Diode fibres for fabric-based optical communications.

Semiconductor diodes are basic building blocks of modern computation, communications and sensing1. As such, incorporating them into textile-grade fibres can increase fabric capabilities and functions2,  to encompass, for example,  fabric-based communications or physiological monitoring. However, processing challenges have so far precluded the realization of semiconducting diodes of high quality in thermally drawn fibres. Here we demonstrate a scalable thermal drawing process of electrically connected diode fibres. We begin by constructing a macroscopic preform that hosts discrete diodes internal to the structure alongside hollow channels through which conducting copper or tungsten wires are fed. As the preform is heated and drawn into a fibre, the conducting wires approach the diodes until they make electrical contact, resulting in hundreds of diodes connected in parallel inside a single fibre. Two types of in-fibre device are realized: light-emitting and photodetecting p-i-n diodes. An inter-device spacing smaller than 20 centimetres is achieved, as well as light collimation and focusing by a lens designed in the fibre cladding. Diode fibres maintain performance throughout ten machine-wash cycles, indicating the relevance of this approach to apparel applications. To demonstrate the utility of this approach, a three-megahertz bi-directional optical communication link is established between two fabrics containing receiver-emitter fibres. Finally, heart-rate measurements with the diodes indicate their potential for implementation in all-fabric physiological-status monitoring systems. Our approach provides a path to realizing ever more sophisticated functions in fibres, presenting  the prospect of a fibre 'Moore's law' analogue  through the increase of device density and function in thermally drawn textile-ready fibres.

Exploring antiviral and anti-inflammatory effects of thiol drugs in COVID-19.

The redox status of the cysteine-rich SARS-CoV-2 spike glycoprotein (SARS-2-S) is important for the binding of SARS-2-S to angiotensin-converting enzyme 2 (ACE2), suggesting that drugs with a functional thiol group ("thiol drugs") may cleave cystines to disrupt SARS-CoV-2 cell entry. In addition, neutrophil-induced oxidative stress is a mechanism of COVID-19 lung injury, and the antioxidant and anti-inflammatory properties of thiol drugs, especially cysteamine, may limit this injury. To first explore the antiviral effects of thiol drugs in COVID-19, we used an ACE-2 binding assay and cell entry assays utilizing reporter pseudoviruses and authentic SARS-CoV-2 viruses. We found that multiple thiol drugs inhibit SARS-2-S binding to ACE2 and virus infection. The most potent drugs were effective in the low millimolar range, and IC50 values followed the order of their cystine cleavage rates and lower thiol pKa values. To determine if thiol drugs have antiviral effects in vivo and to explore any anti-inflammatory effects of thiol drugs in COVID-19, we tested the effects of cysteamine delivered intraperitoneally to hamsters infected with SARS-CoV-2. Cysteamine did not decrease lung viral infection, but it significantly decreased lung neutrophilic inflammation and alveolar hemorrhage. We speculate that the concentration of cysteamine achieved in the lungs with intraperitoneal delivery was insufficient for antiviral effects but sufficient for anti-inflammatory effects. We conclude that thiol drugs decrease SARS-CoV-2 lung inflammation and injury, and we provide rationale for future studies to test if direct (aerosol) delivery of thiol drugs to the airways might also result in antiviral effects.

GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy.

GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism.

The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors.

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.

Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin.

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.

Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series.

Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.

Photoalignment layers for liquid crystals from the di-π-methane rearrangement.

Photoalignment of nematic liquid crystals is demonstrated using a di-π-methane rearrangement of a designed polymer. The alignment mechanism makes use of the strong coupling of the liquid crystal directors to dibenzobarrelene groups. The large structural changes that accompany photoisomerization effectively passivate segments of the polymer, allowing the remaining dibenzobarrelene groups to dominate the director alignment. Photoisomerization requires triplet sensitization, and the polymer was designed to have a uniaxially fixed rigid structure and rapid triplet energy transfer from the proximate benzophenone units to the dibenzobarrelene groups. The isomerization was observed to be regiospecific, and thin films showed alignment.

Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2- (2,5-difluorophenyl)-5-(4,6-dihydropyrrolo [3,4-c]pyrazol-5-(1H)-yl)tetrahydro-2H-pyran-3-amine (23) [corrected].

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.

Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists.

Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.

Inhalation delivery of nucleic acid gene therapies in preclinical drug development.

INTRODUCTION: Inhaled gene therapy programs targeting diseases of the lung have seen increasing interest in recent years, though as of yet no product has successfully entered the market. Preclinical research to support such programs is critically important in maximizing the chances of developing successful candidates. AREAS COVERED: Aspects of inhalation delivery of gene therapies are reviewed, with a focus on preclinical research in animal models. Various barriers to inhalation delivery of gene therapies are discussed, including aerosolization stresses, aerosol behavior in the respiratory tract, and disposition processes post-deposition. Important aspects of animal models are considered, including determinations of biologically relevant determinations of dose and issues related to translatability. EXPERT OPINION: Development of clinically-efficacious inhaled gene therapies has proven difficult owing to numerous challenges. Fit-for-purpose experimental and analytical methods are necessary for determinations of biologically relevant doses in preclinical animal models. Further developments in disease-specific animal models may aid in improving the translatability of results in future work, and we expect to see accelerated interests in inhalation gene therapies for various diseases. Sponsors, researchers, and regulators are encouraged to engage in early and frequent discussion regarding candidate therapies, and additional dissemination of preclinical methodologies would be of immense value in avoiding common pitfalls.

Design and validation of an exposure system for efficient inter-animal SARS-CoV-2 airborne transmission in Syrian hamsters.

IMPORTANCE: The main route of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is airborne. However, there are few experimental systems that can assess the airborne transmission dynamics of SARS-CoV-2 in vivo. Here, we designed, built, and characterized a hamster transmission caging and exposure system that allows for efficient SARS-CoV-2 airborne transmission in Syrian hamsters without contributions from fomite or direct contact transmission. We successfully measured SARS-CoV-2 viral RNA in aerosols and demonstrated that SARS-CoV-2 is transmitted efficiently at either a 1:1 or 1:4 infected index to naïve recipient hamster ratio. This is meaningful as a 1:4 infected index to naïve hamster ratio would allow for simultaneous comparisons of various interventions in naïve animals to determine their susceptibility to infection by aerosol transmission of SARS-CoV-2. Our SARS-CoV-2 exposure system allows for testing viral airborne transmission dynamics and transmission-blocking therapeutic strategies against SARS-CoV-2 in Syrian hamsters.

Leveraging a smartphone to perform time-gated luminescence measurements.

Empowered by advanced on-board sensors, high-performance optics packages and ever-increasing computational power, smartphones have democratized data generation, collection, and analysis. Building on this capacity, many platforms have been developed to enable its use as an optical sensing platform for colorimetric and fluorescence measurements. In this paper, we report the ability to enable a smartphone to perform laboratory quality time-resolved analysis of luminescent samples via the exploitation of the rolling shutter mechanism of the native CMOS imager. We achieve this by leveraging the smartphone's standard image capture applications, commercially available image analysis software, and housing the device within a UV-LED containing case. These low-cost modifications enable us to demonstrate the smartphone's analytical potential by performing tasks ranging from authentication and encryption to the interrogation of packaging, compounds, and physical phenomena. This approach underscores the power of repurposing existing technologies to extend the reach and inclusivity of scientific exploration, opening new avenues for data collection and analysis.

Observed Reductions in the Infectivity of Bioaerosols Containing Bovine Coronavirus Under Repetitively Pulsed RF Exposure.

OBJECTIVE: The purpose of the present study is to investigate the inactivation of bioaerosols containing Bovine Coronavirus, BCoV, under repetitively pulsed radio frequency (RF) electromagnetic exposure. METHODS: These experiments were performed in a waveguide containing a flowing aerosol stream and were limited to a single RF waveform: ∼2 µs square envelope, 5.6 GHz, 4.8 kHz repetition rate. Aerosol streams were exposed to RF electric field amplitudes in the range of 41.9 +/-6.2 kV/m. Under laminar flow conditions, 75% of the total collected aerosol stream spends 0.85 seconds or less in the RF exposure region. RESULTS: Application of the RF waveform changed mean survival rate of the aerosolized BCoV by -0.58 decades (roughly a 74% reduction) and impacted the variance and standard deviation of the experimental results, with the RF exposure data showing an 800% increase in variance and 196% increase in standard deviation over the control results. Experimental results were compared to those from an analytic electromagnetic-heating inactivation model. CONCLUSION: The comparison indicated the feasibility that the observed reduction in BCoV survival rate might be due to a combination of thermal effects and non-thermal electric field effects. SIGNIFICANCE: Developing better insight into the mechanisms of inactivation is important for understanding the potential limits of efficacy for this method. Additionally, these results contribute an important baseline for the impact of electromagnetic fields on aerosolized pathogens.

Spontaneous Coronary Artery Dissection and Its Management: A Case Report.

We illustrate a notable case of an elderly male presenting to a community hospital with six out of 10 substernal chest discomfort and electrocardiogram changes consistent with an anterolateral myocardial infarction. Percutaneous Coronary Intervention (PCI) was initiated following aspirin and anticoagulation administration, which further revealed a critical distal left main spontaneous coronary artery dissection (SCAD). Cardiothoracic and Vascular Surgery consults led to the recommendation of emergent two-vessel Coronary Artery Bypass Grafting (CABG). The patient's clinical status resolved to full recovery and was discharged on postoperative day five. The incidence of SCAD in older men has not been well documented in current literature. Prevalence in older males is 0.02%. However, it rises to 10.8% in females less than 50 years of age and with acute coronary syndromes (ACS) and ST-segment elevation. Our aim is to incorporate this case report into the current literature and help improve early diagnosis and treatment based on current recommendations.

Effects of soluble guanylate cyclase stimulator on renal function in ZSF-1 model of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. MATERIALS AND METHODS: The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. RESULTS: While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. CONCLUSION: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy.

Halo-A Universal Fluorescence Reader Based Threat Agent Detection Platform-A Proof of Concept Study Using SARS-CoV-2 Assays.

Polymerase chain reaction (PCR) remains the gold standard in disease diagnostics due to its extreme sensitivity and specificity. However, PCR tests are expensive and complex, require skilled personnel and specialized equipment to conduct the tests, and have long turnaround times. On the other hand, lateral flow immunoassay-based antigen tests are rapid, relatively inexpensive, and can be performed by untrained personnel at the point of care or even in the home. However, rapid antigen tests are less sensitive than PCR since they lack the inherent target amplification of PCR. It has been argued that rapid antigen tests are better indicators of infection in public health decision-making processes to test, trace, and isolate infected people to curtail further transmission. Hence, there is a critical need to increase the sensitivity of rapid antigen tests and create innovative solutions to achieve that goal. Herein, we report the development of a low-cost diagnostic platform, enabling rapid detection of SARS-CoV-2 under field or at-home conditions. This platform (Halo™) is a small, highly accurate, consumer-friendly diagnostic reader paired with fluorescently labeled lateral flow assays and custom software for collection and reporting of results. The focus of this study is to compare the analytical performance of HaloTM against comparable tests that use either colloidal gold nanoparticles or fluorescence-based reporters in simulated nasal matrix and not in clinical samples. Live virus data has demonstrated limit of detection performance of 1.9 TCID50/test in simulated nasal matrix for the delta variant, suggesting that single-assay detection of asymptomatic SARS-CoV-2 infections may be feasible. Performance of the system against all tested SARS CoV-2 virus variants showed comparable sensitivities indicating mutations in SARS-CoV-2 variants do not negatively impact the assay.

Interrupted energy transfer: highly selective detection of cyclic ketones in the vapor phase.

We detail our efforts toward the selective detection of cyclic ketones, e.g. cyclohexanone, a component of plasticized explosives. Thin films comprised of a conjugated polymer are used to amplify the emission of an emissive receptor via energy transfer. We propose that the energy transfer is dominated by an electron-exchange mechanism to an upper excited state of the fluorophore followed by relaxation and emission to account for the efficient energy transfer in the absence of appreciable spectral overlap. Exposure to cyclic ketones results in a ratiometric fluorescence response. The thin films show orthogonal responses when exposed to cyclic ketones versus acyclic ketones. We demonstrate that the exquisite selectivity is the result of a subtle balance between receptor design and the partition coefficient of molecules into the polymer matrix.

Nonlinear transmission line-driven apparatus for short-pulse microwave exposure of aerosolized pathogens.

A system capable of exposing a flowing aerosol stream to short duration (2-4 ns), high-power RF waveforms is described. The system utilizes a C-band gyromagnetic nonlinear transmission line source having peak power outputs ranging as high as 80 kW at a center frequency of 4.2 GHz. RF electric field magnitudes of up to 280 kV/m ± 17% are achieved within the aerosol flow region of the RF exposure apparatus.