility to adequately describe disease pathology. We introduce a new semi-automated analysis program, MyoSight, which is designed to facilitate image analysis of skeletal muscle cross sections and provide additional flexibility in the analyses. Results We describe staining and imaging methods that generate high-quality images of immunofluorescent-labelled cross sections from mouse skeletal muscle. Using these methods, we can analyze up to 5 different fluorophores in a single image, allowing simultaneous analyses of perinuclei, central nuclei, fiber size, and fiber-type distribution. MyoSight displays high reproducibility among users, and the data generated are in close agreement with data obtained from manual analyses of cross-sectional area (CSA), fiber number, fiber-type distribution, and number and localization of myonuclei. Furthermore, MyoSight clearly delineates changes in these parameters in muscle sections from a mouse model of Duchenne muscular dystrophy (mdx). Conclusions MyoSight is a new program based on an algorithm that can be optimized by the user to obtain highly accurate fiber size, fiber-type identification, and perinuclei and central nuclei per fiber measurements. MyoSight combines features available separately in other programs, is user friendly, and provides visual outputs that allow the user to confirm the accuracy of the analyses and correct any inaccuracies. We present MyoSight as a new program to facilitate the analyses of fiber type and CSA changes arising from injury, disease, exercise, and therapeutic interventions.

Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS

In their study, the authors discuss the potential of thermal weathering on airless bodies. As a case study, they use boulder and fracture morphologies on asteroid Bennu.

Background: Pericarditis caused by Methicillin-resistant Staphylococcus aureus (MRSA) is a rare infection, often seen in patients with chronic kidney disease, immunosuppression, or previous pericardial disease. The presentation can be dramatic with acute illness leading to septic and/or obstructive shock due to pericardial tamponade. Occasionally disease can have a more protracted, indolent, subacute clinical course. Case report: We report a case of a 57-year-old male patient with a previous history of smoking and moderate alcohol use who presented with progressive dyspnea and cough. He was found to have a disseminated MRSA infection with pericarditis complicated by pericardial tamponade. Urgent pericardiocentesis yielded 1.1 liters of purulent fluid that grew MRSA. MRSA was also isolated from the blood and pleural fluid. The patient underwent left thoracotomy, decortication, and pericardial window and completed 3 weeks of intravenous vancomycin therapy, concluding in an excellent outcome. Conclusion: Bacterial pericarditis is an exceptionally rare form of pericarditis which been traditionally associated with chronic medical conditions requiring a prolonged healthcare stay. However, it has lately been observed in healthy individuals with social habits such as smoking and alcohol consumption. Bacterial pericarditis must be recognized in a timely fashion and managed aggressively to prevent a devastating outcome. A multidisciplinary approach is advised, which includes a combination of pericardial drainage and aggressive antibiotic therapy. Such treatment often yields a positive outcome and good long-term prognosis.

The mechanical processes that convert an initially fluffy chondrule fine-grained rim (FGR) into a more compact structure remain poorly characterized. Given the presence of shocks in protoplanetary disks, we use numerical simulations to test the hypothesis that dust-laden shocks in the solar nebula contributed to FGR modification. We use the iSALE2D shock physics code to model the collision of dusty nebular shock fronts (which we term “dust clouds”) into chondrule surfaces that host a porous FGR. In our simulations, dust particles are modeled as dunite disks. The dust radii follow the Mathis–Rumpl–Nordsieck distribution of interstellar grains. Chondrules are modeled as rectangular dunite slabs. We vary the impact speed v _imp , the fractional abundance f _cloud of dust grains in the impacting shock, and the fractional abundance f _FGR of dust grains in the pre-existing FGR. We thus compute dust temperatures and pressures resulting from the collisions, as well as the net mass accretion of dust by the FGRs. Dust temperatures increase upon impact, depending on the kinetic energy of the dust cloud and on f _FGR . Dust rims with a higher f _FGR heat up more than those with a lower f _FGR , with possibly important implications for the composition and structure of FGRs. Maximum impact pressures increase with f _cloud . Fine-grained rims can experience mass gain from the impacting cloud, but in some instances, mass is lost from the rim. We find qualitative similarities in the topography of the FGR–chondrule interface between our simulations and petrographic analyses of the Paris CM chondrite by other authors.

An 83-year-old gentleman with a history of 23-mm Hancock-II-bioprosthetic aortic valve (BAV) replacement ten-years prior presented with symptoms of dyspnea and lower extremity edema. During the preceding seven-years, he had been noted to have asymptomatic increased mean transvalvular gradients (MG; 36–50 mmHg) felt to be due to either early bioprosthetic degeneration, pannus formation, or patient–prosthesis mismatch. An echocardiogram at the time of symptom development demonstrated significant flow acceleration through the aortic valve, mild regurgitation, and severely increased MG (48 mmHg) with prolonged acceleration time (AT, 140 msec). A trial of warfarin anticoagulation resulted in dramatic improvement after only 6 weeks with laminar flow through the AV, near-total resolution of regurgitation, and a decrease in MG to 14 mmHg and AT to 114 msec. These findings strongly suggest that BAV thrombosis was the predominant mechanism responsible for the longstanding high MG. Our case highlights that BAV thrombosis should be considered in the differential of elevated gradients regardless of the age of prosthesis, and that a trial of warfarin anticoagulation may be beneficial even if elevated gradients have been present for a prolonged period. Valvular gradients are often abnormal long before a formal diagnosis; however, these may reverse quickly with anticoagulation therapy.

In the expanding era of antibiotic resistance, new strains of Staphylococcus aureus have emerged which possess resistance to traditionally used antibiotics (MRSA). Our review aimed to systematically synthesize information on previously described MRSA pericarditis cases. The only criterion for inclusion was the isolation of MRSA from the pericardial space. Our review included 30 adult and 9 pediatric patients (aged: 7 months to 78 years). Comorbid conditions were seen in most adult patients, whereas no comorbidities were noted amongst the pediatric patients. Pericardial effusion was found in 94.9% of cases, with evidence of tamponade in 83.8%. All cases isolated MRSA from pericardial fluid and 25 cases (64.1%) had positive blood cultures for MRSA. Pericardiocentesis and antibiotics were used in all patients. The mortality rate amongst adults was 20.5%, with a mean survival of 21.8 days, and attributed to multi-organ failure associated with septic shock. No mortality was observed in the pediatric population. In adult patients, there was no statistical difference in symptom duration, antibiotic duration, presence of tamponade, age, and sex in relation to survival. Conclusion: MRSA pericarditis often presents with sepsis and is associated with significant mortality. As such, a high clinical suspicion is needed to proceed with proper tests such as echocardiography and pericardiocentesis. In more than one third of the cases, MRSA pericarditis occurs even in the absence of documented bacteremia.

Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.

(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1–3 and 6–12 months after. Protocolized echocardiogram measurements including tricuspid annular plane systolic excursion (TAPSE) and RV global longitudinal strain were made with blinding to clinical information. Forty-nine individuals (65% female), aged 0–29 years at the time of prostacyclin initiation were included. Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Over the study period, prostacyclin analogues were associated with improvement in TAPSE ( P = 0.007), RV strain ( P

Right atrial (RA) mechanics have been studied infrequently in children in the past due to technical constraints. With the advent of strain imaging, RA physiology can now be studied in greater detail. The principal aim of this study was to describe functional changes in right heart mechanics of children with idiopathic pulmonary arterial hypertension (PAH), by using new applications of RA strain. In this retrospective study, we evaluated RA mechanics of 20 patients (age range = 3–23 years) with PAH and 18 control patients. RA longitudinal strain (RALS) and longitudinal displacement (LD) were calculated by speckle-tracking echocardiography. RALS was plotted against LD, producing a characteristic strain-displacement (S-D) loop. Standard indices of right heart function and right heart catheterization data were obtained. Patients were clinically subdivided into “compensated” and “decompensated” PAH. A chart review was performed to identify patients who subsequently developed adverse outcomes, including death, awaiting or received lung and/or heart transplantation. RALS was significantly lower in decompensated PAH compared with both controls and compensated PAH. Area enclosed by S-D loops differed significantly between the compensated and decompensated PAH subgroups (5.33 [3.90–9.44] versus 1.83 [1.17–2.36], P

Yeast DNA postreplication repair (PRR) bypasses replication-blocking lesions to prevent damage-induced cell death. PRR employs two different mechanisms to bypass damaged DNA, namely translesion synthesis (TLS) and error-free PRR, which are regulated via sequential ubiquitination of proliferating cell nuclear antigen (PCNA). We previously demonstrated that error-free PRR utilizes homologous recombination to facilitate template switching. To our surprise, genes encoding the Mre11-Rad50-Xrs2 (MRX) complex, which are also required for homologous recombination, are epistatic to TLS mutations. Further genetic analyses indicated that two other nucleases involved in double-strand end resection, Sae2 and Exo1, are also variably required for efficient lesion bypass. The involvement of the above genes in TLS and/or error-free PRR could be distinguished by the mutagenesis assay and their differential effects on PCNA ubiquitination. Consistent with the observation that the MRX complex is required for both branches of PRR, the MRX complex was found to physically interact with Rad18 in vivo. In light of the distinct and overlapping activities of the above nucleases in the resection of double-strand breaks, we propose that the interplay between distinct single-strand nucleases dictate the preference between TLS and error-free PRR for lesion bypass.