Showing papers by "Seth M. Cohen published in 2021"

25 Years of Reticular Chemistry.

Abstract: At its core, reticular chemistry has translated the precision and expertise of organic and inorganic synthesis to the solid state. While initial excitement over metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) was undoubtedly fueled by their unprecedented porosity and surface areas, the most profound scientific innovation of the field has been the elaboration of design strategies for the synthesis of extended crystalline solids through strong directional bonds. In this contribution we highlight the different classes of reticular materials that have been developed, how these frameworks can be functionalized, and how complexity can be introduced into their backbones. Finally, we show how the structural control over these materials is being extended from the molecular scale to their crystal morphology and shape on the nanoscale, all the way to their shaping on the bulk scale.

How Reproducible Are Surface Areas Calculated from the BET Equation

Abstract: Porosity and surface area analysis play a prominent role in modern materials science, where 123 their determination spans the fields of natural sciences, engineering, geology and medical 124 research. At the heart of this sits the Brunauer-Emmett-Teller (BET) theory,[1] which has been 125 a remarkably successful contribution to the field of materials science. The BET method was 126 developed in the 1930s and is now the most widely used metric for the estimation of surface 127 areas of porous materials.[2] Since the BET method was first developed, there has been an 128 explosion in the field of nanoporous materials with the discovery of synthetic zeolites,[3] 129 nanostructured silicas,[4–6] metal-organic frameworks (MOFs),[7] and others. Despite its 130 widespread use, the manual calculation of BET surface areas causes a significant spread in 131 reported areas, resulting in reproducibility problems in both academia and industry. To probe 132 this, we have brought together 60 labs with strong track records in the study of nanoporous 133 materials. We provided eighteen adsorption isotherms and asked these researchers to 134 calculate the corresponding BET areas, resulting in a wide range of values for each one. We 135 show here that the reproducibility of BET area determination from identical isotherms is a 136 largely ignored issue, raising critical concerns over the reliability of reported BET areas in 137 the literature. To solve this major issue, we have developed a new computational approach 138 to accurately and systematically determine the BET area of nanoporous materials. Our 139 software, called BET Surface Identification (BETSI), expands on the well-known Rouquerol 140 criteria and makes, for the first time, an unambiguous BET area assignment possible.

Anti-SARS-CoV-2 Antibody Levels Measured by the AdviseDx SARS-CoV-2 Assay Are Concordant with Previously Available Serologic Assays but Are Not Fully Predictive of Sterilizing Immunity.

Abstract: With the availability of widespread SARS-CoV-2 vaccination, high-throughput quantitative anti-spike protein serological testing will likely become increasingly important. Here, we investigated the performance characteristics of the recently FDA-authorized semiquantitative anti-spike protein AdviseDx SARS-CoV-2 IgG II assay compared to the FDA-authorized anti-nucleocapsid protein Abbott Architect SARS-CoV-2 IgG, Roche Elecsys anti-SARS-CoV-2-S, EuroImmun anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA), and GenScript surrogate virus neutralization assays and examined the humoral response associated with vaccination, natural protection, and vaccine breakthrough infection. The AdviseDx assay had a clinical sensitivity at 14 days after symptom onset or 10 days after PCR detection of 95.6% (65/68; 95% confidence interval [CI], 87.8 to 98.8%), with two discrepant individuals seroconverting shortly thereafter. The AdviseDx assay demonstrated 100% positive percent agreement with the four other assays examined using the same symptom onset or PCR detection cutoffs. Using a recently available WHO international standard for anti-SARS-CoV-2 antibody, we provide assay unit conversion factors to international units for each of the assays examined. We performed a longitudinal survey of healthy vaccinated individuals, finding that median AdviseDx immunoglobulin levels peaked 7 weeks after first vaccine dose at approximately 4,000 IU/ml. Intriguingly, among the five assays examined, there was no significant difference in antigen binding level or neutralizing activity between two seropositive patients protected against SARS-CoV-2 infection in a previously described fishing vessel outbreak and five health care workers who experienced vaccine breakthrough of SARS-CoV-2 infection, all with variants of concern. These findings suggest that protection against SARS-CoV-2 infection cannot currently be predicted exclusively using in vitro antibody assays against wild-type SARS-CoV-2 spike. Further work is required to establish protective correlates for SARS-CoV-2 infection.

Metal complexes for therapeutic applications

Abstract: Metal complexes have been widely used for applications in the chemical and physical sciences due to their unique electronic and stereochemical properties. For decades the use of metal complexes for medicinal applications has been postulated and demonstrated. The distinct characteristics of metal complexes, including their molecular geometries (that are not readily accessed by organic molecules) as well as their ligand exchange, redox, catalytic, and photophysical reactions, give these compounds the potential to interact and react with biomolecules in unique ways and by distinct mechanisms of action. Herein, the potential of metal complexes to act as components of bioactive therapeutic compounds is discussed.

Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State.

Abstract: Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOC) and had a median Ct of 20.2 (IQR=17.1-23.3). When compared to 5174 contemporaneous samples sequenced in our laboratory, VOC were significantly enriched among breakthrough infections (p < .05).

Re(I) Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS-CoV-2 Main Cysteine Protease.

Abstract: Since its outbreak, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has impacted the quality of life and cost hundreds-of-thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3-chymotrypsin-like protease (3CLpro ), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CLpro inhibitors are organic, non-covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. ReI tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CLpro . Preliminary studies indicate the selective inhibition of 3CLpro over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CLpro cysteine protease.

Metal Complexes as Antiviral Agents for SARS-CoV-2.

Abstract: The severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the infectious agent responsible for COVID-19 - has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS-CoV-2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS-CoV-2. Herein, the metal complexes that have been reported to show antiviral activity against SARS-CoV-2 or one of its target proteins are described and their proposed mechanisms of action are discussed.

Low Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Among Pregnant and Postpartum Patients With Universal Screening in Seattle, Washington.

Abstract: We found a low prevalence of SARS-CoV-2 (2.7% [5/188]) among pregnant and postpartum patients after initiating universal testing. Prevalence among symptomatic patients (22.2% [4/18]) was similar to initial targeted screening approaches (19.1% [8/42]). Among 170 asymptomatic patients, two were positive or inconclusive, respectively; repeat testing at 24 hours was negative.

Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State

Abstract: Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOC) and had a median Ct of 20.2 (IQR=17.1-23.3). When compared to 5174 contemporaneous samples sequenced in our laboratory, VOC were significantly enriched among breakthrough infections (p < .05).

Green MIP-202(Zr) Catalyst: Degradation and Thermally Robust Biomimetic Sensing of Nerve Agents.

Abstract: Rapid and robust sensing of nerve agent (NA) threats is necessary for real-time field detection to facilitate timely countermeasures. Unlike conventional phosphotriesterases employed for biocatalytic NA detection, this work describes the use of a new, green, thermally stable, and biocompatible zirconium metal-organic framework (Zr-MOF) catalyst, MIP-202(Zr). The biomimetic Zr-MOF-based catalytic NA recognition layer was coupled with a solid-contact fluoride ion-selective electrode (F-ISE) transducer, for potentiometric detection of diisopropylfluorophosphate (DFP), a F-containing G-type NA simulant. Catalytic DFP degradation by MIP-202(Zr) was evaluated and compared to the established UiO-66-NH2 catalyst. The efficient catalytic DFP degradation with MIP-202(Zr) at near-neutral pH was validated by 31P NMR and FT-IR spectroscopy and potentiometric F-ISE and pH-ISE measurements. Activation of MIP-202(Zr) using Soxhlet extraction improved the DFP conversion rate and afforded a 2.64-fold improvement in total percent conversion over UiO-66-NH2. The exceptional thermal and storage stability of the MIP-202/F-ISE sensor paves the way toward remote/wearable field detection of G-type NAs in real-world environments. Overall, the green, sustainable, highly scalable, and biocompatible nature of MIP-202(Zr) suggests the unexploited scope of such MOF catalysts for on-body sensing applications toward rapid on-site detection and detoxification of NA threats.

Strong, Ductile MOF–Poly(urethane urea) Composites

Abstract: Metal–organic framework (MOF)–polymer hybrid materials have been investigated for use in personal protective equipment (PPE) for combating chemical threats. However, few of these composite material...

Mimicking the Electron Transport Chain and Active Site of [FeFe] Hydrogenases in One Metal-Organic Framework: Factors That Influence Charge Transport.

Abstract: [FeFe] hydrogenase (H2ase) enzymes are effective proton reduction catalysts capable of forming molecular dihydrogen with a high turnover frequency at low overpotential. The active sites of these enzymes are buried within the protein structures, and substrates required for hydrogen evolution (both protons and electrons) are shuttled to the active sites through channels from the protein surface. Metal-organic frameworks (MOFs) provide a unique platform for mimicking such enzymes due to their inherent porosity which permits substrate diffusion and their structural tunability which allows for the incorporation of multiple functional linkers. Herein, we describe the preparation and characterization of a redox-active PCN-700-based MOF (PCN = porous coordination network) that features both a biomimetic model of the [FeFe] H2ase active site as well as a redox-active linker that acts as an electron mediator, thereby mimicking the function of [4Fe4S] clusters in the enzyme. Rigorous studies on the dual-functionalized MOF by cyclic voltammetry (CV) reveal similarities to the natural system but also important limitations in the MOF-enzyme analogy. Most importantly, and in contrast to the enzyme, restrictions apply to the total concentration of reduced linkers and charge-balancing counter cations that can be accommodated within the MOF. Successive charging of the MOF results in nonideal interactions between linkers and restricted mobility of charge-compensating redox-inactive counterions. Consequently, apparent diffusion coefficients are no longer constant, and expected redox features in the CVs of the materials are absent. Such nonlinear effects may play an important role in MOFs for (electro)catalytic applications.

Controlled Two-Dimensional Alignment of Metal-Organic Frameworks in Polymer Films.

Abstract: Controlling the alignment of metal-organic framework (MOF) particles is valueable for fully exploiting the anisotropic properties and porous structure of these materials. Herein, we propose a simple, one-step method that can control the two-dimensional (2D) alignment of MOF particles over large areas. Orientational control is achieved without consideration of the underlying lattice parameters or the need for particle surface modification, but instead was achieved by selection of the casting solvent on a water surface. Two distinct types of MOF particles, a hexagonal bifrustum morphology of MIL-96 and an octahedral morphology of the UiO-66 family were aligned and captured in a polydimethylsiloxane (PDMS) matrix using this approach. This work provides opportunities for studying and utilizing the anisotropic properties of MOFs in thin film applications.

Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis

Abstract: ObjectiveAdjuvant management for laryngotracheal stenosis (LTS) may involve inhaled corticosteroids, but metered dose inhalers are designed for pulmonary drug delivery. Comprehensive analyses of dr...

Remote Detection of HCN, HF, and Nerve Agent Vapors Based on Self-Referencing, Dye-Impregnated Porous Silicon Photonic Crystals.

Abstract: A one-dimensional photonic crystal is prepared from porous silicon (pSi) and impregnated with a chemically specific colorimetric indicator dye to provide a self-referenced vapor sensor for the selective detection of hydrogen fluoride (HF), hydrogen cyanide (HCN), and the chemical nerve agent diisopropyl fluorophosphate (DFP). The photonic crystal is prepared with two stop bands: one that coincides with the optical absorbance of the relevant activated indicator dye and the other in a spectrally "clear" region, to provide a reference. The inner pore walls of the pSi sample are then modified with octadecylsilane to provide a hydrophobic interior, and the indicator dye of interest is then loaded into the mesoporous matrix. Remote analyte detection is achieved by measurement of the intensity ratio of the two stop bands in the white light reflectance spectrum, which provides a means to reliably detect colorimetric changes in the indicator dye. Indicator dyes were chosen for their specificity for the relevant agents: rhodamine-imidazole (RDI) for HF and DFP, and monocyanocobinamide (MCbi) for HCN. The ratiometric readout allows detection of HF and HCN at concentrations (14 and 5 ppm, respectively) that are below their respective IDLH (immediately dangerous to life and health) concentrations (30 ppm for HF; 50 ppm for HCN); detection of DFP at a concentration of 114 ppb is also demonstrated. The approach is insensitive to potential interferents such as ammonia, hydrogen chloride, octane, and the 43-component mixture of VOCs known as EPA TO-14A, and to variations in relative humidity (20-80% RH). Detection of HF and HCN spiked into the complex mixture EPA TO-14A is demonstrated. The approach provides a general means to construct robust remote detection systems for chemical agents.

Correspondence on SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response" by Bonelli et al ."

Abstract: Bonelli et al recently reported reduced humoral responses to the BNT162b2 mRNA vaccine in five patients on rituximab therapy; in two patients with repopulated B cells, a low-level Spike protein antibody response occurred, but three patients with no detectable B-cells had no measurable antibody response to the vaccine.1 Of great interest, they reported that interferon-γ T-cell responses to SARS-CoV-2 Spike peptides were present in all five patients, irrespective of the antibody response to the vaccine. It has been reported that patients on B-cell depleting therapy are at increased risk for hospitalisation and death from SARS-CoV-2 infection.2 In February 2021, the American College of Rheumatology (ACR) COVID-19 Taskforce published consensus guidelines regarding vaccine timing in immunosuppressed patients, despite the paucity of data available at that time on vaccine efficacy in patients on targeted B cell therapy.3 Moreover, the guidelines specifically …

Photorelease of a metal-binding pharmacophore from a Ru(II) polypyridine complex

Abstract: The adoption of compounds that target metalloenzymes comprises a relatively low (<5%) percentage of all FDA approved therapeutics. Metalloenzyme inhibitors typically coordinate to the active site metal ions and therefore contain ligands with charged or highly polar functional groups. While these groups may generate highly water-soluble compounds, this functionalization can also limit their pharmacological properties. To overcome this drawback, drug candidates can be formulated as prodrugs. While a variety of protecting groups have been developed, increasing efforts have been devoted towards the use of caging groups that can be removed upon exposure to light to provide spatial and temporal control over the treatment. Among these, the application of Ru(ii) polypyridine complexes is receiving increased attention based on their attractive biological and photophysical properties. Herein, a conjugate consisting of a metalloenzyme inhibitor and a Ru(ii) polypyridine complex as a photo-cage is presented. The conjugate was designed using density functional theory calculations and docking studies. The conjugate is stable in an aqueous solution, but irradiation of the complex with 450 nm light releases the inhibitor within several minutes. As a model system, the biochemical properties were investigated against the endonucleolytic active site of the influenza virus. While showing no inhibition in the dark in an in vitro assay, the conjugate generated inhibition upon light exposure at 450 nm, demonstrating the ability to liberate the metalloenzyme inhibitor. The presented inhibitor-Ru(ii) polypyridine conjugate is an example of computationally-guided drug design for light-activated drug release and may help reveal new avenues for the prodrugging of metalloenzyme inhibitors.

Simulation Meets Experiment: Unraveling the Properties of Water in Metal-Organic Frameworks Through Vibrational Spectroscopy

Abstract: In nanoporous materials, guest–host interactions affect the properties and function of both adsorbent and adsorbate molecules. Due to their structural and chemical diversity, metal-organic frameworks (MOFs), a common class of nanoporous materials, have been shown to be able to efficiently and, often, selectively adsorb various types of guest molecules. In this study, we characterize the structure and dynamics of water confined in ZIF-90. Through the integration of experimental and computational infrared (IR) spectroscopy, we probe the structure of heavy water (D2O) adsorbed in the pores, disentangling the fundamental framework–water and water–water interactions. The experimental IR spectrum of D2O in ZIF-90 displays a blue-shifted OD-stretch band compared to liquid D2O. The analysis of the IR spectra simulated at both classical and quantum levels indicates that the D2O molecules preferentially interact with the carbonyl groups of the framework and highlights the importance of including nuclear quantum effects and taking into account Fermi resonances for a correct interpretation of the OD-stretch band in terms of the underlying hydrogen-bonding motifs. Through a systematic comparison with the experimental spectra, we demonstrate that computational spectroscopy can be used to gain quantitative, molecular-level insights into framework–water interactions that determine the water adsorption capacity of MOFs as well as the spatial arrangements of the water molecules inside the MOF pores which, in turn, are key to the design of MOF-based materials for water harvesting.

Association between Dysphagia and Surgical Outcomes across the Continuum of Frailty.

Abstract: This study examined the relationship between dysphagia and adverse outcomes across frailty conditions among surgical patients ≥50 years of age. A retrospective cohort analysis of surgical hospitalizations in the Healthcare Cost and Utilization Project's National Inpatient Sample among patients ≥50 years of age undergoing intermediate/high risk surgery not involving the larynx, pharynx, or esophagus. Of 3,298,835 weighted surgical hospitalizations, dysphagia occurred in 1.2% of all hospitalizations and was higher in frail patients ranging from 5.4% to 11.7%. Dysphagia was associated with greater length of stay, higher total costs, increased non-routine discharges, and increased medical/surgical complications among both frail and non-frail patients. Dysphagia may be an independent risk factor for poor postoperative outcomes among surgical patients ≥50 years of age across frailty conditions and is an important consideration for providers seeking to reduce risk in vulnerable surgical populations.

Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme.

Abstract: Insulin-degrading enzyme (IDE) is a human mononuclear Zn2+-dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation. Despite its name, IDE is also critically involved in the hydrolysis of several other disparate peptide hormones, including glucagon, amylin, and the amyloid β-protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type 2 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active-site metal ion have yet to be fully explored. In an effort to discover new, metal-binding inhibitors of IDE, a library of ~350 metal-binding pharmacophores was screened against IDE, resulting in the identification of 1-hydroxypyridine-2-thione (1,2-HOPTO) as an effective metal-binding scaffold. Screening of a focused library of HOPTO compounds identified 3-sulfonamide derivatives of 1,2-HOPTO to have good activity against IDE (Ki values of ~50 µM). Further structure-activity relationship studies yielded several thiophene-sulfonamide HOPTO derivatives with good, broad-spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

Abstract: Objectives:To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subgl...

Synthesis of tetranuclear rhenium(I) tricarbonyl metallacycles

Abstract: Re(I) tricarbonyl complexes have received much attention due to their attractive photochemical, electrochemical, and biological properties. Beyond simple mononuclear complexes, multinuclear assemblies offer greater structural diversity and properties. Despite previous reports on the preparation of di-, tri-, or tetranuclear Re(I) tricarbonyl assemblies, the synthesis of these supramolecular structures remains challenging due to overall low yields or tedious purification protocols. Herein, the facile preparation and characterization of tetranuclear Re(I) tricarbonyl metallacycles with a square geometry is reported using a tetrazole-based ligand. The synthesis of the metallacycle was optimized using different metal precursors, solvents, temperatures, and reagent concentrations. Finally, the scope of suitable tetrazole-based ligands was explored to produce several tetranuclear Re(I) tricarbonyl-based metallacycles.

A preliminary assessment of guideline adherence and clinical variation in oral cancer treatment: a MarketScan database study

Abstract: To assess variations in adherence to guideline-recommended processes of care for oral cavity cancer patients. Retrospective study using a U.S. healthcare research database (MarketScan). Index diagnoses were considered from 2010 to 2012 with follow-up from 2013 to 2014. Diagnostic and procedure codes were utilized to identify oral cavity patients with a defined treatment modality. Compliance with guideline-recommended processes of care, which included pre-treatment imaging, thyroid-function testing (TFTs), multidisciplinary consultation and gastrostomy-tube insertion rates, were assessed. A total of 2752 patients were identified. Surgery alone was the most common treatment (60.8%), followed by surgery with adjuvant chemoradiotherapy (20.4%) and surgery with adjuvant radiotherapy (18.8%). Head/neck and chest imaging were obtained in 60% and 62.5% of patients respectively. Significant geographical differences in head and neck imaging were observed between North-central (64%), South (58.4%) and West (56.1%) regions (p = 0.026). Differences in chest imaging were also present between North-east (65%) and West (56.8%; p = 0.007). TFTs were obtained in 54.4% of the patients after radiation treatment, and 18.6% of patients had multidisciplinary consultation during the 6 months before and 3 months after initiation of treatment. During the year after treatment initiation, 21.2% of patients underwent G-tube placement, with significantly higher rates in patients receiving triple modality treatment (58%) when compared to surgery plus radiation (27%) and surgery alone (15%; p < 0.01). Adherence to evidence-based practices was low based on the database coding. These data suggest a potential to improve adherence and increase the routine use of practices delineated in national clinical practice guidelines. This study reflects a suboptimal adherence to guidelines based on the database employed. This study should be considered by healthcare providers and efforts should be maximized to follow the processes of care which have proven to impact on patient's outcomes.