Discovery and characterization of novel TRPML1 agonists.

Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies. SAR studies on conformationally locked macrocyclic analogs further improved the TRPML1 agonist potency while retaining the selectivity.

Supramolecular Enhancement of Electrochemical Nitrate Reduction Catalyzed by Cobalt Porphyrin Organic Cages for Ammonia Electrosynthesis in Water.

The electrochemical nitrate (NO3 - ) reduction reaction (NO3 RR) to ammonia (NH3 ) represents a sustainable approach for denitrification to balance global nitrogen cycles and an alternative to traditional thermal Haber-Bosch processes. Here, we present a supramolecular strategy for promoting NH3 production in water from NO3 RR by integrating two-dimensional (2D) molecular cobalt porphyrin (CoTPP) units into a three-dimensional (3D) porous organic cage architecture. The porphyrin box CoPB-C8 enhances electrochemical active site exposure, facilitates substrate-catalyst interactions, and improves catalyst stability, leading to turnover numbers and frequencies for NH3 production exceeding 200,000 and 56 s-1 , respectively. These values represent a 15-fold increase in NO3 RR activity and 200-mV improvement in overpotential for the 3D CoPB-C8 box structure compared to its 2D CoTPP counterpart. Synthetic tuning of peripheral alkyl substituents highlights the importance of supramolecular porosity and cavity size on electrochemical NO3 RR activity. These findings establish the incorporation of 2D molecular units into 3D confined space microenvironments as an effective supramolecular design strategy for enhancing electrocatalysis.

Engineering high throughput screening platforms of cervical cancer.

Cervical cancer is the second leading cause of cancer-related death in women under 40 and is one of the few cancers to have an increased incidence rate and decreased survival rate over the last 10 years. One in five patients will have recurrent and/or distant metastatic disease and these patients face a 5-year survival rate of less than 17%. Thus, there is a pressing need to develop new anticancer therapeutics for this underserved patient population. However, the development of new anticancer drugs remains a challenge, as only 7% of novel anticancer drugs are approved for clinical use. To facilitate identification of novel and effective anticancer drugs for cervical cancer, we developed a multilayer multicellular platform of human cervical cancer cell lines and primary human microvascular endothelial cells that interfaces with high throughput drug screening methods to evaluate the anti-metastatic and anti-angiogenic drug efficacy simultaneously. Through the use of design of experiments statistical optimization, we identified the specific concentrations of collagen I, fibrinogen, fibronectin, GelMA, and PEGDA in each hydrogel layer that maximized both cervical cancer invasion and endothelial microvessel length. We then validated the optimized platform and assessed its viscoelastic properties. Finally, using this optimized platform, we conducted a targeted drug screen of four clinically relevant drugs on two cervical cancer cell lines. Overall, this work provides a valuable platform that can be used to screen large compound libraries for mechanistic studies, drug discovery, and precision oncology for cervical cancer patients.

Sulfonamide Prodrugs with a Two-Stage Release Mechanism for the Efficient Delivery of the TLR4 Antagonist TAK-242.

We previously demonstrated that the potent TLR4 inhibitor TAK-242 could be covalently conjugated to pancreatic islets using a linker that afforded an effective sustained delivery of the active drug after transplant. This drug-eluting tissue achieved local inhibition of TLR4-linked inflammation and proved beneficial to the islet graft survival. Here, we describe a new family of prodrugs with a modular design featuring a self-immolative para-aminobenzyl spacer bonded directly to the TAK-242 sulfonamide nitrogen, a tether for bioconjugation, and a ß-eliminative arylsulfone "trigger". The inclusion of the para-aminobenzyl spacer affords a more stable prodrug which exhibits complex drug-release kinetics due to a two-stage release mechanism. This manuscript reports the preparation and characterization of several TAK-242 prodrugs fitted with different triggers and linkers and demonstrates that these second-generation prodrugs effectively release TAK-242 while avoiding nonproductive sulfonamide hydrolysis.

Synergistic Porosity and Charge Effects in a Supramolecular Porphyrin Cage Promote Efficient Photocatalytic CO2 Reduction.

We present a supramolecular approach to catalyzing photochemical CO2 reduction through second-sphere porosity and charge effects. An iron porphyrin box (PB) bearing 24 cationic groups, FePB-2(P), was made via post-synthetic modification of an alkyne-functionalized supramolecular synthon. FePB-2(P) promotes the photochemical CO2 reduction reaction (CO2 RR) with 97 % selectivity for CO product, achieving turnover numbers (TON) exceeding 7000 and initial turnover frequencies (TOFmax ) reaching 1400 min-1 . The cooperativity between porosity and charge results in a 41-fold increase in activity relative to the parent Fe tetraphenylporphyrin (FeTPP) catalyst, which is far greater than analogs that augment catalysis through porosity (FePB-3(N), 4-fold increase) or charge (Fe p-tetramethylanilinium porphyrin (Fe-p-TMA), 6-fold increase) alone. This work establishes that synergistic pendants in the secondary coordination sphere can be leveraged as a design element to augment catalysis at primary active sites within confined spaces.

Early and Late Mortality Predictors in Patients with Acute Aortic Dissection Type B.

Background/Aim: Despite technological advances in diagnosis and treatment, in-hospital mortality with acute aortic dissection type B is still about 11%. The purpose of this study was to assess the risk factors for early and long-term adverse outcomes in patients with acute aortic dissection type B treated medically or with conventional open surgery. Methods: The present study included 104 consecutive patients with acute aortic dissection type B treated in our Center from January 1st, 1998 to January 1st, 2007. Patient demographic and clinical characteristics as well as in-hospital complications were reviewed. Univariate and multivariate testing was performed to identify the predictors of in-hospital (30-day) and late (within 9 years) mortality. Results: 92 (88.5%) patients were treated medically, while 12 (11.5%) patients with complicated acute aortic dissection type B were treated by open surgical repair. In-hospital complications occurred in 35.7% patients, the most often being acute renal failure (28%), hypotension/shock (24%), mesenteric ischemia (12%), and limb ischemia (8%). The in-hospital mortality rate was 15.7% and the 9-year mortality rate was 51.9%. Independent predictors of early mortality in patients with acute aortic dissection type B were uncontrolled hypertension (HR-20.69) and a dissecting aorta diameter >4.75 cm (HR-6.30). Independent predictors of late mortality were relapsing pain (HR-7.93), uncontrolled hypertension (HR-7.25), and a pathologic difference in arterial blood pressure (>20 mmHg) (HR-5.33). Conclusion: Knowledge of key risk factors may help with a better choice of treatment and mortality reduction in acute aortic dissection type B patients.

Multifunctional Charge and Hydrogen-Bond Effects of Second-Sphere Imidazolium Pendants Promote Capture and Electrochemical Reduction of CO2 in Water Catalyzed by Iron Porphyrins.

Microenvironments tailored by multifunctional secondary coordination sphere groups can enhance catalytic performance at primary metal active sites in natural systems. Here, we capture this biological concept in synthetic systems by developing a family of iron porphyrins decorated with imidazolium (im) pendants for the electrochemical CO2 reduction reaction (CO2 RR), which promotes multiple synergistic effects to enhance CO2 RR and enables the disentangling of second-sphere contributions that stem from each type of interaction. Fe-ortho-im(H), which poises imidazolium units featuring both positive charge and hydrogen-bond capabilities proximal to the active iron center, increases CO2 binding affinity by 25-fold and CO2 RR activity by 2000-fold relative to the parent Fe tetraphenylporphyrin (Fe-TPP). Comparison with monofunctional analogs reveals that through-space charge effects have a greater impact on catalytic CO2 RR performance compared to hydrogen bonding in this context.

Identification of stomatal-regulating molecules from de novo arylamine collection through aromatic C-H amination.

Stomata-small pores generally found on the leaves of plants-control gas exchange between plant and the atmosphere. Elucidating the mechanism that underlies such control through the regulation of stomatal opening/closing is important to understand how plants regulate photosynthesis and tolerate against drought. However, up-to-date, molecular components and their function involved in stomatal regulation are not fully understood. We challenged such problem through a chemical genetic approach by isolating and characterizing synthetic molecules that influence stomatal movement. Here, we describe that a small chemical collection, prepared during the development of C-H amination reactions, lead to the discovery of a Stomata Influencing Molecule (SIM); namely, a sulfonimidated oxazole that inhibits stomatal opening. The starting molecule SIM1 was initially isolated from screening of compounds that inhibit light induced opening of dayflower stomata. A range of SIM molecules were rapidly accessed using our state-of-the-art C-H amination technologies. This enabled an efficient structure-activity relationship (SAR) study, culminating in the discovery of a sulfonamidated oxazole derivative (SIM*) having higher activity and enhanced specificity against stomatal regulation. Biological assay results have shed some light on the mode of action of SIM molecules within the cell, which may ultimately lead to drought tolerance-conferring agrochemicals through the control of stomatal movement.

Pulmonary Function Testing in Patients With E-Cigarette, or Vaping, Product Use-Associated Lung Injury.

In 2019 there was an outbreak of respiratory illnesses amongst people who used E-cigarettes. This phenomenon was labeled 'EVALI' which stands for "Electronic cigarette (E-cigarette), or Vaping, Product Use-Associated Lung Injury" and is a life-threatening illness of the lungs associated with E-cigarette use. It is believed to be caused by certain chemicals in E-cigarette cartridges, such as vitamin E acetate, but the exact pathophysiological mechanism is yet to be elucidated. Since 2019, the CDC has recorded over 2800 cases in the United States with over 60 deaths. Though many people recover from EVALI, the long-term implications on pulmonary health are unknown. The purpose of this retrospective study was to demonstrate the pulmonary function test (PFT) findings in a group of patients who recovered from a diagnosis of EVALI. We reviewed the cases of 23 adult patients who presented to two major academic hospitals of the Northwell Health System with confirmed EVALI and followed up in our outpatient clinics with PFTs. Most patients had significantly reduced diffusion capacity (DLCO) demonstrating loss of functioning alveolar units. Given that average follow-up was over a month after discharge, this leads us to believe that EVALI can lead to persistent lung damage. However, further follow-up would be necessary to identify the full impact of E-cigarette use on the pulmonary function.

Biodiversity and antimicrobial potential of bacterial endophytes from halophyte Salicornia brachiata.

Extreme natural habitats like halophytes, marsh land, and marine environment are suitable arena for chemical ecology between plants and microbes having environmental impact. Endophytes are an ecofriendly option for the promotion of plant growth and to serve as sustainable resource of novel bioactive natural products. The present study, focusing on biodiversity of bacterial endophytes from Salicornia brachiata, led to isolation of around 336 bacterial endophytes. Phylogenetic analysis of 63 endophytes revealed 13 genera with 27 different species, belonging to 3 major groups: Firmicutes, Proteobacteria, and Actinobacteria. 30% endophytic isolates belonging to various genera demonstrated broad-spectrum antibacterial and antifungal activities against a panel of human, plant, and aquatic infectious agents. An endophytic isolate Bacillus amyloliquefaciens 5NPA-1, exhibited strong in-vitro antibacterial activity against human pathogen Staphylococcus aureus and phytopathogen Xanthomonas campestris. Investigation through LC-MS/MS-based molecular networking and bioactivity-guided purification led to the identification of three bioactive compounds belonging to lipopeptide class based on 1H-, 13C-NMR and MS analysis. To our knowledge, this is the first report studying bacterial endophytic biodiversity of Salicornia brachiata and the isolation of bioactive compounds from its endophyte. Overall, the present study provides insights into the diversity of endophytes associated with the plants from the extreme environment as a rich source of metabolites with remarkable agricultural applications and therapeutic properties.

N-Heterocyclic Carbenes Reduce and Functionalize Copper Oxide Surfaces in One Pot.

Benzimidazolium hydrogen carbonate salts have been shown to act as N-heterocyclic carbene precursors, which can remove oxide from copper oxide surfaces and functionalize the resulting metallic surfaces in a single pot. Both the surfaces and the etching products were fully characterized by spectroscopic methods. Analysis of surfaces before and after NHC treatment by X-ray photoelectron spectroscopy demonstrates the complete removal of copper(II) oxide. By using 13 C-labelling, we determined that the products of this transformation include a cyclic urea, a ring-opened formamide and a bis-carbene copper(I) complex. These results illustrate the potential of NHCs to functionalize a much broader class of metals, including those prone to oxidation, greatly facilitating the preparation of NHC-based films on metals other than gold.

Increased Intact Proinsulin in the Oral Glucose Challenge Sample is an Early Indicator for Future Type 2 Diabetes Development - Case Reports and Evidence from the Literature.

BACKGROUND: Increased intact proinsulin in plasma is a highly specific biomarker for a major disruption of insulin-processing in the pancreatic ß-cells with associated insulin resistance. Increased intact proinsulin in morning fasting plasma indicates not only incipient diabetes, but also increased risk of macrovascular events in the patient - of ten times before an actual diagnosis of diabetes - due to the convergence of ß-cell dysfunction, insulin resistance, and chronic systemic inflammation. This has raised the question as to whether a marked increase in intact proinsulin levels after oral glucose load in healthy subjects might be considered as indicative for ß-cell dysfunction and prediabetes. METHODS: A previous study from 2011 examined, inter alia, intact proinsulin levels in blood samples from twenty healthy study participants at baseline and two hours after an oral glucose tolerance test (OGTT) with 75 g glucose. Seventeen of the participants showed normal glucose levels at baseline and at two hours compared to 4 participants with normal intact proinsulin levels at baseline but increased intact proinsulin levels at two hours. RESULTS: All four patients went on to develop type 2 diabetes in the following 5 years. None of the other subjects from the previous investigation developed type 2 diabetes. CONCLUSIONS: As also confirmed by recent literature, intact proinsulin provides a powerful, easily measured biomarker for ß-cell dysfunction and insulin resistance in type 2 diabetes, as well as risk of future cardiovascular events regardless of the stage of diabetes.

Acute Respiratory Failure Associated With Vaping.

The use of e-cigarettes to deliver aerosolized nicotine has gained popularity in recent years. Numerous reports have cited the development of acute pulmonary disease linked to vaping nicotine as well as marijuana-based products. As cultural attitudes evolve and policies shift toward the legalization of marijuana, its use has become more prevalent. Given the increased prevalence of marijuana consumption and e-cigarette usage, better insight into its potential to cause lung toxicity is warranted. The clinical, radiographic, and histopathologic characteristics of lung injury associated with vaping, particularly with marijuana-based products, have yet to be well described in the literature. We present eight patients, most of whom were admitted recently to our institution with acute respiratory failure following vaping. The majority of patients were young, with a median age of 31.5 years (range, 24-62 years) and with no known underlying lung disease. This case series highlights common clinical findings as well as the varied radiographic and histopathologic features of acute respiratory failure associated with vaping predominantly marijuana-based products. As more cases of vaping-associated pulmonary injury unfold, data will be available to further characterize this emerging disease entity. Improved understanding of disease pathogenesis and its clinical course will help clinicians determine optimal management and follow-up strategies for this patient population.

Simulation Training for Critical Care Airway Management: Assessing Translation to Clinical Practice Using a Small Video-Recording Device.

BACKGROUND: Critical care airway management (CCAM) is a key skill for critical care physicians. Simulation-based training (SBT) may be an effective modality in training intensivists in CCAM. RESEARCH QUESTION: Is SBT of critical care fellows an effective means of providing training in CCAM, in particular in urgent endotracheal intubation? STUDY DESIGN AND METHODS: Thirteen first-year pulmonary critical care medicine (PCCM) fellows at an academic training program underwent SBT with a computerized patient simulator (CPS) in their first month of fellowship training. At the end of the training period, the fellows underwent video-based scoring using a 46-item checklist (of which 40 points could be scored) while performing a complete CCAM sequence on the CPS. They were then tested, using video-based scoring on their first real-life CCAM. Maintenance of skill at CCAM was assessed during the fellows' second and third year of training, using the same scoring method. RESULTS: For the first-year fellows, the score on the CPS was 38.3 ± 0.75 SD out of a maximum score of 40. The score on their first real-life patient CCAM was 39.0 ± 0.81 SD (P = .003 for equivalence; 95% CI for difference between real-life patient CCAM and CPS scores, 0.011-1.373). Sixteen second- and third-year fellows were tested at a real-life CCAM event later in their fellowship to examine for maintenance of skill. The mean maintenance of skill score of this group was 38.7 ± 1.14 SD. INTERPRETATION: Skill acquired through SBT of critical care fellows for CCAM transfers effectively to the real-life patient care arena. Second- and third-year fellows who had initially received SBT maintained skill at CCAM.

N-Heterocyclic carbene and thiol micropatterns enable the selective deposition and transfer of copper films.

Microcontact printed patterns of N-heterocyclic carbenes (NHCs) and thiols were prepared on gold substrates and utilized as templates for the creation of metallic Cu structures using electroplating. The presence of the NHC in the pattern is essential to enable the transfer of the resulting copper microstructures to a second substrate.

Single-Photon Single-Flux Coupled Detectors.

In this work, we present a novel device that is a combination of a superconducting nanowire single-photon detector and a superconducting multilevel memory. We show that these devices can be used to count the number of detections through single-photon to single-flux conversion. Electrical characterization of the memory properties demonstrates single-flux quantum (SFQ) separated states. Optical measurements using attenuated laser pulses with different mean photon number, pulse energies and repetition rates are shown to differentiate single-photon detection from other possible phenomena, such as multiphoton detection and thermal activation. Finally, different geometries and material stacks to improve device performance, as well as arraying methods, are discussed.

Temporal characterization of femtosecond laser pulses using tunneling ionization in the UV, visible, and mid-IR ranges.

To generalize the applicability of the temporal characterization technique called "tunneling ionization with a perturbation for the time-domain observation of an electric field" (TIPTOE), the technique is examined in the multicycle regime over a broad wavelength range, from the UV to the IR range. The technique is rigorously analyzed first by solving the time-dependent Schrödinger equation. Then, experimental verification is demonstrated over an almost 5-octave wavelength range at 266, 1800, 4000 and 8000 nm by utilizing the same nonlinear medium - air. The experimentally obtained dispersion values of the materials used for the dispersion control show very good agreement with the ones calculated using the material dispersion data and the pulse duration results obtained for 1800 and 4000 nm agree well with the frequency-resolved optical gating measurements. The universality of TIPTOE arises from its phase-matching-free nature and its unprecedented broadband operation range.

Robust, Highly Luminescent Au13 Superatoms Protected by N-Heterocyclic Carbenes.

Gold superatom nanoclusters stabilized entirely by N-heterocyclic carbenes (NHCs) and halides are reported. The reduction of well-defined NHC-Au-Cl complexes produces clusters comprised of an icosahedral Au13 core surrounded by a symmetrical arrangement of nine NHCs and three chlorides. X-ray crystallography shows that the clusters are characterized by multiple CH-π and π-π interactions, which rigidify the ligand and likely contribute to the exceptionally high photoluminescent quantum yields observed, up to 16.0%, which is significantly greater than that of the most luminescent ligand-protected Au13 superatom cluster. Density functional theory analysis suggests that clusters are 8-electron superatoms with a wide HOMO-LUMO energy gap of 2 eV. Consistent with this, the clusters have high stability relative to phosphine stabilized clusters.

N-heterocyclic carbene-functionalized magic-number gold nanoclusters.

Magic-number gold nanoclusters are atomically precise nanomaterials that have enabled unprecedented insight into structure-property relationships in nanoscience. Thiolates are the most common ligand, binding to the cluster via a staple motif in which only central gold atoms are in the metallic state. The lack of other strongly bound ligands for nanoclusters with different bonding modes has been a significant limitation in the field. Here, we report a previously unknown ligand for gold(0) nanoclusters-N-heterocyclic carbenes (NHCs)-which feature a robust metal-carbon single bond and impart high stability to the corresponding gold cluster. The addition of a single NHC to gold nanoclusters results in significantly improved stability and catalytic properties in the electrocatalytic reduction of CO2. By varying the conditions, nature and number of equivalents of the NHC, predominantly or exclusively monosubstituted NHC-functionalized clusters result. Clusters can also be obtained with up to five NHCs, as a mixture of species.

N-Heterocyclic Carbenes in Materials Chemistry.

N-Heterocyclic carbenes (NHCs) have become one of the most widely studied class of ligands in molecular chemistry and have found applications in fields as varied as catalysis, the stabilization of reactive molecular fragments, and biochemistry. More recently, NHCs have found applications in materials chemistry and have allowed for the functionalization of surfaces, polymers, nanoparticles, and discrete, well-defined clusters. In this review, we provide an in-depth look at recent advances in the use of NHCs for the development of functional materials.