Selective Oligonucleotide and MRNA Pull-Down with Shielded Covalent Probes

Shielded covalent (SC) probes combine programmable base pairing, molecular conformation change, and activatable covalent crosslinking to achieve selective and durable capture of nucleic acid targets, including efficient discrimination of SNPs. Capture yields appear consistent with the thermodynamics of probe/target hybridization, allowing rational probe design. We will demonstrate RNA pull-down using surface-immobilized SC probes, exploiting covalent target capture to remove unwanted material using stringent washes, and then reversing the crosslinks to recover the targets. RNA pull-downs using SC probes will provide a powerful framework for exploring the in vivo binding partners of RNAs

Can Deliberative Democracy Work in Hierarchical Organizations?

Some measure of equality is necessary for deliberative democracy to work well, yet empirical scholarship consistently points to the deleterious effect that hierarchy and inequalities of epistemological authority have on deliberation. This article tests whether real-world deliberative forums can overcome these challenges. Contrary to skeptics, it concludes that the act of deliberation itself and the presence of trained moderators ameliorate inequalities of epistemological authority, thus rendering deliberative democracy possible, even within hierarchical organizations

Alimentación de los leptocéfalos de las anguilas gusano Myrophis spp. (Teleostei: Perciformes: Ophichthidae) basada en protistas y partículas, y la potencial contribución energética de los grandes protozoos aloricados

The food sources of the leptocephali of the teleostean superorder Elopomorpha have been controversial, yet observations on the leptocephali of the worm eels, Myrophis spp. (family Ophichthidae) collected in the northern Gulf of Mexico indicate active, not passive, feeding. Leptocephali had protists in their alimentary canals. Estimates of the physiological energetics of worm eels indicate that large aloricate protozoa including ciliates could provide substantial energy to these leptocephali toward the end of the premetamorphic and metamorphic stages, given the low energy requirements of metamorphosing leptocephali. Global ocean warming will likely force a shift in oceanic food webs; a shift away from large protozoa toward smaller protists is possible. Such a disruption of the oceanic food webs could further compromise the survival of leptocephali.Las fuentes de alimento de los leptocéfalos del superorden de los teleósteos Elopomorpha ha sido controvertida. Sin embargo, las observaciones realizadas en leptocéfalos de las anguilas gusano, Myrophis spp. (Familia Ophichthidae) recolectados en el norte del Golfo de México indican una alimentación activa, no pasiva. Los leptocéfalos tenían protistas en sus tubos digestivos. Las estimaciones de la fisiología energética de las anguilas gusano indican que, dados los bajos requerimientos energéticos de los leptocéfalos durante la metamorfosis, los grandes protozoos ciliados aloricados, incluyendo ciliados, podrían proporcionar sustancial energía a estos leptocéfalos hacia el final de las etapas premetamórficas y metamórficas. El calentamiento global de los océanos es probable que fuerce un cambio en las redes alimenticias oceánicas; y es posible un desplazamiento de los grandes protozoos hacia pequeños protistas. Estas perturbaciones de las redes alimenticias oceánicas podrían poner en peligro la supervivencia de los leptocéfalos

Local Production and Developing Core Regions: Ceramic Characterization in the Lake Pátzcuaro Basin, Western Mexico

A core region is the first place for expected shifts in archaeological materials before, during, and after political changes like state emergence and imperial consolidation. Yet, studies of ceramic production have shown that there are sometimes limited or more subtle changes in the ceramic economy throughout such political fluctuations. This article synthesizes recent efforts to address political economic changes via geochemical characterization (neutron activation analysis; NAA) in the Lake Pátzcuaro Basin in western Mexico. This region was home to the Purépecha state and then empire (Tarascan; ca. AD 1350-1530), one of the most powerful kingdoms in the Americas before European arrival. The combined ceramic dataset from four sites in the region result in eight geochemical groups. Our analysis indicates that the region experienced long-term and relatively stable ceramic production that was not substantially altered by the emergence of the state and empire. In addition, we find evidence for (1) dispersed, localized production; (2) long-lived compositional ceramic recipes; and (3) a complex ceramic economy with differential community participation. We discuss why documenting local ceramic production and craft production more generally is important for the study of past political economies

Diesel particulate matter emission factors and air quality implications from in–service rail in Washington State, USA

AbstractWe sought to evaluate the air quality implications of rail traffic at two sites in Washington State. Our goals were to quantify the exposure to diesel particulate matter (DPM) and airborne coal dust from current trains for residents living near the rail lines and to measure the DPM and black carbon emission factors (EFs). We chose two sites in Washington State, one at a residence along the rail lines in the city of Seattle and one near the town of Lyle in the Columbia River Gorge (CRG). At each site, we made measurements of size–segregated particulate matter (PM1, PM2.5 and PM10), CO2 and meteorology, and used a motion–activated camera to capture video of each train for identification. We measured an average DPM EF of 0.94g/kg diesel fuel, with an uncertainty of 20%, based on PM1 and CO2 measurements from more than 450 diesel trains. We found no significant difference in the average DPM EFs measured at the two sites. Open coal trains have a significantly higher concentration of particles greater than 1μm diameter, likely coal dust. Measurements of black carbon (BC) at the CRG site show a strong correlation with PM1 and give an average BC/DPM ratio of 52% from diesel rail emissions. Our measurements of PM2.5 show that living close to the rail lines significantly increases PM2.5 exposure. For the one month of measurements at the Seattle site, the average PM2.5 concentration was 6.8μg/m3 higher near the rail lines compared to the average from several background locations. Because the excess PM2.5 exposure for residents living near the rail lines is likely to be linearly related to the diesel rail traffic density, a 50% increase in rail traffic may put these residents over the new U.S. National Ambient Air Quality Standards, an annual average of 12μg/m3

Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents

© 2024 The Author(s). Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms.Peer reviewe

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study

BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge

Therapeutic Intervention for Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS): A Systematic Review and Meta-Analysis

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has been treated with several different interventions with limited success. This meta-analysis aims to review all trials reporting on therapeutic intervention for CP/CPPS using the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). Methods We searched Medline, PubMed, the Cochrane Pain, Palliative & Supportive Care Trials, the Cochrane Register of Controlled Trials, CINAHL, ClinicalTrials.gov, and the NIDDK website between 1947 and December 31, 2011 without language or study type restrictions. All RCTs for CP/CPPS lasting at least 6 weeks, with a minimum of 10 participants per arm, and using the NIH-CPSI score, the criterion standard for CP/CPPS, as an outcome measure were included. Data was extracted from each study by two independent reviewers. Gillbraith and I-squared plots were used for heterogeneity testing and Eggers and Peters methods for publication bias. Quality was assessed using a component approach and meta-regression was used to analyze sources of heterogeneity. Results: Mepartricin, percutaneous tibial nerve stimulation (PTNS), and triple therapy comprised of doxazosin + ibuprofen + thiocolchicoside (DIT) resulted in clinically and statistically significant reduction in NIH-CPSI total score. The same agents and aerobic exercise resulted in clinically and statistically significant NIH-CPSI pain domain score reduction. Acupuncture, DIT, and PTNS were found to produce statistically and clinically significant reductions in the NIH-CPSI voiding domain. A statistically significant placebo effect was found for all outcomes and time analysis showed that efficacy of all treatments increased over time. Alpha-blockers, antibiotics, and combinations of the two failed to show statistically or clinically significant NIH-CPSI reductions. Conclusion: Results from this meta-analysis reflect our current inability to effectively manage CP/CPPS. Clinicians and researchers must consider placebo effect and treatment efficacy over time and design studies creatively so we can more fully elucidate the etiology and role of therapeutic intervention in CP/CPPS.