Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

Primitive macrophages enable long-term vascularization of human heart-on-a-chip platforms.

The intricate anatomical structure and high cellular density of the myocardium complicate the bioengineering of perfusable vascular networks within cardiac tissues. In vivo neonatal studies highlight the key role of resident cardiac macrophages in post-injury regeneration and angiogenesis. Here, we integrate human pluripotent stem-cell-derived primitive yolk-sac-like macrophages within vascularized heart-on-chip platforms. Macrophage incorporation profoundly impacted the functionality and perfusability of microvascularized cardiac tissues up to 2 weeks of culture. Macrophages mitigated tissue cytotoxicity and the release of cell-free mitochondrial DNA (mtDNA), while upregulating the secretion of pro-angiogenic, matrix remodeling, and cardioprotective cytokines. Bulk RNA sequencing (RNA-seq) revealed an upregulation of cardiac maturation and angiogenesis genes. Further, single-nuclei RNA sequencing (snRNA-seq) and secretome data suggest that macrophages may prime stromal cells for vascular development by inducing insulin like growth factor binding protein 7 (IGFBP7) and hepatocyte growth factor (HGF) expression. Our results underscore the vital role of primitive macrophages in the long-term vascularization of cardiac tissues, offering insights for therapy and advancing heart-on-a-chip technologies.

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Small Island Developing States: addressing the intersecting challenges of non-communicable diseases, food insecurity, and climate change.

Small Island Developing States (SIDS) include 37 UN member countries sharing economic, environmental, and social vulnerabilities and intractable health challenges. In over 80% of SIDS, more than one in six adults die prematurely from a non-communicable disease (NCD), with poor diet being a major factor. Complex upstream food system determinants include marginalised local food production and reliance on low nutritional quality food imports. These drivers need to be seen against colonial and post-colonial political-economic legacies as well as the environmental and climate crises that challenge local production systems. A range of policy commitments (eg, the 2023 Bridgetown Declaration on NCDs and Mental Health) highlight these complex interdependencies and call for cross-sectoral food system policies to improve food security, food sovereignty, and nutrition, including integrating measures for climate change adaptation and mitigation. Although addressing these intersecting challenges will also depend on global efforts, the unique approach of SIDS can inform other settings.

Endosymbioses Have Shaped the Evolution of Biological Diversity and Complexity Time and Time Again.

Life on Earth comprises prokaryotes and a broad assemblage of endosymbioses. The pages of Molecular Biology and Evolution and Genome Biology and Evolution have provided an essential window into how these endosymbiotic interactions have evolved and shaped biological diversity. Here, we provide a current perspective on this knowledge by drawing on decades of revelatory research published in Molecular Biology and Evolution and Genome Biology and Evolution, and insights from the field at large. The accumulated work illustrates how endosymbioses provide hosts with novel phenotypes that allow them to transition between adaptive landscapes to access environmental resources. Such endosymbiotic relationships have shaped and reshaped life on Earth. The early serial establishment of mitochondria and chloroplasts through endosymbioses permitted massive upscaling of cellular energetics, multicellularity, and terrestrial planetary greening. These endosymbioses are also the foundation upon which all later ones are built, including everything from land-plant endosymbioses with fungi and bacteria to nutritional endosymbioses found in invertebrate animals. Common evolutionary mechanisms have shaped this broad range of interactions. Endosymbionts generally experience adaptive and stochastic genome streamlining, the extent of which depends on several key factors (e.g. mode of transmission). Hosts, in contrast, adapt complex mechanisms of resource exchange, cellular integration and regulation, and genetic support mechanisms to prop up degraded symbionts. However, there are significant differences between endosymbiotic interactions not only in how partners have evolved with each other but also in the scope of their influence on biological diversity. These differences are important considerations for predicting how endosymbioses will persist and adapt to a changing planet.

Elephants in the Room - Analyzing Local Discourses for Sustainable Management of Bannerghatta National Park, South India.

Landscape governance challenges, particularly in peri-urban contexts like the Bannerghatta National Park (BNP) region in South India, exemplify 'wicked' problems due to their inherent complexities. These challenges arise from a mix of conflicting interests, policy ambiguities, and sociocultural dynamics, which often blur the definition of problems and hinder effective solutions. Despite apparent options for resolution, stakeholder disagreements and deep uncertainties about implementation strategies complicate governance. This study, therefore, has two broad objectives. The first objective is to analyze the local discourses surrounding planned policy interventions around the BNP region in South India. Based on the findings, the second objective is to draw insights for sustainable natural resource governance research and practice. We applied Q-methodology to understand the discourses that underpin various conflicts in the rapidly urbanizing elephant corridor at BNP. We elicited information on how various local actors frame solutions to current collective action challenges in the BNP landscape and their perspectives on the proposed eco-sensitive zone notification, as well as the functioning of current policy interventions concerning conservation and development. The study uncovers the micropolitics and power regimes underpinning various natural resource governance challenges and demonstrates the utility of the Q-methodology in bringing diverse perspectives together in response to 'wicked' governance challenges.

Exploring practices, challenges, and priorities for human health and ecological risk assessments in Indigenous communities in Canada.

Indigenous peoples in Canada are disproportionately exposed to environmental contaminants and may face elevated health risks related to their unique cultural, spiritual, and economic relationships with the land, including the use of traditional food systems. However, to date, institutionalized approaches to assess risks to human and ecological health from contaminants have not been well developed or implemented with Indigenous community contexts in mind. There is regulatory interest in developing new approach methods for risk assessment, and thus an opportunity to increase their relevance to Indigenous communities in which they will be ultimately applied. Therefore, we conducted an anonymous mixed-methods survey of those involved with risk assessment in Indigenous communities in Canada to: (1) understand risk assessment practice in Indigenous communities, (2) explore challenges with conventional assessment methods and compare these across sectors, and (3) gather perspectives on the development of new approaches. In all, 38 completed survey responses were received (14% response rate). Respondents were from Indigenous community environment and health offices (21% of respondents), Indigenous governments (8%), federal and provincial governments (21%), and academia (45%). Risk communication was seen as the most challenging part of risk assessment (71% responded "difficult"), and nearly all respondents agreed that time (86%), cost (76%), and resource availability (86%) were "moderate" to "serious" problems. Few respondents (16%) had heard of "new approach methods" for risk assessment, and 76% of respondents (and 100% of community-based respondents) agreed on the need to develop improved risk assessment approaches. To modernize risk assessment, respondents recommended advancing cumulative risk assessment methods, improving risk communication, and promoting Indigenous leadership and Traditional Knowledge in assessment activities. Integr Environ Assess Manag 2024;00:1-16. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

SingleQ: a comprehensive database of single-cell expression quantitative trait loci (sc-eQTLs) cross human tissues.

Mapping of expression quantitative trait loci (eQTLs) and other molecular QTLs can help characterize the modes of action of disease-associated genetic variants. However, current eQTL databases present data from bulk RNA-seq approaches, which cannot shed light on the cell type- and environment-specific regulation of disease-associated genetic variants. Here, we introduce our Single-cell eQTL Interactive Database which collects single-cell eQTL (sc-eQTL) datasets and provides online visualization of sc-eQTLs across different cell types in a user-friendly manner. Although sc-eQTL mapping is still in its early stage, our database curates the most comprehensive summary statistics of sc-eQTLs published to date. sc-eQTL studies have revolutionized our understanding of gene regulation in specific cellular contexts, and we anticipate that our database will further accelerate the research of functional genomics. Database URL: http://www.sqraolab.com/scqtl.

The Montana Interfacility Blood Network: A Novel Lifesaving "Hand-off" for the Optimal Care of Rural Patients.

Purpose: The state of Montana encompasses and defines rural health care as it is known in the United States (US) today. This vast area is punctuated by pockets of health care availability with varying access to blood products for transfusion. Furthermore, timely transport is frequently challenged by weather that may limit air transportation options, resulting in multiple hours in ground transport to definitive care. Patients and Methods: The Montana State Trauma Care Committee (MT-STCC) developed the Montana Interfacility Blood Network (MT-IBN) to ensure blood availability in geographically distanced cases where patients may otherwise not survive. The index case that led to the formal development of the MT-IBN is described, followed by a second case illustrating the IBN process. Results: This process and development manuscript details the innovative efforts of MT-STCC to develop this fledgling idea unique to rural US health care. We review guidelines that have been developed to define broad aspects of the MT-IBN including the reason to share resources, proper packaging, paperwork necessary for transfer, and how to provide resources directly to the patient. Finally, we describe implementation within the state. Conclusion: The MT-IBN was developed by MT-STCC to facilitate the hand-off of lifesaving blood to patients being transported by ground to definitive care in Montana without having to stop at an intermediary facility. This has already led to lives saved in areas that are limited in blood availability due to rurality.

Editorial Commentary: Anterior Cruciate Ligament Repair or Reconstruction With Internal Bracing, for Properly Indicated Patients, Is Safe, Biocompatible, and Biomimetic.

Anterior cruciate ligament (ACL) reconstruction with internal bracing (IB)-and ACL repair with IB when indicated-reduces graft or repair failure. IB is safe and protects ligament reconstructions and repairs. The IB construct should not be misunderstood as a synthetic ligament. To be effective, suture tape must be independently secured with the knee in full extension, reflecting the terminal length of the ACL. Regardless of graft type, the graft must be cyclically tensioned independent of the IB to allow for creep, and when properly performed, this significantly increases the ultimate tensile strength of the construct and reduces graft elongation, without stress shielding. Thus, the generic term "suture augmentation" may be misleading because the successful results reported apply to the IB technique. In our experience, the failure rate after ACL reconstruction with IB is 1% at the 5-year follow-up period. Notably, these results were achieved without an additional lateral extra-articular procedure.

Animal play and evolution: Seven timely research issues about enigmatic phenomena.

The nature of play in animals has been long debated, but progress is being made in characterizing play and its variants, documenting its distribution across vertebrate and invertebrate taxa, describing its mechanisms and development, and proposing testable theories about its origins, evolution, and adaptive functions. To achieve a deeper understanding of the functions and evolution of play, integrative and conceptual advances are needed in neuroscience, computer modeling, phylogenetics, experimental techniques, behavior development, and inter- and intra-specific variation. The special issue contains papers documenting many of these advances. Here, we describe seven timely areas where further research is needed to understand this still enigmatic class of phenomena more fully. Growing empirical and theoretical evidence reveals that play has been crucial in the evolution of behavior and psychology but has been underestimated, if not ignored, in both empirical and theoretical areas of evolutionary biology and neuroscience. Play research has important ramifications for understanding the evolution of cognition, emotion, and culture, and research on animals can be both informative and transformative.

Population Diversity at the Single-Cell Level.

Population-scale single-cell genomics is a transformative approach for unraveling the intricate links between genetic and cellular variation. This approach is facilitated by cutting-edge experimental methodologies, including the development of high-throughput single-cell multiomics and advances in multiplexed environmental and genetic perturbations. Examining the effects of natural or synthetic genetic variants across cellular contexts provides insights into the mutual influence of genetics and the environment in shaping cellular heterogeneity. The development of computational methodologies further enables detailed quantitative analysis of molecular variation, offering an opportunity to examine the respective roles of stochastic, intercellular, and interindividual variation. Future opportunities lie in leveraging long-read sequencing, refining disease-relevant cellular models, and embracing predictive and generative machine learning models. These advancements hold the potential for a deeper understanding of the genetic architecture of human molecular traits, which in turn has important implications for understanding the genetic causes of human disease. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 25 is August 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

SURGE: uncovering context-specific genetic-regulation of gene expression from single-cell RNA sequencing using latent-factor models.

Genetic regulation of gene expression is a complex process, with genetic effects known to vary across cellular contexts such as cell types and environmental conditions. We developed SURGE, a method for unsupervised discovery of context-specific expression quantitative trait loci (eQTLs) from single-cell transcriptomic data. This allows discovery of the contexts or cell types modulating genetic regulation without prior knowledge. Applied to peripheral blood single-cell eQTL data, SURGE contexts capture continuous representations of distinct cell types and groupings of biologically related cell types. We demonstrate the disease-relevance of SURGE context-specific eQTLs using colocalization analysis and stratified LD-score regression.

Boundary Spanning Methodological Approaches for Collaborative Moose Governance in Eeyou Istchee.

Natural resource governance challenges are often highly complex, particularly in Indigenous contexts. These challenges involve numerous landscape-level interactions, spanning jurisdictional, disciplinary, social, and ecological boundaries. In Eeyou Istchee, the James Bay Cree Territory of northern Quebec, Canada, traditional livelihoods depend on wild food species like moose. However, these species are increasingly being impacted by forestry and other resource development projects. The complex relationships between moose, resource development, and Cree livelihoods can limit shared understandings and the ability of diverse actors to respond to these pressures. Contributing to this complexity are the different knowledge systems held by governance actors who, while not always aligned, have broadly shared species conservation and sustainable development goals. This paper presents fuzzy cognitive mapping (FCM) as a methodological approach used to help elicit and interpret the knowledge of land-users concerning the impacts of forest management on moose habitat in Eeyou Istchee. We explore the difficulties of weaving this knowledge together with the results of moose GPS collar analysis and the knowledges of scientists and government agencies. The ways in which participatory, relational mapping approaches can be applied in practice, and what they offer to pluralistic natural resource governance research more widely, are then addressed.

Chromosome-level genome assembly of the aster leafhopper (Macrosteles quadrilineatus) reveals the role of environment and microbial symbiosis in shaping pest insect genome evolution.

Leafhoppers comprise over 20,000 plant-sap feeding species, many of which are important agricultural pests. Most species rely on two ancestral bacterial symbionts, Sulcia and Nasuia, for essential nutrition lacking in their phloem and xylem plant sap diets. To understand how pest leafhopper genomes evolve and are shaped by microbial symbioses, we completed a chromosomal-level assembly of the aster leafhopper's genome (ALF; Macrosteles quadrilineatus). We compared ALF's genome to three other pest leafhoppers, Nephotettix cincticeps, Homalodisca vitripennis, and Empoasca onukii, which have distinct ecologies and symbiotic relationships. Despite diverging ~155 million years ago, leafhoppers have high levels of chromosomal synteny and gene family conservation. Conserved genes include those involved in plant chemical detoxification, resistance to various insecticides, and defence against environmental stress. Positive selection acting upon these genes further points to ongoing adaptive evolution in response to agricultural environments. In relation to leafhoppers' general dependence on symbionts, species that retain the ancestral symbiont, Sulcia, displayed gene enrichment of metabolic processes in their genomes. Leafhoppers with both Sulcia and its ancient partner, Nasuia, showed genomic enrichment in genes related to microbial population regulation and immune responses. Finally, horizontally transferred genes (HTGs) associated with symbiont support of Sulcia and Nasuia are only observed in leafhoppers that maintain symbionts. In contrast, HTGs involved in non-symbiotic functions are conserved across all species. The high-quality ALF genome provides deep insights into how host ecology and symbioses shape genome evolution and a wealth of genetic resources for pest control targets.

Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.

The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics.

The other side of the coin: An integrative review connecting pay and health.

The organizational sciences have long been interested in the effects of various compensation strategies, and on enhancing employee health. Research examining the connection between pay and health, however, remains a relative rarity. The work that has been done is scattered across disparate disciplines and lacks a unified framework for systematically exploring the effects of pay on health. We argue that greater insecurity at work, as well as rising discontent over wages and work conditions, necessitates a richer understanding of the ways in which organizational pay affects employee psychological, physiological, and behavioral health. We first conduct a comprehensive review of existing research across a broad range of disciplines, taking note of the different ways that pay is conceptualized and the impact it has on employee health. We identify critical knowledge gaps in why and when pay is related to health, noting several disciplinary trends. Drawing on prominent theories of occupational health, we then build a theoretical framework that illustrates three mechanisms underlying the effect of pay on health. We further advance prior work by integrating allostatic load theory to explain how pay gets "under the skin" to affect health, while also identifying relevant moderators and boundary conditions. Taken together, our review integrates findings from a variety of disciplines and facilitates knowledge building across these fields to generate a more comprehensive understanding of the connection between pay and health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

An unusual stroke mimic: A case report.

Hypokalaemic paralysis is a rare disorder characterized by rapid onset of symmetrical flaccid skeletal muscle weakness in the presence of reduced serum potassium levels. It is categorized as primary or secondary depending on the aetiology. Asymmetric or unilateral muscle weakness in hypokalaemic patients is a rare presentation. In patients with comorbid cardiovascular risk factors, this atypical manifestation can mimic acute stroke. Only a few of such cases have been reported in the literature. This report discusses the case of a 46-year-old hypertensive Ghanaian woman who presented to a District Hospital with sudden-onset right-sided flaccid weakness and a high blood pressure. Acute stroke was ruled out with computed tomography scan of the brain. Further laboratory evaluation demonstrated reduced serum potassium level, which was corrected with subsequent dramatic resolution of the muscle weakness.