Accelerated Closure of Diabetic Wounds by Efficient Recruitment of Fibroblasts upon Inhibiting a 14-3-3/ROCK Regulatory Axis.

Chronic non-healing wounds negatively impact quality of life and are a significant financial drain on health systems. The risk of infection that exacerbates comorbidities in patients necessitates regular application of wound care. Understanding the mechanisms underlying impaired wound healing are therefore a key priority to inform effective new-generation treatments. In this study, we demonstrate that 14-3-3-mediated suppression of signaling through ROCK is a critical mechanism that inhibits the healing of diabetic wounds. Accordingly, pharmacological inhibition of 14-3-3 by topical application of the sphingo-mimetic drug RB-11 to diabetic wounds on a mouse model of type II diabetes accelerated wound closure more than 2-fold than vehicle control, phenocopying our previous observations in 14-3-3ζ-knockout mice. We also demonstrate that accelerated closure of the wounded epidermis by 14-3-3 inhibition causes enhanced signaling through the Rho-ROCK pathway and that the underlying cellular mechanism involves the efficient recruitment of dermal fibroblasts into the wound and the rapid production of extracellular matrix proteins to re-establish the injured dermis. Our observations that the 14-3-3/ROCK inhibitory axis characterizes impaired wound healing and that its suppression facilitates fibroblast recruitment and accelerated re-epithelialization suggest new possibilities for treating diabetic wounds by pharmacologically targeting this axis.

The best defense is a good offense: Anti-predator behavior of the common octopus (Octopus vulgaris) against conger eel attacks.

We present the description of defensive behavior in wild Octopus vulgaris against conger eel (Conger conger) attacks based on three video sequences recorded by recreational SCUBA divers in the eastern Atlantic off the coast of Galicia (NW Spain) and in the Cantabrian Sea (NW Spain). These records document common traits in defensive behavior: (1) the octopuses enveloped the conger eel's head to obscure its view; (2) they covered the eel's gills in an attempt to suffocate it; (3) they released ink; (4) the octopuses lost some appendages because of the fight. In the third video, the octopus did not exhibit the defensive behavior described in the first two videos due to an inability to utilize its arms in defense, and the conger eel's success in capturing octopuses is discussed. Additionally, both the cost that the octopus could face by losing some arms during the fight and whether the experience it acquires can be an advantage for future encounters are analyzed. The defensive behavior exhibited by octopuses in this study highlights their ability to survive in a hostile environment and serves as an example of the extensive repertoire of anti-predator strategies employed by these cephalopods.

Analysis of Fluid Balance and Urine Values in Elite Soccer Players: Impact of Different Environments, Playing Positions, Sexes, and Competitive Levels.

Exercise can disrupt the fluid balance, hindering performance and athlete health. Limited data exist on fluid balance responses in varying climates, sexes, and ages. This study aimed to measure and compare fluid balance and urine values among elite soccer players during training at high and low temperatures, examining the differences between sexes, playing positions, and competitive levels within men's soccer. During the 2022-2023 competitive season, a descriptive observational study was conducted on 87 soccer players from an elite Spanish soccer team. The study found that none of the groups exceeded weight loss values of 1.5% of their body mass. Additionally, the soccer players studied experienced higher weight loss, fluid intake, and a higher sweat rate (SR) during summer training compared to winter training. During the summer, male U23-21 soccer players exhibited higher levels of weight loss, fluid intake, and a higher SR compared to female soccer players or the U19-17 male category. No significant differences were found between playing positions. In conclusion, differences in the fluid balance were observed based on the climatic conditions, competitive level, and sex.

Mutational biases favor complexity increases in protein interaction networks after gene duplication.

Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis.

Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. "Basal-like" breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10-15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Characterization and phylogenetic analysis of the complete plastid genome of Theobroma bicolor (Malvaceae) from Peru.

Theobroma bicolor Bonpl. 1806 is distributed in the Neotropics from southern Mexico to the Peruvian and Brazilian Amazon. High-throughput sequencing of T. bicolor from Peru (KUELAP2926) resulted in the assembly of its complete plastid genome (GenBank accession number OQ557154). The chloroplast genome of T. bicolor is A + T-rich (62.97%), having 160,317 bp in size and containing 130 genes; including a pair of inverted repeat regions (IRs) of 25,462 bp separated by a large single copy region (LSC) of 89,221 bp and a small single copy region (SSC) of 20,172 bp. This plastid genome is similar in length, content, and organization to other members of the genus Theobroma. Phylogenetic analyses of T. bicolor support its sistership to the clade comprising T. cacao and T. grandiflorum. This study may contribute valuable information to the phylogenetic relationships within the genus Theobroma.

Prevalence of hepatic steatosis and fibrosis in apparently healthy airline pilots: A transient elastography study.

Background and Aim: Airline pilots (APs) are often characterized by a sedentary lifestyle, predisposing them to adverse cardiometabolic consequences. In this cross-sectional study, we used transient elastography (TE) to investigate the prevalence of hepatic steatosis and fibrosis among apparently healthy APs. Materials and Methods: The study cohort consisted of 137 male APs of Caucasian descent who voluntarily underwent TE. To evaluate the extent and severity of hepatic steatosis and fibrosis, we employed established cutoff values for the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Results: Of the APs, 34 (24.8%) were diagnosed with TE-defined steatosis. Specifically, 25 APs (18.2%) exhibited mild steatosis, 6 (4.4%) moderate steatosis, and 3 (2.2%) severe steatosis. The majority of participants (80 APs or 58.4%) showed no signs of liver fibrosis based on LSM values. However, 49 APs (35.8%) were diagnosed with mild fibrosis (F1), 7 (5.1%) with significant fibrosis (F2), and one (0.7%) with advanced fibrosis (F3). None of the pilots had F4 (cirrhosis). In multivariable linear regression analysis, BMI was the sole independent predictor of both CAP (ß=0.34, p<0.001) and LSM (ß=0.41, p<0.001) values in our sample of male APs. Conclusion: TE is a straightforward and convenient non-invasive method for detecting hepatic steatosis and fibrosis in high-risk occupational groups such as APs.

Dual inhibition of airway inflammation and fibrosis by common ß cytokine receptor blockade.

BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common ß (ßc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. OBJECTIVE: To determine the pathogenesis of ßc receptor-mediated inflammation and remodeling in severe asthma and to investigate ßc antagonism as a therapeutic strategy for mixed granulocytic airway disease. METHODS: ßc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human ßc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of ßc was used to block ßc signaling. RESULTS: ßc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. CONCLUSIONS: ßc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-ßc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

Minimal Effect of Messaging on Engagement in a Digital Anxiety Intervention.

This study evaluated the effectiveness of different recruitment messages for encouraging enrollment in a digital mental health intervention (DMHI) for anxiety among 1,600 anxious patients in a large healthcare system. Patients were randomly assigned to receive a standard message, or one of five messages designed to encourage enrollment: Three messages offered varying financial incentives, one message offered coaching, and one message provided consumer testimonials. Patients could then click a link in the message to visit the DMHI website, enroll, and start the first session. We examined the effects of message features and message length (short vs. long) on rates of site clicks, enrollment, and starting the first session. We also tested whether demographic and clinical factors derived from patients' electronic health records were associated with rates of enrollment and starting the first session to understand the characteristics of patients most likely to use DMHIs in this setting. Across messages, 19.4% of patients clicked a link to visit the DMHI website, but none of the messages were significantly associated with rates of site clicks, enrollment, or starting the first session. Females (vs. males) had a greater probability of enrollment. No other demographic or clinical variables were significantly associated with enrollment or starting the first session. Findings provide guidance for resource allocation decisions in larger scale DMHI implementations in healthcare settings.

Impact of Job Types on Plasma Neurotrophins Levels: A Preliminary Study in Airline Pilots, Construction Workers, and Fitness Instructors.

BACKGROUND: Neurotrophins (NTs) encompass a group of closely associated proteins regulating various aspects of neuronal growth and survival. The potential association between work-related factors and the levels of circulating NTs has not been extensively examined. In this preliminary investigation, we evaluated plasma concentrations of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in a cohort of healthy individuals from three distinct professional categories, each with unique work environments and lifestyle factors. METHODS: The study involved 60 men from three professional fields: airline pilots, construction laborers, and fitness trainers (20 participants per category) recruited during routine occupational health appointments. Plasma levels of NTs were measured using commercially available immunoassays and compared in the three professional groups. RESULTS: Among the professions studied, fitness instructors displayed the highest concentrations of BDNF and NGF, with airline pilots ranking second, and construction workers showing the lowest levels. Significantly decreased NT-3 levels were observed in airline pilots compared to fitness instructors and construction workers, but no differences were found between the latter two occupations. NT-4 levels were similar across all three occupational groups. CONCLUSIONS: Our pilot results suggest that plasma concentrations of NTs, which are involved in various aspects of neuronal and cognitive functioning, may display significant differences among healthy individuals depending on their occupation. These observations warrant additional research to explore potential implications for the field of occupational medicine.

Reduction in the Cocoa Spontaneous and Starter Culture Fermentation Time Based on the Antioxidant Profile Characterization.

In current systems, the fermentation spontaneous process produces fermented beans of heterogeneous quality due to the fermentation time. This study demonstrated that the fermentation time should be reduced. For this purpose, the physicochemical parameters, antioxidant profile, and volatile compounds were characterized in two types of fermentation (spontaneous and starter culture) for 168 h in cocoa from three altitude levels. Multivariate analysis (cluster and PCA) was used to discriminate the fermentation stages. We found three stages in all fermentations, where the first two stages (0 h to 96 h) were characterized by a higher antioxidant potential of the cocoa bean and the presence of desirable volatile compounds such as acids, alcohols, aldehydes, ketones, and esters, which are precursors of cocoa aroma; however, prolonged fermentation times affected the antioxidant profile of the bean. In addition, the use of a starter culture facilitates the release of compounds in a shorter time (especially alcohols and esters). It is concluded that it is necessary to reduce the fermentation time under these conditions in the region of Amazonas.

The local microenvironment drives activation of neutrophils in human brain tumors.

Neutrophils are abundant immune cells in the circulation and frequently infiltrate tumors in substantial numbers. However, their precise functions in different cancer types remain incompletely understood, including in the brain microenvironment. We therefore investigated neutrophils in tumor tissue of glioma and brain metastasis patients, with matched peripheral blood, and herein describe the first in-depth analysis of neutrophil phenotypes and functions in these tissues. Orthogonal profiling strategies in humans and mice revealed that brain tumor-associated neutrophils (TANs) differ significantly from blood neutrophils and have a prolonged lifespan and immune-suppressive and pro-angiogenic capacity. TANs exhibit a distinct inflammatory signature, driven by a combination of soluble inflammatory mediators including tumor necrosis factor alpha (TNF-ɑ) and Ceruloplasmin, which is more pronounced in TANs from brain metastasis versus glioma. Myeloid cells, including tumor-associated macrophages, emerge at the core of this network of pro-inflammatory mediators, supporting the concept of a critical myeloid niche regulating overall immune suppression in human brain tumors.

Refractive Error Changes Due to COVID-19 Pandemic Confinement in Children from Puerto Rico: A Retrospective Study.

SIGNIFICANCE: The progression of myopia increased in children after the pandemic confinement. A myopic shift in the refractive error of the Hispanic population was found regardless of the refractive status of the school-aged children studied. PURPOSE: This study aimed to evaluate the refractive error in Puerto Rican children before and after the COVID-19 pandemic. We were interested in whether there was a significant change in refractive error attributed to online learning during the pandemic lockdown. METHODS: A retrospective record review of children aged 7 to 18 years who underwent a comprehensive visual evaluation between 2018 and 2021 at the Inter American Eye Institute in Puerto Rico was performed. The spherical equivalent pre- and post-lockdown was compared. The study excluded the best-corrected visual acuities worse than 20/40, any corneal or retinal disease, and amblyopia. RESULTS: In total, 801 records were included in this study. The mean age was 12.7 ± 3.2 years, with 50.3% male and 49.7% female children. The mean spherical equivalent for the right and left eyes was similar ( r = 0.93, P ≤ .001). A significant difference in the mean spherical equivalent was found pre- and post- lockdown (0.22 ± 0.59 D, t800 = 10.44, P ≤ .001). A myopic shift post-lockdown was significant for all ages except those in the 7- (0.13 ± 0.79 D, t28 = 0.84, P = .40) and 8-year-old range (0.12 ± 0.65 D, t40 = 1.22, P = .23), respectively. No significant change was found between sexes before (0.16 ± 0.12 D; t799 = 1.38, P = .16) and after (0.15 ± 0.13 D; t799 = 1.19, P = .23) confinement. CONCLUSIONS: The current study revealed a significant myopic shift in Hispanic school-aged children as a result of the pandemic confinement.

Mild Depressive Symptoms in Airline Pilots Associated With Impaired Executive Functions.

INTRODUCTION: While significant efforts have been made to understand the influence of depression-related impairments on executive functioning within the general population, the specific impact on airline pilots remains largely unexplored. Considering the crucial role that cognitive abilities play in the realm of aircraft piloting, it is imperative to probe into the potential repercussions of depressive symptoms on executive functions (EFs) among this professional cohort. OBJECTIVES:  This study aims to explore the associations between depressive symptoms and EFs in a convenience sample of airline pilots. METHODS:  Male airline pilots (n = 100) underwent the Beck Depression Inventory II (BDI-II) to gauge both the presence and intensity of depressive symptoms. The Stroop Color and Word Test (SCWT), the Digit Span Task (DST), and the Wisconsin Card Sorting Test (WCST) were used to assess EFs. RESULTS:  Of the entire sample of pilots, 88% (n = 88) demonstrated minimal depressive symptoms with a BDI-II score ranging from 0 to 13. The remaining 12% (n = 12) exhibited mild depression, with scores between 14 and 19. Pilots suffering from mild depression demonstrated prolonged color and word times and a higher time interference (TI) score on the SCWT. Moreover, these individuals exhibited lower scores on the DST across both the forward digit span (FDS) and backward digit span (BDS) subtests. Finally, the presence of mild depression correlated with an increased number of total errors, encompassing both perseverative and non-perseverative errors, in the WCST. After adjusting for potential confounding variables, we found an independent association between BDI-II scores and total errors in the WCST. CONCLUSION: Our research points to substantial differences in EFs between airline pilots demonstrating mild depression and those exhibiting minimal depressive symptoms. This information can catalyze heightened consciousness about the psychological welfare of pilots.

Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.

Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN); however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. SIGNIFICANCE: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.

Impact of different job types on serum cytokine levels in apparently healthy individuals: A comparative study among airline pilots, construction workers, and fitness instructors.

BACKGROUND: The impact of occupational factors on serum cytokine concentrations has not been extensively explored. In this preliminary investigation, we measured the amounts of 12 cytokines in the serum of healthy individuals, comparing three diverse professional categories (aviation pilots, building laborers, and exercise trainers) with distinct work settings and lifestyle factors. METHODS: The study sample comprised 60 men from three distinct professional fields - airline pilots, construction laborers, and fitness trainers (20 participants per category) - who were enlisted during regular outpatient occupational health appointments. Serum levels of interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-α, and IFN-γ were measured on a Luminex® platform using a specific kit. Cytokine levels were compared among the three professional groups to determine any significant differences. RESULTS: Among the three occupational groups, fitness instructors demonstrated elevated IL-4 concentrations in comparison to both airline pilots and construction laborers, with no significant difference between the latter two professions. Additionally, a stepwise increase in IL-6 levels was identified, commencing with fitness instructors presenting the lowest quantities, succeeded by construction workers, and culminating with airline pilots, who displayed the most elevated concentrations. CONCLUSION: Serum cytokine levels in healthy individuals can exhibit variations based on their occupation. Given the unfavorable cytokine profile detected in airline pilots, it is crucial for the aviation sector to tackle potential health concerns within their employees.

Phosphorus recovery from aqueous product of hydrothermal carbonization of cow manure.

The work studies the recovery of nutrients (phosphorus and nitrogen) from the process water of acid-assisted hydrothermal carbonization (HTC) of cow manure. Three organic acids (formic acid, oxalic acid, and citric acid) and sulfuric acid were evaluated as additives in HTC. Using 0.3 M sulfuric acid, more than 99% of phosphorus and 15.6% of nitrogen from manure are extracted and dissolved during HTC at 170 °C with 10 min reaction time in a batch reactor. Nutrients (mainly phosphorus) were recovered through precipitation from process water by raising the ionic strength of the solution by addition of salts of magnesium and ammonia, and by raising the pH to 9.5. Subsequently, phosphorus-rich solids were recovered containing almost all (greater than 95%) of the dissolved phosphorus in the sulfuric and formic acid assisted runs. Morphology and qualitative chemical analysis of the precipitates were determined. It is shown by XRD that the precipitate formed from process water generated by HTC with oxalic acid is crystalline, although the diffraction pattern could not be matched with any expected substance.

IgE receptor of mast cells signals mediator release and inflammation via adaptor protein 14-3-3ζ.

BACKGROUND: Mast cells (MCs) are tissue-resident immune cells that mediate IgE-dependent allergic responses. Downstream of FcεRI, an intricate network of receptor-specific signaling pathways and adaptor proteins govern MC function. The 14-3-3 family of serine-threonine phosphorylation-dependent adapter proteins are known to organize intracellular signaling. However, the role of 14-3-3 in IgE-dependent activation remains poorly defined. OBJECTIVE: We sought to determine whether 14-3-3 proteins are required for IgE-dependent MC activation and whether 14-3-3 is a viable target for the treatment of MC-mediated inflammatory diseases. METHODS: Genetic manipulation of 14-3-3ζ expression in human and mouse MCs was performed and IgE-dependent mediator release assessed. Pharmacologic inhibitors of 14-3-3 and 14-3-3ζ knockout mice were used to assess 14-3-3ζ function in a MC-dependent in vivo passive cutaneous anaphylaxis (PCA) model of allergic inflammation. Expression and function of 14-3-3ζ were assessed in human nasal polyp tissue MCs. RESULTS: IgE-dependent mediator release from human MCs was decreased by 14-3-3ζ knockdown and increased by 14-3-3ζ overexpression. Deletion of the 14-3-3ζ gene decreased IgE-dependent activation of mouse MCs in vitro and PCA responses in vivo. Furthermore, the 14-3-3 inhibitor, RB-11, which impairs dimerization of 14-3-3, inhibited cultured MC and polyp tissue MC activation and signaling downstream of the FcεRI receptor and dose-dependently attenuated PCA responses. CONCLUSION: IgE/FcεRI-mediated MC activation is positively regulated by 14-3-3ζ. We identify a critical role for this p-Ser/Thr-binding protein in the regulation of MC FcεRI signaling and IgE-dependent immune responses and show that this pathway may be amenable to pharmacologic targeting.

Trophic ecology of Octopus vulgaris paralarvae along the Iberian Canary current eastern boundary upwelling system.

Our knowledge of the diet of wild octopus paralarvae, Octopus vulgaris, is restricted to the first 2 weeks of its planktonic phase when they are selective hunters found near the coastline. These small paralarvae, bearing only three suckers per arm, are transported by oceanic currents from the coast towards offshore waters, where they complete the planktonic phase over 2 months. Here, we have investigated the trophic ecology of O. vulgaris paralarvae in two contrasting upwelling sub-regions of the Iberian Canary current (ICC) eastern boundary upwelling system and have evaluated dietary change as paralarvae develop (inferred by counting the number of suckers per arm, ranging from three to 15) along the coastal-oceanic gradient during their planktonic phase. Using high-throughput amplicon sequencing, we have characterised the diet of 100 paralarvae collected along the Northwest Iberian Peninsula (n = 65, three to five suckers per arm) and off the west coast of Morocco (n = 35, three to 15 suckers per arm), identifying up to 87 different prey species. The diet of paralarvae varied along the ICC, with crabs (53.4%), siphonophores (12.2%), copepods (12.3%), cnidarians (8.4%) and pteropods (3.7%) accounting for 90% of the variability detected off NW Iberian Peninsula, whereas off W Morocco, crabs (46.2%), copepods (23.1%), cnidarians (12.9%), krill (9.3%) and fishes (4.2%) explained 95.6% of the variability observed using frequency of observance (FOO%) data. Ontogenetic changes in the diet based on groups of paralarvae with similar numbers per arm were evidenced by the decreasing contribution of coastal meroplankton and an increase in oceanic holoplankton, including siphonophores, copepods, pteropods and krill. Trophic niche breadth values ranged from 0.06 to 0.67, with averaged values ranging from 0.23 to 0.33 (generalist = 1 and specialist = 0), suggesting that O. vulgaris paralarvae are selective predators through their ontogenetic transition between coastal and oceanic environments.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/ßc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/ßc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/ßc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. SIGNIFICANCE: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.