195 research outputs found
Extent and mechanism of sealing in transected giant axons of squid and earthworms
Transected axons are often assumed to seal at their cut
ends by the formation of continuous membrane barriers that
allow for the restoration of function in the axonal stumps.
We have used several electrophysiological measures (membrane
potential, input resistance, injury current density) and
several morphological measures (phase-contrast, video-enhanced
differential interference contrast, light, and electron
microscopies) of living and fixed material to assess the extent
and mechanism of sealing within hours after transecting
giant axons of squid (Loligo pealeiand Sepioteuthis lessoniana)
and earthworms (Lumbricus terrestris). Our electrophysiological
data suggest that the proximal and distal ends
of transected squid giant axons do not completely seal within
2.5 hr in physiological saline. In contrast, the same set of
measures suggest that proximal and distal ends of transected
earthworm giant axons seal within 1 hr in physiological
saline. Our morphological data show that the cut ends
of both squid and earthworm axons constrict, but that a 20-
70-am-diameter opening always remains at the cut end that
is filled with vesicles. Axonal transection induces the formation
of vesicles that are observed in the axoplasm within
minutes in standard salines and that rapidly migrate to the
cut ends. These injury-induced vesicles are loosely packed
near the cut ends of squid giant axons, which do not functionally
seal within 2.5 hr of transection. In contrast, vesicles
formed a tightly packed plug at the cut ends of earthworm
medial giant axons, which do functionally seal within 1 hr of
transection in physiological saline. Since we detect no single
continuous membrane that spans the cut end, sealing does
not appear to occur by the fusion of constricted axolemmal
membrane or the formation of a membranous partition at the
cut end. Rather, our data are consistent with the hypothesis
that a tightly packed vesicular plug is responsible for sealing
of earthworm giant axons.This work was supported in part by NIH Grant NS31256 and ONR Grant N00014-90-J-1137 to H.M.F., an NIAAA fellowship to T.L.K., and an ATP grant to G.D.B.Neuroscienc
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Endocytotic formation of vesicles and other membranous structures induced by Ca2+ and axolemmal injury
Vesicles and/or other membranous structures that form after
axolemmal damage have recently been shown to repair (seal)
the axolemma of various nerve axons. To determine the origin
of such membranous structures, (1) we internally dialyzed isolated
intact squid giant axons (GAs) and showed that elevation
of intracellular Ca21 .100 uM produced membranous structures
similar to those in axons transected in Ca21-containing
physiological saline; (2) we exposed GA axoplasm to Ca21-
containing salines and observed that membranous structures
did not form after removing the axolemma and glial sheath but
did form in severed GAs after .99% of their axoplasm was
removed by internal perfusion; (3) we examined transected GAs
and crayfish medial giant axons (MGAs) with time-lapse confocal
fluorescence microscopy and showed that many injuryinduced
vesicles formed by endocytosis of the axolemma; (4)
we examined the cut ends of GAs and MGAs with electron
microscopy and showed that most membranous structures
were single-walled at short (5–15 min) post-transection times,
whereas more were double- and multi-walled and of probable
glial origin after longer (30–150 min) post-transection times; and
(5) we examined differential interference contrast and confocal
images and showed that large and small lesions evoked similar
injury responses in which barriers to dye diffusion formed amid
an accumulation of vesicles and other membranous structures.
These and other data suggest that Ca21 inflow at large or small
axolemmal lesions induces various membranous structures (including
endocytotic vesicles) of glial or axonal origin to form,
accumulate, and interact with each other, preformed vesicles,
and/or the axolemma to repair the axolemmal damage.This work was supported by grants from National Institutes of Health (NIH;
NS31256) and the State of Texas (Advanced Technology 3658-446).Neuroscienc
In Situ Probes of the First Galaxies and Reionization: Gamma-ray Bursts
The first structures in the Universe formed at z>7, at higher redshift than
all currently known galaxies. Since GRBs are brighter than other cosmological
sources at high redshift and exhibit simple power-law afterglow spectra that is
ideal for absorption studies, they serve as powerful tools for studying the
early universe. New facilities planned for the coming decade will be able to
obtain a large sample of high-redshift GRBs. Such a sample would constrain the
nature of the first stars, galaxies, and the reionization history of the
Universe.Comment: 8 pages, 3 figures, science white paper submitted to the US Astro2010
Decadal Surve
Using Simulations as a Starting Point for Constructing Meaningful Learning Games
For many school administrators and decision makers, the term “video games” holds numerous cultural associations which make their adoption in the education space challenging. Additionally, the term is so broad that it can sometimes be difficult to communicate explicitly a desire to build learning experiences that go beyond the Drill and Kill edutainment titles that currently dominate most people’s perceptions of educational games. By contrast, the term “simulations” is often well respected among educators, particularly in the natural sciences. With “simulation” already being a full genre of video games, it would seem natural that researchers are beginning to explore the overlaps between simulation games and pedagogical goals that go beyond those found in Drill and Kill games. In this chapter, we survey some of the relevant research concerning both simulations and video games and outline practical pathways through which we can leverage the interest and frameworks designed for simulation construction to facilitate the introduction of video game concepts and experiences into the classroom environment. In particular, we report on the use of Starlogo TNG, a graphical programming environment in which kids themselves can create simulation-based video games, for deepening children’s understanding of scientific concepts
The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy
Patients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy
Biomarkers of Nutrition for Development (BOND)—Iron Review
This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health. The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation
Assessing the feasibility of adaptation options: methodological advancements and directions for climate adaptation research and practice
The Paris Agreement put adaptation prominently on the global climate action agenda. Despite a surge in research and praxis-based knowledge on adaptation, a critical policy roadblock is synthesizing and assessing this burgeoning evidence. We develop an approach to assess the multidimensional feasibility of adaptation options in a robust and transparent manner, providing direction for global climate policy and identifying knowledge gaps to further future climate research. The approach, which was tested in the IPCC Special Report on 1.5 °C (SR1.5) to assess 23 adaptation options, is underpinned by a systematic review of recent literature, expert elicitation, and iterative peer review. It responds to the challenge of limited agreement on adaptation indicators, lack of fine-scale adaptation data, and challenges of assessing synergies and trade-offs with mitigation. The findings offer methodological insights into how future assessments such as the IPCC Assessment Report (AR) six and regional, national, and sectoral assessment exercises could assess adaptation feasibility and synthesize the growing body of knowledge on climate change adaptation
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.
Abstract
BACKGROUND:
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.
METHODS:
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.
RESULTS:
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.
CONCLUSIONS:
Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)
Direct and Rapid Description of the Individual Ionic Currents of Squid Axon Membrane by Ramp Potential Control
Computations based upon the Hodgkin-Huxley equations and experimental data from squid axons show that ramp functions can be used as commands to a voltage clamp system to selectively observe either the fast (sodium) or slow (potassium) process in axon membranes without chemical separation techniques or computer assistance. Each process is characterized directly (on line) and rapidly (real time) by generating a current-potential curve on an oscilloscope for fast or slow rates of change of membrane potential (ramps). The speed and directness of this method of characterizing each of the essential axonal events permit quantitative measurement of the kinetics of rapid effects on these processes due to various pharmacological agents such as tetrodotoxin and tetraethylammonium ion or other experimental changes in the membrane environment
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