cssi/SciSciGPT-SciSciNet huggingface dataset:
mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice.

Summary Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA-KO mice express high levels of two proteins involved in DNA repair, O-6-methylguanine-DNA methyltransferase (MGMT) and N-myc downstream-regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post-transcriptional mechanisms. We show that the CCR4-NOT complex, a post-transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long-lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post-transcriptional regulation involving specific alteration in the CCR4-NOT complex, whose modulation could control multiple aspects of the aging process.
Thermal transport by phonons and electrons in aluminum, silver, and gold from first principles

Mode-dependent phonon and electron transport properties in Al, Ag, and Au are predicted using density functional theory and lattice dynamics calculations. The predicted thermal conductivities, electrical conductivities, electron-phonon coupling coefficients, and electron-phonon mass enhancement parameters are in agreement with experimental measurements. At a temperature of 100 K, the phonon contribution to the total thermal conductivity of Al is 5% in bulk and increases to 15% for a 50 nm thick film. In all three metals, phonons with mean free paths between 1 and 10 nm are the dominate contributors to the thermal conductivity at a temperature of 300 K, while the relevant electron mean free paths are 10--100 nm. Despite similar atomic masses, the phonon thermal conductivity of Al is an order of magnitude smaller than that of silicon due to a larger three-phonon phase space and stronger anharmonicity. These results will impact the interpretation of thermoreflectance experiments that can resolve carrier-level contributions to thermal conductivity.
Customized ECG beat classifier using mixture of experts

Reports an effort to develop a user-adaptation (customization) algorithm which, with minimal human supervision, is capable of adapting the performance of an ECG beat classification algorithm to the special characteristics of individual patients. In the authors' algorithm, they assume a black box ECG beat classifier, and a small set of user-specific training data, edited by human experts, are given. The objective is to devise a method to take advantage of the small user-specific training data set to achieve high classification rate rather than using the black box ECG beat classifier alone.
Predictors of Bone Mineral Density among Asian Indians in Northern Mississippi: A Pilot Study

Background: Osteoporosis is a systemic skeletal disorder characterized by low bone mineral density (BMD) that leads to an increase in bone fragility, causing an individual to be at an increased risk for fractures. Asian-Indians are at an increased risk for developing osteoporosis. Considering the number of Asian-Indians in the US is rapidly growing, they likely could be an underappreciated population at risk for bone fractures. The aim of this study was to investigate bone health and determine the factors affecting BMD in Asian-Indians living in the US. Methods: Asian-Indians residing in Northern Mississippi ( n = 87) were enrolled in this cross-sectional study from June 2013 to August 2014. Eligible participants completed a self-administered Osteoporosis Risk Factor Assessment questionnaire. BMD and body composition were measured using a dual energy x-ray absorptiometry scan (DXA). Results: Eight-seven Asian-Indians (male: 62.1%) participated, with the average age being 28.49 yr old (SD = 6.62). Overall, 31.0% and 48.3% had low femoral neck BMD and spinal BMD, respectively. Multiple regression analysis revealed that age, percent body fat, and body mass index (BMI) significantly predicted BMD at femur neck ( P <0.05). Additionally, percent body fat, BMI, childhood milk consumption, and gender were statistically significant predictors of spinal BMD ( P <0.05). Conclusion s : The findings from this study should be beneficial to healthcare providers that work with Asian-Indian population groups. Health promotion programs focusing on osteoporosis prevention are needed among Asian-Indians to prevent the risk of fractures.
The use of ECMO for gastroschisis and omphalocele: Two decades of experience.

Abstract Purpose The aim was to review the respiratory failure causes and outcomes of infants with omphalocele or gastroschisis receiving ECMO and reported to the Extracorporeal Life Support Organization (ELSO). Methods Gastroschisis and omphalocele infants supported with ECMO and reported to the ELSO Registry between 1992 and 2015 were retrospectively reviewed. Clinical variables, diagnosis of respiratory failure (pulmonary hypertension (PHN), congenital heart defects (CHD), congenital diaphragmatic hernia (CDH), and sepsis), and outcomes were recorded. Univariate analysis was performed using Student's t -test for continuous or Fisher's exact test for categorical variables. Results Fifty-two infants with gastroschisis (41) (79%) or omphalocele (11) (21%) were identified. The survival to discharge rate of 51% for gastroschisis remained stable and was significantly higher ( P =0.05). The overall mortality rate for omphalocele was 82%. Omphalocele had significantly more PHN ( P P P =0.04) had significantly more sepsis ( P =0.02), and none had a CDH. Conclusion Infants with gastroschisis requiring ECMO support have significantly better survival than omphaloceles, and respiratory failure is significantly associated with sepsis. The majority of omphalocele infants die despite ECMO, and respiratory failure is associated PHN and CDH. The association of omphalocele, PHN, and CDH merits further investigation. Study type and evidence level Retrospective comparative study of Registry Database, Level 3.
CROWDLEARNING: Towards Collaborative Problem-Posing at Scale

This paper presents a new pedagogical paradigm ``Crowdlearning'', where students experience deeper learning through collaboratively creating learning materials for each other. Crowdlearning practice is envisioned to produce large ``banks'' of subject matter problems generated by students themselves, in a crowdsourced way, as the students learn new subjects; these problems can then serve as learning and assessment materials usable at scale. This paper overviews the motivation for the development of Crowdlearning as a teaching practice and the theoretical drivers behind it. The paper then reports on preliminary field studies and experiences suggesting that Crowdlearning has a solid potential for adoption in STEM.
Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review.

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial–mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.
Mathematical Problem Solving Instruction for Students with Autism Spectrum Disorder

Mathematical problem solving is a central theme of K-12 mathematics and an essential skill for college and career readiness. However, problem solving is a challenging task for many young students, especially for students with cognitive difficulties because it requires not only mathematics skills but also reading comprehension, reasoning, and ability to transform words and numbers into the appropriate operations. This chapter is designed to provide helpful suggestions for teaching students with autism spectrum disorder (ASD) who have math problem solving difficulties. The emphasis is made on the visual supports that aid students with ASD to develop abstract and conceptual understanding and apply the learned concepts in real-life problem solving. The following are topics included in this chapter: (1) the general guidelines for math instruction targeting students with ASD; (2) teaching problem solving based on the concrete-representational-abstract (CRA) approach; (3) teaching students in concrete level using manipulative; and (4) teaching students at semiabstract level: schema-based instruction (SBI) for students with ASD. Several lesson ideas are also included in the chapter to illustrate the visual strategies and SBI for problem solving skills.
Large-size niobium disulfide nanoflakes down to bilayers grown by sulfurization

Atomically thin layers of group VB transition metal dichalcogenides (TMDs) provide a unique platform for studying two-dimensional (2D) superconductivity and charge density waves. Thus far, the bottom-up synthesis of these 2D TMDs has often involved precursors that are corrosive or toxic, and their lateral sizes are typically only a few micrometers. In this paper, we report the growth of NbS2 nanoflakes with a thickness down to bilayers and a lateral dimension up to tens of micrometers without using harsh chemical species. NbS2 nanoflakes either standing or lying with respect to the sapphire substrate were obtained by sulfurization of niobium oxide films that were prepared via pulsed laser deposition. Standing nanoflakes are considered to grow epitaxially on the sapphire substrate according to their ordered orientation, while lying nanoflakes with random orientations were grown directly on top of the niobium oxide films. The Raman spectra of the 3R-phase exhibit strong dependence on the layer thickness, where the A1 mode softens as the layer number decreases. In contrast to the stable bulk NbS2, the ultra-thin nanoflakes were oxidized on their top surfaces after prolonged exposure to air, as revealed by X-ray photoelectron spectroscopy. Our work explores an important route to synthesize large-size NbS2 nanoflakes and studies the oxidation process, which is a critical factor to consider if practical applications should be realized in the future.
Acoustic-Gravity Waves from Impulsive Sources in the Atmosphere

A numerical model for acoustic-gravity waves (AGWs) has been developed incorporating wave periods from ∼3 h to 0.10 s that are typically produced during meteor-fireball (or bolide) entry into the atmosphere. With relatively minor extensions, this model works equally well for rockets and missiles and other impulsive, elevated atmospheric sources. This chapter represents an extension of work originally presented at the Meteoroids 2007 Conference in Barcelona, Spain, and that originally began long ago. The equations being solved (currently written explicitly in Cartesian coordinates) were developed self consistently to model conditions applicable to the smallest bolides detectable at ground level at close ranges for any source height as well as the largest, most deeply penetrating bolides, at ranges up to ∼one earth radius from the source. Source modeling expressed in terms of the size of the line source blast wave relaxation radius is allowed to vary reliably from ∼1 m to as large as ∼36 km. In this work, an entry modeling capability has also been used that links satellite and/or ground-based near-optical pass-band photometry of the bolide in the near-field to either linear or quasilinear far-field locations. The geometrical acoustics, wave normal limit as well as the full wave theory developed previously for kt class and larger nuclear explosions in steady state, range-independent, perfectly stratified model atmospheres with horizontal mean winds have been used. Geometrical theory alternatives approaches such as Gaussian beam tracing theory are also included as needed to accurately model the signals from the smallest bolides at the closest ranges. Atmospheric waves produced during bolide entry (assuming a Dirac Delta function or a Heaviside step function type source) include Lamb waves, weak shock waves at relatively close range, infrasonic acoustical waves, and ducted acoustical signals propagating in the stratospheric or thermospheric sound channels. The ducted waves were modeled initially using the predicted near-field, line source, wave amplitude time series, allowing for weakly nonlinear propagation effects, with AGW dispersion as a function of range, etc. For the ducted waves made use of exact, ideal waveguide mode theory solutions. These later solutions predict the ducted modes that are allowed for a specified atmospheric sound and horizontal wind speed profile. In this chapter, predictions for the small blast wave, close range limit as well for a much larger blast wave at much longer range are both illustrated. The latter limit is indicative of the relatively low rate of detections made by the International Monitoring System (IMS) global infrasound network, whereas the former limit is indicative of the numerous AGWs detected by the Southern Ontario Meteor Network (SOMN) operated by the Physics and Astronomy Department at the University of Western Ontario.
Genetic and Genomic Approaches to Complex Lung Diseases Using Mouse Models

Common lung diseases are likely to be multifactorial and multigenic. In addition, the lung exhibits a limited set of biological and physiological responses, so different lung diseases exhibit significant overlap in phenotype. This complexity in the development and manifestation of lung disease poses significant challenges for developing complete and accurate models of disease. Nonetheless, a layered strategy that includes in vitro and in vivo systems can offset these limitations. In vitro systems have evolved from simple organ culture to intricate procedures for cell culture that exhibit high fidelity to behavior in vivo. Similarly, in vivo systems have evolved from traditional physiology-based models in large animals and rodents to genetic modification of mice using targeted and conditional systems. Complex traits may be studied in inbred, recombinant, or congenic strains of mice, and single gene effects may be segregated naturally or experimentally. Ultimately, results from these in vitro and in vivo models identify candidate genes for further study in humans.
The impact and prospect of natural product discovery in agriculture: New technologies to explore the diversity of secondary metabolites in plants and microorganisms for applications in agriculture.

EMBO Reports (2018) 19: e46824[OpenUrl][1][FREE Full Text][2] Natural products (NPs) are small organic molecules of < 1,500 Da that are produced mostly by microorganisms and plants, and many of them have enormously benefited human health and agriculture. As NPs have co‐evolved together with their molecular targets, they possess potent bioactivities and selectivities, which their producers use to kill or limit the growth of competitors by inhibiting vital metabolic enzymes. These chemicals are structurally complex and can include multiple stereocenters and intricate ring systems along with a plethora of functional groups that serve as warheads, hydrogen bond donors/acceptors, or target recognition moieties. > Humans have been using the potent action of NPs for multiple purposes from medicinal to cosmetic and recreational use as well as in agriculture. Humans have been using the potent action of NPs for multiple purposes from medicinal to cosmetic and recreational use as well as in agriculture. During the golden age of NP discovery from the 1960s to the 1980s, scientists in academia and industry identified and characterized an impressive list of NPs that are still being used today: The antibiotic compounds penicillin or amphotericin, the cholesterol‐lowering lovastatin, or the cancer drug taxol are just a few examples of how these microbial ecological weapons were repurposed for combatting diseases. ### Global demand for new NPs In agriculture, NPs have been applied as fungicides, insecticides, and herbicides that have contributed substantially to the increases of crop yield and quality worldwide. From 1997 to 2010, NPs and their derivatives made up about 36% of all new registered pesticide ingredients [1]. For example, spinosyn and avermectin, produced by soil‐borne bacteria Saccharopolyspora spinose and Streptomyces avermitilis , can effectively paralyze insects through hyperexcitation of their nervous system (Fig 1). The discovery of avermectin by Satoshi Ōmura was awarded the 2015 Nobel Prize in Physiology or Medicine. Phosphinothricin, … [1]: {openurl}?query=rft.jtitle%253DEMBO%2BReports%26rft_id%253Dinfo%253Adoi%252F10.15252%252Fembr.201846824%26rft_id%253Dinfo%253Apmid%252F30361392%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=embor&resid=19/11/e46824&atom=%2Fembor%2F19%2F11%2Fe46824.atom
Antisocial personality and risks of cause-specific mortality: results from the Epidemiologic Catchment Area study with 27 years of follow-up

Little is known about the effect of antisocial personality disorder (ASPD) on the risks of cause-specific mortality in the community. This study aimed to close this gap by evaluating if ASPD increases risks of cause-specific mortality in population-based residential and institutionalized samples with 27 years of follow-up. Data were collected in four metropolitan sites as part of the Epidemiologic Catchment Area (ECA) study during 1979–1983. Records were linked to the National Death Index through the end of 2007. Cox proportional hazards models adjusted for propensity weights and sample weights were fitted to estimate the effect of ASPD on the hazard of dying. 420 respondents with ASPD (median survival age 71.0 years) and 15,367 without ASPD (median survival age 84.6 years) were included in this study. Those with ASPD were more likely to die from all causes (HR = 4.46; 95% CI = 2.44–8.16), suicide (HR = 2.81; 95% CI = 1.03–7.65), malignant neoplasms (HR = 4.09; 95% CI = 2.66–6.28), chronic lower respiratory disease (HR = 5.67; 95% CI = 2.92–11.0), and human immunodeficiency virus infection (HR = 8.07; 95% CI = 2.03–32.1), but not from accidents (HR = 0.58; 95% CI = 0.17–1.93) or heart disease (HR = 1.09; 95% CI = 0.43–2.76). Our findings demonstrate that antisocial personality disorder is a strong predictor of all-cause mortality, and cause-specific mortality. Early identification, treatment, and prevention of ASPD are important public mental health initiatives that could reduce premature mortality among this vulnerable population.
Insights into bombesin receptors and ligands: Highlighting recent advances

This following article is written for Prof. Abba Kastin's Festschrift, to add to the tribute to his important role in the advancement of the role of peptides in physiological, as well as pathophysiological processes. There have been many advances during the 35 years of his prominent role in the Peptide field, not only as editor of the journal Peptides, but also as a scientific investigator and editor of two volumes of the Handbook of Biological Active Peptides [146,147]. Similar to the advances with many different peptides, during this 35 year period, there have been much progress made in the understanding of the pharmacology, cell biology and the role of (bombesin) Bn receptors and their ligands in various disease states, since the original isolation of bombesin from skin of the European frog Bombina bombina in 1970 [76]. This paper will briefly review some of these advances over the time period of Prof. Kastin 35 years in the peptide field concentrating on the advances since 2007 when many of the results from earlier studies were summarized [128,129]. It is appropriate to do this because there have been 280 articles published in Peptides during this time on bombesin-related peptides and it accounts for almost 5% of all publications. Furthermore, 22 Bn publications we have been involved in have been published in either Peptides [14,39,55,58,81,92,93,119,152,216,225,226,231,280,302,309,355,361,362] or in Prof. Kastin's Handbook of Biological Active Peptides [137,138,331].
Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma

Purpose: Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell–derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. Patients and Methods: We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. Results: Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9–NA] with a progression-free survival of 14.5 months (95% CI, 11.9–NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. Conclusions: Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
Planning for Professional Productivity with Bullet Journals

This column outlines the Bullet Journal method of tracking tasks, events, and notes. It includes information about how the method works, how the method has been useful for the author, and what other librarians say about its effectiveness.
Early onset neurocirculatory response to static handgrip is associated with greater blood pressure variability in women with posttraumatic stress disorder

The novel findings of the current study are that women with posttraumatic stress disorder (PTSD) exhibited augmented sympathetic neural and pressor responses at the first 30 s of submaximal isometr...
Multifunctional monomer acts as co-initiator and crosslinker to provide autonomous strengthening with enhanced hydrolytic stability in dental adhesives.

Abstract Objective The purpose of this study was to evaluate a new synthesized multifunctional monomer, aminosilane functionalized methacrylate (ASMA), containing polymerizable methacrylate, tertiary amine, and methoxysilane functionalities in dental adhesive formulations, and to investigate the polymerization kinetics, leachates, thermal and mechanical properties of copolymers. Methods Adhesive contained HEMA/BisGMA (45/55, w/w) was used as a control, and mixtures based on HEMA/BisGMA/ASMA at the mass ratio of 45/(55-x)/x were used as experimental adhesive. Adhesives were characterized with regard to water miscibility, photo-polymerization behavior (Fourier transform infrared spectroscopy, FTIR), leached co-monomers (high performance liquid chromatography, HPLC), thermal properties (modulated differential scanning calorimeter, MDSC), and mechanical properties (dynamic mechanical analyzer, DMA). Stress relaxation times and the corresponding moduli, obtained from stress relaxation tests, are used in a simulated linear loading case. Results As compared to the control, ASMA-containing adhesives showed higher water miscibility, lower viscosity, improved monomer-to-polymer conversion, significantly greater Tg and rubbery modulus. HPLC results indicated a substantial reduction of leached HEMA (up to 85 wt%) and BisGMA (up to 55 wt%) in ethanol. The simulation reveals that the ASMA-containing adhesive becomes substantially stiffer than the control. Significance ASMA monomer plays multiple roles, i.e. it serves as both a co-initiator and crosslinker while also providing autonomous strengthening and enhanced hydrolytic stability in the adhesive formulations. This multifunctional monomer offers significant promise for improving the durability of the adhesive at the composite/tooth interface.
Anaplastic large cell lymphoma mimicking a psoas abscess

Abstract We report a case of Anaplastic Large Cell Lymphoma mimicking a psoas abscess in a 6-year-old girl which posed significant diagnostic challenges. She presented with a vague two-month history of anaemia, fevers and back and abdominal pain. Axial imaging including MRI suggested a diffuse, inflammatory lesion in the right psoas muscle and she was commenced on an intravenous antibiotic therapy regimen but with little improvement. An open biopsy was performed and histology confirmed Anaplastic Lymphoma Kinase 1 positive ALCL. To our knowledge, this is only the second case of ALCL with the tissues adjacent the psoas muscle as the primary extra nodal site in the paediatric population.
Notes on the language of the Hismaic Inscriptions and a re-reading of Line 1 of the Madaba Hismaic Inscription

One of the longest Hismaic inscriptions yet discovered comes from the region of Madaba, Jordan. It was published first in an Arabic article by Khraysheh in 2000 and was re-edited by Graf and Zwettler four years later. Both editions remark on the striking similarity in language and style between this text and Classical Arabic. Indeed, this inscription and a closely related text from Uraynibah West, also published by Graf and Zwettler in the same article, are among the best witnesses to the Arabic of this region during the Nabataean period. This article will offer a few remarks on the language of the Hismaic inscriptions and then provide a new reading of line 4 of the Madaba inscription, which had previously evaded satisfactory interpretation.
Practical Considerations and Opportunities for SGLT2 Inhibitor Prescription in Heart Failure

Appropriate selection of anti-hyperglycemic agents that are both safe and effective is critical to improve outcomes for individuals with heart failure. Although emerging evidence supports the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors for heart failure patients with or without diabetes, barriers to prescribing these agents still exist. This comprehensive review will focus on evidence supporting SGLT2 inhibitors for patients with heart failure and practical considerations when prescribing these agents in clinical practice. Based on evidence of improved cardiovascular outcomes for patients initiated on SGLT2 inhibitors, guidelines recommend the use of these agents for people with type 2 diabetes mellitus and cardiovascular disease, or at high cardiovascular risk, to reduce cardiovascular events and lower risk of heart failure hospitalization, independent of hemoglobin A1c. Additional trials are either underway or completed assessing SGLT2 inhibitors for people with heart failure without diabetes mellitus. Despite the positive evidence and guideline recommendations, SGLT2 inhibitors remain under-utilized in clinical practice. In addition to cost and insurance requirements, concern regarding concomitant complex medication regimens and potential adverse events may impede prescribing. Innovative models, such as pharmacist-led cardio-endocrinology and heart failure medication optimization clinics, can be implemented to ensure safe prescribing and monitoring of SGLT2 inhibitors.
Thermal tolerance and environmental persistence of a protozoan parasite in monarch butterflies.

Abstract Many parasites have external transmission stages that persist in the environment prior to infecting a new host. Understanding how long these stages can persist, and how abiotic conditions such as temperature affect parasite persistence, is important for predicting infection dynamics and parasite responses to future environmental change. In this study, we explored environmental persistence and thermal tolerance of a debilitating protozoan parasite that infects monarch butterflies. Parasite transmission occurs when dormant spores, shed by adult butterflies onto host plants and other surfaces, are later consumed by caterpillars. We exposed parasite spores to a gradient of ecologically-relevant temperatures for 2, 35, or 93 weeks. We tested spore viability by feeding controlled spore doses to susceptible monarch larvae, and examined relationships between temperature, time, and resulting infection metrics. We also examined whether distinct parasite genotypes derived from replicate migratory and resident monarch populations differed in their thermal tolerance. Finally, we examined evidence for a trade-off between short-term within-host replication and long-term persistence ability. Parasite viability decreased in response to warmer temperatures over moderate-to-long time scales. Individual parasite genotypes showed high heterogeneity in viability, but differences did not cluster by migratory vs. resident monarch populations. We found no support for a negative relationship between environmental persistence and within-host replication, as might be expected if parasites invest in short-term reproduction at the cost of longer-term survival. Findings here indicate that dormant spores can survive for many months under cooler conditions, and that heat dramatically shortens the window of transmission for this widespread and virulent butterfly parasite.
The Biomechanics of Diabetic Foot Amputation

According to the International Diabetes Federation, approximately 463 million adults live with diabetes mellitus (DM), a number projected to increase to 700 million by 2045; a diabetic foot ulcer (DFU) will occur in about 15% of that population. Multiple factors contribute to the development of those wounds including diabetic peripheral neuropathy, biomechanical imbalances, trauma, and peripheral vascular disease. In addition, 85% of all lower limb amputations in patients with diabetes are preceded by a DFU resulting in significant biomechanical challenges for these patients, many of who never become ambulatory again. Prior to surgical intervention, patients come with inherited and acquired biomechanical imbalances or weaknesses such as equinus, severe pronation/supination, mid and forefoot deformities, and muscle weakness unrelated to their other diseases. Surgeons may not take these into consideration when making decisions about amputation level. Choosing the wrong level of amputation in an attempt to "preserve the foot" often sets up the patient to future failure and multiple amputations until a final resolution of the problem. The purpose of this review is to discuss specific biomechanical and quality of life issues associated with lower extremity amputations and identify the most functional levels for lower extremity amputation in compromised patients with a DFU. By reviewing recent data on these amputations, the authors hope to help surgeons choose the appropriate level for intervention and highlight areas of weakness in the literature requiring further investigation.
Fingolimod-related cryptococcal meningoencephalitis and immune reconstitution inflammatory syndrome in a patient with multiple sclerosis

Abstract Fingolimod is an oral medication for multiple sclerosis that sequesters certain subsets of lymphocytes in lymph nodes, reducing egress into blood and their subsequent CNS migration. The initial multi-site randomized Phase III controlled trials found rates of infection similar to those in control groups. However, post-marketing surveillance has revealed an association with several opportunistic infections, including cryptococcosis. We report a case of fingolimod-related cryptococcal meningoencephalitis and IRIS after drug discontinuation and suggest a surveillance and risk mitigation strategy.
Abstract 268: DNA-launched HPV E7 nanoparticle vaccine induces potent anti-tumor cytolytic T-cell responses

Nanotechnology-based approaches have provided promising tools for development of novel cancer immunotherapeutic immunogens through the decoration of multiple antigens on nanoparticle scaffolds. However, challenges with inducing robust cytolytic T cell responses critical to anti-tumor immunity, as well as purification and scalability, have hampered their clinical translation. To address these challenges, here we present the design and characterization of a DNA-launched nanoparticle vaccine displaying the HPV E7 epitope for inducing anti-tumor immune responses. We designed a nanovaccine construct by scaffolding the HPV E7 epitope with bacterial enzyme lumazine synthase. We demonstrate that through electroporation-facilitated DNA vaccination encoding the antigen-scaffold construct, this nanovaccine self-assembles in vivo into nanoparticles displaying 60 copies of the antigen on its surface. Compared to vaccination with CpG-adjuvanted HPV E7 peptide, the DNA-launched nanovaccine induced significantly greater antigen-specific CD8+ T cell responses upon stimulation with the HPV E7 peptide as well as with the epitope natively expressed on the target tumor cells. In a flank model of TC-1 lung cancer, the DNA-launched nanovaccine achieved complete tumor protection in 70% of mice when administered prophylactically. With therapeutic treatment, the nanovaccine achieved complete tumor regression in 60% of mice. In addition, anti-tumor immunity was retained upon rechallenge over 100 days after initial tumor challenge, supporting the induction of immune memory. These promising results, along with its facile characterization and scalability, support that DNA-launched nanovaccines that self-assemble in vivo can induce significant anti-tumor cellular immunity and are ideally positioned for study in clinical translation. Citation Format: Kevin Liaw, Ziyang Xu, Nicholas Tursi, Neethu Chokkalingam, Daniel Kulp, David Weiner. DNA-launched HPV E7 nanoparticle vaccine induces potent anti-tumor cytolytic T-cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 268.
Influence of sex and habitat on the size and shape of anal and dorsal fins of the blackstripe topminnow Fundulus notatus

The size and shape of the anal and dorsal fin in the blackstripe topminnow Fundulus notatus from lake and stream habitats across multiple ages and sexes were examined. Differences in the size and shape of anal and dorsal fins were sex-specific and not related to habitat differences. Males have longer and more pointed anal fins and longer, larger and more pointed dorsal fins than females. These sex differences occur predominantly in the older age class. The angle (i.e. pointedness) of the dorsal and anal fins is tightly correlated suggesting that fins follow a similar growth trajectory as individuals become sexually mature.
Supporting statistical, graphic/cartographic, and domain literacy through online learning activities: MapStats for Kids

This paper reports on a Digital Government pilot project, MapStats for Kids - a sub-project within the Quality Graphics for Federal Statistical Summaries (dgQG) project. MapStats for Kids will contribute toward a long-term goal of providing web-based support for statistical, graphic/cartographic, and domain literacy through online learning activities that are fun for young web-site visitors to use.
Functional Specialization and Topographic Segregation of Hippocampal Astrocytes

Astrocytes have been suggested to play several roles in the complex control of brain microenvironment. However, they have been generally considered to constitute a homogeneous population of cells. Here we show that at least three electrophysiologically distinct types of astrocytes can be found in the mature hippocampus. These subpopulations of glia were characterized by expression of different ion currents. In astrocytes exposed to elevated K+, Cs+ prevented influx of K+ only in cells with inwardly rectifying currents (IIR). The topographic distribution of glia with Cs+-sensitive inward rectifying currents (involved in K+ buffering) was nonuniform. Cs+-sensitive astrocytes were predominantly found in CA3 radiatum, whereas most CA1 astrocytes were Cs+-insensitive. Functional significance of the spatial segregation of glial cells with inward rectification was addressed in slices that were bathed in Cs+-containing media. Under these conditions, neuronal stimulation induced spontaneous epileptiform activity, which first appeared in CA3 and was then synaptically propagated to CA1. Intracellular labeling of astrocytes with biocytin revealed that CA1 astrocytes are characterized by a high degree of cell-to-cell coupling; in contrast, cell labeling in CA3 revealed smaller groups and occasionally individual cells. Three individual biocytin-labeled cells had electrophysiological properties indistinguishable from Cs+-sensitive astrocytes but had morphology typical of oligodendroglia. These results provide evidence for a role of K+ uptake via IIR into astrocytes. The segregated expression of potassium channels in a subpopulation of astrocytes suggests that functionally specialized cell types are involved in K+ homeostasis.
Do You Have Any Skin in the Game

This idiom gets right to what bothers me most about this most recent "Why .1. are we still here?" conversation. Beyond the immediate metaphor, "skin in the game" indicates a person entering a space in which something is already in play. In financial circles, the price to play necessitates an investment--a risk. When Nellie McKay wrote her now famous PMLA guest column, "Naming the Problem That Led to the Question 'Who Shall Teach African American Literature?'; or, Are We Ready to Disband the Wheatley Court?," she spoke insistently about both the risks and the necessities of saying what needs to be said, especially when no one wants to hear it. No one in the academy wants to be questioned about why this person or that group is not in the room/sitting at the table/engaged in the discussion, because the question implies, at best, indifference and, at worst, a systemic ambivalence that feeds something much more sinister. This question too often seems unspeakable and too often goes unspoken: What do you really believe, and (how) does that inform your praxis? The interconnectedness of individual praxis and institutional best practices is key. Any scholar editing a volume or organizing a symposium, or any academic organization choosing an editor or panel, might do well simply to practice the same due diligence afforded fields of study predominantly about empowered (in this case white) subjects. What is the likelihood that a group of earnest, intelligent scholars would edit, let's say, a collection on British literature in England and not include a representative number of British scholars? Can we imagine a scenario in which those same scholars were specialists in American, Irish, or postcolonial literature yet published on an important topic in English literature with a highly respected press with nary an objection raised? These questions point to the obvious yet so often obfuscated issue at hand. The importance of the "who" seems to differ significantly depending on what and who is being studied. To my mind, Foreman's call to address Foucault's question "how does it happen" (qtd. in Foreman 307) through what she characterizes as "self-reflection [and] accountability" is not asking for much (307). One could ask that all those who "exercise power" do so while consistently questioning the cultural ethics of their decisions that affect the work and those who produce and benefit from it. Or, one could simply ask that each power broker apply the same academic practices across the board, in every field. Serious academic players should be expected to conduct substantive and in-depth surveys of the terrain to gauge what is already in play and who is on the field. And they should be expected to know that a high level of previous investment is required to be an entitled contributor to an academic venture. …
Marijuana Use and Its Association with Participation, Navigation, and Enrollment in Health Research among African Americans.

This analysis examined the association between marijuana (Mj) use, willingness to participate, navigation and enrollment in health research among African Americans. Data from HealthStreet, a community-engagement model implemented in North Central Florida that reduces health disparities by engaging and linking community members to medical and social services and health research opportunities, were analyzed to determine willingness of African American Mj users to participate, be navigated to and enroll in health research studies. Among 1,496 African American community members, 8.0% were current Mj users, 30.3% were past Mj users and 61.7% reported never using Mj. Current and past Mj users were more willing to volunteer for a research study that only involved the use of medical records, required an overnight stay in a hospital or clinic, or might require use of medical equipment compared to those who never used Mj. Current Mj users were significantly less likely to be navigated (95% CI: 0.21–0.58) to health ...
Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides

Extracellular ATP, at micromolar concentrations, induces significant functional changes in a wide variety of cells and tissues. ATP can be released from the cytosol of damaged cells or from exocytotic vesicles and/or granules contained in many types of secretory cells. There are also efficient extracellular mechanisms for the rapid metabolism of released nucleotides by ecto-ATPases and 5'-nucleotidases. The diverse biological responses to ATP are mediated by a variety of cell surface receptors that are activated when ATP or other nucleotides are bound. The functionally identified nucleotide or P2-purinergic receptors include 1) ATP receptors that stimulate G protein-coupled effector enzymes and signaling cascades, including inositol phospholipid hydrolysis and the mobilization of intracellular Ca2+ stores; 2) ATP receptors that directly activate ligand-gated cation channels in the plasma membranes of many excitable cell types; 3) ATP receptors that, via the rapid induction of surface membrane channels and/or pores permeable to ions and endogenous metabolites, produce cytotoxic or activation responses in macrophages and other immune effector cells; and 4) ADP receptors that trigger rapid ion fluxes and aggregation responses in platelets. Current research in this area is directed toward the identification and structural characterization of these receptors by biochemical and molecular biological approaches.
Nitrogen Balance in Men with Adequate and Deficient Energy Intake at Three Levels of Work

Two studies were conducted to investigate the effects of mild exercise on nitrogen balance in men given diets supplying adequate or slightly limiting energy. In experiment A the diet supplied 91 mg N/kg body weight (0.57 g protein/kg, the FAO/WHO safe level of intake) as egg white; in experiment B the same source was used to provide the 1980 NRC-RDA for adult males, 128 mg N/kg body weight (0.8 g protein/kg). By adjusting energy intake and activity, periods of energy equilibrium and negative energy balance (-15%) were achieved at three levels of activity (X for exercise): no programmed work (0.85X), 1 hour of treadmill walking (1.0X) and 1 hour each of treadmill and cycle ergometry (1.15X). "True" nitrogen balance (TNbal) was more positive or less negative during periods of energy equilibrium as compared to those of energy deficit. This effect of energy balance on TNbal increased with physical activity. At the lower protein intake the mean difference in TNbal between the period of energy equilibrium and that of energy deficit at 1.0X was 0.19 g N/day (nonsignificant difference) and 0.54 g N/day at 1.15X. When protein intake was increased, the difference in TNbal between periods of equilibrium and deficit was significant at all levels of activity: 0.65 g N/day at 0.85X, 0.93 g N/day at 1.0X and 1.09 g N/day at 1.15X. Physical activity was anabolic when energy balance was maintained. In experiment A the addition of 1 hour of exercise (1.0X to 1.15X) spared 2.5 mg N/kg body weight; reducing activity by 1 hour (1.0X to 0.85X) cost 1.4 mg N/kg body weight. In experiment B, TNbal was more positive with increased activity (by 5.9 mg N/kg body weight) and more negative (by 11.5 mg N/kg body weight) when the men were sedentary. During periods of energy deficit, the anabolic effect of activity was also present, although less markedly. When activity increased from 1 to 2 hours in experiment A, TNbal improved by 2.1 mg N/kg body weight and in experiment B, by 3.5 mg N/kg body weight. Thus, circumstances of negative energy balance with adequate protein intake are better tolerated when the energy deficit is generated by physical activity than when it derives from reduced intake; the picture when protein intake is marginal requires further investigation.
Resource Misallocations, Externalities, and Environmentalism: A U.S.-Canadian Analysis

It is a truism among economists that only if the full costs and benefits of economic activity are taken into account by the entrepreneur, will resources be allocated in a Pareto Optimal manner. Under present economic conditions, however, some manufacturers are able to impose costs, particularly pollution or disposal costs, onto third parties. As a result, the actual social costs of such activities are greater than the recorded private costs. At present, the benefits of these goods need be equal to or greater than only the lower private costs, not the higher social costs, if the enterprise is to be able to at least break even and thus continue in operation. This being the case, it follows that the value of at least some of these presently produced goods and services will fall below the total or social costs, and should not be produced at all, if wealth is to be maximized.