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\"As cryptocurrency rose in popularity during the pandemic, new converts bought into the idea that crypto would not only make them rich, but would usher in imminent revolutions across art, finance, politics, and gaming. Cryptocurrency caught the zeitgeist through figures like FTX CEO Sam Bankman-Fried, who only two years later would be convicted of one of the most calamitous acts of financial fraud in US history. During his meteoric rise, Sam Bankman-Fried outflanked idealists in the movement like Vitalik Buterin, who sought to build fairer, more democratic systems through Ethereum. Bankman-Fried pursued a growth-obsessed, by-any-means approach to crypto, which proved seductive to those who just wanted to get rich. But this Silicon Valley-like approach also drove the creation of a spate of high-risk financial instruments that mirrored those of the 2008 financial crisis. Accused of misleading investors and mishandling funds, Bankman-Fried became a target of prosecutors. Now, Cryptomania unfolds the tumultuous twenty months inside this male-dominated, overhyped industry that led to its downfall. Drawing on exclusive reporting and an extensive network in the global NFT community, Andrew Chow chronicles the battle for crypto's soul, and the human toll of its economic meltdown--from the conmen and eccentrics driving the bubble to the victims caught in its burst\"-- Amazon.com.

Background: Elbow dislocation is the second most common large joint dislocation in athletes, frequently occurring in contact and high-impact sports such as football, wrestling, and gymnastics. While these injuries typically result from a fall onto an outstretched hand with the elbow in near full extension, both nonoperative and surgical treatments have demonstrated high success rates in restoring elbow function, enabling athletes to return to sport (RTS) with favorable functional outcomes. Purpose/Hypothesis: The purpose of this systematic review was to evaluate RTS rate, time to return, and functional outcomes in athletes following elbow dislocation. It was hypothesized that most athletes would successfully return to their sport regardless of treatment modality and that nonoperative treatment would be associated with a shorter recovery timeline compared with surgical intervention. Study Design: Systematic review; Level of evidence, 4. Methods: PubMed, Embase, Cochrane, and Web of Science were searched through March 20, 2025, for studies that investigated the management of elbow dislocation in athletes. Data were extracted on mechanism of injury, dislocation treatment, complications, follow-up duration, and outcome parameters, including RTS, return to the same level of play, time to return, and elbow outcome scores. Results: A total of 9 studies covering 970 athletes met the inclusion criteria for analysis. Across the studies that reported sex and age, 328 of 417 (78.7%) of the athletes were male, with a weighted mean age of 29.6 years. The mean follow-up was 72 months across the 5 studies that provided follow-up data. Across 8 of the 9 studies, 97 of 417 athletes with elbow dislocations (23.3%) underwent surgical treatment, while 320 received nonoperative management. Across 5 studies of 161 dislocations, only 18 cases (11.2%) resulted in complications. Return to any sporting activity, reported for 274 athletes across 7 studies, was observed in 99.3% of patients (n = 272/274) after a mean of 11.4 ± 7.7 weeks. On average, athletes treated nonoperatively returned sooner (8.95 weeks) than surgically treated athletes (16.3 weeks). Mayo Elbow Performance Score, Elbow Self-Assessment Score, and subjective elbow value scores demonstrated excellent elbow performance after injury. Conclusion: The results supported the hypothesis that athletes with elbow dislocation demonstrated excellent functional outcomes and high RTS rates, with most returning within 10 weeks. Most returned regardless of treatment, with nonoperative management generally associated with a shorter return timeline than surgical intervention.

Key Points The study of animals with global knockouts of genes encoding various cytokines, cytokine receptors and transcription factors has been crucial for understanding the development and homeostatic requirements of monocytes, macrophages and dendritic cells. Depletion models — such as those using clodronate liposomes or animals that express the diphtheria toxin receptor under the control of a myeloid cell-specific gene promoter — have allowed for inducible and more precise elimination of various mononuclear phagocyte populations. Crossing mice that express Cre recombinase under the control of myeloid cell-specific promoters with animals that have 'floxed' genes has been used to achieve cell-type specific deletion of a particular gene. Identifying myeloid promoters with improved specificity for particular mononuclear phagocyte populations will be crucial in order to more precisely dissect the different functions of particular populations. Molecular profiling of specific mononuclear phagocyte populations will help to identify more specific promoters and candidate genes to analyse functionally. The development of new humanized mouse models holds the promise of accelerating the study of the human mononuclear phagocyte compartment. Immunologists are making good progress in unravelling the intricacies of the mononuclear phagocyte system, and this is largely due to recent technological advances. This article describes the current tools that exist for studying the origins and functions of mononuclear phagocytes and discusses the future technologies that will enable further progress in the field. The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells. Tissue phagocytes share several cell surface markers, phagocytic capability and myeloid classification; however, the factors that regulate the differentiation, homeostasis and function of macrophages and dendritic cells remain largely unknown. The purpose of this manuscript is to review the tools that are currently available and those that are under development to study the origin and function of mononuclear phagocytes.

Background: Wrestling is a high-impact sport characterized by rapid, forceful movements, posing a considerable injury risk to athletes who are often evaluated in emergency departments (EDs) across the United States. This study examines the principal mechanics, distributions, and epidemiological trends of wrestling-related injuries. Hypothesis: (1) Upper extremity injuries would be the most common, (2) young men would be the most affected group, and (3) sprains/strains would be the most frequent diagnosis. Study Design: Descriptive epidemiology study. Methods: Patients evaluated at US EDs for wrestling-related injuries between January 1, 2015, and December 31, 2024, were identified using the National Electronic Injury Surveillance System database. Patient characteristics, injury location, diagnosis, disposition, and mechanisms of injury were recorded. Data analysis was calculated using national estimates (NEs) and linear regression to assess trends and associations. Results: From 2015 to 2024, US EDs reported approximately 10,508 cases (NE, 370,089) of wrestling-related visits. Of these, 88.4% involved males (NE, 326,985). Pediatric patients (≤18 years of age) accounted for the majority of injuries, accounting for 84.9% of all cases (NE, 314,166), with a mean age of 15.9 ± 6.2 years for the entire cohort. The lowest number of wrestling-related injuries occurred in 2020 (NE, 20,270), while the highest number was reported in 2024 (NE, 57,026). The most commonly injured body regions were the shoulder (15.2%; NE, 56,150) and head (13.1%; NE, 48,619). Sprains and strains represented the most frequent injury type at 27.6% (NE, 102,253). Conclusion: This study showed that males constituted the predominant majority of ED visits from wrestling injuries, with shoulder and neck strains being the most prevalent. The significant rise in injuries from 2020 to 2024 highlights the necessity for preventative measures and heightened awareness of wrestling safety, especially in recreational environments, where occurrences are notably elevated.

Romiplostim is a novel thrombopoiesis-stimulating peptibody consisting of a carrier Fc domain and a peptide domain that binds to the thrombopoietin receptor (TPOR) on platelets and platelet precursors. Similar to endogenous thrombopoietin, romiplostim activates the TPOR to stimulate the growth and maturation of megakaryocytes, resulting in increased production of platelets in the circulation. Binding of romiplostim to TPOR on the platelets and megakaryocytes presumably triggers subsequent internalization and degradation. Therefore, increased platelet counts following romiplostim treatment results in increased elimination of the drug. The TPOR target-mediated process is saturable, resulting in nonlinear volume of distribution and clearance of romiplostim. Therefore, target-mediated disposition plays a decreasing role in drug elimination with increasing romiplostim serum concentration. Conversely, nonspecific elimination processes such as renal clearance play an increasing role with increasing romiplostim serum concentration. Limited pharmacokinetics data demonstrated that the exposure to romiplostim was lower after multiple dose administrations than after the first dose, although large inter-subject variability was observed. Large inter- and intra-subject variability in the platelet response was also observed at a given dose. These findings suggest considerable heterogeneity of disease in patients with primary immune thrombocytopenia and support the need for individual dose adjustments based on platelet counts.

Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer. Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.

Chow et al . report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in a mouse model of polycythemia vera, pointing to a potential new therapeutic strategy for this disease. Findings similar to these are reported in an accompanying paper by Ramos et al . A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169 + macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169 + macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2 V617F -driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169 + macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. We describe GeneVector, a scalable framework for dimensionality reduction implemented as a vector space model using mutual information between gene expression. Unlike other methods, including principal component analysis and variational autoencoders, GeneVector uses latent space arithmetic in a lower dimensional gene embedding to identify transcriptional programs and classify cell types. In this work, we show in four single cell RNA-seq datasets that GeneVector was able to capture phenotype-specific pathways, perform batch effect correction, interactively annotate cell types, and identify pathway variation with treatment over time. In single-cell RNA-seq analyses, it would be critical to measure the relationships between genes. Here, the authors develop a framework for single-cell dimensionality reduction that incorporates gene-specific relationships - GeneVector -, and use it for tasks such as annotating cell types and analysing pathway variation after treatment.

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53 dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR -mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR -mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.