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81.
Ke Xia James T. Hagan Li Fu Brian S. Sheetz Somdatta Bhattacharya Fuming Zhang Jason R. Dwyer Robert J. Linhardt 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(11)
The application of solid-state (SS) nanopore devices to single-molecule nucleic acid sequencing has been challenging. Thus, the early successes in applying SS nanopore devices to the more difficult class of biopolymer, glycosaminoglycans (GAGs), have been surprising, motivating us to examine the potential use of an SS nanopore to analyze synthetic heparan sulfate GAG chains of controlled composition and sequence prepared through a promising, recently developed chemoenzymatic route. A minimal representation of the nanopore data, using only signal magnitude and duration, revealed, by eye and image recognition algorithms, clear differences between the signals generated by four synthetic GAGs. By subsequent machine learning, it was possible to determine disaccharide and even monosaccharide composition of these four synthetic GAGs using as few as 500 events, corresponding to a zeptomole of sample. These data suggest that ultrasensitive GAG analysis may be possible using SS nanopore detection and well-characterized molecular training sets.Glycosaminoglycans (GAGs) are linear anionic polysaccharides found on cell surfaces and in the extracellular matrix in all animals. GAGs comprise an important class of biopolymers that are ubiquitous in nature and exhibit a number of critical functional roles including biological recognition and signaling (1–3). Such processes play critical roles in physiology, such as in development and wound healing, and pathophysiology, such as cancer and infectious disease. Sulfated GAGs result from template-independent synthesis in the Golgi of animal cells (4, 5) and are polydisperse, heteropolysaccharides comprising variable disaccharide repeating units that are classified by these repeating units. Like nucleic acids, sulfated GAGs are made up of repeating units that comprise a linear sequence (Fig. 1). Unlike the nucleic acids, GAGs have far more complicated structures and number of possible sequences and they present severe challenges to both synthesis and characterization. Thus, we undertook to chemoenzymatically synthesize defined GAGs and characterize these using solid-state nanopore analysis.Open in a separate windowFig. 1.Structures of four synthetic GAG samples. Polysaccharide NSH is made up of N-sulfoglucosamine (GlcNS) and glucuronic acid (GlcA),NS2S is made up with GlcNS and 2-O-sulfo-iduronic acid (IdoA2S), NS6S is made up with 6-O-sulfo-N-sulfoheparosan (GlcNS6S) and GlcA, and NS6S2S is made up with GlcNS6S and IdoA2S.Despite their structural complexities, sulfated GAGs often contain well-defined domain structures that are responsible for their diverse biological functions, yet even this level of structural complexity poses a significant general challenge to structural analysis and sequencing. The simple, short-chain, chondroitin sulfate GAG component of bikunin has been sequenced using liquid chromatography–tandem mass spectrometry (LC-MS/MS) (6). While LC-MS/MS is capable of sequencing such simple, short-chain GAGs, it is not yet able to distinguish all of the many isobaric isomers of the variably sulfated saccharide residues and uronic acid epimers commonly encountered in more structurally complex GAGs, such as heparan sulfate (HS) (7). NMR has been applied to determine GAG structures but often requires milligram amounts of samples. HS/heparin is made up of →4)-β-d-glucuronic acid (GlcA) [or α-l-iduronic acid (IdoA)] (1→4)-α-d-glucosamine (GlcN) [1→ repeating units with 2-O-sulfo (S) groups on selected uronic acid residues and 3- and/or 6-O-S and N-S or N-acetyl (Ac) group substitutions on the glucosamine residues] (Fig. 1). GAG structural analysis presents challenges beyond their chemical complexity. There are no amplification methods to detect small numbers of GAG chains, whereas nucleic acid analysis can rely on PCR. Similarly, there are few GAG-specific antibodies or aptamers (8), and no natural GAG chromophores or fluorophores (9), in contrast to the many used for protein sensing. Ultrasensitive (zeptomole) detection methods of modified GAGs, based on fluorescence resonance energy transfer (FRET) (10), DNA bar coding (11), and dye-based nanosensors (12) have been demonstrated, but their application to sequencing is particularly challenging because of the high level of structural complexity of sulfated GAGs.Nanopore single-molecule detection is now routinely applied to DNA (13, 14) and RNA (15–17) biopolymers, and is increasingly applied to protein characterization (18–22). In brief, a nanopore is a nanofluidic channel ∼10 nm long and <100 nm in diameter, serving as the sole fluid connection between two reservoirs of electrolyte separated by an otherwise impermeable membrane (Fig. 2A). On applying a voltage across this nanopore, the passage of supporting electrolyte ions results in a “baseline,” or open-pore current, i0. The passage of a biopolymer analyte through this nanopore disrupts the flow of supporting electrolyte ions, often as a current blockage. This temporary reduction in ionic current is called an “event,” and its magnitude (mean blockage ratio over the dwell time, ⟨fb⟩=⟨i⟩Td/⟨i0⟩) and its temporal features [dwell time (Td)] (Fig. 2 B and C) depend on the size and shape of the nanopore, the biopolymer analyte, and the applied voltage and interfacial charge distributions. Indeed, the passage of DNA through engineered protein nanopore devices produces current blockages that can be applied in sequencing, and the widespread use of these commercial protein nanopore DNA sequencing devices is increasing (23, 24). Despite this success with protein nanopores, the potential benefits of (abiotic) solid-state (SS) nanopores have continued to drive development efforts. Such a transition to the freely size-tunable SS platform (25, 26), however, is vital for the application of nanopores to the characterization of branched glycans (27). Yet the use of SS nanopores in even the better-established DNA sensing regime remains challenging. The application of nanopore sensing to glycans, while promising, remains profoundly exploratory using nanopores of any kind. The transition to the SS nanopores is accompanied by significant changes in pore geometry, chemistry, characteristics, and potential analyte–pore interactions and sensing modalities, so that there is a critical need for studies in the realm of nanopore glycomics (27, 28). For example, outcomes of early nanopore studies on a structurally simple unsulfated GAG, hyaluronan (HA, →4)- β -GlcA (1 → 3)- β -GlcNAc (1→), while providing some information on HA size does not provide definitive structural information (29, 30). SS nanopore analysis of two sulfated GAGs, heparin and a heparin contaminant, oversulfated chondroitin sulfate, using a silicon nitride SS nanopore was able to qualitatively identify these GAGs by either the magnitude or duration of characteristic current blockages (28). SS nanopore data on GAGs, analyzed using a machine-learning (ML) algorithm (i.e., a support vector machine [SVM]), distinguished heparin and chondroitin sulfate oligosaccharides and unfractionated heparin and low molecular weight heparin with >90% accuracy (31).Open in a separate windowFig. 2.Nanopore characteristics of four samples. (A) Schematic of the nanopore configuration. Anionic GAGs driven by electrophoresis to and through the pore with a negative applied voltage would be detected if they perturbed the open-pore current. (B) A representative current trace and events from polysaccharide NS6S2S test using an ∼6-nm-diameter nanopore. Measurements were collected using a −150-mV applied-voltage (details in Results and Discussion, and Materials and Methods) (C) Scatter plots of dwell time vs. current blockage ratio for four polysaccharides. To remove the bias of event numbers in human image recognition, all plots contain only the first 2,475 events. (D) PCA visualization of the embedded images from the four unique GAGs. The blue circles and region represent NSH, the red X and region represents NS2S, the green triangle and region represents NS6S, and the brown cross and region represents NS6S2S. The algorithm clusters signals from each GAG based on scatter plot images. Each insert shows one 500-events image from each sample class. All 500-events images are in SI Appendix, Fig. S12.Nanopore studies on GAGs, and glycans more broadly, have been severely limited by the lack of a library of structurally defined standards. The uniformity of sulfated GAGs prepared from animal sources is difficult to control and exhibits significant sequence heterogeneity and polydispersity (32). HS is particularly problematic as even for a small HS hexasaccharide, composed of an IdoA/GlcA:GlcNS/GlcNAc sequence with 12 available sites for random sulfation, there are 32,768 possible sequences. Recently, chemoenzymatic synthesis has made inroads in the preparation of high-purity sulfated HS GAGs from heparosan (→4)- β -GlcA (1→4)- β -GlcNAc (1→) (33). HS GAGs of approximately the same chain length and polydispersity and having a single repeating disaccharide unit (SI Appendix, Table S1) including, NSH (→4)- β -GlcA (1→4)- β -GlcNS (1→), NS2S (→4)-α α -IdoA2S (1 → 4)- β -GlcNS (1→), NS6S (→4)- β -GlcA (1→4)- β -GlcNS6S(1→)), NS6S2S (→4)- α -IdoA2S (1→4)- β -GlcNS6S (1→) have been prepared (see Materials and Methods and ref. 34) (Fig. 1). Here we use our recently developed synthetic technique, which has proven difficult to benchmark, in conjunction with a nanopore technique, which has only just begun to be applied to glycomics and has been severely challenged by the lack of available high-quality samples, to develop a fully integrated approach for the nanopore analysis of complex carbohydrates. 相似文献
82.
M. Nemati G. B. Loozen N. van der Wekken G. van de Belt H. P. Urbach N. Bhattacharya S. Kenjeres 《Biomedical optics express》2015,6(10):4037-4050
A preliminary comparative measurement between particle imaging velocimetry (PIV) and laser speckle contrast analysis (LASCA) to study pulsatile flow using ventricular assist device in a patient-specific carotid artery phantom is reported. These full-field optical techniques have both been used to study flow and extract complementary parameters. We use the high spatial resolution of PIV to generate a full velocity map of the flow field and the high temporal resolution of LASCA to extract the detailed frequency spectrum of the fluid pulses. Using this combination of techniques a complete study of complex pulsatile flow in an intricate flow network can be studied.OCIS codes: (100.0100) Image processing, (170.0170) Medical optics and biotechnology, (230.0230) Optical devices, (290.0290) Scattering 相似文献
83.
Kevin F. Erickson Matthew Mell Wolfgang C. Winkelmayer Glenn M. Chertow Jay Bhattacharya 《Journal of the American Society of Nephrology : JASN》2015,26(8):1990-1997
Medicare reimbursement policy encourages frequent provider visits for patients with ESRD undergoing hemodialysis. We hypothesize that patients seen more frequently by their nephrologist or advanced practitioner within the first 90 days of hemodialysis are more likely to undergo surgery to create an arteriovenous (AV) fistula or place an AV graft. We selected 35,959 patients aged ≥67 years starting hemodialysis in the United States from a national registry. We used multivariable regression to evaluate the associations between mean visit frequency and AV fistula creation or graft placement in the first 90 days of hemodialysis. We conducted an instrumental variable analysis to test the sensitivity of our findings to potential bias from unobserved characteristics. One additional visit per month in the first 90 days of hemodialysis was associated with a 21% increase in the odds of AV fistula creation or graft placement during that period (95% confidence interval, 19% to 24%), corresponding to an average 4.5% increase in absolute probability. An instrumental variable analysis demonstrated similar findings. Excluding visits in months when patients were hospitalized, one additional visit per month was associated with a 10% increase in odds of vascular access surgery (95% confidence interval, 8% to 13%). In conclusion, patients seen more frequently by care providers in the first 90 days of hemodialysis undergo earlier AV fistula creation or graft placement. Payment policies that encourage more frequent visits to patients at key clinical time points may yield more favorable health outcomes than policies that operate irrespective of patients’ health status. 相似文献
84.
Continuous noninvasive cardiac output in children: is this the next generation of operating room monitors? Initial experience in 402 pediatric patients
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85.
86.
Mainak Mukhopadhyay Sayak Roy Mridul Bera Guruprasad Bhattacharya 《Current Cardiology Reviews》2020,16(4):341
Introduction Sleep-related problems like sleep apnea are increasing tremendously mostly owing to the disordered lifestyle the present generation is leading which is added like a topping on the base of obesity and metabolic syndrome. The burden on the society is huge taking into consideration the work-time loss and health-related financial issues arising out of these sleep disorders with obstructive sleep apnea (OSA) leading the way. Early diagnosis can prevent several complications of OSA. Cardiovascular diseases, including various arrhythmias, arising due to OSA, are described previously.Case Presentation Herein, an interesting case of OSA, whose pacemaker installation to rectify the long pause could be avoided by simple correction of his OSA using continuous positive airway pressure, is presented. This 49-year-old male patient was diagnosed with severe OSA by using polysomnography and all his significant sinus pauses (highest one with 7.8 sec) during holter ECG monitoring were found to be occurring at night and correcting his OSA with continuous positive airway pressure (CPAP) treatment reverted all those sinus pauses and the need for any further intervention with pacemaker was discarded.Discussion OSA is caused by either partial or complete obstruction of the upper airway, and there is the simultaneously attenuated upper airway dilator muscle tone while the patient is sleeping. The gold standard test designed for the assessment of OSA is polysomnography, as approved by the American Academy of Sleep Medicine and CPAP has been found to be universally beneficial in treating OSA related complications. Physiologically, the ACC/AHA guidelines recommend pacing only in patients with prolonged asymptomatic pauses occurring during wakefulness. This case report proved the above mentioned claim of CPAP treatment. 相似文献
87.
88.
Jonathan W. Riess Nupur Bhattacharya Kim R. M. Blenman Joel W. Neal Gloria Hwang Philippe Pultar 《Immunopharmacology and immunotoxicology》2014,36(2):182-186
Context: Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.Objective: Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.Methods: Talactoferrin was administered orally at 1.5?g bid weeks 1–12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.Results: Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.Conclusion: Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF. 相似文献
89.
Yatin Mehta Abhinav Gupta Subhash Todi SN Myatra D. P. Samaddar Vijaya Patil Pradip Kumar Bhattacharya Suresh Ramasubban 《Indian Journal of Critical Care Medicine》2014,18(3):149-163
These guidelines, written for clinicians, contains evidence-based recommendations for the prevention of hospital acquired infections Hospital acquired infections are a major cause of mortality and morbidity and provide challenge to clinicians. Measures of infection control include identifying patients at risk of nosocomial infections, observing hand hygiene, following standard precautions to reduce transmission and strategies to reduce VAP, CR-BSI, CAUTI. Environmental factors and architectural lay out also need to be emphasized upon. Infection prevention in special subsets of patients - burns patients, include identifying sources of organism, identification of organisms, isolation if required, antibiotic prophylaxis to be used selectively, early removal of necrotic tissue, prevention of tetanus, early nutrition and surveillance. Immunodeficient and Transplant recipients are at a higher risk of opportunistic infections. The post tranplant timetable is divided into three time periods for determining risk of infections. Room ventilation, cleaning and decontamination, protective clothing with care regarding food requires special consideration. Monitoring and Surveillance are prioritized depending upon the needs. Designated infection control teams should supervise the process and help in collection and compilation of data. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, de-escalation, optimizing dosing, active use of information technology among other measure. The recommendations in these guidelines are intended to support, and not replace, good clinical judgment. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. 相似文献
90.