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BACKGROUND: The balanced transfusion of blood components plays a leading role in traumatic hemostatic resuscitation. Yet, previous whole blood studies have only focused on urban trauma center settings. OBJECTIVE: To compare component vs whole blood therapy on wastage rates and mortality in the rural setting. METHODS: This study was a nonrandomized, retrospective, observational, single-center study on a cold-stored whole blood program implementation for adult massive transfusions from 2020 to 2022 at a Level II trauma center. Trauma registry data determined the facility's whole blood needs and facilitated sustainable blood supplies. Whole blood use protocols were established, and utilization and laboratory compliance for incompatible ABO antibody hemolysis was monitored and reviewed monthly at stakeholder and trauma services meetings. RESULTS: From 2018 to 2019, the facility initiated component therapy massive transfusions every 9 days (n = 41). Therefore, four units of low-titer, O-positive whole blood delivered fortnightly was determined to provide patient coverage and minimize wastage. Across the study time frame (2020-2022), there were n = 68 hemodynamically unstable patients, consisting of those receiving whole blood, n = 37, and patients receiving component therapy, n = 31. Mortality rates were significantly lower (p = .030) in the whole blood population (n = 3, 8%) compared to those solely receiving component therapy (n = 9, 29%). Wastage rates were constantly evaluated; in 2021, 43.4% was not utilized, and in 2022, this was reduced to 38.7%. Anecdotally, nurses appreciated the ease of administration and documentation of transfusing whole blood, as it negated ratio compliance. CONCLUSION: This evidence-based whole blood program provides vital care to severely injured trauma patients in a vast, rural region.

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Rodent jaws evolved structurally to support dual functionality, for either biting or chewing food. Rodent hands also function dually during food handling, for actively manipulating or statically holding food. How are these oral and manual functions coordinated? We combined electrophysiological recording of muscle activity and kilohertz kinematic tracking to analyze masseter and hand actions as mice of both sexes handled food. Masseter activity was organized into two modes synchronized to hand movement modes. In holding/chewing mode, mastication occurred as rhythmic (∼5 Hz) masseter activity while the hands held food below the mouth. In oromanual/ingestion mode, bites occurred as lower-amplitude aperiodic masseter events that were precisely timed to follow regrips (by ∼200 ms). Thus, jaw and hand movements are flexibly coordinated during food handling: uncoupled in holding/chewing mode, and tightly coordinated in oromanual/ingestion mode as regrip-bite sequences. Key features of this coordination were captured in a simple model of hierarchically orchestrated mode-switching and intra-mode action sequencing. We serendipitously detected an additional masseter-related action, tooth-sharpening, identified as bouts of higher-frequency (∼13 Hz) rhythmic masseter activity, which was accompanied by eye displacement, including rhythmic proptosis, attributable to masseter contractions. Collectively, the findings demonstrate how a natural, complex, and goal-oriented activity is organized as an assemblage of distinct modes and complex actions, adapted for the divisions of function arising from anatomical structure. These results reveal intricate, high-speed coordination of disparate effectors, and show how natural forms of dexterity can serve as a model for understanding the behavioral neurobiology of multi-body-part coordination in general.Significance statement Survival hinges on efficiently handling and ingesting food. During food handling, mice switch between statically holding and actively manipulating food with the hands, and also between biting with the incisors or chewing with the molars. Using masseter electromyography and kilohertz frame rate video, we show that the two modes of hand movement and of jaw movement are tightly linked, with holding co-occurring with chewing and handling with biting. On faster timescales, biting is precisely timed to occur after rapid sequences of manipulative hand movements. Our findings reveal fast, intricate, hierarchical coordination of hand and jaw movements, show how morphology influences the organization of complex behavior, and establish food handling as a model for neurobiological studies of multi-body-part coordination.

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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.

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WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the "WIN" site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild-type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood-borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood-borne cancers and forecast expanded utility of WINi against other cancer types.

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In mice, the first liver-resident macrophages, known as Kupffer cells (KCs), are thought to derive from yolk sac (YS) hematopoietic progenitors that are specified prior to the emergence of the hematopoietic stem cell (HSC). To investigate human KC development, we recapitulated YS-like hematopoiesis from human pluripotent stem cells (hPSCs) and transplanted derivative macrophage progenitors into NSG mice previously humanized with hPSC-liver sinusoidal endothelial cells (LSECs). We demonstrate that hPSC-LSECs facilitate stable hPSC-YS-macrophage engraftment for at least 7 weeks. Single-cell RNA sequencing (scRNA-seq) of engrafted YS-macrophages revealed a homogeneous MARCO-expressing KC gene signature and low expression of monocyte-like macrophage genes. In contrast, human cord blood (CB)-derived macrophage progenitors generated grafts that contain multiple hematopoietic lineages in addition to KCs. Functional analyses showed that the engrafted KCs actively perform phagocytosis and erythrophagocytosis in vivo. Taken together, these findings demonstrate that it is possible to generate human KCs from hPSC-derived, YS-like progenitors.

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BACKGROUND: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-ß (TGF-ß) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). PATIENTS AND METHODS: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. RESULTS: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. CONCLUSIONS: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

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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.

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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.

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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.

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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.

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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.

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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;20:1677-1692. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

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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.

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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.

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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.

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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.

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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.

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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.

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