Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition

Severe bronchospasm and acute respiratory failure associated with inhaled prostacyclin therapy

Prostacyclin therapy is a mainstay of the management of pulmonary arterial hypertension (PAH). Inhaled prostacyclins present safe and effective options for the management of PAH that limit systemic side effects. We describe the first reported case of life-threatening bronchospasm and acute respiratory failure associated with inhaled prostacyclin administration

Optimizing cell therapy by sorting cells with high extracellular vesicle secretion

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. Here, we utilize a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach is applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibit distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintain high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improves heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy

Ultrasound-Compatible Electrode for Functional Electrical Stimulation

Functional electrical stimulation (FES) is a vital method in neurorehabilitation used to reanimate paralyzed muscles, enhance the size and strength of atrophied muscles, and reduce spasticity. FES often leads to increased muscle fatigue, necessitating careful monitoring of the patient’s response. Ultrasound (US) imaging has been utilized to provide valuable insights into FES-induced fatigue by assessing changes in muscle thickness, stiffness, and strain. Current commercial FES electrodes lack sufficient US transparency, hindering the observation of muscle activity beneath the skin where the electrodes are placed. US-compatible electrodes are essential for accurate imaging and optimal FES performance, especially given the spatial constraints of conventional US probes and the need to monitor muscle areas directly beneath the electrodes. This study introduces specially designed body-conforming US-compatible FES (US-FES) electrodes constructed with a silver nanowire/polydimethylsiloxane (AgNW/PDMS) composite. We compared the performance of our body-conforming US-FES electrode with a commercial hydrogel electrode. The findings revealed that our US-FES electrode exhibited comparable conductivity and performance to the commercial one. Furthermore, US compatibility was investigated through phantom and in vivo tests, showing significant compatibility even during FES, unlike the commercial electrode. The results indicated that US-FES electrodes hold significant promise for the real-time monitoring of muscle activity during FES in clinical rehabilitative applications

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance

Harmonizing heterogeneous transcriptomics datasets for machine learning-based analysis to identify spaceflown murine liver-specific changes

NASA has employed high-throughput molecular assays to identify sub-cellular changes impacting human physiology during spaceflight. Machine learning (ML) methods hold the promise to improve our ability to identify important signals within highly dimensional molecular data. However, the inherent limitation of study subject numbers within a spaceflight mission minimizes the utility of ML approaches. To overcome the sample power limitations, data from multiple spaceflight missions must be aggregated while appropriately addressing intra- and inter-study variabilities. Here we describe an approach to log transform, scale and normalize data from six heterogeneous, mouse liver-derived transcriptomics datasets (ntotal = 137) which enabled ML-methods to classify spaceflown vs. ground control animals (AUC ≥ 0.87) while mitigating the variability from mission-of-origin. Concordance was found between liver-specific biological processes identified from harmonized ML-based analysis and study-by-study classical omics analysis. This work demonstrates the feasibility of applying ML methods on integrated, heterogeneous datasets of small sample size

Racial and ethnic differences in the degree of participation and retention in a decentralized cohort study of COVID-19 immunization in patients with inflammatory bowel diseases

Introduction: Disparities in the recruitment of minority populations in research are well-documented. However, the degree of participation and retention of minorities following enrollment is less known, particularly in decentralized studies. Although decentralized clinical research methods may allow researchers to engage broader study populations with less participation burden, they may present different retention challenges. To evaluate racial and ethnic differences in the degree of participation after enrollment in a decentralized study, we analyzed data from a cohort of patients with inflammatory bowel diseases following COVID-19 immunization. Methods: We compared by race and ethnicity the following post-enrollment participation metrics: response to > 50% of follow-up surveys, donation of a blood sample for antibody testing, consent to use of bio samples for future research, and withdrawal prior to study completion. Results: Overall, we observed higher levels of post-enrollment study participation among non-Hispanic White (NHW) participants as compared to Black or Hispanic participants: 95% of NHW participants completed follow-up versus 87% of Black participants and 91% of Hispanic participants, 73% of NHW participants provided bio samples versus 64% Black participants and 67% Hispanic participants, and 65% of NHW participants provided consent for future research versus 62% of Black participants and 52% of Hispanic participants. Conclusions: Our findings demonstrate that the degree of study participation after enrollment in this decentralized study differed by race and ethnicity, indicating that attention to diversity, equity, and inclusion is needed not only in clinical research recruitment but also throughout study administration

Interrogating the “Ivorian Miracle”: From Independence Success to Civil Wars

Post-colonial Côte d’Ivoire represents the story of an economically prosperous nation succumbing to the negative effects of economic globalization led by the IMF’s structural adjustment reforms. Internal divisions over ethnic tensions fueled by the politicization of citizenship and belonging added to this trajectory. From the “Ivorian miracle,” an autonomous agricultural economy led by small cocoa farmers, to the country’s involvement with the IMF and the push for economic and political liberalization, the post-colonial history of Cote D’Ivoire has included major episodes of turbulence. The introduction of the concept of Ivoirité—a nativist ideology aimed at classifying between native Ivorians and Ivorians with immigrant ancestry with regard to citizenship status and political participation—would cause ethnic and regional tensions in the country to boil over. Françafrique and other myriad forms of neocolonialist politics that ensure the maintenance of French influence in West Africa also undermined the economic development of the Ivorian state. This article focuses on the involvement of international institutions in the post-colonial journey of the Ivorian state, analyzing the discourse of democracy in the African continent, in a state where the fluidity of citizenship and ethnicity has always created tensions and civil wars

Work-Related Stress and Psychological Distress among Law Enforcement Officers: The Carolina Blue Project

Law enforcement is a stressful occupation that places significant psychological demands on those serving in this role. However, little is known about the severity of work-related stress and psychological distress among law enforcement officers (LEOs) in North Carolina (NC). This cross-sectional study examined the severity of work-related stress and psychological distress among 283 LEOs in NC. The Maslach Burnout Inventory, the Operational Police Stress Questionnaire, the Depression, Anxiety, and Stress Scale, and the Post-Traumatic Stress Disorder (PTSD) Checklist were used to assess burnout, operational police stress, depression, anxiety, stress, and PTSD among LEOs. Descriptive statistics, independent t-tests, Mann–Whitney U tests, one-way ANOVA, and Kruskal–Wallis tests were performed. Rural and male LEOs reported higher burnout levels related to depersonalization (i.e., increased mental distance from one’s job) compared with their urban and female counterparts. LEOs exposed to toxic materials or performing patrol duties exhibited higher operational police stress levels than those who did not. Caucasian LEOs exhibited higher depression, anxiety, and stress than their African American counterparts. Rural LEOs and LEOs who were exposed to toxic materials displayed higher levels of PTSD than their counterparts. Our findings highlight the need for increased mental health support and better working environments for LEOs