Search

Objective:Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer’s disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants’ personal devices in their everyday environments.Methods:We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65–97 years) and 22 individuals with very mild dementia (ages 61–88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies.Results:First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants.Conclusions:Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.

SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR- Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but further processing in lung cells required TMPRSS2 while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.One-sentence summaryRational treatment strategies for SARS-CoV-2 derived from human PSC models

Although behavioral studies of whole animals are usually undertaken on rats and mice, studies in crustaceans offer an alternative group that provides new evolutionary insights into the relationship between physiology and behavior. In the cherry shrimp Neocaridina davidi (Bouvier, 1904), food-seeking movement increases in response to glutamate (MSG), decreases when exposed to dopamine, and increases when exposed to glucose. Activity of shrimp individuals was observed in 4l tanks over twenty minutes after individuals were exposed to treatments applied directly into the water. Glutamate-stimulated seeking behavior was statistically similar to seeking behavior after exposure to food pellet filtrate. Glucose also stimulated seeking behavior, but with a reduction over time, whereas MSG-stimulated seeking behavior increased over time. Insulin reduced activity but showed no effect when paired with glucose, whereas dopamine increased activity when paired with glucose. This was contrary to the reduced activity observed when dopamine was paired with MSG. The decrease in activity after exposure to dopamine also contrasts with vertebrate (rat) models where dopaminergic drugs such as caffeine and cocaine are stimulants. The stimulatory effect of dopamine paired with glucose was unexpected given its inhibitory effect on its own or when paired with MSG. This crustacean-based model aims to give new insights regarding the role of inhibitory and stimulatory neurotransmitters on the behavior of whole crustacean individuals. These mechanisms show different results than predicted by vertebrate models, implying either differences in underlying physiology, problems with the vertebrate models, or both.

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis., Immune cells are important regulators of adipose tissue function, including adaptive thermogenesis. Here the authors show that mice with Krüppel-like factor 3 (KLF3) deficiency in bone marrow-derived cells have increased adipose tissue beiging which may at least in part be due to altered eosinophil paracrine signaling.

Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C(+) monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.

Fibroblast activation is a hallmark feature of pathological remodeling of the heart and represents an attractive target for therapeutic intervention. Pharmacological inhibition of chromatin remodeling enzymes reduces cardiac fibrosis, but the underlying transcriptional regulatory mechanisms remain poorly understood. Using single-cell genomics to profile alterations in the transcriptional and chromatin landscape during stress-induced cardiac remodeling, Alexanian et al. discovered a critical role for Mesenchyme Homeobox 1 in the regulation of myofibroblast activation and cardiac fibrosis. We briefly review these important findings and comment on the significance of their work.

The Krüppel-like factor (KLF) family of transcription factors play critical roles in haematopoiesis. KLF1, the founding member of the family, has been implicated in the control of both erythropoiesis and megakaryopoiesis. Here we describe a novel system using an artificial dominant negative isoform of KLF1 to investigate the role of KLF1 in the erythroid/megakaryocytic switch in vivo. We developed murine cell lines stably overexpressing a GST-KLF1 DNA binding domain fusion protein (GST-KLF1 DBD), as well as lines expressing GST only as a control. Interestingly, overexpression of GST-KLF1 DBD led to an overall reduction in erythroid features and an increase in megakaryocytic features indicative of a reduced function of endogenous KLF1. We simultaneously compared in vivo DNA occupancy of both endogenous KLF1 and GST-KLF1 DBD by ChIP qPCR. Here we found that GST-KLF1 DBD physically displaces endogenous KLF1 at a number of loci, providing novel in vivo evidence of direct competition between DNA binding proteins. These results highlight the role of KLF1 in the erythroid/megakaryocyte switch and suggest that direct competition between transcription factors with similar consensus sequences is an important mechanism in transcriptional regulation.

This article explores the extent to which the research focus areas of the 100 proposals generated by the International Coaching Research Forum (ICRF) in 2008 have been addressed in substantive, primary and evidence-based research. Abstracts of English-language, peer-reviewed research on coaching published from January 2008 to June 2012 were compiled and reviewed and key trends in relation to coverage of research focus areas suggested by the ICRF proposals are summarised. Major gaps remaining in coaching research are identified and priorities for the coaching topics to be studied are recommended, based on the 2008 ICRF proposals.

The anterior approach to the spine is becoming an increasingly important avenue to treat spine conditions. Most of the literature reporting on the exposure uses an access surgeon assisting the spine surgeon to expose and prepare the spine for implant.To compare perioperative parameters and complications in anterior lumbar spine surgery with the exposure performed either by a spine surgeon or a general surgeon.A retrospective cohort study comparing perioperative parameters and complications of anterior lumbar spine surgery.A retrospective review was completed on 96 consecutive patients who underwent anterior spine surgery between Levels L3 and S1 from 1995 to 2008. Patient and surgery characteristics including demographics, comorbidities, perioperative parameters, and complications were logged. In the first 56 consecutive patients, a general surgeon completed the exposure, with an additional patient who later had the exposure performed by a general surgeon because of extensive prior abdominal surgeries. In the next 39 patients, the orthopedic surgeon completed the exposure.When the operation was performed solely by a spine surgeon, the estimated blood loss, operative time, and hospital stay was 204 mL, 2.80 hours, and 3.5 days, respectively. In the procedures completed with the aid of a general surgeon, it was found that the same parameters were 420 mL, 3.93 hours, and 4.7 days, respectively, and statistically significantly less in the group without the assistance of the general surgeon (p=.0007, p=.0003, and p=.0006, respectively). Fewer complications also were observed in that group (p.00001). The most common complication was an ileus. Major complications including retrograde ejaculation, iliac vein bleeding, peritoneal rent requiring repair, dyspareunia, or scrotal/penile swelling were only observed in the group with the assistance of the general surgeon.This study indicated that a spine surgeon can successfully and safely carry out the anterior exposure to the spine without the aid of an access surgeon.

This is the author's accepted manuscript, post peer-review. The original published version can be found at: http://dx.doi.org/10.1080/03071022.2011.538553

The norm of American national life is war. From colonial origins to the present, Americans have never seen a generation that was not preoccupied with wars, threats of wars, and military interventions on foreign soils. This is not something Americans—or American historians—are trained to think about. In American memory and mythology, the United States is, at heart, a nation of peace; it unleashes the quiver of war as a last resort and only when pushed. In like manner religion, especially what we now call evangelical Protestantism, has been a conspicuous presence in American wars from the seventeenth century to the present. American wars are sacred wars and American religion, with some notable exceptions, is martial at the very core of its being. The ties between war and religion are symbiotic and the two grew up inextricably intertwined.

Nanoplasmonics — the nanoscale manipulation of surface plasmons (fluctuations in the electron density at a metallic surface) — could revolutionize applications ranging from sensing and biomedicine to imaging and information technology. But first, we need a simple and efficient method for actively generating coherent plasmonic fields. This is in theory possible with the spaser, first proposed in 2003 as a device that generates and amplifies surface plasmons in the same way that a laser generates and amplifies photons. Now Noginov et al. present the first unambiguous experimental demonstration of spasing, using 44-nm diameter nanoparticles with a gold core and dye-doped silica shell. The system generates stimulated emission of surface plasmons in the same way as a laser generates stimulated emission of coherent photons, and has been used to implement the smallest nanolaser reported to date, and the first operating at visible wavelengths. Nanoplasmonics promises to revolutionize applications ranging from sensing and biomedicine to imaging and information technology, but its full development is hindered by the lack of devices that can generate coherent plasmonic fields. In theory, this is possible with a so-called 'spaser' — analogous to a laser — which would generate stimulated emission of surface plasmons. This is now realized experimentally, and should enable many new technological developments. One of the most rapidly growing areas of physics and nanotechnology focuses on plasmonic effects on the nanometre scale, with possible applications ranging from sensing and biomedicine to imaging and information technology1,2. However, the full development of nanoplasmonics is hindered by the lack of devices that can generate coherent plasmonic fields. It has been proposed3 that in the same way as a laser generates stimulated emission of coherent photons, a ‘spaser’ could generate stimulated emission of surface plasmons (oscillations of free electrons in metallic nanostructures) in resonating metallic nanostructures adjacent to a gain medium. But attempts to realize a spaser face the challenge of absorption loss in metal, which is particularly strong at optical frequencies. The suggestion4,5,6 to compensate loss by optical gain in localized and propagating surface plasmons has been implemented recently7,8,9,10 and even allowed the amplification of propagating surface plasmons in open paths11. Still, these experiments and the reported enhancement of the stimulated emission of dye molecules in the presence of metallic nanoparticles12,13,14 lack the feedback mechanism present in a spaser. Here we show that 44-nm-diameter nanoparticles with a gold core and dye-doped silica shell allow us to completely overcome the loss of localized surface plasmons by gain and realize a spaser. And in accord with the notion that only surface plasmon resonances are capable of squeezing optical frequency oscillations into a nanoscopic cavity to enable a true nanolaser15,16,17,18, we show that outcoupling of surface plasmon oscillations to photonic modes at a wavelength of 531 nm makes our system the smallest nanolaser reported to date—and to our knowledge the first operating at visible wavelengths. We anticipate that now it has been realized experimentally, the spaser will advance our fundamental understanding of nanoplasmonics and the development of practical applications.

We propose a finite element approach to treat the problem of the hydrogen atom in a static electric field. We show the efficiency of a L2 basis set, i.e. B-spline functions. Particular attention is placed on the problem of the normalization in the context of parabolic coordinates. The method is applied to the study of hydrogen photoionization from the fundamental (1s) and excited (n = 2,3,4) states in a weak external DC electric field. Oscillator strengths have been calculated in the region of the field-free atomic threshold. The pertinence of the finite element approach is also discussed for the study of Stark energies of hydrogen. The results are compared with other accurate calculations when available.