30 research outputs found
Role of intact hydrogen-bond networks in multiproton-coupled electron transfer
The essential role of a well-defined hydrogen-bond network in achieving chemically reversible multiproton translocations triggered by one-electron electrochemical oxidation/reduction is investigated by using pyridylbenzimidazole-phenol models. The two molecular architectures designed for these studies differ with respect to the position of the N atom on the pyridyl ring. In one of the structures, a hydrogen-bond network extends uninterrupted across the molecule from the phenol to the pyridyl group. Experimental and theoretical evidence indicates that an overall chemically reversible two-proton-coupled electron-transfer process (E2PT) takes place upon electrochemical oxidation of the phenol. This E2PT process yields the pyridinium cation and is observed regardless of the cyclic voltammogram scan rate. In contrast, when the hydrogen-bond network is disrupted, as seen in the isomer, at high scan rates (ÎŒ1000 mV s-1) a chemically reversible process is observed with an E1/2 characteristic of a one-proton-coupled electron-transfer process (E1PT). At slow cyclic voltammetric scan rates (<1000 mV s-1) oxidation of the phenol results in an overall chemically irreversible two-proton-coupled electron-transfer process in which the second proton-transfer step yields the pyridinium cation detected by infrared spectroelectrochemistry. In this case, we postulate an initial intramolecular proton-coupled electron-transfer step yielding the E1PT product followed by a slow, likely intermolecular chemical step involving a second proton transfer to give the E2PT product. Insights into the electrochemical behavior of these systems are provided by theoretical calculations of the electrostatic potentials and electric fields at the site of the transferring protons for the forward and reverse processes. This work addresses a fundamental design principle for constructing molecular wires where protons are translocated over varied distances by a Grotthuss-type mechanism.Fil: Guerra, Walter DamiĂĄn. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - CĂłrdoba. Instituto de Investigaciones en FĂsico-quĂmica de CĂłrdoba. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Instituto de Investigaciones en FĂsico-quĂmica de CĂłrdoba; Argentina. Arizona State University; Estados UnidosFil: Odella, Emmanuel. Arizona State University; Estados Unidos. Universidad Nacional de RĂo Cuarto. Facultad de Ciencias Exactas FisicoquĂmicas y Naturales. Departamento de QuĂmica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Secor, Maxim. University of Yale; Estados UnidosFil: Goings, Joshua J.. University of Yale; Estados UnidosFil: Urrutia, MarĂa N.. Arizona State University; Estados UnidosFil: Wadsworth, Brian L.. Arizona State University; Estados UnidosFil: Gervaldo, Miguel Andres. Universidad Nacional de RĂo Cuarto. Facultad de Ciencias Exactas FisicoquĂmicas y Naturales. Instituto de Investigaciones en TecnologĂas EnergĂ©ticas y Materiales Avanzados. - Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - CĂłrdoba. Instituto de Investigaciones en TecnologĂas EnergĂ©ticas y Materiales Avanzados; ArgentinaFil: Sereno, Leonides Edmundo. Universidad Nacional de RĂo Cuarto. Facultad de Ciencias Exactas FisicoquĂmicas y Naturales. Departamento de QuĂmica; ArgentinaFil: Moore, Thomas A.. Arizona State University; Estados UnidosFil: Moore, Gary F.. Arizona State University; Estados UnidosFil: Hammes-Schiffer, Sharon. University of Yale; Estados UnidosFil: Moore, Ana L.. University of Yale; Estados Unido
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Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.
The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline â„50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline â„50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance
The Astropy Problem
The Astropy Project (http://astropy.org) is, in its own words, "a community
effort to develop a single core package for Astronomy in Python and foster
interoperability between Python astronomy packages." For five years this
project has been managed, written, and operated as a grassroots,
self-organized, almost entirely volunteer effort while the software is used by
the majority of the astronomical community. Despite this, the project has
always been and remains to this day effectively unfunded. Further, contributors
receive little or no formal recognition for creating and supporting what is now
critical software. This paper explores the problem in detail, outlines possible
solutions to correct this, and presents a few suggestions on how to address the
sustainability of general purpose astronomical software
Mergers, AGN, and 'Normal' Galaxies: Contributions to the Distribution of Star Formation Rates and Infrared Luminosity Functions
We use a novel method to predict the contribution of normal star-forming
galaxies, merger-induced bursts, and obscured AGN, to IR luminosity functions
(LFs) and global SFR densities. We use empirical halo occupation constraints to
populate halos with galaxies and determine the distribution of normal and
merging galaxies. Each system can then be associated with high-resolution
hydrodynamic simulations. We predict the distribution of observed luminosities
and SFRs, from different galaxy classes, as a function of redshift from z=0-6.
We provide fitting functions for the predicted LFs, quantify the uncertainties,
and compare with observations. At all redshifts, 'normal' galaxies dominate the
LF at moderate luminosities ~L* (the 'knee'). Merger-induced bursts
increasingly dominate at L>>L*; at the most extreme luminosities, AGN are
important. However, all populations increase in luminosity at higher redshifts,
owing to increasing gas fractions. Thus the 'transition' between normal and
merger-dominated sources increases from the LIRG-ULIRG threshold at z~0 to
bright Hyper-LIRG thresholds at z~2. The transition to dominance by obscured
AGN evolves similarly, at factor of several higher L_IR. At all redshifts,
non-merging systems dominate the total luminosity/SFR density, with
merger-induced bursts constituting ~5-10% and AGN ~1-5%. Bursts contribute
little to scatter in the SFR-stellar mass relation. In fact, many systems
identified as 'ongoing' mergers will be forming stars in their 'normal'
(non-burst) mode. Counting this as 'merger-induced' star formation leads to a
stronger apparent redshift evolution in the contribution of mergers to the SFR
density.Comment: 16 pages, 9 figures (+appendices), accepted to MNRAS. A routine to
return the galaxy merger rates discussed here is available at
http://www.cfa.harvard.edu/~phopkins/Site/mergercalc.htm
Dynamics of Dynamin during Clathrin Mediated Endocytosis in PC12 Cells
Members of the dynamin super-family of GTPases are involved in disparate cellular pathways. Dynamin1 and dynamin2 have been implicated in clathrin-mediated endocytosis. While some models suggest that dynamin functions specifically at the point of vesicle fission, evidence also exists for a role prior to fission during vesicle formation and it is unknown if there is a role for dynamin after vesicle fission. Although dynamin2 is ubiquitously expressed, dynamin1 is restricted to the nervous system. These two structurally similar endocytic accessory proteins have not been studied in cells that endogenously express both.The present study quantitatively assesses the dynamics of dynamin1 and dynamin2 during clathrin-mediated endocytosis in PC12 cells, which endogenously express both proteins. Both dynamin isoforms co-localized with clathrin and showed sharp increases in fluorescence intensity immediately prior to internalization of the nascent clathrin-coated vesicle. The fluorescence intensity of both proteins then decreased with two time constants. The slower time constant closely matched the time constant for the decrease of clathrin intensity and likely represents vesicle movement away from the membrane. The faster rate may reflect release of dynamin at the neck of nascent vesicle following GTP hydrolysis.This study analyses the role of dynamin in clathrin-mediated endocytosis in a model for cellular neuroscience and these results may provide direct evidence for the existence of two populations of dynamin associated with nascent clathrin-coated vesicles
Mammal responses to global changes in human activity vary by trophic group and landscape
Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in humanâwildlife interactions along gradients of human influence.Peer reviewe
Synonymous but not the same: the causes and consequences of codon bias
Despite their name, synonymous mutations have significant consequences for cellular processes in all taxa. As a result, an understanding of codon bias is central to fields as diverse as molecular evolution and biotechnology. Although recent advances in sequencing and synthetic biology have helped resolve longstanding questions about codon bias, they have also uncovered striking patterns that suggest new hypotheses about protein synthesis. Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts
Costs and consequences of large-scale vector control for malaria.
BACKGROUND: Five large insecticide-treated net (ITN) programmes and two indoor residual spraying (IRS) programmes were compared using a standardized costing methodology. METHODS: Costs were measured locally or derived from existing studies and focused on the provider perspective, but included the direct costs of net purchases by users, and are reported in 2005 USD. Effectiveness was estimated by combining programme outputs with standard impact indicators. FINDINGS: Conventional ITNs: The cost per treated net-year of protection ranged from USD 1.21 in Eritrea to USD 6.05 in Senegal. The cost per child death averted ranged from USD 438 to USD 2,199 when targeting to children was successful.Long-lasting insecticidal nets (LLIN) of five years duration: The cost per treated-net year of protection ranged from USD 1.38 in Eritrea to USD 1.90 in Togo. The cost per child death averted ranged from USD 502 to USD 692.IRS: The costs per person-year of protection for all ages were USD 3.27 in KwaZulu Natal and USD 3.90 in Mozambique. If only children under five years of age were included in the denominator the cost per person-year of protection was higher: USD 23.96 and USD 21.63. As a result, the cost per child death averted was higher than for ITNs: USD 3,933-4,357. CONCLUSION: Both ITNs and IRS are highly cost-effective vector control strategies. Integrated ITN free distribution campaigns appeared to be the most efficient way to rapidly increase ITN coverage. Other approaches were as or more cost-effective, and appeared better suited to "keep-up" coverage levels. ITNs are more cost-effective than IRS for highly endemic settings, especially if high ITN coverage can be achieved with some demographic targeting
Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.
Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top-selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. However, the mechanisms underlying the deleterious effects of these drugs on auditory cells remain to be fully characterized. In this study, we report cellular, genomic, and proteomic experiments revealing that cytotoxicity by APAP and NAPQI involves two different pathways in Immortomouse-derived HEI-OC1 cells, implicating ROS overproduction, alterations in ER morphology, redistribution of intra-cisternal chaperones, activation of the eIF2α-CHOP pathway, as well as changes in ER stress and protein folding response markers. Thus, both oxidative and ER stress are part of the cellular and molecular mechanisms that contribute to the cytotoxic effects of APAP and NAPQI in these cells. We suggest that these in vitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system