Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers.

INTRODUCTION: Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies. METHODS: Nuclear invagination was assayed by immunofluorescence in the brain, and in cultured neurons before and after extracellular tau oligomer (xcTauO) exposure. Nucleocytoplasmic transport was assayed in cultured neurons. Gene expression was investigated using nanoString nCounter technology and quantitative reverse transcription polymerase chain reaction. RESULTS: Invaginated nuclei were twice as abundant in human AD as in cognitively normal adults, and were increased in mouse neurodegeneration models. In cultured neurons, nuclear invagination was induced by xcTauOs by an intracellular tau-dependent mechanism. xcTauOs impaired nucleocytoplasmic transport, increased histone H3 trimethylation at lysine 9, and altered gene expression, especially by increasing tau mRNA. DISCUSSION: xcTauOs may be a primary cause of nuclear invagination in vivo, and by extension, impair nucleocytoplasmic transport and induce pathogenic gene expression changes. HIGHLIGHTS: Extracellular tau oligomers (xcTauOs) cause neuronal nuclei to invaginate. xcTauOs alter nucleocytoplasmic transport, chromatin structure, and gene expression. The most upregulated gene is MAPT, which encodes tau. xcTauOs may thus drive a positive feedback loop for production of toxic tau.

Effect of Anionic Lipids on Mammalian Plasma Cell Membrane Properties.

The effect of lipid composition on models of the inner leaflet of mammalian cell membranes has been investigated. Grazing incidence X-ray diffraction and X-ray and neutron reflectivity have been used to characterize lipid packing and solvation, while electrochemical and infrared spectroscopic methods have been employed to probe phase behavior in an applied electric field. Introducing a small quantity of the anionic lipid dimyristoylphosphatidylserine (DMPS) into bilayers of zwitterionic dimyristoylphosphatidylethanolamine (DMPE) results in a significant change in the bilayer response to an applied field: the tilt of the hydrocarbon chains increases before returning to the original tilt angle on detachment of the bilayer. Equimolar mixtures, with slightly closer chain packing, exhibit a similar but weaker response. The latter also tend to incorporate more solvent during this electrochemical phase transition, at levels similar to those of pure DMPS. Reflectivity measurements reveal greater solvation of lipid layers for DMPS > 30 mol %, matching the greater propensity for DMPS-rich bilayers to incorporate water. Taken together, the data indicate that the range of 10-35 mol % DMPS provides optimum bilayer properties (in flexibility and function as a barrier), which may explain why the DMPS content of cell membranes tends to be found within this range.

One size does not fit all: diversity of length-force properties of obliquely striated muscles.

Obliquely striated muscles occur in 17+ phyla, likely evolving repeatedly, yet the implications of oblique striation for muscle function are unknown. Contrary to the belief that oblique striation allows high force output over extraordinary length ranges (i.e. superelongation), recent work suggests diversity in operating length ranges and length-force relationships. We hypothesize oblique striation evolved to increase length-force relationship flexibility. We predict that superelongation is not a general characteristic of obliquely striated muscles and instead that length-force relationships vary with operating length range. To test these predictions, we measured length-force relationships of five obliquely striated muscles from inshore longfin squid, Doryteuthis pealeii: tentacle, funnel retractor and head retractor longitudinal fibers, and arm and fin transverse fibers. Consistent with superelongation, the tentacle length-force relationship had a long descending limb, whereas all others exhibited limited descending limbs. The ascending limb at 0.6P0 was significantly broader (P<0.001) for the tentacle length-force relationship (0.43±0.04L0; where L0 is the preparation length that produced peak isometric stress, P0) than for the arm (0.29±0.03L0), head retractor (0.24±0.06L0), fin (0.20±0.04L0) and funnel retractor (0.27±0.03L0). The fin's narrow ascending limb differed significantly from those of the arm (P=0.004) and funnel retractor (P=0.012). We further characterized the tentacle preparation's maximum isometric stress (315±78 kPa), maximum unloaded shortening velocity (2.97±0.55L0 s-1) and ultrastructural traits (compared with the arm), which may explain its broader length-force relationship. Comparison of obliquely striated muscles across taxa revealed length-force relationship diversity, with only two species exhibiting superelongation.

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

Vectored jets power arms-first and tail-first turns differently in brief squid with assistance from fins and keeled arms.

Squids maneuver to capture prey, elude predators, navigate complex habitats and deny rivals access to mates. Despite the ecological importance of this essential locomotive function, limited quantitative data on turning performance and wake dynamics of squids are available. To better understand the contribution of the jet, fins and arms to turns, the role of orientation (i.e. arms first versus tail first) in maneuvering, and the relationship between jet flow and turning performance, kinematic and 3D velocimetry data were collected in tandem from brief squid, Lolliguncula brevis. The pulsed jet, which can be vectored to direct flows, was the primary driver of most turning behaviors, producing flows with the highest impulse magnitude and angular impulse about the main axis of the turn (yaw) and secondary axes (roll and pitch). The fins and keeled arms played subordinate but important roles in turning performance, contributing to angular impulse, stabilizing the maneuver along multiple axes and/or reducing rotational resistance. Orientation affected turning performance and dynamics, with tail-first turns being associated with greater impulse and angular impulse, longer jet structures, higher jet velocities and greater angular turning velocities than arms-first turns. Conversely, arms-first turns involved shorter, slower jets with less impulse, but these directed short pulses resulted in lower minimum length-specific turning radii. Although the length-to-diameter ratio (L/D) of ejected jet flow was a useful metric for characterizing vortical flow features, it, by itself, was not a reliable predictor of angular velocity or turning radii, which reflects the complexity of the squid multi-propulsor system.

SARS-CoV-2 Incidence in K-12 School Districts with Mask-Required Versus Mask-Optional Policies - Arkansas, August-October 2021.

Masks are effective at limiting transmission of SARS-CoV-2, the virus that causes COVID-19 (1), but the impact of policies requiring masks in school settings has not been widely evaluated (2-4). During fall 2021, some school districts in Arkansas implemented policies requiring masks for students in kindergarten through grade 12 (K-12). To identify any association between mask policies and COVID-19 incidence, weekly school-associated COVID-19 incidence in school districts with full or partial mask requirements was compared with incidence in districts without mask requirements during August 23-October 16, 2021. Three analyses were performed: 1) incidence rate ratios (IRRs) were calculated comparing districts with full mask requirements (universal mask requirement for all students and staff members) or partial mask requirements (e.g., masks required in certain settings, among certain populations, or if specific criteria could not be met) with school districts with no mask requirement; 2) ratios of observed-to-expected numbers of cases, by district were calculated; and 3) incidence in districts that switched from no mask requirement to any mask requirement were compared before and after implementation of the mask policy. Mean weekly district-level attack rates were 92-359 per 100,000 persons in the community* and 137-745 per 100,000 among students and staff members; mean student and staff member vaccination coverage ranged from 13.5% to 18.6%. Multivariable adjusted IRRs, which included adjustment for vaccination coverage, indicated that districts with full mask requirements had 23% lower COVID-19 incidence among students and staff members compared with school districts with no mask requirements. Observed-to-expected ratios for full and partial mask policies were lower than ratios for districts with no mask policy but were slightly higher for districts with partial policies than for those with full mask policies. Among districts that switched from no mask requirement to any mask requirement (full or partial), incidence among students and staff members decreased by 479.7 per 100,000 (p<0.01) upon implementation of the mask policy. In areas with high COVID-19 community levels, masks are an important part of a multicomponent prevention strategy in K-12 settings (5).

Inequities in Telehealth Use Associated with Payer Type During the COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has prompted a shift in health care delivery and compelled a heavier reliance on telehealth. The objective of this study was to determine if differences in coverage policies by payer type resulted in differential telehealth use during the first 3 months of the COVID-19 pandemic. In this population-based cohort study of low-income Arkansans, Medicaid beneficiaries enrolled in the traditional Primary Care Case Management (PCCM) program were compared with Medicaid beneficiaries covered through premium assistance in private Qualified Health Plans (QHPs). Methods: A retrospective review was conducted of insurance claims records from June 1, 2019, to June 30, 2020, for synchronous telehealth and mobile health (m-health) visits, as well as other forms of telehealth. To establish the baseline equivalence of enrollees in the two groups, propensity score matching design was used on demographic and geographic characteristics, Charlson Comorbidity Index, broadband availability, and prior service utilization. Results: Compared with enrollees in the PCCM program, Medicaid expansion enrollees in QHPs had higher odds of having had at least one telehealth visit (adjusted odds ratio [aOR] = 1.35, 95% confidence interval [CI]: 1.29-1.42) during the early phase of the COVID-19 pandemic. Categorizing utilizations by domain, QHP enrollees were more likely to use synchronous telehealth (aOR = 1.31; 95% CI: 1.25-1.37) and m-health (aOR = 5.91; 95% CI: 4.25-8.21). A higher proportion of QHP enrollees also had at least one mental or behavioral health telehealth session (aOR = 1.13; 95% CI: 1.07-1.19). Conclusions: Our study demonstrated that within low-income populations, payer type was associated with inequitable access to telehealth during the early phase of the COVID-19 pandemic.

A compact instrument for gamma-ray burst detection on a CubeSat platform II: Detailed design, assembly and validation.

The Gamma-ray Module, GMOD, is a miniaturised novel gamma-ray detector which will be the primary scientific payload on the Educational Irish Research Satellite (EIRSAT-1) 2U CubeSat mission. GMOD comprises a compact (25 mm × 25 mm × 40 mm) cerium bromide scintillator coupled to a tiled array of 4 × 4 silicon photomultipliers, with front-end readout provided by the IDE3380 SIPHRA. This paper presents the detailed GMOD design and the accommodation of the instrument within the restrictive CubeSat form factor. The electronic and mechanical interfaces are compatible with many off-the-shelf CubeSat systems and structures. The energy response of the GMOD engineering qualification model has been determined using radioactive sources, and an energy resolution of 5.4% at 662 keV has been measured. EIRSAT-1 will perform on-board processing of GMOD data. Trigger results, including light-curves and spectra, will be incorporated into the spacecraft beacon and transmitted continuously. Inexpensive hardware can be used to decode the beacon signal, making the data accessible to a wide community. GMOD will have scientific capability for the detection of gamma-ray bursts, in addition to the educational and technology demonstration goals of the EIRSAT-1 mission. The detailed design and measurements to date demonstrate the capability of GMOD in low Earth orbit, the scalability of the design for larger CubeSats and as an element of future large gamma-ray missions.

Enrollee Experience with Providers in the Arkansas Medicaid Expansion Program.

BACKGROUND: Patient ratings of their healthcare experience as a quality measure have become critically important since the implementation of the Affordable Care Act (ACA). The ACA enabled states to expand Medicaid eligibility to reduce uninsurance nationally. Arkansas gained approval to use Medicaid funds to purchase a qualified health plan (QHP) through the ACA marketplace for newly eligible beneficiaries. OBJECTIVE: We compare patient-reported satisfaction between fee-for-service Medicaid and QHP participants. DESIGN: The Consumer Assessment of Healthcare Providers and Systems (CAHPS) was used to identify differences in Medicaid and QHP enrollee healthcare experiences. Data were analyzed using a regression discontinuity design. PARTICIPANTS: Newly eligible Medicaid expansion participants enrolled in Medicaid during 2013 completed the Consumer Assessment of Health Providers and Systems (CAHPS) survey in 2014. Survey data was analyzed for 3156 participants (n = 1759 QHP/1397 Medicaid). MEASURES: Measures included rating of personal and specialist provider, rating of all healthcare received, and whether the provider offered to communicate electronically. Demographic and clinical characteristics of the enrollees were controlled for in the analyses. METHODS: Regression-discontinuity analysis was used to evaluate differential program effects on positive ratings as measured by the CAHPS survey while controlling for demographic and health characteristics of participants. KEY RESULTS: Adjusted logistic regression models for overall healthcare (OR = 0.71, 95%CI = 0.56-0.90, p = 0.004) and personal doctor (OR = 0.68, 95%CI = 0.53-0.87, p = 0.002) predicted greater satisfaction among QHP versus Medicaid participants. Results were not significant for specialists or for use of electronic communication with provider. CONCLUSIONS: Using a quasi-experimental statistical approach, we were able to control for observed and unobserved heterogeneity showing that among participants with similar characteristics, including income, QHP participants rated their personal providers and healthcare higher than those enrolled in Medicaid. Access to care, utilization of care, and healthcare and health insurance literacy may be contributing factors to these results.

A compact instrument for gamma-ray burst detection on a CubeSat platform I: Design drivers and expected performance.

The Educational Irish Research Satellite 1 (EIRSAT-1) is a 2U CubeSat being developed under ESA's Fly Your Satellite! programme. The project has many aspects, which are primarily educational, but also include space qualification of new detector technologies for gamma-ray astronomy and the detection of gamma-ray bursts (GRBs). The Gamma-ray Module (GMOD), the main mission payload, is a small gamma-ray spectrometer comprising a 25 mm × 25 mm × 40 mm cerium bromide scintillator coupled to an array of 16 silicon photomultipliers. The readout is provided by IDE3380 (SIPHRA), a low-power and radiation tolerant readout ASIC. GMOD will detect gamma-rays and measure their energies in a range from tens of keV to a few MeV. Monte Carlo simulations were performed using the Medium Energy Gamma-ray Astronomy Library to evaluate GMOD's capability for the detection of GRBs in low Earth orbit. The simulations used a detailed mass model of the full spacecraft derived from a very high-fidelity 3D CAD model. The sky-average effective area of GMOD on board EIRSAT-1 was found to be 10 cm2 at 120 keV. The instrument is expected to detect between 11 and 14 GRBs, at a significance greater than 10σ (and up to 32 at 5σ), during a nominal one-year mission. The shape of the scintillator in GMOD results in omni-directional sensitivity which allows for a nearly all-sky field of view.

Higher Rates of Preventive Health Care With Commercial Insurance Compared With Medicaid: Findings From the Arkansas Health Care Independence "Private Option" Program.

BACKGROUND: A requirement of the Arkansas Medicaid Section 1115 demonstration waiver was to evaluate the level of care received for Medicaid expansion eligible beneficiaries enrolled in commercial Qualified Health Plans (QHPs) in the Health Care Independence "Private Option" Program. This allowed for a direct comparison of Medicaid and commercial system performance serving similar newly covered adults. RESEARCH DESIGN: In 2014, assignment to either Medicaid or a QHP was made based upon a psychometrically derived continuous composite score to exceptional health care needs assessment screener using a sharp a priori threshold cutpoint. Using a regression discontinuity design we compared preventive care (flu vaccination and screening rates) services in the 2 programs over 3 years. RESULTS: Compared with Medicaid enrollees, a higher percentage of QHP enrollees consistently received eligible preventive care screenings with 15.3, and 6.9% more receiving at least 1 or all eligible screenings, respectively. For individual preventive care outcomes and compared with Medicaid enrollees over the 3 years under study, a higher percentage of eligible QHP enrollees received a flu shot, cholesterol screenings, glycated hemoglobin assessment, and cervical and breast cancer periodic assessments. No differences were found for colorectal periodic assessments. CONCLUSIONS: These findings suggest that at least for preventive services, the Medicaid federal equal access requirement is not being met for those within Medicaid fee-for-service coverage. This persisted across all 3 years of the program. Differential payment rates for services between Medicaid and QHPs are likely a major contributing factor.

Impact of an Episode-Based Payment Initiative by Commercial Payers in Arkansas on Procedure Volume: an Observational Study.

BACKGROUND: Episode-based payment (EBP) is gaining traction among payers as an alternative to fee-for-service reimbursement. However, there is concern that EBP could influence the number of episodes. OBJECTIVE: To examine how procedure volume changed after the introduction of EBP in 2013 and 2014 under the Arkansas Health Care Payment Improvement Initiative. DESIGN: Using 2011-2016 commercial claims data, we estimate a difference-in-differences model to assess the impact of EBP on the probability of a beneficiary having an episode for four procedures that were reimbursed under EBP in Arkansas: total joint replacement, cholecystectomy, colonoscopy, and tonsillectomy. PARTICIPANTS: Commercially insured beneficiaries in Arkansas serve as our treatment group, while commercially insured beneficiaries in neighboring states serve as our comparison group. INTERVENTIONS: Statewide implementation of EBP for various clinical conditions by two of Arkansas' largest commercial insurers. MAIN MEASURES: For a given procedure type, the primary outcomes are the annual rate of procedures (number of procedures per 1000 beneficiaries) and the probability of a beneficiary undergoing that procedure in a given quarter. KEY RESULTS: The relationship between EBP and procedure volume varies across procedures. After EBP was implemented, the probability of undergoing colonoscopy increased by 17.2% (point estimate, 2.63; 95% CI, 1.18 to 4.08; p < 0.001; Arkansas pre-period mean, 15.29). The probability of undergoing total joint replacement increased by 9.9% (point estimate, 0.091; 95% CI, - 0.011 to 0.19; p = 0.08; Arkansas pre-period mean, 0.91), though this effect is not significant. There is no discernable impact on cholecystectomy or tonsillectomy volume. CONCLUSIONS: We do not find clear evidence of deleterious volume expansion. However, because the impact of EBP on procedure volume may vary by procedure, payers planning to implement EBP models should be aware of this possibility.

Suction adhesion in the gliding joint of a cephalopod.

We have discovered features of the nuchal joint in the squid, Doryteuthispealeii, that are unique compared with moveable joints in other animals. The joint's function is unclear but it allows the head to glide toward and away from the mantle. The head glides along the joint with ease yet disarticulating the joint perpendicular to the axis of movement requires considerable force. After disarticulation, the joint components can be repositioned and full function restored immediately. Thus, an unknown attachment mechanism prevents the joint from being disarticulated yet permits gliding. We show that the joint was formed by the articulation of the nuchal cartilage and a heretofore-undescribed organ that we named the nuchal 'joint pad'. The joint pad is composed predominantly of muscle, connective tissue and cartilage organized into two distinct regions: a ventral cartilaginous layer and a dorsal muscular layer. Disarticulating the nuchal joint at a displacement rate of 5 mm s-1 required 1.5 times greater stress (i.e. force per unit area) than at 1 mm s-1 The force required to disarticulate the joint increased with nuchal cartilage area0.91 and with nuchal cartilage length1.88 The stress required to shear the nuchal joint was nearly three orders of magnitude lower than that required to disarticulate the joint. Stimulation of the joint pad dorso-ventral musculature resulted in significantly greater shear force required to move the joint (P=0.004). Perforating the nuchal cartilage decreased the stress required to disarticulate the joint to nearly zero. The results support the hypothesis that suction is the attachment mechanism.

Snus: a compelling harm reduction alternative to cigarettes.

Snus is an oral smokeless tobacco product which is usually placed behind the upper lip, either in a loose form or in portioned sachets, and is primarily used in Sweden and Norway. The purpose of this review is to examine the reported effects of snus use in relation to specified health effects, namely lung cancer, cardiovascular disease, pancreatic cancer, diabetes, oral cancer and non-neoplastic oral disease. The review also examines the harm reduction potential of snus as an alternative to cigarettes by comparing the prevalence of snus use and cigarette smoking, and the reported incidence of tobacco-related diseases across European Union countries. The scientific literature generally indicates that the use of snus is not a significant risk factor for developing lung cancer, cardiovascular disease, pancreatic cancer or oral cancer. Studies investigating snus use and diabetes have reported that high consumption of snus (estimated as being four or more cans per week) may be associated with a higher risk of developing diabetes or components of metabolic syndrome; however, overall results are not conclusive. Snus use is associated with the presence of non-neoplastic oral mucosal lesions which are reported to heal rapidly once use has stopped. The most recent Eurobarometer data from 2017 reported that Sweden had the lowest prevalence of daily cigarette use in the European Union at 5% whilst daily "oral tobacco" use was reported to be 20%. European data published by the World Health Organisation in 2018 indicated that Sweden had the lowest rate of tobacco-related mortality and the lowest incidence of male lung cancer. Overall, prevalence statistics and epidemiological data indicate that the use of snus confers a significant harm reduction benefit which is reflected in the comparatively low levels of tobacco-related disease in Sweden when compared with the rest of Europe. The available scientific data, including long-term population studies conducted by independent bodies, demonstrates that the health risks associated with snus are considerably lower than those associated with cigarette smoking.

New approaches for assessing squid fin motions: coupling proper orthogonal decomposition with volumetric particle tracking velocimetry.

Squid, which swim using a coupled fin/jet system powered by muscular hydrostats, pose unique challenges for the study of locomotion. The high flexibility of the fins and complex flow fields generated by distinct propulsion systems require innovative techniques for locomotive assessment. For this study, we used proper orthogonal decomposition (POD) to decouple components of the fin motions and defocusing digital particle tracking velocimetry (DDPTV) to quantify the resultant 3D flow fields. Kinematic footage and DDPTV data were collected from brief squid, Lolliguncula brevis [3.1-6.5 cm dorsal mantle length (DML)], swimming freely in a water tunnel at speeds of 0.39-7.20 DML s-1 Both flap and wave components were present in all fin motions, but the relative importance of the wave components was higher for arms-first swimming than for tail-first swimming and for slower versus higher speed swimming. When prominent wave components were present, more complex interconnected vortex ring wakes were observed, while fin movements dominated by flapping resulted in more spatially separated vortex ring patterns. Although the jet often produced the majority of the thrust for steady rectilinear swimming, our results demonstrated that the fins can contribute more thrust than the jet at times, consistently produce comparable levels of lift to the jet during arms-first swimming, and can boost overall propulsive efficiency. By producing significant drag signatures, the fins can also aid in stabilization and maneuvering. Clearly, fins play multiple roles in squid locomotion, and when coupled with the jet, allow squid to perform a range of swimming behaviors integral to their ecological success.

Radiofrequency and Cryo-Ablation Effect on Transvenous Pacing and Defibrillatory Lead Integrity: An In Vitro Study.

INTORDUCTION: Medical societies and cardiac implantable electronic device (CIED) manufacturers recommend avoiding close or direct contact between the body of transvenous leads and ablation catheters used to treat cardiac arrhythmias. These recommendations are made despite the lack of clinical studies. However, the target myocardium for successful ablation can be contiguous to CIED leads. METHODS AND RESULTS: We examine in vitro the effects of direct application of radiofrequency (RF) and cryo-ablation energy on the integrity and functionality of CIED leads (excluding the pacing electrodes and defibrillation coils). A saline bath was created to mimic the body milieu. CIED leads, including all commercially available lead insulation materials, were connected to a CIED pulse generator and placed in direct contact with an ablation catheter in the tissue bath. RF and cryo-ablation energy were delivered under various conditions, including maximal ablation power, temperature, and impedance via the RF generator. CIED lead functionality, reflective of conductor integrity, was evaluated through lead impedance monitoring during ablation. CIED leads were then visually inspected, and examined with optic and electron microscopy as per protocol. A total of 42 leads were studied. All leads showed the absence of insulation damage at the site of ablation visually and with microscopy. Lead functionality was also preserved in all leads. CONCLUSION: Catheter ablation in contact with CIED leads using radiofrequency or cryo-ablation in vitro did not affect lead body integrity and function despite aggressive ablation settings. It may be reasonable to perform ablation in contact with the body of CIED leads when clinically necessary.

Volumetric flow imaging reveals the importance of vortex ring formation in squid swimming tail-first and arms-first.

Squids use a pulsed jet and fin movements to swim both arms-first (forward) and tail-first (backward). Given the complexity of the squid multi-propulsor system, 3D velocimetry techniques are required for the comprehensive study of wake dynamics. Defocusing digital particle tracking velocimetry, a volumetric velocimetry technique, and high-speed videography were used to study arms-first and tail-first swimming of brief squid Lolliguncula brevis over a broad range of speeds [0-10 dorsal mantle lengths (DML) s(-1)] in a swim tunnel. Although there was considerable complexity in the wakes of these multi-propulsor swimmers, 3D vortex rings and their derivatives were prominent reoccurring features during both tail-first and arms-first swimming, with the greatest jet and fin flow complexity occurring at intermediate speeds (1.5-3.0 DML s(-1)). The jet generally produced the majority of thrust during rectilinear swimming, increasing in relative importance with speed, and the fins provided no thrust at speeds >4.5 DML s(-1). For both swimming orientations, the fins sometimes acted as stabilizers, producing negative thrust (drag), and consistently provided lift at low/intermediate speeds (<2.0 DML s(-1)) to counteract negative buoyancy. Propulsive efficiency (η) increased with speed irrespective of swimming orientation, and η for swimming sequences with clear isolated jet vortex rings was significantly greater (η=78.6±7.6%, mean±s.d.) than that for swimming sequences with clear elongated regions of concentrated jet vorticity (η=67.9±19.2%). This study reveals the complexity of 3D vortex wake flows produced by nekton with hydrodynamically distinct propulsors.

A missense variant in CST3 exerts a recessive effect on susceptibility to age-related macular degeneration resembling its association with Alzheimer's disease.

Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are degenerative, multifactorial diseases involving age-related accumulation of extracellular deposits linked to dysregulation of protein homeostasis. Here, we strengthen the evidence that an nsSNP (p.Ala25Thr) in the cysteine proteinase inhibitor cystatin C gene CST3, previously confirmed by meta-analysis to be associated with AD, is associated with exudative AMD. To our knowledge, this is the first report highlighting a genetic variant that increases the risk of developing both AD and AMD. Furthermore, we demonstrate that the risk associated with the mutant allele follows a recessive model for both diseases. We perform an AMD-CST3 case-control study genotyping 350 exudative AMD Caucasian individuals. Bringing together our data with the previously reported AMD-CST3 association study, the evidence of a recessive effect on AMD risk is strengthened (OR = 1.89, P = 0.005). This effect closely resembles the AD-CST3 recessive effect (OR = 1.73, P = 0.005) previously established by meta-analysis. This resemblance is substantiated by the high correlation between CST3 genotype and effect size across the two diseases (R(2) = 0.978). A recessive effect is in line with the known function of cystatin C, a potent enzyme inhibitor. Its potency means that, in heterozygous individuals, a single functional allele is sufficient to maintain its inhibitory function; only homozygous individuals will lack this form of proteolytic regulation. Our findings support the hypothesis that recessively acting variants account for some of the missing heritability of multifactorial diseases. Replacement therapy represents a translational opportunity for individuals homozygous for the mutant allele.

Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release.

UNLABELLED: Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or "viroporin," whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. CONCLUSION: This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA.

Determination of Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products by Inductively Coupled Plasma/Mass Spectrometry: Collaborative Study, Final Action 2011.19.

AOAC First Action Method 2011.19: Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products, was collaboratively studied. This method uses microwave digestion of samples with nitric acid, hydrogen peroxide, and internal standard followed by simultaneous detection of the elements by an inductively coupled plasma (ICP)/MS instrument equipped with a collision/reaction cell. During this collaborative study, nine laboratories from four different countries, using seven different models of ICP/MS instruments, analyzed blind duplicates of seven infant, pediatric, and adult nutritional formulas. One laboratory's set of data was rejected in its entirety. The method demonstrated acceptable repeatability and reproducibility and met the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Standard Method Performance Requirements (SMPRs®) for almost all of the matrixes analyzed. The Cr, Mo, and Se SPIFAN requirement for repeatability was ≤5% RSD. The SMPR called for a reproducibility of ≤15% RSD for products with ultratrace element concentrations above the targeted LOQ of 20 µg/kg Cr/Mo and 10 µg/kg Se (as ready-to-feed). During this collaborative study, RSDr ranged from 1.0 to 7.0% and RSDR ranged from 2.5 to 13.4% across all three ultratrace elements.