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Over the past decades, atomic force microscopy (AFM) has emerged as an increasingly powerful tool to study the dynamics of biomolecules at nanometer length scales. However, the more stochastic the nature of such biomolecular dynamics, the harder it becomes to distinguish them from AFM measurement noise. Rapid, stochastic dynamics are inherent to biological systems comprising intrinsically disordered proteins. One role of such proteins is in the formation of the transport barrier of the nuclear pore complex (NPC): the selective gateway for macromolecular traffic entering or exiting the nucleus. Here, we use AFM to observe the dynamics of intrinsically disordered proteins from two systems: the transport barrier of native NPCs and the transport barrier of a mimetic NPC made using a DNA origami scaffold. Analyzing data recorded with 50–200 ms temporal resolution, we highlight the importance of drift correction and appropriate baseline measurements in such experiments. In addition, we describe an autocorrelation analysis to quantify time scales of observed dynamics and to assess their veracity—an analysis protocol that lends itself to the quantification of stochastic fluctuations in other biomolecular systems. The results reveal the surprisingly slow rate of stochastic, collective transitions inside mimetic NPCs, highlighting the importance of FG-nup cohesive interactions.

..... Dear Dave: My wife and I are big fans of tic-tac-toe, and we try to play it whenever we're not too tired after work. The problem is, whenever she [...]

33 Voices de la Luna 2024commute D Ellis Phelps along this roadway — once a huge limestone plateau exploded now in pathetic piles— yellow cranes stretch metal necks cell phone towers spike the sky concrete heats the streets cars crawl in long lines — spit and hiss poison wild grass white & dry rises— her thirst an audible call creosote telephone poles soldier the shoulder barbed wire stands guard in every yard privacy fencing each greedy claim dividing the plains [Extracted from the article]

Nuclear pore complexes (NPCs) form gateways that control molecular exchange between the nucleus and the cytoplasm. They impose a diffusion barrier to macromolecules and enable the selective transport of nuclear transport receptors with bound cargo. The underlying mechanisms that establish these permeability properties remain to be fully elucidated but require unstructured nuclear pore proteins rich in Phe-Gly (FG)-repeat domains of different types, such as FxFG and GLFG. While physical modeling and in vitroapproaches have provided a framework for explaining how the FG network contributes to the barrier and transport properties of the NPC, it remains unknown whether the number and/or the spatial positioning of different FG-domains along a cylindrical, ∼40 nm diameter transport channel contributes to their collective properties and function. To begin to answer these questions, we have used DNA origami to build a cylinder that mimics the dimensions of the central transport channel and can house a specified number of FG-domains at specific positions with easily tunable design parameters, such as grafting density and topology. We find the overall morphology of the FG-domain assemblies to be dependent on their chemical composition, determined by the type and density of FG-repeat, and on their architectural confinement provided by the DNA cylinder, largely consistent with here presented molecular dynamics simulations based on a coarse-grained polymer model. In addition, high-speed atomic force microscopy reveals local and reversible FG-domain condensation that transiently occludes the lumen of the DNA central channel mimics, suggestive of how the NPC might establish its permeability properties.

The poem "in the beginning " by d. ellis phelps is presented. First Line: now is the time to begin the beginning ; Last Line: to be the silence in which we begin .

This article is based on a lecture I was originally invited to deliver at Aberystwyth in the University of Wales in honour of the late Sir Thomas Parry-Williams (one of my earliest University teachers) and to do so on a topic which, I feel sure, would have met with his approval. He had himself studied with several of the most renowned and gifted scholars of the early part of this century, Edward Anwyl at Aberystwyth, John Rhys at Oxford, Rudolf Thurneysen at Freiburg im Breisgau, and Joseph Loth and Joseph Vendryes at the Sorbonne in Paris. He was one of the great scholarly and cultural heroes of my boyhood days and of my youth, a truly renowned scholar, literary figure and critic. His teaching days in the Department of Welsh at the University College of Wales at Aberystwyth spanned five decades, from 1914 to 1952 (he held the Chair of Welsh there with great distinction from 1920 to 1952). I treasure the memory of having been a member of a large post-war first year undergraduate class in his Department as long ago as 1947.

Presents the short story "Mom, Having Died," by D. Ellis Dickerson.

In this study we quantify small hive beetle (Aethina tumida Murray) and Cape honeybee (A.m. capensis Esch., an African subspecies) behaviours that are associated with beetle confinement in an effort to understand why Cape bees can withstand large beetle infestations. Four observation hives were each inoculated with 25 beetles and were observed for 11–17 days. Data collected included guard bee (worker bees who guard beetle confinement sites) and confined beetle behaviour. There was considerable colony variation for many bee and beetle behaviours. Overall, there were more beetle guards during evening, which was likely an effort to keep increasingly active beetles contained. About one-fifth of the beetles were found at the comb periphery although the colonies suffered no ill effects. Although beetles reached the combs, the bees were able to prevent beetle reproduction. Our data suggest that confinement is more likely an initial defence against invading beetles and not the sole reason African subspecies of honeybees are usually immune to beetle infestations while European bees are not.

Presents the short story "Postcretaceous Era," by D. Ellis Dickerson.

Tumor-selective delivery of doxorubicin by a prostate-specific antigen (PSA)-targeted peptide conjugate prodrug of doxorubicin was demonstrated in a nude mouse xenograft model of human prostate cancer. The prodrug (referred to as doxorubicin conjugate) contains doxorubicin linked to a seven-amino acid peptide conjugate that was designed to increase delivery of doxorubicin to tumor sites through the hydrolytic properties of PSA, which prostate tumors express in high amounts. Following i.p. administration of the doxorubicin conjugate to mice, tumor exposure to doxorubicin was increased 2.5-fold as compared with that achieved after an equimolar dose of doxorubicin itself. However, in heart tissue, the site of clinical dose-limiting toxicity, doxorubicin concentrations observed after administration of doxorubicin conjugate were substantially lower than those in mice that received doxorubicin itself. While the prodrug provided selective delivery of doxorubicin to tumor tissue, there was substantial non-PSA-specific formation of doxorubicin in laboratory animals, a factor that would limit the extent of therapeutic gain of the prodrug. Following i.v. administration to mice, rats, dogs, and monkeys, about one-third of the dose was metabolized to doxorubicin. In tumor-bearing mice, the fraction of the dose metabolized to doxorubicin appeared even higher. This is likely the result of conjugate conversion to doxorubicin by both PSA-specific (in tumor) and non-PSA-specific proteolytic activities. In vitro studies provided further support for the PSA specificity of metabolism; LNCaP cells mediated rapid metabolism of the conjugate, while DuPRO-1 cells, which are deficient in PSA, were incapable of metabolism.

BACKGROUND: Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath. AIMS: To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy. METHODS: Eighty three patients with retained bile duct stones were treated. All patients received intravenous benzodiazepine sedation and pethidine analgesia. Stones were targeted by fluoroscopy following injection of contrast via a nasobiliary drain or T tube. Residual fragments were cleared at endoscopic retrograde cholangiopancreatography. RESULTS: Complete stone clearance was achieved in 69 (83%) patients and in 18 of 24 patients (75%) who required more than one ESWL treatment. Stone clearance was achieved in all nine patients (100%) with intrahepatic stones and also in nine patients (100%) referred following surgical exploration of the bile duct. Complications included six cases of cholangitis and one perinephric haematoma which resolved spontaneously. CONCLUSION: Using the Storz Modulith, 83% of refractory bile duct calculi were cleared with a low rate of complications. These results confirm that ESWL is an excellent alternative to surgery in those patients in whom endoscopic techniques have failed.

The absorption and disposition of rizatriptan (MK-0462, Maxalt(TM)), a selective 5-HT(1B/1D) receptor agonist used in the treatment of migraine headaches, was investigated in humans. In a two-period, single i.v. (3 mg, 30-min infusion), and single oral (10 mg) dose study with [(14)C]rizatriptan in six healthy human males, total recovery of radioactivity was approximately 94%, with unchanged rizatriptan and its metabolites being excreted mainly in the urine (89% i.v. dose, 82% p.o. dose). Approximately 26 and 14% of i.v. and oral rizatriptan doses, respectively, were excreted in urine as intact parent drug. In a second, high-dose study (60 mg p.o.), five metabolites excreted into urine were identified using liquid chromatography-tandem mass spectrometry and NMR methods. They were triazolomethyl-indole-3-acetic acid, rizatriptan-N(10)-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate, and N(10)-monodesmethyl-rizatriptan. Urinary excretion of triazolomethyl-indole-3-acetic acid after i.v. and oral administrations of rizatriptan accounted for 35 and 51% of the dose, respectively, whereas the corresponding values for rizatriptan-N(10)-oxide were 4 and 2% of the dose. Plasma clearance (CL) and renal clearance (CL(r)) were 1325 and 349 ml/min, respectively, after i.v. administration. A similar CL(r) value was obtained after oral administration (396 ml/min). The primary route of rizatriptan elimination occurred via nonrenal route(s) (i.e., metabolism) because the CL(r) of rizatriptan accounted for 25% of total CL. Furthermore, the CL(r) was higher than normal glomerular filtration rate ( approximately 130 ml/min), indicating that this compound was actively secreted by renal tubules. The absorption of rizatriptan was approximately 90%, but it experienced a moderate first-pass effect, resulting in a bioavailability estimate of 47%.

Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either (3)H-label incorporated into the phenyl ring of the tyrosinyl residue or (14)C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [(14)C]tirofiban. However, male rat liver microsomes converted a limited amount of the substrate to a more polar metabolite (I) and a relatively less polar metabolite (II). The formation of I was sex dependent and resulted from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was identified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridine-5'-diphospho-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [(14)C]tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 73%, respectively. Metabolite I and unchanged tirofiban represented 70 and 30% of the urinary radioactivity, respectively. Tirofiban represented >90% of the biliary radioactivity. At least three minor biliary metabolites represented the remainder of the radioactivity. One of them was identified as I. Another was identified as II. When dogs received 1 mg/kg i.v. of [(3)H]tirofiban, most of the radioactivity was recovered in the feces as unchanged tirofiban. The plasma half-life of tirofiban was short in both rats and dogs, and tirofiban was not concentrated in tissues other than those of the vasculature and excretory organs.

The poem "seam of unrest" by D. Ellis Phelps is presented. First Line: does this soil mourn your words; Last Line: but what lives: verdant coil unending urn.

The poem "heaven scent" by d. ellis phelps is presented. First Line: i love the scent. Last Line: children dance.

The poem "a kind of reverence" by D. Ellis Phelps is presented. First Line: his head stuck between her hind quarters the calf suckles; Last Line: for days.

The poem "Rest these lovers" by D. Ellis Phelps is presented. First Line: above my head; Last Line: ——will rise again.

(without abstract)

The use of electrolyte additives to form a passive solid-electrolyte interphase (SEI) at one or both electrodes is a common method for improving lithium-ion cell lifetime and performance. This work follows the chemical and electrochemical processes involved in SEI formation on graphite electrodes for two Lewis acid-base adducts, pyridine boron trifluoride (PBF) and pyridine phosphorus pentafluoride (PPF). The combination of experimental methods (electrochemistry, in situ volumetric measurements, gas chromatography, isothermal microcalorimetry, and X-ray photoelectron spectroscopy) with quantum chemistry models (density functional theory) provides new insight into the interfacial chemistry. PBF and PPF are reduced at ∼1.3 V vs. Li/Li+and ∼1.4 V, respectively. This is followed by radical coupling to form 4,4′-bipyridine adducts, hydrogen transfer to ethylene carbonate solvent molecules, and reduction of the solvent to produce lithium ethyl carbonate. The reduced bipyridine adducts, Li2(PBF)2and Li2(PPF)2, are shown to compose part of the SEI at the negative electrode surface.

The first examples of rhenacarborane complexes with nitrosyl ligands have been prepared and used to synthesise alkylidene(nitrosyl)rhenacarboranes and a novel complex in which a conjoined carboranyl–iminium group is bound to rhenium both through the η5-C2B3 face of the cage and the iminium carbon atom.

Introduction. We analyzed the ability of four balance assessments to predict falls in people with Parkinson Disease (PD) prospectively over six and 12 months. Materials and Methods. The BESTest, Mini-BESTest, Functional Gait Assessment (FGA), and Berg Balance Scale (BBS) were administered to 80 participants with idiopathic PD at baseline. Falls were then tracked for 12 months. Ability of each test to predict falls at six and 12 months was assessed using ROC curves and likelihood ratios (LR). Results. Twenty-seven percent of the sample had fallen at six months, and 32% of the sample had fallen at 12 months. At six months, areas under the ROC curve (AUC) for the tests ranged from 0.8 (FGA) to 0.89 (BESTest) with LR+ of 3.4 (FGA) to 5.8 (BESTest). At 12 months, AUCs ranged from 0.68 (BESTest, BBS) to 0.77 (Mini-BESTest) with LR+ of 1.8 (BESTest) to 2.4 (BBS, FGA). Discussion. The various balance tests were effective in predicting falls at six months. All tests were relatively ineffective at 12 months. Conclusion. This pilot study suggests that people with PD should be assessed biannually for fall risk.

We report detailed investigations of the face processing abilities of four patients who had shown symptoms involving delusional misidentification. One (GC) was diagnosed as a Frégoli case, and the other three (SL, GS, and JS) by symptoms of intermetamorphosis. The face processing tasks examined their ability to recognize emotional facial expressions, identify familiar faces, match photographs of unfamiliar faces, and remember photographs of faces of unfamiliar people. The Frégoli patient (GC) was impaired at identifying familiar faces, and severely impaired at matching photographs of unfamiliar people wearing different disguises to undisguised views. Two of the intermetamorphosis patients (SL and GS) also showed impaired face processing abilities, but the third US) performed all tests at a normal level. These findings constrain conceptions of the relation between delusional misidentification, face processing impairment, and brain injury.

An experiment is reported where subjects were presented with familiar or unfamiliar faces for supraliminal durations or for durations individually assessed as being below the threshold for recognition. Their electrodermal responses to each stimulus were measured and the results showed higher peak amplitude skin conductance responses for familiar than for unfamiliar faces, regardless of whether they had been displayed supraliminally or subliminally. A parallel is drawn between elevated skin conductance responses to subliminal stimuli and findings of covert recognition of familiar faces in prosopagnosic patients, some of whom show increased electrodermal activity (EDA) to previously familiar faces. The supraliminal presentation data also served to replicate similar work by Tranel et al (1985). The results are considered alongside other data indicating the relation between non-conscious, “automatic” aspects of normal visual information processing and abilities which can be found to be preserved without awareness after brain injury.

Investigation of P.T., a man who experienced reduplicative delusions, revealed significant impairments on tests of recognition memory for faces and understanding of emotional facial expressions. On formal tests of his recognition abilities, P.T. showed reduplication to familiar faces, buildings, and written names, but not to familiar voices. Reduplication may therefore have been a genuinely visual problem in P.T.'s case, since it was not found to auditory stimuli. This is consistent with hypotheses which propose that the basis of reduplication can lie in part in malfunction of the visual system.