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Progress in the management of patients with myelodysplastic syndromes (MDS) has been hampered by the inability to detect cytogenetic abnormalities in 40-60% of cases. We prospectively analyzed matched pairs of bone marrow and buccal cell (normal) DNA samples from 51 MDS patients by single nucleotide polymorphism (SNP) arrays, and identified somatically acquired clonal genomic abnormalities in 21 patients (41%). Among the 33 patients with normal bone marrow cell karyotypes, 5 (15%) had clonal, somatically acquired aberrations by SNP array analysis, including 4 with segmental uniparental disomies (UPD) and 1 with three separate microdeletions. Each abnormality was detected more readily in CD34+ cells than in unselected bone marrow cells. Paired analysis of bone marrow and buccal cell DNA from each patient was necessary to distinguish true clonal genomic abnormalities from inherited copy number variations and regions with apparent loss of heterozygosity. UPDs affecting chromosome 7q were identified in two patients who had a rapidly deteriorating clinical course despite a low-risk International Prognostic Scoring System score. Further studies of larger numbers of patients will be needed to determine whether 7q UPD detected by SNP array analysis will identify higher risk MDS patients at diagnosis, analogous to those with 7q cytogenetic abnormalities.

Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights. [ABSTRACT FROM AUTHOR]

PURPOSE: To describe a case of Wernicke's encephalopathy in a 15-year-old female patient with anorexia nervosa--restricting type. METHOD: The patient and family were interviewed. Literature relevant to the case was reviewed prior to diagnosis. RESULTS: The patient reported a 30-kg weight loss over a 6-month period, following a strict diet deplete in thiamine without vitamin supplementation. The patient reported a carbohydrate binge for 5 days prior to admission. Her clinical presentation, confusion, ataxia, nystagmus, and magnetic resonance imaging demonstrating bilateral subthalamic hyperdensities were consistent with Wernicke's encephalopathy. Nutritional stabilization and parenteral thiamine replacement resulted in rapid improvement of her ataxia and nystagmus and contributed to her recovery. CONCLUSIONS: Wernicke's encephalopathy should be considered in patients with anorexia nervosa. Thiamine therapy could be considered in cases of anorexia nervosa with significant confusion. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with heparin-platelet factor 4 (PF4) antibodies, particularly platelet-activating ones, are at risk for heparin-induced thrombocytopenia if administered heparin. We determined the heparin-PF4 antibody prevalence in emergency department (ED) patients presenting with chest pain or symptoms of thrombosis. METHODS: Admission samples from 324 ED patients with chest pain or symptoms of thrombosis were tested for heparin-PF4 antibodies and, if positive, platelet-activating antibodies. RESULTS: Twenty-four (7.4%; 95% confidence interval, 4.8%-10.8%) patients had heparin-PF4 antibodies. Seropositivity occurred in 18 (9.2%) of 196 patients recently (< or =6 months) hospitalized vs 6 (4.7%) of 128 not recently hospitalized (P = .19), and in 16/231 (6.9%) patients with chest pain vs 8/93 (8.6%) with other thrombosis (P = .64). Of 22 seropositive patients retested, 8 (7 recently hospitalized) had platelet-activating antibodies. CONCLUSION: Heparin-PF4 antibody prevalence is 7.4% in ED patients with chest pain or thrombosis, with approximately 1 in 3 seropositive patients having platelet-activating antibodies. Alternative, nonheparin anticoagulation would be prudent in these at-risk patients. Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients receiving heparin for thromboprophylaxis or treatment may have new or recurrent venous thromboembolism (VTE) if immune-mediated heparin-induced thrombocytopenia (HIT) occurs or for other reasons, eg, if anticoagulation fails. We estimated from the literature how frequently a patient presenting with VTE during or following heparin therapy has HIT-associated VTE. METHODS: A comprehensive, systematic literature search was conducted to identify studies using unfractionated or low-molecular-weight heparin (LMWH) for thromboprophylaxis or treatment in which new or recurrent VTE and serologically confirmed HIT were reported. From extracted study data, the proportion of patients with HIT-associated VTE relative to any VTE was calculated by heparin type and mode of administration. RESULTS: We identified 10 studies, some with multiple arms, that used unfractionated heparin (IV administration, 5 studies; subcutaneous administration, 3 studies) or subcutaneous LMWH (5 studies) and met analysis criteria. Across these studies, 386 of 6,219 heparin-treated patients had VTE, including 32 patients who also had HIT. The frequency of HIT-associated VTE among heparin-treated patients with VTE was comparable between IV and subcutaneous unfractionated heparin therapy (13.2% [17 of 129 patients] vs 12.4% [14 of 113 patients]; odds ratio, 1.07; 95% confidence interval, 0.50 to 2.3; p > 0.99) yet significantly different between unfractionated heparin and LMWH therapy (12.8% [31 of 242 patients] vs 0.7% [1 of 144 patients]; odds ratio, 21.0; 95% confidence interval, 2.8 to 156; p < 0.001). CONCLUSIONS: VTE is associated with HIT infrequently (< 1%) in LMWH-treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded. [ABSTRACT FROM AUTHOR]

There is a growing body of evidence demonstrating that exposure of cells to reactive oxygen species (ROS) leads to oxidative modification of nucleic acids, proteins, and lipids, and that such modifications can contribute to the development of a number of diseases and aging. This raises the question: If ROS are so damaging to cells, why have cells selected ROS to trigger activation of so many cell signaling pathways? [ABSTRACT FROM AUTHOR]

Background: The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear.Methods: We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation.Results: We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation.Conclusions: JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis. [ABSTRACT FROM AUTHOR]

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction., (© 2024. The Author(s).)

Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs. Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies. See related commentary by Khabusheva and Goodell, p. 1768., (©2024 American Association for Cancer Research.)

Single-cell transcriptomics is valuable for uncovering individual cell properties, particularly in highly heterogeneous systems. However, this technique often results in the analysis of many well-characterized cells, increasing costs and diluting rare cell populations. To address this, we developed PURE-seq (PIP-seq for Rare-cell Enrichment and Sequencing) for scalable sequencing of rare cells. PURE-seq allows direct cell loading from FACS into PIP-seq reactions, minimizing handling and reducing cell loss. PURE-seq reliably captures rare cells, with 60 minutes of sorting capturing tens of cells at a rarity of 1 in 1,000,000. Using PURE-seq, we investigated murine long-term hematopoietic stem cells and their transcriptomes in the context of hematopoietic aging, identifying Egr1 as a potential master regulator of hematopoiesis in the aging context. PURE-seq offers an accessible and reliable method for isolating and sequencing cells that are currently too rare to capture successfully with existing methods.

The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population., (Copyright © 2024 American Society of Hematology.)

While the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥ 60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML ≥ 60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-risk, 11% had intermediate-risk, and 78% had adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P<0.001) but did not stratify favorable-risk from intermediate-risk (P=0.71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (N=316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P<0.05). A "mutation-score" was calculated for each combination of these mutations, assigning adverse-risk patients into two risk groups: -1 to 0 points ("Beat-AML-intermediate") vs 1+ points ("Beat-AML-adverse"). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined "Beat-AML-favorable-risk", in addition to mutation scoring within the ELN adverse-risk. This approach redefines risk for older ND AML and proposes refined Beat-AML-favorable- (22%), Beat-AML-intermediate- (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively, P<0.001; C-index: 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making., (Copyright © 2024 American Society of Hematology.)

Purpose: Indicators of poor mental health increased during the COVID-19 pandemic among emerging adults aged 18-24 years, a group already at elevated risk. This study explores associations between contextual and personal stressors with symptoms of emerging adults' anxiety and depression, assessing both multidimensional and distinct measures of stress., Methods: Using Census Household Pulse Surveys from emerging adults aged 18 to 24 years (N = 71,885) and administrative data from April 23, 2020 to March 29, 2021, we estimated logistic regression models adjusted for state and wave fixed effects., Results: Rates of elevated anxiety and depressive symptoms rose dramatically among emerging adults during the first year of the COVID-19 pandemic. Results indicate that potential contextual stressors-state COVID-19 rates and state COVID-19 mitigation policies limiting social interactions (stay-at-home orders, restaurant closures, large gathering restrictions, and mask mandates)-were not significantly associated with symptoms. In contrast, personal economic stressors (nonemployment, household income loss, food insecurity, housing insecurity, lacking health insurance) and disruptions to education were associated significantly with elevated anxiety and depressive symptoms, with greater numbers of stressors associated with worse well-being., Discussion: Emerging adults reported persistently high levels of elevated anxiety and depressive symptoms during the first year of the pandemic, outcomes associated not with COVID-19 rates or mitigation policies, but with economic inequities, and other personal stressors heightened by the pandemic. Providing targeted support for young adults, including ensuring access to mental health supports, health care, and economic relief, is critical., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Paracoccus denitrificans has a classical cytochrome-dependent electron transport chain and two alternative oxidases. The classical transport chain is very similar to that in eukaryotic mitochondria. Thus, P. denitrificans can serve as a model of the mammalian mitochondrion that may be more tractable in elucidating mechanisms of regulation of energy production than are mitochondria. In a previous publication we reported detailed studies on respiration in P. denitrificans grown aerobically on glucose or malate. We noted that P. denitrificans has large stores of lactate under various growth conditions. This is surprising because P. denitrificans lacks an NAD + -dependent lactate dehydrogenase. The aim of this study was to investigate the mechanisms of lactate oxidation in P. denitrificans. We found that the bacterium grows well on either d-lactate or l-lactate. Growth on lactate supported a rate of maximum respiration that was equal to that of cells grown on glucose or malate. We report proteomic, metabolomic, and biochemical studies that establish that the metabolism of lactate by P. denitrificans is mediated by two non-NAD + -dependent lactate dehydrogenases. One prefers d-lactate over l-lactate (D-iLDH) and the other prefers l-lactate (L-iLDH). We cloned and produced the D-iLDH and characterized it. The K m for d-lactate was 34 μM, and for l-lactate it was 3.7 mM. Pyruvate was not a substrate, rendering the reaction unidirectional with lactate being converted to pyruvate for entry into the TCA cycle. The intracellular lactate was ∼14 mM such that both isomers could be metabolized by the enzyme. The enzyme has 1 FAD per molecule and utilizes a quinone rather than NAD  +  as an electron acceptor. D-iLDH provides a direct entry of lactate reducing equivalents into the cytochrome chain, potentially explaining the high respiratory capacity of P. denitrificans in the presence of lactate., (Published by Elsevier Inc.)

Background: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking., Methods: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice., Results: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy., Conclusions: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models., Competing Interests: Competing interests: AGK, ICL, RJB, and A Daniyan have filed provisional patent applications covering applications of membrane-proximal CD33 binders for cellular therapy. A Dunbar, YP, and RL are supported by National Cancer Institute P01 CA108671 11 (RL). DM and KKH are supported by an MSK Geoffrey Beene Cancer Research Award. RL is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis. He receives research support from and consulted for Celgene and Roche and has consulted for Incyte, Janssen, Astellas, Morphosys and Novartis, and has received honoraria from AstraZeneca, Roche, Lilly and Amgen for invited lectures and from Gilead for grant reviews. JJB has consulted for Avrobio, Sobi, BlueRock, Sanofi, Omeros, Advanced Clinical, MERCK, Bluebird Bio and is on the Data Safety Monitoring Board/Advisory Board for Advanced Clinical. RJB has licensed intellectual property to and collects royalties from BMS, Caribou, and Sanofi. RJB received research funding from BMS. RJB is a consultant to BMS, Atara Biotherapeutics Inc, Cargo Tx, Triumvira and was a consultant for CoImmune but ended in the past 3 months and Gracell Biotechnologies Inc but ended employment in the past 24 months. RJB is a member of the scientific advisory board for Triumvira, Cargo Tx and was a member of the scientific advisory board for CoImmune, but that ended in the past 3 months., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates 1-3 . Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34 + cells from patients with myeloproliferative neoplasms with JAK2 V617F -mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2 V617F -mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2 V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo., Significance: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: In vivo studies of cancer biology and assessment of therapeutic efficacy are critical to advancing cancer research and ultimately improving patient outcomes. Murine cancer models have proven to be an invaluable tool in pre-clinical studies. In this context, multi-parameter flow cytometry is a powerful method for elucidating the profile of immune cells within the tumor microenvironment and/or play a role in hematological diseases. However, designing an appropriate multi-parameter panel to comprehensively profile the increasing diversity of immune cells across different murine tissues can be extremely challenging., Methods: To address this issue, we designed a panel with 13 fixed markers that define the major immune populations -referred to as the backbone panel- that can be profiled in different tissues but with the option to incorporate up to seven additional fluorochromes, including any marker specific to the study in question., Results: This backbone panel maintains its resolution across different spectral flow cytometers and organs, both hematopoietic and non-hematopoietic, as well as tumors with complex immune microenvironments., Discussion: Having a robust backbone that can be easily customized with pre-validated drop-in fluorochromes saves time and resources and brings consistency and standardization, making it a versatile solution for immuno-oncology researchers. In addition, the approach presented here can serve as a guide to develop similar types of customizable backbone panels for different research questions requiring high-parameter flow cytometry panels., Competing Interests: WX has received research support from Stemline Therapeutics. SL serves on the scientific advisory board and has equity in ORIC Pharmaceuticals, Blueprint Medicines, Mirimus Inc, Senecea Therapeutics, Faeth Therapeutics, and PMV Pharmaceuticals. RL is a scientific advisor to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, and Isoplexis, and sits on the supervisory board of Qiagen. RL has also received research support from Ajax, Zentalis, and Abbvie, and has consulted for Incyte, Janssen, Novartis, and AstraZeneca. Additionally, RL has received honoraria from AstraZeneca and Kura for invited lectures, and from Gilead for grant reviews. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Longhini, Fernández-Maestre, Kennedy, Wereski, Mowla, Xiao, Lowe, Levine and Gardner.)