Differential regulation of bladder pain and voiding function by sensory afferent populations revealed by selective optogenetic activation

Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function in vivo via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons (Trpv1Cre;Ai32, the majority of nociceptors) and Nav1.8+ neurons (Scn10aCre;Ai32, nociceptors and some mechanosensitive fibers). In spinal cord, eYFP+ fibers in Trpv1Cre;Ai32 mice were observed predominantly in dorsal horn (DH) laminae I-II, while in Scn10aCre;Ai32 mice they extended throughout the DH, including a dense projection to lamina X. Fiber density correlated with number of retrogradely-labeled eYFP+ dorsal root ganglion neurons (82.2% Scn10aCre;Ai32 vs. 62% Trpv1Cre;Ai32) and degree of DH excitatory synaptic transmission. Photostimulation of peripheral afferent terminals significantly increased visceromotor responses to noxious bladder distension (30–50 mmHg) in both transgenic lines, and to non-noxious distension (20 mmHg) in Scn10aCre;Ai32 mice. Depolarization of ChR2+ afferents in Scn10aCre;Ai32 mice produced low- and high-amplitude bladder contractions respectively in 53% and 27% of stimulation trials, and frequency of high-amplitude contractions increased to 60% after engagement of low threshold (LT) mechanoreceptors by bladder filling. In Trpv1Cre;Ai32 mice, low-amplitude contractions occurred in 27% of trials before bladder filling, which was pre-requisite for light-evoked high-amplitude contractions (observed in 53.3% of trials). Potential explanations for these observations include physiological differences in the thresholds of stimulated fibers and their connectivity to spinal circuits

Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection

Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection

Spectral Models for Early Time SN 2011fe Observations

We use observed UV through near IR spectra to examine whether SN 2011fe can be understood in the framework of Branch-normal SNe Ia and to examine its individual peculiarities. As a benchmark, we use a delayed-detonation model with a progenitor metallicity of Z_solar/20. We study the sensitivity of features to variations in progenitor metallicity, the outer density profile, and the distribution of radioactive nickel. The effect of metallicity variations in the progenitor have a relatively small effect on the synthetic spectra. We also find that the abundance stratification of SN 2011fe resembles closely that of a delayed detonation model with a transition density that has been fit to other Branch-normal Type Ia supernovae. At early times, the model photosphere is formed in material with velocities that are too high, indicating that the photosphere recedes too slowly or that SN 2011fe has a lower specific energy in the outer ~0.1 M_sun than does the model. We discuss several explanations for the discrepancies. Finally, we examine variations in both the spectral energy distribution and in the colors due to variations in the progenitor metallicity, which suggests that colors are only weak indicators for the progenitor metallicity, in the particular explosion model that we have studied. We do find that the flux in the U band is significantly higher at maximum light in the solar metallicity model than in the lower metallicity model and the lower metallicity model much better matches the observed spectrum.Comment: 9 pages, 14 figures, MNRAS, in press, fixed typ

Are Preserved Farms Actively Engaged in Agriculture and Conservation?

This study addresses the question of whether farms enrolled in land preservation programs are actively engaged in agricultural or conservation activities. Data are drawn from an original survey administered to preserved farm owners in the states of New Jersey, Maryland, and Delaware in 2011. “Actively engaged” is defined as investment in conservation projects, buildings, equipment, or irrigation since the land was preserved. Affirmative answers to the survey’s investment questions range from a low of 19% for irrigation to a high of 69% for equipment. Special attention was paid to differences between lifestyle farmers and small and large commercial farmers, which are classified using the USDA typology developed in 2000. Regression analysis estimates differences in investment behavior across these groups as well as farm tenure categories, controlling for farm size, program/state location, and demographic variables. Only owners who employ tenants or managers exclusively on their land were found to invest significantly less than the largest professional farmers, and they did so across all four types of investment. This study’s findings support preservation goals articulated by legislators and program administrators, because (1) agricultural and land stewardship investments appear to be widespread on preserved farms, partly due to administrators’ preference for larger parcels, (2) there is no evidence that “hobby farmers” are disproportionately attracted to farmland preservation programs – in fact the opposite seems to be true – while those that exist in our sample behave similarly to the largest commercial farmers, (3) although tenant farming is associated in the sample with lower rates of investment, it is less common on preserved farms than on all farms in the three study states. The matter of land tenure, highlighted in this as in other studies, has not yet become a primary focus of either farm-behavioral research or state agricultural policy

Tribute to Professor Joan Shaughnessy

A tribute to Professor Joan Shaughnessy, who served on the faculty of the Washington and Lee University School of Law from 1983 to 2022. A recognized scholar and teacher in areas of civil procedure, federal courts, evidence, family law, and poverty law, Shaun was appointed as W&L\u27s inaugural Roger D. Groot Professor of Law in 2012

Improving recruitment to clinical trials with a register of a million patients who agree to the use of their clinical records for research in the Scottish Health Research Register (SHARE)

The UK's technical ability to identify people eligible for medical research is not yet matched by a practical capability to approach them directly to ask them to consider participation in those studies. The consequence is that recruitment to research is more difficult than necessary and some projects fail. This makes Britain a less attractive location to undertake clinical research than it should be. In order to overcome this increasingly important obstacle, we wanted to develop a register of Scottish residents who wish to be considered for participation in a range of studies. This was an oral presentation given at the Clinical Trials Methodology conference 2011, 4-5 October 2011, Bristol, UK

Capillary Density of Skeletal Muscle: A Contributing Mechanism for Exercise Intolerance in Class II–III Chronic Heart Failure Independent of Other Peripheral Alterations

AbstractOBJECTIVESThe study was conducted to determine if the capillary density of skeletal muscle is a potential contributor to exercise intolerance in class II–III chronic heart failure (CHF).BACKGROUNDPrevious studies suggest that abnormalities in skeletal muscle histology, contractile protein content and enzymology contribute to exercise intolerance in CHF.METHODSThe present study examined skeletal muscle biopsies from 22 male patients with CHF compared with 10 age-matched normal male control patients. Aerobic capacities, myosin heavy chain (MHC) isoforms, enzymes, and capillary density were measured.RESULTSThe patients with CHF demonstrated a reduced peak oxygen consumption when compared to controls (15.0 ± 2.5 vs. 19.8 ± 5.0 ml·kg−1·min−1, p <0.05). Using cell-specific antibodies to directly assess vascular density, there was a reduction in capillary density in CHF measured as the number of endothelial cells/fiber (1.42 ± 0.28 vs. 1.74 ± 0.35, p = 0.02). In CHF, capillary density was inversely related to maximal oxygen consumption (r = 0.479, p = 0.02). The MHC IIx isoform was found to be higher in patients with CHF versus normal subjects (28.5 ± 13.6 vs. 19.5 ± 9.4, p <0.05).CONCLUSIONSThere was a significant reduction in microvascular density in patients with CHF compared with the control group, without major differences in other usual histologic and biochemical aerobic markers. The inverse relationship with peak oxygen consumption seen in the CHF group suggests that a reduction in microvascular density of skeletal muscle may precede other skeletal muscle alterations and play a critical role in the exercise intolerance characteristic of patients with CHF

Obtaining New Insights for Biodiversity Conservation from Broad-Scale Citizen Science Data

Increasing public engagement in volunteer science1, either through data collection2 or processing3, is both raising public awareness of science and gathering useful information for scientists. While the payoffs of citizen science4 are potentially large, achieving them requires new approaches to data management and analysis that can only result from strong cross-disciplinary collaborations. This is especially true in ecology and conservation biology, where historically the understanding of species&#x2019; responses to environmental change has been constrained by the limited spatial5 or temporal scale6 of available data. Here we describe collaborative research in ecology, computer science, and statistics to generate essential information for conservation management of North American birds: accurate dynamic bird distributions models based on habitat associations across much of North America. Unique is our ability to describe the broad-scale dynamics of seasonal bird distributions and the associated seasonal patterns of habitat use. Our source of bird distribution data is eBird7, an online bird checklist program that currently gathers more than 74,000 checklists monthly from a large network of contributors. Our results were made possible through a data intensive scientific workflow8 that includes analytical methods merged from the fields of machine learning and statistics. We believe that this novel approach of data collection, synthesis, analysis, and visualization will serve as a hallmark for future research initiatives, with broad applicability across many scientific domains