Publications by authors named "Stephen Lee"

537 Publications

Systems analysis of miRNA biomarkers to inform drug safety.

Arch Toxicol 2021 Sep 12. Epub 2021 Sep 12.

MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK.

microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.
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http://dx.doi.org/10.1007/s00204-021-03150-9DOI Listing
September 2021

Light emission from plasmonic nanostructures.

J Chem Phys 2021 Aug;155(6):060901

Department of Chemistry, Rice University, 6100 Main Street, Houston, Texas 77005, USA.

The mechanism of light emission from metallic nanoparticles has been a subject of debate in recent years. Photoluminescence and electronic Raman scattering mechanisms have both been proposed to explain the observed emission from plasmonic nanostructures. Recent results from Stokes and anti-Stokes emission spectroscopy of single gold nanorods using continuous wave laser excitation carried out in our laboratory are summarized here. We show that varying excitation wavelength and power change the energy distribution of hot carriers and impact the emission spectral lineshape. We then examine the role of interband and intraband transitions in the emission lineshape by varying the particle size. We establish a relationship between the single particle emission quantum yield and its corresponding plasmonic resonance quality factor, which we also tune through nanorod crystallinity. Finally, based on anti-Stokes emission, we extract electron temperatures that further suggest a hot carrier based mechanism. The central role of hot carriers in our systematic study on gold nanorods as a model system supports a Purcell effect enhanced hot carrier photoluminescence mechanism. We end with a discussion on the impact of understanding the light emission mechanism on fields utilizing hot carrier distributions, such as photocatalysis and nanothermometry.
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http://dx.doi.org/10.1063/5.0053320DOI Listing
August 2021

NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice.

Sci Rep 2021 Aug 12;11(1):16409. Epub 2021 Aug 12.

Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.
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http://dx.doi.org/10.1038/s41598-021-95720-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361163PMC
August 2021

No COVID-19 climate silver lining in the US power sector.

Nat Commun 2021 08 3;12(1):4675. Epub 2021 Aug 3.

Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.

Recent studies conclude that the global coronavirus (COVID-19) pandemic decreased power sector CO emissions globally and in the United States. In this paper, we analyze the statistical significance of CO emissions reductions in the U.S. power sector from March through December 2020. We use Gaussian process (GP) regression to assess whether CO emissions reductions would have occurred with reasonable probability in the absence of COVID-19 considering uncertainty due to factors unrelated to the pandemic and adjusting for weather, seasonality, and recent emissions trends. We find that monthly CO emissions reductions are only statistically significant in April and May 2020 considering hypothesis tests at 5% significance levels. Separately, we consider the potential impact of COVID-19 on coal-fired power plant retirements through 2022. We find that only a small percentage of U.S. coal power plants are at risk of retirement due to a possible COVID-19-related sustained reduction in electricity demand and prices. We observe and anticipate a return to pre-COVID-19 CO emissions in the U.S. power sector.
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http://dx.doi.org/10.1038/s41467-021-24959-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333368PMC
August 2021

Lifestyle Factors and Parkinson's Disease Risk in a Rural New England Case-Control Study.

Parkinsons Dis 2021 2;2021:5541760. Epub 2021 Jul 2.

Geisel School of Medicine at Dartmouth, Rubin Building, Lebanon, NH, USA.

Introduction: Parkinson's disease (PD) is an age-related neurodegenerative disease likely caused by complex interactions between genetic and environmental risk factors. Exposure to pesticides, toxic metals, solvents, and history of traumatic brain injury have been implicated as environmental risk factors for PD, underscoring the importance of identifying risk factors associated with PD across different communities.

Methods: We conducted a questionnaire-based case-control study in a rural area on the New Hampshire/Vermont border, enrolling PD patients and age- and sex-matched controls from the general population between 2017 and 2020. We assessed frequent participation in a variety of recreational and occupational activities and surveyed potential chemical exposures.

Results: Suffering from "head trauma or a concussion" prior to diagnosis was associated with a fourfold increased risk of PD. Adjustment for head trauma negated any risk of participation in "strenuous athletic activities." We observed a 2.7-fold increased risk of PD associated with activities involving lead (adjusted =0.038).

Conclusion: Implicating these factors in PD risk favors public health efforts in exposure mitigation while also motivating future work mechanisms and intervention opportunities.
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http://dx.doi.org/10.1155/2021/5541760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270694PMC
July 2021

Development of a prediction model for clinically important outcomes of acute diverticulitis.

Am J Emerg Med 2021 Jul 9;50:27-35. Epub 2021 Jul 9.

Department of Surgery, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea. Electronic address:

Objective: Acute diverticulitis (AD) is a common disease with various outcomes. When AD is diagnosed in the emergency department (ED), the ED clinician must determine the patient's treatment strategy whether the patient can be discharged, needs to be admitted to the general ward, ICU, or needs surgical consultation. This study aimed to identify potential risk factors for clinically important outcomes (CIOs) and to develop a prediction model for CIOs in AD to aid clinical decision making in the ED.

Methods: Retrospective data from between 2013 and 2017 in an ED in an urban setting were reviewed for adult AD. Potential risk factors were age, sex, past medical history, symptoms, physical exams, laboratory results, and imaging results. A CIO was defined as a case with one of the following outcomes: hospital death, ICU admission, surgery or invasive intervention, and admission for 7 or more days. The prediction model for CIOs was developed using potential risk factors. Model discrimination and calibration were assessed using the area under the curve (AUC) and 95% confidence intervals (CIs) and the Hosmer-Lemeshow (HL) test, respectively. Model validation was conducted using 500 random bootstrap samples.

Results: Of the final 337 AD patients, 63 patients had CIOs. Six potential factors (age, abdominal pain (≥ 3 days), anorexia, rebound tenderness, white blood cell count (> 15,000/μl), C-reactive protein (> 10 mg/dL), and CT findings of a complication) were used for the final model. The AUC (95% CI) for CIOs was 0.875 (0.826-0.923), and χ was 2.969 (p-value = 0.936) with the HL test. Validation using bootstrap samples resulted in an optimism-corrected AUC of 0.858 (0.856-0.861).

Conclusion: A prediction model for clinically important outcomes of AD visiting a single ED showed good discrimination and calibration power with an acceptable range.
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http://dx.doi.org/10.1016/j.ajem.2021.06.071DOI Listing
July 2021

Single limb electrocardiogram using vector mapping: Evaluation and validation of a novel medical device.

J Electrocardiol 2021 Jul-Aug;67:136-141. Epub 2021 Jun 30.

Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, FL, United States; Tiger Tech Solutions, Inc., Miami, FL, United States.

Introduction: The Tiger Tech Warfighter Monitor (WFM) is a novel single-limb device for ECG acquisition. The WFM provides true (not derived) single limb Electrocardiogram monitoring (ECG) to provide heart rate and R-R interval monitoring between QRS complexes. Herein, we evaluate the diagnostic accuracy of the WFM heart rate, R-R interval monitoring, and heart rate variability monitoring in comparison to a 2‑lead chest ECG.

Methods: Data was collected under Institutional Review Board (IRB) approval. Patients available within our institution's pre-operative holding unit were randomly selected to undergo simultaneous chest and WFM ECG monitoring. 3-5-min measurements were taken depending on the patient's availability. Data was saved to two separate mobile phones and time-stamped for synchronization. A proprietary Tiger Tech extraction algorithm was used to tag proper features on both the WFM 1-Limb ECG and Chest ECG data files. A separate algorithm was then used to compare the beat-to-beat variations between the ECGs.

Results: Data was extracted and analyzed on 26 subjects. Linear regression of heart rate analysis revealed excellent correlations with an R of 0.99 (p < 0.05). Similar linear regression evaluation of R-R interval correlation demonstrated a mean R value of 0.95 (p < 0.05). Statistically significant correlation was achieved in all 26 included study participants. Heart rate variability also achieved excellent correlation (SDNN R = 0.997, RMSSD R = 0.995, LnRMSSD R = 0.992, p << 0.05).

Conclusion: Results demonstrate that the WFM achieves excellent correlation with chest ECG for heart rate, R-R internals, and heart rate variability.
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http://dx.doi.org/10.1016/j.jelectrocard.2021.06.003DOI Listing
June 2021

Structural Features in Some Layered Hybrid Copper Chloride Perovskites: ACuCl or ACuCl.

Inorg Chem 2021 Aug 9;60(15):11014-11024. Epub 2021 Jul 9.

School of Chemistry and EaStChem, University of St Andrews, St Andrews, KY16 9ST, United Kingdom.

We present three new hybrid copper(II) chloride layered perovskites of generic composition ACuCl or ACuCl, which exhibit three distinct structure types. (-PdH)CuCl (-PdH = protonated -phenylenediamine) adopts a Dion-Jacobson (DJ)-like layered perovskite structure type and exhibits a very large axial thermal contraction effect upon heating, as revealed via variable-temperature synchrotron X-ray powder diffraction (SXRD). This can be attributed to the contraction of an interlayer block, via a slight repositioning of the -PdH moiety. (3-AbaH)CuCl (3-AbaH = protonated 3-aminobenzoic acid) and (4-AbaH)CuCl (4-AbaH = protonated 4-aminobenzoic acid) possess the same generic formula as Ruddlesden-Popper (RP) layered perovskites, ABX, but adopt different structures. (4-AbaH)CuCl adopts a near-staggered structure type, whereas (3-AbaH)CuCl adopts a near-eclipsed structure type, which resembles the DJ rather than the RP family. (3-AbaH)CuCl also displays static disorder of the [CuCl] layers. The crystal structures of each are discussed in terms of the differing nature of the templating molecular species, and these are compared to related layered perovskites. Preliminary magnetic measurements are reported, suggesting dominant ferromagnetic interactions.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00705DOI Listing
August 2021

Endemic Xanthium strumarium poisoning in cattle in flooded areas of the Araguari River, Minas Gerais, Brazil.

Toxicon 2021 Sep 2;200:23-29. Epub 2021 Jul 2.

Graduate Program in Animal Science in the Tropics, Escola de Medicina Veterinária e Zootecnia, Universidade Federal da Bahia, Salvador, Bahia, Brazil. Electronic address:

In this paper, we describe poisoning outbreaks of Xanthium strumarium in cattle on the borders of the Araguari River, Southeastern Brazil. In this region, several hydroelectric plants promote transient flooding, which creates a favorable environment for the invasion of X. strumarium in extensive areas, often as the predominant species in those areas. The outbreaks occurred between July and September (dry season). Bovines of all ages were affected, including suckling animals. Mortality varied from 2% to 5.5%. The animals exhibited ataxia, weakness, loss of balance, recumbency, and the majority were found dead. Laboratory results showed a marked increase in the serum activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. Histological and ultrastructural changes in the liver consisted of centrilobular necrosis and hemorrhage. On toxicological evaluation, the dicotyledons contained 0.30 μg/mg of atractyloside and 0.37 μg/mg of carboxyatractyloside. Considerable economic loss has occurred in this region due to the lack of knowledge regarding X. strumarium as a toxic plant and its adaptation to the environmental and climatic conditions of the region, which have made the condition endemic.
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http://dx.doi.org/10.1016/j.toxicon.2021.06.019DOI Listing
September 2021

Sex differences in mortality after an acute coronary syndrome increase with lower country wealth and higher income inequality.

Rev Esp Cardiol (Engl Ed) 2021 Jun 23. Epub 2021 Jun 23.

Departamento de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain; Grupo de Investigación Cardiovascular Traslacional Multidisciplinaria, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (CIBERCV), Spain. Electronic address:

Introduction And Objectives: Although several factors associated with sex differences in the management and outcomes after acute coronary syndrome (ACS) have been reported, little is known about the influence of socioeconomic factors on sex disparities. Our aim was to evaluate the influence of country wealth and income inequality on national sex differences in mortality after ACS.

Methods: Sex differences in 2-year postdischarge mortality were evaluated in 23 489 ACS patients from the EPICOR and EPICOR Asia registries. Adjusted Cox regression models by country-based terciles of gross national income per capita and income inequality were used.

Results: Women (24.3%) were older than men (65.5 vs 59.4 years, P <.001), had more comorbidities, were less often revascularized (63.6% vs 75.6%, P <.001) and received fewer guideline recommended therapies at discharge. Compared with men, a higher percentage of women died during follow-up (6.4% vs 4.9%, P <.001). The association between sex and mortality changed direction from hazard ratio (HR) 1.32 (95%CI, 1.17-1.49) in the univariate assessment to HR 0.76 (95%CI, 0.67-0.87) after adjustment for confounders. These differences were more evident with increasing country wealth (HR = 0.85; 95%CI, 0.72-1.00; HR = 0.66; 95%CI, 0.50-0.87; HR = 0.60; 95%CI, 0.40-0.90; trend test P = .115) and with decreasing income inequality (HR = 0.54; 95%CI, 0.36-0.81; HR = 0.66; 95%CI, 0.50-0.88; HR = 0.87; 95%CI, 0.74-1.03; trend test P = .031).

Conclusions: Women with ACS living in high socioeconomic countries showed a lower postdischarge mortality risk compared with men. This risk was attenuated in countries with poorer socioeconomic background, where adjusted mortality rates were similar between women and men.
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http://dx.doi.org/10.1016/j.rec.2021.05.006DOI Listing
June 2021

Impact of the COVID-19 Pandemic on Emergency Department Transfers to a Higher Level of Care.

West J Emerg Med 2021 May 17;22(3):561-564. Epub 2021 May 17.

Kingman Regional Medical Center Emergency Medicine, Kingman, Arizona.

Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, a reduction in emergency department (ED) visits was seen nationally according to the US Centers for Disease Control and Prevention. However, no data currently exists for the impact of ED transfers to a higher level of care during this same time period. The primary objective of the study was to determine whether the COVID-19 pandemic affected the rate of non-COVID-19 transfers from a rural community ED.

Methods: We completed a retrospective chart review of all ED patients who presented to Kingman Regional Medical Center in Kingman, Arizona, from March 1-June 31, 2019 and March 1-June 31, 2020. To ensure changes were not due to seasonal trends, we examined transfer rates from the same four-month period in 2019 and 2020. Patients were included in the study if they were transferred to an outside facility for a higher level of care not related to COVID-19.

Results: Between the time periods studied there was a 25.33% (P = 0.001) reduction in total ED volume and a 21.44% (P = 0.009) reduction in ED transfers to a higher level of care. No statistical difference was noted in ED transfer volume following adjustment for decreased ED volumes. Transfers for gastroenterology (45%; P = 0.021), neurosurgery (29.2%; P = 0.029), neurology (76.3%; P < 0.001), trauma (37.5%; P = 0.039), urology (41.8%; P = 0.012), and surgery (56.3%; P = 0.028) all experienced a decrease in transfer rates during the time period studied. When gender was considered, males exhibited an increased rate of transfers to psychiatric facilities (P = 0.018).

Conclusion: Significant reductions in both ED volume and transfers have coincided with the emergence of the COVID-19 pandemic. Further research is needed to determine how the current pandemic has affected patient care.
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http://dx.doi.org/10.5811/westjem.2021.3.50907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203003PMC
May 2021

Wavelength-Dependent Photothermal Imaging Probes Nanoscale Temperature Differences among Subdiffraction Coupled Plasmonic Nanorods.

Nano Lett 2021 06 1;21(12):5386-5393. Epub 2021 Jun 1.

Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.

Plasmonic structures confine electromagnetic energy at the nanoscale, resulting in local, inhomogeneous, controllable heating, but reading out the temperature using optical techniques poses a difficult challenge. Here, we report on the optical thermometry of individual gold nanorod trimers that exhibit multiple wavelength-dependent plasmon modes resulting in measurably different local temperature distributions. Specifically, we demonstrate how photothermal microscopy encodes different wavelength-dependent temperature profiles in the asymmetry of the photothermal image point spread function. These asymmetries are interpreted through companion numerical simulations to reveal how thermal gradients within the trimer can be controlled by exciting its hybridized plasmon modes. We also find that plasmon modes that are optically dark can be excited by focused laser beam illumination, providing another route to modify thermal profiles beyond wide-field illumination. Taken together these findings demonstrate an all-optical thermometry technique to actively create and measure nanoscale thermal gradients below the diffraction limit.
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http://dx.doi.org/10.1021/acs.nanolett.1c01740DOI Listing
June 2021

Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer.

Nat Commun 2021 05 24;12(1):3039. Epub 2021 May 24.

Department of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.

The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
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http://dx.doi.org/10.1038/s41467-021-23171-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144406PMC
May 2021

Application of a sub-0.1-mm implantable mote for in vivo real-time wireless temperature sensing.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Department of Electrical Engineering, Columbia University, New York, NY 10027, USA.

There has been increasing interest in wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. Here, we present such an implant that uses a conventional ultrasound imager for wireless powering and data communication and acts as a probe for real-time temperature sensing, including the monitoring of body temperature and temperature changes resulting from therapeutic application of ultrasound. The sub-0.1-mm, sub-1-nW device, referred to as a mote, achieves aggressive miniaturization through the monolithic integration of a custom low-power temperature sensor chip with a microscale piezoelectric transducer fabricated on top of the chip. The small displaced volume of these motes allows them to be implanted or injected using minimally invasive techniques with improved biocompatibility. We demonstrate their sensing functionality in vivo for an ultrasound neurostimulation procedure in mice. Our motes have the potential to be adapted to the distributed and localized sensing of other clinically relevant physiological parameters.
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http://dx.doi.org/10.1126/sciadv.abf6312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104878PMC
May 2021

Use of Herbarium Voucher Specimens To Investigate Phytochemical Composition in Poisonous Plant Research.

J Agric Food Chem 2021 Apr 2;69(14):4037-4047. Epub 2021 Apr 2.

Missouri Botanical Garden, 4344 Shaw Boulevard, St. Louis, Missouri 63110, United States.

Poisonous plants cause large losses to the livestock industry through death, reduced production efficiency, reproductive dysfunction, and compromised harvesting of rangeland and pasture forages. Research investigating poisonous plants is complex because there are hundreds of genera of toxic plants representing thousands of species. To investigate the effects of poisonous plants on livestock, a clear understanding of the taxonomic identity of the plant and the ability to collect the plant in sufficient quantities for scientific studies is required. Subsequently, the active principles must be defined and investigated in the taxa of interest to better predict risk and make recommendations to reduce losses. Herbaria are collections of preserved plant specimens and are an important resource in poisonous plant research. Voucher specimens have often been used in the identification of the plant for the experimental reproduction of suspected livestock poisoning associated with a spontaneous case. More recently, herbarium specimens have been used to investigate the chemical composition of toxic plants as well as the distribution of different chemotypes over the landscape. The primary purpose of this review is to highlight the chemical analysis of herbarium specimens in poisonous plant research.
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http://dx.doi.org/10.1021/acs.jafc.1c00708DOI Listing
April 2021

Soft, skin-interfaced sweat stickers for cystic fibrosis diagnosis and management.

Sci Transl Med 2021 03;13(587)

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60202, USA.

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.
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http://dx.doi.org/10.1126/scitranslmed.abd8109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351625PMC
March 2021

Chemical Interface Damping of Surface Plasmon Resonances.

Acc Chem Res 2021 Apr 31;54(8):1950-1960. Epub 2021 Mar 31.

ConspectusMetal nanoparticles have been utilized for a vast amount of plasmon enhanced spectroscopies and energy conversion devices. Their unique optical properties allow them to be used across the UV-vis-NIR spectrum tuned by their size, shape, and material. In addition to utility in enhanced spectroscopy and energy/charge transfer, the plasmon resonance of metal nanoparticles is sensitive to its surrounding environment in several ways. The local refractive index determines the resonance wavelength, but plasmon damping, as indicated by the homogeneous line width, also depends on the surface properties of the metal nanoparticles. Plasmon oscillations can decay through interband, intraband, radiation, and surface damping. While the first three damping mechanisms can be modeled based on bulk dielectric data using electromagnetic simulations, surface damping does not depend on the material properties of the nanoparticle alone but rather on the interface composition between the nanoparticle and its surrounding environment. In this Account, we will discuss three different metal nanoparticle interfaces, identifying the surface damping contribution from chemical interface damping and how it manifests itself in different interface types. On the way to uncovering the various damping contributions, we use three different single-particle spectroscopic techniques that are essential to measuring homogeneous plasmon line widths: darkfield scattering, photothermal heterodyne imaging, and photoluminescence microscopies. Obtaining the homogeneous plasmon spectrum through single-particle spectroscopy is paramount to measuring changes in plasmon damping, where even minor size and shape heterogeneities can completely obfuscate the broadening caused by surface damping. Using darkfield scattering spectroscopy, we first describe a model for chemical interface damping by expanding upon the surface damping contribution to the plasmon resonance line width to include additional influences due to adsorbed molecules. Based on the understanding of chemical interface damping as a surface damping mechanism, we then carefully compare how two molecular isomers lead to greatly different damping rates upon adsorption to gold nanorods due to differences in the formation of image dipoles within the metal nanoparticles. This plasmon damping dependence on the chemical identity of the interface is strongly correlated with the chemical's electronegativity. A similar damping trend is observed for metal oxide semiconductors, where the metal oxide with greater electron affinity leads to larger interface damping. However, in this case, the mechanism is different for the metal oxide interfaces, as damping occurs through charge transfer into interfacial states. Finally, the damping effect of catalytic metal nanoislands on gold nanorods is compared for the three spectroscopic methods mentioned. Through correlated single-particle scattering, absorption, and photoluminescence spectroscopy, the mechanism for metal-metal interface damping is determined most likely to arise from an enhanced absorption, although charge transfer cannot be ruled out. From this body of research, we conclude that chemical interface damping is a major component of the total damping rate of the plasmon resonance and critically depends on the chemical interface of the metallic nanoparticles. Plasmon damping occurs through distinct mechanisms that are important to differentiate when considering the purpose of the plasmonic nanoparticle: enhanced spectroscopy, energy conversion, or catalysis. It must also be noted that many of the mechanisms are currently indifferentiable, and thus, new single-particle spectroscopic methods are needed to further characterize the mechanisms underlying chemical interface damping.
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http://dx.doi.org/10.1021/acs.accounts.0c00872DOI Listing
April 2021

Clinical, pathologic, and toxicologic characterization of (lance-leaf sage) poisoning in cattle fed contaminated hay.

J Vet Diagn Invest 2021 May 10;33(3):538-547. Epub 2021 Mar 10.

Colorado State University, Veterinary Diagnostic Laboratory, Fort Collins, CO.

(lance-leaf sage)-contaminated alfalfa hay was fed to ~500 mixed-breed beef cattle. Within hours of exposure, nearly half of the cattle developed lethargy, anorexia, depression, and recumbency, followed by bellowing, colic, and death. Even though the uneaten contaminated hay was removed the first day, nearly 100 animals died within the first 48 h. Three of these cattle were examined postmortem, and tissues and hay samples were collected for microscopic and chemical analysis. Several days later, a smaller number of the clinically poisoned cattle developed neurologic disease with aberrant behavior, aggression, icterus, blindness, exhaustion, and death. A total of 165 cattle were fatally poisoned. Poisoned cattle had swollen, dark, mottled livers that had a prominent nutmeg-like lobular pattern on cut section. Histologically, there was severe centrilobular-to-panlobular hepatic necrosis with marked hepatocellular swelling, degeneration, and necrosis. The surviving cattle developed liver disease characterized by altered serum biochemical analyses and microscopic hepatocellular degeneration and necrosis. In subsequent biopsies and analysis, these lesions resolved within 6-7 mo. After confirming toxicity of the hay in cattle, goats, and mice, followed by a mouse bioassay-guided chemical fractionation process, was identified as the contaminant in the hay responsible for the hepatotoxicity. has not been reported previously to cause fatal hepatotoxicity in livestock in North America, to our knowledge.
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http://dx.doi.org/10.1177/1040638721995784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120075PMC
May 2021

Synthetic Biology towards Engineering Microbial Lignin Biotransformation.

Trends Biotechnol 2021 Oct 9;39(10):1037-1064. Epub 2021 Mar 9.

Department of Chemical and Biomolecular Engineering, Clemson University, 206 South Palmetto Boulevard, Clemson, SC 29634, USA; Current address: Department of Chemical and Biomolecular Engineering, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA. Electronic address:

Lignin is the second most abundant biopolymer on earth and is a major source of aromatic compounds; however, it is vastly underutilized owing to its heterogeneous and recalcitrant nature. Microorganisms have evolved efficient mechanisms that overcome these challenges to depolymerize lignin and funnel complex mixtures of lignin-derived monomers to central metabolites. This review summarizes recent synthetic biology efforts to enhance lignin depolymerization and aromatic catabolism in bacterial and fungal hosts for the production of both natural and novel bioproducts. We also highlight difficulties in engineering complex phenotypes and discuss the outlook for the future of lignin biological valorization.
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http://dx.doi.org/10.1016/j.tibtech.2021.02.003DOI Listing
October 2021

Impact of age on the comparison between short-term vs 12-month dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: 2-Year follow-up results of the REDUCE trial.

Atherosclerosis 2021 03 16;321:39-44. Epub 2021 Feb 16.

AOU Maggiore della Carità, Eastern Piedmont University, Novara, Italy. Electronic address:

Background And Aims: The impact of advanced age on the optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary revascularization (PCI) is still greatly debated. Therefore, the aim of the present sub-analysis of the REDUCE trial was to assess the impact of age on the comparison between a short 3 months vs standard 12 months DAPT in ACS patients treated with the COMBO Dual Stent Therapy.

Methods: The REDUCE trial is a prospective, multicenter, investigator-initiated study that randomized ACS patients undergoing PCI with the COMBO drug eluting stent to either 3 or 12 months of DAPT. The study population was divided according to age (
Results: From June 2014 to May 2016, 1496 patients were included in the study, of whom 205 (13.7%) ≥75 years of age. Among them, 50.7% of the elderly and 50.2% of younger patients were assigned to the 3-month DAPT treatment. Baseline characteristics were well matched between the two arms, except for a higher rate of males (p=0.02) and a reduced number of lesions on the right coronary artery (p=0.02) in elderly patients treated for the short DAPT duration. Median follow-up was 682.5 days [IQR:667-731]. At 12 months, no difference in the primary endpoint was observed according to DAPT duration in both patients aged ≥75 years (22.1% vs 18.8%, HR [95%CI] = 1.6 [0.73-3.5], p=0.24) and younger ones (9.7% vs 10.9%, HR [95%CI] = 0.85 [0.59-1.27], p=0.44; p INT = 0.15). Results were confirmed after correction for baseline differences among the elderly (adjusted HR [95%CI] = 1.7 [0.75-3.9], p=0.21). Comparable rates of survival, thrombotic (MI, stent thrombosis, TVR, stroke) and bleeding events were observed with the two DAPT strategies, with no impact of age.

Conclusions: The present study shows that among ACS patients randomized in the REDUCE trial, a 3-month DAPT strategy was comparable to a standard 12-month DAPT at a 2-year follow-up for both ischemic and bleeding endpoints, in elderly and younger patients. Thus, despite presenting the limitations of a subgroup analysis, our study strengthens the feasibility of a shorter DAPT duration even among high-risk subsets of ACS patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.02.006DOI Listing
March 2021

Efficacy of a new dispatcher-assisted cardiopulmonary resuscitation protocol with audio call-to-video call transition.

Am J Emerg Med 2021 06 24;44:26-32. Epub 2021 Jan 24.

Laboratory of Emergency Medical Services, Seoul National University Hospital Biomedical Research Institute; National EMS Control Center, National Fire Agency, Sejong, Korea. Electronic address:

Background: Video call based dispatcher-assisted cardiopulmonary resuscitation (V-DACPR) has been suggested to improve the quality of bystander cardiopulmonary resuscitation. In the current system, dispatchers must convert the audio calls to video calls to provide V-DACPR. We aimed to develop new audio call-to-video call transition protocols and test its efficacy and safety compared to conventional DACPR(C-DACPR).

Methods: This was a randomized controlled simulation trial that compared the quality of bystander chest compression that was performed under three different DACPR protocols: C-DACPR, V-DACPR with rapid transition, and V-DACPR with delayed transition. Adult volunteers excluding healthcare providers were recruited for the trial. The primary outcome of the study was the mean proportion of adequate hand positioning during chest compression.

Results: Simulation results of 131 volunteers were analyzed. The mean proportion of adequate hand positioning was highest in V-DACPR with rapid transition (V-DACPR with rapid transition vs. C-DACPR: 92.7% vs. 82.4%, p = 0.03). The mean chest compression depth was deeper in both V-DACPR groups than in the C-DACPR group (V-DACPR with rapid transition vs. C-DACPR: 40.7 mm vs. 35.9 mm, p = 0.01, V-DACPR with delayed transition vs. C- DACPR: 40.9 mm vs. 35.9 mm, p = 0.01). Improvement in the proportion of adequate hand positioning was observed in the V-DACPR groups (r = 0.25, p < 0.01 for rapid transition and r = 0.19, p < 0.01 for delayed transition).

Conclusion: Participants in the V-DACPR groups performed higher quality chest compression with higher appropriate hand positioning and deeper compression depth compared to the C-DACPR group.
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http://dx.doi.org/10.1016/j.ajem.2021.01.049DOI Listing
June 2021

Local translation in nuclear condensate amyloid bodies.

Proc Natl Acad Sci U S A 2021 02;118(7)

Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136;

Biomolecular condensates concentrate molecules to facilitate basic biochemical processes, including transcription and DNA replication. While liquid-like condensates have been ascribed various functions, solid-like condensates are generally thought of as amorphous sites of protein storage. Here, we show that solid-like amyloid bodies coordinate local nuclear protein synthesis (LNPS) during stress. On stimulus, translationally active ribosomes accumulate along fiber-like assemblies that characterize amyloid bodies. Mass spectrometry analysis identified regulatory ribosomal proteins and translation factors that relocalize from the cytoplasm to amyloid bodies to sustain LNPS. These amyloidogenic compartments are enriched in newly transcribed messenger RNA by Heat Shock Factor 1 (HSF1). Depletion of stress-induced ribosomal intergenic spacer noncoding RNA (rIGSRNA) that constructs amyloid bodies prevents recruitment of the nuclear protein synthesis machinery, abolishes LNPS, and impairs the nuclear HSF1 response. We propose that amyloid bodies support local nuclear translation during stress and that solid-like condensates can facilitate complex biochemical reactions as their liquid counterparts can.
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http://dx.doi.org/10.1073/pnas.2014457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896321PMC
February 2021

Long-Term Antithrombotic Therapy and Clinical Outcomes in Patients with Acute Coronary Syndrome and Renal Impairment: Insights from EPICOR and EPICOR Asia.

Am J Cardiovasc Drugs 2021 Jul 4;21(4):471-482. Epub 2021 Feb 4.

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

Background: Information is lacking on long-term management of patients with acute coronary syndrome (ACS) and chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m).

Objectives: Our objectives were to describe antithrombotic management patterns and outcomes in patients with ACS with varying renal function from the EPICOR (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients; NCT01171404) and EPICOR Asia (NCT01361386) studies.

Methods: EPICOR and EPICOR Asia were prospective observational studies of patients who survived hospitalization for ACS and were enrolled at discharge in 28 countries across Europe, Latin America, and Asia. The studies were conducted from 2010 to 2013 and from 2011 to 2014, respectively. This analysis evaluated patient characteristics and oral antithrombotic management patterns and outcomes up to 2 years post-discharge according to admission eGFR: ≥ 90, 60-89, 30-59, or < 30 mL/min/1.73 m.

Results: Among 22,380 patients with available data, eGFR < 60 mL/min/1.73 m was observed in 16.7%. Patients with poorer renal function were older, were at greater cardiovascular risk, and had more prior cardiovascular disease and bleeding. Patients with CKD underwent fewer cardiovascular interventions and had more in-hospital cardiovascular and bleeding events. Dual antiplatelet therapy was less likely at discharge in patients with eGFR < 30 (82.3%) than in those with ≥ 90 (91.3%) mL/min/1.73 m and declined more sharply during follow-up in patients with low eGFR (p < 0.0001). An adjusted proportional hazards model showed that patients with lower eGFR levels had a higher risk of cardiovascular events and bleeding.

Conclusions: The presence of CKD in patients with ACS was associated with less aggressive cardiovascular management and an increased risk of cardiovascular events.
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http://dx.doi.org/10.1007/s40256-020-00447-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263456PMC
July 2021

Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses.

Nat Commun 2021 01 29;12(1):677. Epub 2021 Jan 29.

Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Neurotransmitter is released synchronously and asynchronously following an action potential. Our recent study indicates that the release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center in mouse hippocampal synapses. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release can lead to maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are likely organized to activate NMDA receptors efficiently.
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http://dx.doi.org/10.1038/s41467-021-21004-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846561PMC
January 2021

Parents' and Students' Perceptions of Telepractice Services for Speech-Language Therapy During the COVID-19 Pandemic: Survey Study.

JMIR Pediatr Parent 2021 Jan 28;4(1):e25675. Epub 2021 Jan 28.

Human Communication, Development, and Information Sciences, Faculty of Education, The University of Hong Kong, Hong Kong.

Background: The ongoing COVID-19 pandemic has resulted in the suspension of face-to-face classes and a considerable increase in the use of telepractice services in speech-language pathology. However, little is known about parents' and students' satisfaction with telepractice services and their preferences for different service delivery modes. These factors may affect therapy effectiveness and the future adoption of telepractice.

Objective: We evaluated students' and parents' perceptions of telepractice efficacy and their preferences for different service delivery modes (ie, on-site practice vs telepractice). We also identified factors that affect parents' and students' preferences for different service delivery modes during the COVID-19 pandemic.

Methods: A 19-question survey on telepractice satisfaction and preferences was administered to 41 Hong Kong Chinese students and 85 parents who received telepractice services from school-based speech-language pathologists during the COVID-19 class suspension period. In addition to providing demographic information and data on the implementation of telepractice services, all participants were asked to rate their perceptions of the efficacy of telepractice services and compare on-site practices to telepractice on a 5-point Likert scale (ie, 1=strongly disagree/prefer the use of on-site speech-language therapy services and 5=strongly agree/prefer the use of telepractice services).

Results: Despite the fact that telepractice efficacy was highly rated by parents (95% CI 3.30-3.66) and students (95% CI 3.21-3.76), both groups believed that telepractice was less effective than on-site practices (parents: 95% CI 2.14-2.52; students: 95% CI 2.08-2.65). Moreover, parents preferred on-site practices over telepractice (95% CI 2.04-2.43), whereas students did not prefer one mode of practice over the other (95% CI 2.74-3.41). A significant association between telepractice efficacy and a preference for telepractice services was found only among the students (τ=.43, P<.001), not the parents (τ=.07; P=.44).

Conclusions: Although telepractice is an acceptable alternative service delivery option for providing speech and language therapy services to school-aged individuals, speech-language therapists and parents must play a more proactive role in telepractice services to facilitate effective communication between clinicians and parents.
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http://dx.doi.org/10.2196/25675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850632PMC
January 2021

Plasma-borne indicators of inflammasome activity in Parkinson's disease patients.

NPJ Parkinsons Dis 2021 Jan 4;7(1). Epub 2021 Jan 4.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related "speck" formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.
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http://dx.doi.org/10.1038/s41531-020-00147-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782812PMC
January 2021

Time to first defibrillation and survival outcomes of out-of-hospital cardiac arrest with refractory ventricular fibrillation.

Am J Emerg Med 2021 02 14;40:96-102. Epub 2020 Dec 14.

Department of Emergency Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Introduction: Timely defibrillation is associated with increased survival in out-of-hospital cardiac arrest (OHCA) cases. This study aimed to determine whether the time to first defibrillation was associated with good neurological outcomes in OHCA patients with refractory ventricular fibrillation.

Methods: Bystander-witnessed adult OHCA patients with presumed cardiac etiology who presented with ventricular fibrillation and received ≥2 successive prehospital defibrillations from emergency medical services between 2013 and 2018 were included. The times from collapse to first defibrillation were categorized into Group 1 (0-5 min), Group 2 (6-10 min), Group 3 (11-15 min), and Group 4 (16-60 min). The primary outcome was a good neurological recovery (cerebral performance category 1-2). Multivariable logistic regression analysis was performed to calculate the adjusted odd ratios (AORs) and 95% confidence intervals (CIs) for outcomes according to time group (Group 1 as the reference) and per 1-min delay.

Results: The study included 5753 patients, with overall rates of 34.4% for survival to discharge and 27.2% for good neurological recovery. The median number of prehospital defibrillations was 3 (interquartile range 2-5). Relative to Group 1, the AORs for good neurological recovery were 0.58 in Group 2 (95% CI: 0.41-0.82), 0.42 in Group 3 (95% CI: 0.29-0.60), and 0.19 in Group 4 (95% CI: 0.13-0.29). When time from collapse to first EMS defibrillation was analyzed as a continuous variable, each 1-min delay was associated with a significant decrease in the likelihood of good neurological recovery (AOR: 0.93, 95% CI: 0.91-0.94).

Conclusions: A short time from collapse to first defibrillation was associated with good neurological recovery among patients with OHCA and refractory ventricular fibrillation. This result suggests that a failed first shock still has a positive effect if it is delivered quickly.
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http://dx.doi.org/10.1016/j.ajem.2020.12.019DOI Listing
February 2021

Skin-interfaced microfluidic system with personalized sweating rate and sweat chloride analytics for sports science applications.

Sci Adv 2020 Dec 11;6(50). Epub 2020 Dec 11.

Epicore Biosystems Inc, Cambridge, MA 02139, USA.

Advanced capabilities in noninvasive, in situ monitoring of sweating rate and sweat electrolyte losses could enable real-time personalized fluid-electrolyte intake recommendations. Established sweat analysis techniques using absorbent patches require post-collection harvesting and benchtop analysis of sweat and are thus impractical for ambulatory use. Here, we introduce a skin-interfaced wearable microfluidic device and smartphone image processing platform that enable analysis of regional sweating rate and sweat chloride concentration ([Cl]). Systematic studies ( = 312 athletes) establish significant correlations for regional sweating rate and sweat [Cl] in a controlled environment and during competitive sports under varying environmental conditions. The regional sweating rate and sweat [Cl] results serve as inputs to algorithms implemented on a smartphone software application that predicts whole-body sweating rate and sweat [Cl]. This low-cost wearable sensing approach could improve the accessibility of physiological insights available to sports scientists, practitioners, and athletes to inform hydration strategies in real-world ambulatory settings.
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http://dx.doi.org/10.1126/sciadv.abe3929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732194PMC
December 2020

Jekyll and Hyde: Activating the Hypoxic Translational Machinery.

Trends Biochem Sci 2021 03 9;46(3):171-174. Epub 2020 Dec 9.

Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address:

Global translational remodeling has emerged as a principal mechanism of biological adaptation. Oxygen deficiency (hypoxia) disables the basal protein synthesis machinery ('Jekyll') and activates a hypoxic translational architecture ('Hyde') to drive translatome remodeling. Independent from mRNA-level fluctuations, this newer paradigm modernizes a field traditionally dominated by the hypoxia-inducible factor (HIF) transcriptional program.
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http://dx.doi.org/10.1016/j.tibs.2020.11.006DOI Listing
March 2021

A translational program that suppresses metabolism to shield the genome.

Nat Commun 2020 11 13;11(1):5755. Epub 2020 Nov 13.

Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.

Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.
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http://dx.doi.org/10.1038/s41467-020-19602-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666154PMC
November 2020
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