Structured bubbling in vibrated gas-fluidized beds of binary granular particles: experiments and simulations.

Mixing and segregation of granular particles on the basis of size and density from vertical vibration or upward gas flow is critical to a wide range of industrial, agricultural and natural processes. Recently, combined vibration and gas flow under certain conditions has been shown to create periodically repeating structured bubbling patterns within a fluidized bed of spherical, monodisperse particles. Here, we demonstrate with experiments and simulations that structured bubbling can form in binary mixtures of particles with different size and density, but with similar minimum fluidization velocities. Structured bubbling leads to particles mixing regardless of initial particle configuration, while exciting particles with only gas flow produces smaller unstructured bubbles which act to segregate particles. Discrete particle simulations match the experimental results qualitatively and, in some regards quantitatively, while continuum particle simulations do not predict mixing in the case of structured bubbling, highlighting areas for future model improvement.

Dynamically structured bubbling in vibrated gas-fluidized granular materials.

The dynamics of granular materials are critical to many natural and industrial processes; granular motion is often strikingly similar to flow in conventional liquids. Food, pharmaceutical, and clean energy processes utilize bubbling fluidized beds, systems in which gas is flowed upward through granular particles, suspending the particles in a liquid-like state through which gas voids or bubbles rise. Here, we demonstrate that vibrating these systems at a resonant frequency can transform the normally chaotic motion of these bubbles into a dynamically structured configuration, creating reproducible, controlled motion of particles and gas. The resonant frequency is independent of particle properties and system size, and a simple harmonic oscillator model captures this frequency. Discrete particle simulations show that bubble structuring forms because of rapid, local transitions between solid-like and fluid-like behavior in the grains induced by vibration. Existing continuum models for gas-solid flows struggle to capture these fluid-solid transitions and thus cannot predict the bubble structuring. We propose a constitutive relationship for solids stress that predicts fluid-solid transitions and hence captures the experimental structured bubbling patterns. Similar structuring has been observed by oscillating gas flow in bubbling fluidized beds. We show that vibrating bubbling fluidized beds can produce a more ordered structure, particularly as system size is increased. The scalable structure and continuum model proposed here provide the potential to address major issues with scale-up and optimal operation, which currently limit the use of bubbling fluidized beds in existing and emerging technologies.

Do Misconceptions About Health-Related Quality of Life Affect General Population Valuations of Health States?

OBJECTIVES: Healthcare resource allocation decisions are often informed by the expected gains in patients' quality-adjusted life-years. Misconceptions about ill-health's consequences for quality of life (QOL) may however affect evaluations of health states by the general population and hence affect resource allocation decisions informed by quality-adjusted life-years. We examine whether people selectively misestimate the QOL consequences of moderate anxiety or depression compared with other dimensions of health, and we test whether informing people of actual changes in QOL associated with health states changes appraisals of their relative undesirability. METHODS: UK general population participants (N = 1259; in 2017) expressed preferences over moderate problems: anxiety or depression, self-care, and pain or discomfort. A randomized control trial design was used whereby a control group was given a functional description of each health state, and 2 intervention groups were additionally given information on the actual differences in either life satisfaction (LS) or day affect (DA) associated with experiencing each health state. RESULTS: The LS (DA) group reported a higher preference for avoiding living with moderate anxiety or depression, being 13.4% (13.9%) more likely to choose it as most undesirable. CONCLUSION: Informing people of the change in LS or DA associated with health states before they appraise them is a feasible way to obtain informed preferences.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro. Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo.

A Rayleigh-Bénard convection instability analog in vibrated gas-fluidized granular particles.

Granular particles subject to both vertical gas flow and vertical vibration are shown experimentally to exhibit structured convection cells in a densely packed yet fluidized state without gas voids traveling through the particles. Continuum gas-granular simulations reproduce the phenomenon and demonstrate that the convection occurs due to buoyant force arising from a positive vertical gradient in bulk solid density competing with viscous force created by interparticle friction. Simulations further show that convection structures persist in a controllable manner when increasing system width.

Gravitational instabilities in binary granular materials.

The motion and mixing of granular media are observed in several contexts in nature, often displaying striking similarities to liquids. Granular dynamics occur in geological phenomena and also enable technologies ranging from pharmaceuticals production to carbon capture. Here, we report the discovery of a family of gravitational instabilities in granular particle mixtures subject to vertical vibration and upward gas flow, including a Rayleigh-Taylor (RT)-like instability in which lighter grains rise through heavier grains in the form of "fingers" and "granular bubbles." We demonstrate that this RT-like instability arises due to a competition between upward drag force increased locally by gas channeling and downward contact forces, and thus the physical mechanism is entirely different from that found in liquids. This gas channeling mechanism also generates other gravitational instabilities: the rise of a granular bubble which leaves a trail of particles behind it and the cascading branching of a descending granular droplet. These instabilities suggest opportunities for patterning within granular mixtures.

Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion.

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Money, well-being, and loss aversion: does an income loss have a greater effect on well-being than an equivalent income gain?

Higher income is associated with greater well-being, but do income gains and losses affect well-being differently? Loss aversion, whereby losses loom larger than gains, is typically examined in relation to decisions about anticipated outcomes. Here, using subjective-well-being data from Germany (N = 28,723) and the United Kingdom (N = 20,570), we found that losses in income have a larger effect on well-being than equivalent income gains and that this effect is not explained by diminishing marginal benefits of income to well-being. Our findings show that loss aversion applies to experienced losses, challenging suggestions that loss aversion is only an affective-forecasting error. By failing to account for loss aversion, longitudinal studies of the relationship between income and well-being may have overestimated the positive effect of income on well-being. Moreover, societal well-being might best be served by small and stable income increases, even if such stability impairs long-term income growth.

Pharmacological characterization of the late phase reduction in lung functions and correlations with microvascular leakage and lung edema in allergen-challenged Brown Norway rats.

Late phase airflow obstruction and reduction in forced vital capacity are characteristic features of human asthma. Airway microvascular leakage and lung edema are also present in the inflammatory phase of asthma, but the impact of this vascular response on lung functions has not been precisely defined. This study was designed to evaluate the role of increased lung microvascular leakage and edema on the late phase changes in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats using pharmacological inhibitors of the allergic inflammatory response. Rats were sensitized and challenged with ovalbumin aerosol and forced expiratory lung functions (FVC, PEF) and wet and dry lung weights were measured 48 h after antigen challenge. Ovalbumin challenge reduced FVC (63% reduction) and PEF (33% reduction) and increased wet (65% increase) and dry (51% increase) lung weights. The antigen-induced reduction in FVC and PEF was completely inhibited by oral treatment with betamethasone and partially attenuated by inhibitors of arachidonic acid metabolism including indomethacin (cyclooxygenase inhibitor), 7-TM and MK-7246 (CRTH2 antagonists) and montelukast (CysLT1 receptor antagonist). Antagonists of histamine H1 receptors (mepyramine) and 5-HT receptors (methysergide) had no significant effects indicating that these pre-formed mast cell mediators were not involved. There was a highly significant (P < 0.005) correlation for the inhibition of FVC reduction and increase in wet and dry lung weights by these pharmacological agents. These results strongly support the hypothesis that lung microvascular leakage and the associated lung edema contribute to the reduction in forced expiratory lung functions in antigen-challenged Brown Norway rats and identify an important role for the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in these responses.

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists.

A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.

Faraday wave instability analog in vibrated gas-fluidized granular particles.

Granular materials are critical to many natural and industrial processes, yet the chaotic flow behavior makes granular dynamics difficult to understand, model, and control, causing difficulties for natural disaster mitigation as well as scale-up and optimization of industrial devices. Hydrodynamic instabilities in externally excited grains often resemble those in fluids, but have different underlying mechanisms, and these instabilities provide a pathway to understand geological flow patterns and control granular flows in industry. Granular particles subject to vibration have been shown to exhibit Faraday waves analogous to those in fluids; however, waves can only form at high vibration strengths and in shallow layers. Here, we demonstrate that combined gas flow and vibration induces granular waves without these limitations to enable structured, controllable granular flows at larger scale with lower energy consumption for potential industrial processes. Continuum simulations reveal that drag force under gas flow creates more coordinated particle motions to allow waves in taller layers as seen in liquids, bridging the gap between waves produced in conventional fluids and granular particles subject to vibration alone.

Evaluating Spray Drying and Co-Precipitation as Manufacturing Processes for Amorphous Solid Dispersions of a Low Tg API.

Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (Tg) can pose challenges to this approach. This study addresses multiple routes towards overcoming issues encountered with a low Tg (∼ 12 °C) API during manufacture of a spray dry intermediate (SDI). Even once formulated as an amorphous solid dispersion (ASD) with HPMCAS-LG, the Tg of the ASD was sufficiently low to require the use of non-ideal solvents, posing safety concerns and ultimately resulting in low yields with frequent process interruptions to resolve product build-up. To resolve challenges with spray drying the HPMCAS-L SDI, higher Tg polymers were assessed during spray drying, and an alternative antisolvent precipitation-based process was evaluated to generate co-precipitated amorphous dispersions (cPAD) with either HPMCAS-L or the additional higher Tg polymers. Both approaches were found to be viable alternatives to achieve single phase ASDs while demonstrating comparable in vitro and in vivo bioperformance compared to the SDI. The results of this effort offer valuable considerations for future early-stage activities for ASDs with low Tg APIs.

Immune monitoring with iTAg MHC Tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study.

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant recipients despite the introduction of posttransplantation viral monitoring and preemptive antiviral therapy. We evaluated the use of HLA class I tetramers in monitoring CMV-specific T-cell recovery to predict patients at risk for CMV-related complications. This prospective multicenter clinical trial obtained nearly 1400 tetramer/allele results in more than 800 biweekly blood samples from 83 patients monitored for 1 year after transplantation. Major HLA types were included (A*0101, A*0201, B*0702, B*0801, B*3501). iTAg MHC Tetramers (Beckman Coulter) were used to enumerate CMV-specific CD8(+) T cells by flow cytometry using a single-platform absolute counting method. Assay variability was 8% or less and results were available within 3 hours. Delayed recovery of CMV-specific T cells (< 7 cells/µL in all blood samples during the first 65 days after transplantation) was found to be a significant risk factor for CMV-related complications; these patients were more likely to develop recurrent or persistent CMV infection (relative risk 2.6, CI 1.2-5.8, P = .01) than patients showing rapid recovery, which was associated with protection from CMV-related complications (P = .004). CMV tetramer-based immune monitoring, in conjunction with virologic monitoring, can be an important new tool to assess risk of CMV-related complications and to guide preemptive therapeutic choices.

Do people become healthier after being promoted?

This paper examines the hypothesis that greater job status makes a person healthier. It begins by successfully replicating the well-known cross-section association between health and job seniority. Then, however, it turns to longitudinal patterns. Worryingly for the hypothesis, the data-on a large sample of randomly selected British workers through time-suggest that people who start with good health go on later to be promoted. The paper can find relatively little evidence that health improves after promotion. In fact, promoted individuals suffer a significant deterioration in their psychological well-being (on a standard General Health Questionnaire (GHQ) mental ill-health measure).

The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria.

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.

Pharmacological characterization of a novel α2C-adrenoceptor agonist N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N'-methylurea (compound A).

We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.