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"Ross, F. Stuart"
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AIFMD II and Evergreen Private Credit Funds for US Managers
Private Credit Funds have staked out a central role in the global economy, topping out at $2.1 trillion as of year-end 2024, with threequarters of the global exposure within the United States.1 Private credit has been gaining market share on syndicated public loans steadily over time. Research for the Federal Reserve suggests that borrowers prefer the flexibility offered by private credit loan structures over syndicated public loans, and that investors prefer the outperformance of private credit loans.2 The International Monetary Fund's (IMF) 2024 Global Stability Report put global regulators on notice that they \"should pay close attention to liquidity and conduct risk in private credit funds, especially retail, that may face higher redemption risks. The community of EU watchers currently awaits final guidance from the European Securities Markets Authority (ESMA) on draft regulatory technical standards (RTS) with final approval by the European Commission later this year. See also, Bank Lending to Private Equity and Private Credit Funds: Insights from Regulatory Data, John D Levin and Antoin Mafroy-Camine, Federal Reserve Bank of Boston SRA Notes, February 5, 2025.
Trade Publication Article
High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines
A method called PRISM rapidly identifies drug candidates that are effective against specific cancer cell lines.
Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control
1
,
2
,
3
,
4
. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity
in vivo
.
Journal Article
Globally important islands where eradicating invasive mammals will benefit highly threatened vertebrates
Invasive alien species are a major threat to native insular species. Eradicating invasive mammals from islands is a feasible and proven approach to prevent biodiversity loss. We developed a conceptual framework to identify globally important islands for invasive mammal eradications to prevent imminent extinctions of highly threatened species using biogeographic and technical factors, plus a novel approach to consider socio-political feasibility. We applied this framework using a comprehensive dataset describing the distribution of 1,184 highly threatened native vertebrate species (i.e. those listed as Critically Endangered or Endangered on the IUCN Red List) and 184 non-native mammals on 1,279 islands worldwide. Based on extinction risk, irreplaceability, severity of impact from invasive species, and technical feasibility of eradication, we identified and ranked 292 of the most important islands where eradicating invasive mammals would benefit highly threatened vertebrates. When socio-political feasibility was considered, we identified 169 of these islands where eradication planning or operation could be initiated by 2020 or 2030 and would improve the survival prospects of 9.4% of the Earth’s most highly threatened terrestrial insular vertebrates (111 of 1,184 species). Of these, 107 islands were in 34 countries and territories and could have eradication projects initiated by 2020. Concentrating efforts to eradicate invasive mammals on these 107 islands would benefit 151 populations of 80 highly threatened vertebrates and make a major contribution towards achieving global conservation targets adopted by the world’s nations.
Journal Article
Cancer therapy shapes the fitness landscape of clonal hematopoiesis
Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in
ASXL1
are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (
TP53
,
PPM1D
,
CHEK2
). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.
Journal Article
Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction
Background
Relaxins are a family of peptides that regulate reproductive physiology in vertebrates. Evidence that this is an evolutionarily ancient role of relaxins has been provided by the discovery of two relaxin-like gonad-stimulating peptides (RGP1 and RGP2) that trigger spawning in starfish. The main aim of this study was to identify the receptor(s) that mediate(s) the effects of RGP1 and RGP2 in starfish.
Results
Here we show that RGP1 and RGP2 belong to a family of peptides that include vertebrate relaxins,
Drosophila
insulin-like peptide 8 (Dilp8), and other relaxin-like peptides in several protostome taxa. An ortholog of the human relaxin receptors RXFP1 and RXFP2 and the
Drosophila
receptor LGR3 was identified in starfish (RXFP/LGR3). In
Drosophila
, but not in humans and other vertebrates, there is a paralog of LGR3 known as LGR4, and here an LGR4-type receptor was also identified in starfish. In vitro pharmacological experiments revealed that both RGP1 and RGP2 act as ligands for RXFP/LGR3 in the starfish
Acanthaster
cf.
solaris
and
Asterias rubens
, but neither peptide acts as a ligand for LGR4 in these species.
Conclusions
Discovery of the RXFP/LGR3-type receptor for RGP1 and RGP2 in starfish provides a new insight into the evolution of relaxin-type signaling as a regulator of reproductive processes. Furthermore, our findings indicate that RXFP/LGR3-type receptors have been lost in several phyla, including urochordates, mollusks, bryozoans, platyhelminthes, and nematodes.
Journal Article
Characteristics and outcomes of COVID-19 patients in New York City’s public hospital system
New York City (NYC) bore the greatest burden of COVID-19 in the United States early in the pandemic. In this case series, we describe characteristics and outcomes of racially and ethnically diverse patients tested for and hospitalized with COVID-19 in New York City's public hospital system.
We reviewed the electronic health records of all patients who received a SARS-CoV-2 test between March 5 and April 9, 2020, with follow up through April 16, 2020. The primary outcomes were a positive test, hospitalization, and death. Demographics and comorbidities were also assessed.
22254 patients were tested for SARS-CoV-2. 13442 (61%) were positive; among those, the median age was 52.7 years (interquartile range [IQR] 39.5-64.5), 7481 (56%) were male, 3518 (26%) were Black, and 4593 (34%) were Hispanic. Nearly half (4669, 46%) had at least one chronic disease (27% diabetes, 30% hypertension, and 21% cardiovascular disease). Of those testing positive, 6248 (46%) were hospitalized. The median age was 61.6 years (IQR 49.7-72.9); 3851 (62%) were male, 1950 (31%) were Black, and 2102 (34%) were Hispanic. More than half (3269, 53%) had at least one chronic disease (33% diabetes, 37% hypertension, 24% cardiovascular disease, 11% chronic kidney disease). 1724 (28%) hospitalized patients died. The median age was 71.0 years (IQR 60.0, 80.9); 1087 (63%) were male, 506 (29%) were Black, and 528 (31%) were Hispanic. Chronic diseases were common (35% diabetes, 37% hypertension, 28% cardiovascular disease, 15% chronic kidney disease). Male sex, older age, diabetes, cardiac history, and chronic kidney disease were significantly associated with testing positive, hospitalization, and death. Racial/ethnic disparities were observed across all outcomes.
This is the largest and most racially/ethnically diverse case series of patients tested and hospitalized for COVID-19 in New York City to date. Our findings highlight disparities in outcomes that can inform prevention and testing recommendations.
Journal Article
Quantum oscillations in the type-II Dirac semi-metal candidate PtSe2
Three-dimensional topological semi-metals carry quasiparticle states that mimic massless relativistic Dirac fermions, elusive particles that have never been observed in nature. As they appear in the solid body, they are not bound to the usual symmetries of space-time and thus new types of fermionic excitations that explicitly violate Lorentz-invariance have been proposed, the so-called type-II Dirac fermions. We investigate the electronic spectrum of the transition-metal dichalcogenide PtSe2 by means of quantum oscillation measurements in fields up to 65 T. The observed Fermi surfaces agree well with the expectations from band structure calculations, that recently predicted a type-II Dirac node to occur in this material. A hole- and an electron-like Fermi surface dominate the semi-metal at the Fermi level. The quasiparticle mass is significantly enhanced over the bare band mass value, likely by phonon renormalization. Our work is consistent with the existence of type-II Dirac nodes in PtSe2, yet the Dirac node is too far below the Fermi level to support free Dirac-fermion excitations.
Journal Article
PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts
in vivo
and is required
in vitro
for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway
in vivo
attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis.
Antifibrotic therapies that target myofibroblast activation are needed to treat chronic liver disease. Here the authors identify an axis of integrin beta-1 expression and Yap-1 and Pak protein signalling that can be interfered with to inhibit myofibroblast function and liver fibrosis
in vivo
.
Journal Article
SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus–cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)–confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of “high responders” maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.
Journal Article