scholarly journals Non-invasive Imaging of Sense of Smell by Tracking the Voltage-Gated Sodium Channel NaV1.7

2021 ◽  
Author(s):  
Dauren Adilbay ◽  
Junior Gonzales ◽  
Paula Demetrio de Souza Franca ◽  
Sheryl Roberts ◽  
Snehal Patel ◽  
...  
Keyword(s):  
Olfactory Epithelium ◽  
Imaging System ◽  
Inverse Correlation ◽  
Fluorescent Imaging ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Congenital Insensitivity ◽  
Radiant Efficiency ◽  
Time Required

Background: Anosmia/hyposmia affects 13.3 million people in the U.S. alone according to the recent U.S. National Health and Nutrition Examination Survey (NHANES). Hundreds of thousands more people with persistent olfactory dysfunction will be added to this number due to the COVID-19 pandemic. Patients with loss-of-function mutations in SCN9A, the gene encoding NaV1.7, experience anosmia in addition to congenital insensitivity to pain. Tsp1a is a recently discovered peptide that inhibits NaV1.7 with high potency and selectivity. In this study, we examined whether a fluorescently tagged version of Tsp1a could be used to visualize normal and damaged mouse olfactory nerves. Methods: Athymic nude mice were intravenously injected with Tsp1a-IR800. As a control, mice were injected with PBS only, and as a blocking control were injected with combination of Tsp1a and Tsp1a-IR800. All mice were imaged in-vivo and epifluorescence images were acquired using an IVIS Spectrum animal imaging system. Semiquantitative analysis of the Tsp1a-IR800 signal was conducted by measuring the average radiant efficiency in the region of the olfactory epithelium/bulb (ROEB). Methimazole was used to chemically ablate the olfactory epithelium. We performed a food buried test to correlate the level of anosmia with the level of radiance efficiency. Results: The area of olfactory epithelium/bulb was clearly visible in epifluorescence in-vivo images of mice receiving the imaging agent. The radiant efficiency was significantly less in both mice injected with PBS and in mice injected with the blocking formulation. The mice after olfactory ablation had a significantly reduced radiant efficiency compared with normal mice. Moreover, there was a statistically significant and inverse correlation between the time required for the mouse to find buried food and the radiant efficiency. We also performed immunohistochemistry using NaV1.7 antibody. Mice after olfactory ablation as well as COVID-19-infected mice had significantly lower expression of NaV1.7 on the level of olfactory epithelium/bulb. Conclusion: We show that the fluorescent imaging of mouse olfactory epithelium/bulb is possible, suggesting that labeled Tsp1a tracers may serve as the first objective diagnostic tool of smell disorders, including those caused by COVID-19.

scholarly journals Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery

2021 ◽  
Vol 187 (1) ◽  
pp. 145-153
Author(s):  
Conor R. Lanahan ◽  
Bridget N. Kelly ◽  
Michele A. Gadd ◽  
Michelle C. Specht ◽  
Carson L. Brown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Real Time ◽  
Imaging System ◽  
Ex Vivo ◽  
Menopausal Status ◽  
Fluorescent Imaging ◽  
Cancer Subtypes ◽  
Surgical Workflow ◽  
Tumor Types

Abstract Purpose Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20–40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. Methods We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. Results Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81–5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. Conclusions Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

scholarly journals Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-β Proteins: Phantom Study

2018 ◽  
Vol 9 ◽  
pp. 117959721878108 ◽  
Author(s):  
David Tes ◽  
Karl Kratkiewicz ◽  
Ahmed Aber ◽  
Luke Horton ◽  
Mohsin Zafar ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Amyloid Β ◽  
The United States ◽  
Fluorescent Imaging ◽  
Fluorescent Properties ◽  
In Vivo Experiments ◽  
The Brain

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-β (Aβ), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aβ proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aβ biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.

Portable and Rapid In Vivo Imaging of Tissue Oxygenation Changes Induced by Skin Perfusion Pressure

2019 ◽  
Vol 42 ◽  
pp. 59-66 ◽  
Author(s):  
Audrey Huong ◽  
Xavier Ngu
Keyword(s):  
Vascular Reactivity ◽  
Imaging System ◽  
Statistical Significance ◽  
Systolic Pressure ◽  
Improve Patient Care ◽  
Healthcare Management ◽  
Oxygen Saturation Level ◽  
Healthy Humans ◽  
Time Required

Current imaging systems available in the study of tissue hemodynamics and vascular reactivity are typically complex and bulky, hence limiting their applications to laboratory use. The aim of this study is to present the dynamics of skin oxygen level with changes in the microcirculatory perfusion monitored using a developed field portable, handheld tri-wavelength imaging system. The skin oxygen saturation level (StO2) was measured in-vivo in a span of 12 minutes in the ventral forearm of seven healthy humans at rest, before and after supra-diastolic and supra-systolic pressure inflations. The findings of this work showed statistical significance in the difference between the mean StO2 values in baseline and that following ischemic episodes with ρ ≤ 0.03. The values returned to baseline, although of different magnitude for each individual, within 2 min (ρ =0.217) during reperfusion could suggest the time required for the resume of normal autoregulation mechanisms and vasomotion reactivities in the recruits. This study concluded that the developed imaging system could find potential application in self-healthcare management and may help to improve patient care in remote or rural locations.

Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy

2012 ◽  
Vol 302 (6) ◽  
pp. E705-E713 ◽  
Author(s):  
Xin Cui ◽  
Yuhui Wang ◽  
Lingjun Meng ◽  
Weihua Fei ◽  
Jingna Deng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
White Adipose Tissue ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Triacylglycerol Content ◽  
Adipocyte Development

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ∼150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes.

scholarly journals A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress

2021 ◽  
Author(s):  
Hans M. Dalton ◽  
Raghuvir Viswanatha ◽  
Ricky Brathwaite ◽  
Jae Sophia Zuno ◽  
Stephanie E. Mohr ◽  
...  
Keyword(s):  
Er Stress ◽  
Therapeutic Targets ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Fructose Metabolism ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen

AbstractPartial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually cause CDGs. While both in vivo models ostensibly cause ER stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

Congenital insensitivity to pain

2018 ◽  
Author(s):  
Bhagat Singh ◽  
Alban Latremoliere ◽  
Michael Costigan
Keyword(s):  
Sensory Processing ◽  
Molecular Mechanisms ◽  
Familial Dysautonomia ◽  
Loss Of Function ◽  
Clinical Genetic ◽  
Gene Encoding ◽  
Congenital Insensitivity ◽  
Ngf Receptor ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

The landmark paper discussed in this chapter is ‘Congenital insensitivity to pain. A clinical, genetic and neurophysiological study of four children from the same family’, published by D. C. Thrush in 1973. The study of patients with congenital conditions that result in pain insensitivity has been invaluable in helping define the molecular mechanisms of sensory processing. These patients share a major defining phenotype (they feel little or no pain from birth), although they often have differing subtle symptoms which belie a host of separate conditions that we have now started to recognize with the advent of molecular genetics (e.g. loss-of-function mutations in the gene encoding Nav1.7, and mutations related to nerve growth factor (NGF)); these include congenital insensitivity to pain with anhydrosis (CIPA; thought to be due to mutations in the gene encoding the NGF receptor NTRK1) and hereditary sensory and autonomic neuropathies (HSANs) such as familial dysautonomia.

Exploring Feasibility of Multicolored CdTe Quantum Dots for In Vitro and In Vivo Fluorescent Imaging

2008 ◽  
Vol 8 (3) ◽  
pp. 1174-1177 ◽  
Author(s):  
Junfeng Su ◽  
Jun Zhang ◽  
Li Liu ◽  
Yalou Huang ◽  
Ralph P. Mason
Keyword(s):  
Quantum Dots ◽  
Fluorescence Imaging ◽  
Water Solubility ◽  
Imaging System ◽  
Fluorescent Imaging ◽  
Cdte Quantum Dots ◽  
Cdte Qds ◽  
Fluorescence Imaging System

We report the use of novel multicolored CdTe quantum dots (QDs) as fluorophores for biological fluorescence imaging. The CdTe QDs were prepared to exhibit emission wavelengths in the green, yellow, and red range by using trifluoroacetic acid (TFA), L-cysteine and thioglycolic acid (TGA) as surface stabilizers, respectively. The particles have good water solubility and photostability. Fluorescence imaging potential was evaluated in vitro and in vivo using a multispectral Maestro CRI Fluorescence Imaging system. The results show that different colored CdTe QDs allow sensitive detection simultaneously or separately both in vitro and in vivo against background fluorescence. The studies indicate that CdTe QDs can provide alternative fluorescent probes for biological imaging.

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