bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials Crovalimab for SCD
Authors: Hsia Allison W , Salvino Marco Aurélio , Antmen Bulent , Asirwa Fredrick Chite , Chonat Satheesh , de Franceschi Lucia , Eleftheriou Perla , Inati Adlette , Mahlangu Johnny , Nur Erfan , Payán-Pernía Salvador , Charania Asad , Gradinaru Diana , Luder Yves , Perretti Thomas , Sreckovic Sasha , Bartolucci Pablo
Published: June 2024

Presentation Date: 6/9/2024

Presentation Start Time: 1:33:00 PM

Background

In sickle cell disease (SCD), a beta-globin gene single point mutation results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell membrane, generating sickled red blood cells and contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). Among patients with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related.1,2 Despite the availability of treatments for VOE prevention, considerable morbidity and mortality remain. Due to a lack of targeted therapies, acute VOE treatment is limited to supportive care.

Nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD, including in vaso-occlusion, hemolysis, inflammation, endothelial activation, thrombogenicity, and end-organ damage.3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous injection after an initial intravenous loading dose.4 Here, we describe the design of two randomized, double-blind, placebo-controlled trials evaluating crovalimab in patients with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824).

Methods

CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs.

Patients between 12 and 55 years of age, weighing ≥40 kg, having a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β0 thalassemia), and N. meningitidis, H. influenzae type B and S. pneumoniae vaccinations are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed.

Conclusions

CROSSWALK-a and CROSSWALK-c are currently actively enrolling patients with SCD in 6 and 7 countries, respectively.

References

1. Ballas et al, Am J Hematol 2005; 79:17–25.

2. Lanzkron et al, Am J Hematol 2010; 85:797–799.

3. Roumenina et al, Am J Hematol 2020; 95:456–464.

4. Röth et al, Blood 2020; 135:912–920.

© American Society of Hematology (2023). Reused with permission.
Point-of-care Diagnostic for Foetal Haemoglobin in Kids for Sickle Cell Disease in Ghana
Authors: Segbefia Catherine , Dei-Adomakoh Yvonne , Mensah Enoch , Thota Priya , Odame Isaac
Published: June 2024

Presentation Date: 6/9/2024

Presentation Start Time: 2:30:00 PM

Background

Sickle cell disease (SCD) is an inherited blood disorder which causes acute and chronic complications and can result in early death. About three-fourth of patients with SCD live in sub-Saharan Africa; in Ghana, 1 in 50 newborns are affected with SCD. Foetal hemoglobin (Hb F) level is a strong modifier of SCD severity. High levels of Hb F inhibit sickling and hemolysis and reduce disease morbidity and mortality. Hb F monitoring is also used to assess adherence and response to disease modifying therapy such as hydroxyurea. Standard hemoglobin electrophoretic techniques are unable to quantify Hb F. In resource-limited settings like Ghana, the use of high-performance liquid chromatography (HPLC) for Hb F quantification is often challenging due to cost and logistic constraints such limited availability of adequate technology and appropriately trained personnel. In this study, we assessed the performance of a low-cost, point-of-care (POC), microchip based cellulose acetate electrophoresis “GazelleTM” compared to HPLC for Hb F quantification in children with SCD in Ghana. GazelleTM is a fast ( < 8 minutes), easy-to-use test which can be performed by minimally trained end-users using only a finger-prick volume of blood.

Methods

This cross-sectional study was conducted at the paediatric SCD Clinic in Korle Bu Teaching Hospital, Accra, Ghana. Study participants were children of ages ≥ 1 year to 16 years who were known to have sickle cell disease and were about to commence or were on hydroxyurea therapy and followed at the SCD clinic.

Results

A total of 532 children were included in the analysis. Gazelle showed a correlation of 0.98 (Pearson correlation) when compared to HPLC.

Conclusions

Haemoglobin variants are quantified by Gazelle offering the ability to monitor disease modifying therapy in SCD such as hydroxyurea, where quantification of Hb F levels is important in assessing treatment adherence and determining response to therapy. Gazelle has the potential to be utilized as a POC test for quantification of Hb F levels in monitoring hydroxyurea therapy for children with SCD, especially in limited-resource settings.
Diagnostic Potential of Platelet-Neutrophil Ratio (PNR) for Stroke Risk in SCD Children
Authors: Efobi Chilota Chibuife , Nri-Ezedi Chisom A , Hyppolite Regine , Darbari Deepika S , Campbell Andrew D
Published: June 2024

Presentation Date: 6/9/2024

Presentation Start Time: 3:00:00 PM

Background

Sickle cell disease (SCD) presents a formidable healthcare challenge, with stroke being a significant complication. The gold standard for stroke risk assessment is transcranial doppler ultrasound (TCD). However, resource constraints often limit TCD availability. This study explores the potential of the platelet-neutrophil ratio (PNR) as a cost-effective and an additional tool for assessing stroke risk in SCD patients.

Methods

This was a retrospective study conducted on 144 SCD HbSS children from Children’s National Hospital, Washington DC, USA as part of the CNH Natural History Study of SCD. TCD values were categorized (based on the STOP Study) as normal, abnormal, or conditional. PNR was calculated from routine complete blood count tests. Statistical analyses were employed to evaluate the association between the platelet-neutrophil ratio and stroke risk.

Results

The platelet-neutrophil ratio (PNR) demonstrated distinctive values across stroke risk categories: 83.83 (58.15-127.65) for normal, 75.69 (64.89-88.6) for conditional, and 62.57 (28.12-64.47) for abnormal (p = 0.031). Following adjustments for age and hydroxyurea intake, a unit increase in PNR was significantly associated with a decreased risk of stroke (OR = 0.975, 95% CI: 0.953-0.998, p = 0.0345). PNR showed superior discriminative performance for stroke risk compared to neutrophils and platelets, with AUC values of 0.81, 0.57, and 0.19, respectively.

Conclusions

This research unveils a promising avenue for more equitable healthcare in SCD management by introducing the platelet-neutrophil ratio (PNR) as a cost-effective and additional tool to assess for stroke risk in poor resource settings. A larger study is needed to validate these findings.
Hyperhemolysis Syndrome in Child with Sickle Cell Disease: Case Report and Literature Review
Authors: Arcara Catherine , Morgan Epley , Sinha Shabnum , Ahmed Rafat , Ostrowicki Renata , Eddington K Allen , Gao Yuanzheng Andrew
Published: June 2024

Presentation Date: 6/8/2024

Presentation Start Time: 6:00:00 PM

Background

Worsening anemia in the setting of various sickle cell disease sequelae is often treated with packed red blood cell (pRBC) transfusion. Hyperhemolysis syndrome (HHS) is a rare and life-threatening complication of transfusion. HHS is the destruction of host RBC and transfused RBC in the absence of red cell antibodies. This is evidenced by declining hemoglobin (Hb) and reticulocyte counts following transfusion, with negative antibody testing. The pathophysiology of HHS continues to be investigated. Proposed mechanisms include bystander hemolysis, erythropoiesis suppression, and macrophage mediated destruction. Hyperhemolysis is typically treated with IVIG and steroids. Goals of treatment include improving Hb and reticulocyte count.

Objective

Describe a case of a 15 year old male with sickle cell SS disease with acute chest syndrome (ACS) complicated by hyperhemolysis syndrome.

Methods

Single case report and literature review

Results

15 year old male with sickle cell disease type SS and history of delayed transfusion reactions who initially presented with right sided chest pain and shortness of breath. Patient found to have acute hypoxic respiratory failure with new infiltrates on chest x-ray consistent with right sided pneumonia progressing to ACS requiring increasing respiratory support and antibiotics. Patient noted to have significant anemia, requiring pRBC transfusions. After PRBC transfusion, he experienced worsening clinical status with increasing oxygen requirements, anemia, reticulocytopenia, thrombocytopenia, and leukocytosis with negative Direct Coombs test, raising concern for acute HHS. Patient demonstrated cyclical pattern of significant anemia necessitating transfusions with expected increase in hemoglobin followed by significant thrombocytopenia, reticulocytopenia, and anemia within 48-72 hours of transfusion. Given history of transfusion reactions and suspected HHS, patient was initiated on IV glucocorticoids with demonstrated resolution of anemia, thrombocytopenia, and reticulocytopenia.

Conclusions

While the exact underlying cause of this patient’s hyperhemolysis remains unknown, he responded immediately to the administration of IV steroids. Both steroids and IVIG together are standard treatment, however this case supports that IV steroids alone are sufficient to treat HHS. IV steroids are more cost effective than IVIG. Furthermore, there is evidence of IVIG induced hemolytic anemia, which would exacerbate the underlying pathologic process in HHS. Being familiar with the presentation of HHS is important to be able to recognize the condition and provide timely treatment.
The Role of Endothelial Cells in Sickle Cell Hemoglobin Clearance: What Do We Know So Far?
Authors: Pradhan-Sundd Tirthadipa , Kaminski Tomasz , Zhang Hong
Published: June 2024

Presentation Date: 6/8/2024

Presentation Start Time: 6:00 PM

Background

Sickle cell disease (SCD) is a monogenic disorder that affects 100,000 African Americans and millions of people worldwide. Intra-erythrocytic polymerization of sickle hemoglobin (HbS) promotes erythrocyte sickling, impaired rheology, ischemia and hemolysis, leading to the development of progressive organ injury in SCD. Liver resident Kupffer cells and monocytes are known to enable the clearance of HbS, however, the role of liver sinusoidal endothelial cells (LSECs) in HbS clearance and liver injury in SCD remains unknown.

Methods

We used real-time intravital imaging, flow cytometry analysis, and confocal imaging of human and mouse primary endothelial cells to investigate their potential function in hemoglobin clearance.

Results

We show for the first time that LSECs are capable of HbS clearance. Hb uptake by LSECs was mediated by micropinocytosis. We show that accumulation of HbS in LSECs promotes endothelial senescence.  Hepatic monocytes were observed to attenuate LSEC senescence by accelerating HbS clearance in the liver of SCD mice, however, this protection was impaired in P-selectin-deficient SCD mice secondary to reduced monocyte recruitment in the liver.

Conclusions

These findings are the first to suggest that LSECs contribute to HbS clearance and HbS induced LSEC-senescence promotes progressive liver injury in SCD mice. Our results provide a novel insight into the pathogenesis of hemolysis induced chronic liver injury in SCD caused by LSEC senescence. Identifying the regulators of LSEC mediated HbS clearance may lead to new therapies to prevent the progression of liver injury in SCD.
“The heavens, the earth and all their hosts” (Gen 2,1). The inventory of the supernatural entities in the Hebrew Bible created with the Elyonim veTachtonim system
Authors: Kosior Wojciech
Published: June 2024

Elyonim veTachtonim is a system of quantitative and qualitative analysis of the traditions involving supernatural entities and, in this article, I showcase its implementation to the construction of the biblical inventory. I start with a review of the printed and electronic resources and recognize their advantages and limitations which informed and motivated the production of the database. Next, I summarize the theoretical and methodological fundamentals of the endeavor and then scrutinize the development process emphasizing the quantitative and qualitative specificities of the biblical inventory. Finally, I sketch out the possible applications of the database and its prospective developments.
Challenges of Providing Optimal and Safe Intrapartum Analgesia in Patients With HELLP Syndrome: A Case Report and Literature Review
Authors: Crane Anise A , Russo Christopher M , Wands Kayla , Gafner Jeffrey L , Burch Robert H
Published: June 2024

HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) Syndrome is a rare but serious complication of pregnancy that can lead to disseminated intravascular coagulation, pulmonary edema, respiratory failure, hepatic and renal injury, and death if not recognized and treated promptly. A 36-year-old nulligravid (G0) active duty Marine at 36 weeks and 1 day gestation with dichorionic diamniotic twins presented to triage for routine cervical examination found to have elevated blood pressures and symptomatic thrombocytopenia, with a suspected diagnosis of HELLP. A multidisciplinary decision was made by anesthesiology, obstetrics and gynecology, and pediatrics to deliver the twins to avoid any further complications. The twins were in cephalic presentation and the patient desired to attempt a vaginal delivery. Due to the patient’s thrombocytopenia, neuraxial anesthesia (spinal and/or epidural) left the patient at a high risk of developing catastrophic complications such as an epidural hematoma, and the subsequent motor block/weakness would likely lessen the patient’s ability to participate in active labor for a vaginal delivery. A Cesarean section under general anesthesia was also to be avoided as the patient’s elevated risk of catastrophic hemorrhage would be worsened by volatile anesthetic agents which cause significant uterine vascular relaxation and reduced uterine muscular tone. Ultimately, the decision was made to provide analgesia through a remifentanil PCA (patient-controlled analgesia) for labor and a ketamine bolus for delivery. The mother delivered both twins vaginally in the operating room without perioperative complication. This case demonstrates the safety of alternate forms of anesthesia for delivery when neuraxial anesthesia is contraindicated.
The Dreaded 3-Minute Wait: Does It Really Prevent Operating Room Fires? The IGNITE Trial
Authors: Keenan Corey , Danis Hillary , Fraley Jim , Roets Jack , Spitzer Holly , Grasso Samuel
Published: June 2024

Introduction

Operating room fires can have devastating consequences and as such must be prevented. There exists a paucity of literature requiring further elucidation regarding manufacturer recommendations of a predefined waiting period prior to patient draping after using alcohol-based surgical antiseptics, in order to reduce the risk of operating room fires.

Methods

This was further investigated by exposing two common alcohol-based surgical antiseptics to electrosurgery and open flames at various power settings and time intervals in an ex vivo porcine model. The simulated surgical site was prepped following manufacturer recommendations and exposed to monopolar electrosurgery at low and high power, using both PURE CUT and COAGULATION modes, and open flame, at 15-s increments after application.

Results

While using PURE CUT mode at both low and high power, no ignition was observed on hairless surgical sites prepped with ChloraPrep® at any time point. However, use of COAGULATION mode at both low and high powers resulted in ignition consistently out to 1-min post-application. Additionally, if the prepped area subjectively appeared wet, especially with pooling of the antiseptic, both COAGULATION mode and open flame caused ignition. Dry time was found to be about 59 s for both prep solutions. It was also observed that the amount of pressure directly correlated with the amount of prep dispersed and increased dry times.

Conclusion

In conclusion, our data suggest an average dry time of less than 1-min, with ignition only observed when the antiseptic was visibly wet. Ignition did not occur on hairless skin with electrocautery on CUT mode using ChloraPrep at any time point. Additionally, ignition on hair-bearing skin was not observed past 3 min, with current manufacturer recommendations stating 1 h wait time for hair-bearing skin. Arbitrarily waiting a specific predetermined dry time until patient draping, as recommended by the manufacturers, may be unnecessary and lead to hours’ worth of time wasted each year. Ongoing research will further investigate the utility of drying the antiseptic after application and its affect on not only preventing ignition but also antimicrobial efficacy.
Understanding stellar populations in thin and thick discs of edge-on galaxies with MUSE – I. The case of the reignited S0 galaxy ESO 544-27
Authors: Somawanshi Devang , Bhattacharya Souradeep , Kataria Manish , Kobayashi Chiaki
Published: June 2024

Edge-on galaxies act as the best laboratories to understand the origin of thin and thick discs in galaxies. Measurement of spatially resolved stellar population properties in such galaxies, particularly age, metallicity, and [α/Fe], are crucial to understanding the formation and evolution of disc galaxies. Such measurements are made possible from stellar population model fits to deep integral field spectroscopic (IFU) observations of resolved galaxies. We utilize archival MUSE IFU observations of the edge-on galaxy ESO 544-27 to uncover the formation history of its thin and thick discs through its stellar populations. We find the thin disc of the galaxy is dominated by an old (>9 Gyr) low [α/Fe] metal-rich stellar population. Its outer thick disc is dominated by an old (>9 Gyr) high [α/Fe] metal-rich component that should have formed with higher star formation efficiency than the Milky Way thick disc. We thus find [α/Fe] dichotomy in ESO 544-27 with its thin and thick discs dominated by low and high [α/Fe] stellar populations, respectively. However, we also find a metal-rich younger (<2 Gyr old) stellar population in ESO 544-27. The galaxy was nearly quenched until its star formation was reignited recently first in the outer and inner thick disc (∼1 Gyr ago) and then in the thin disc (∼600 Myr ago). We thus find that both the low [α/Fe] thin and high [α/Fe] thick discs of ESO 544-27 are inhabited primarily by similarly old metal-rich stellar populations, a contrast to that of other galaxies with known thin and thick disc stellar population properties.
Longitudinal filtering, sponge layers, and equatorial jet formation in a general circulation model of gaseous exoplanets
Authors: Christie D A , Mayne N J , Zamyatina M , Baskett H , Evans-Soma T M , Wood N , Kohary K
Published: June 2024

General circulation models are a useful tool in understanding the three dimensional structure of hot Jupiter and sub-Neptune atmospheres; however, understanding the validity of the results from these simulations requires an understanding of the artificial dissipation required for numerical stability. In this paper, we investigate the impact of the longitudinal filter and vertical ‘sponge’ used in the Met Office’s unified model when simulating gaseous exoplanets. We demonstrate that excessive dissipation can result in counter-rotating jets and a catastrophic failure to conserve angular momentum. Once the dissipation is reduced to a level where a super-rotating jet forms, however, the jet and thermal structure are relatively insensitive to the dissipation, except in the nightside gyres where temperatures can vary by $\sim 100\, \mathrm{K}$. We do find, however, that flattening the latitudinal profile of the longitudinal filtering alters the results more than a reduction in the strength of the filtering itself. We also show that even in situations where the temperatures are relatively insensitive to the dissipation, the vertical velocities can still vary with the dissipation, potentially impacting physical processes that depend on the local vertical transport.
Unveiling the properties of asteroids: linking photopolarimetry to spectral classification
Authors: Prasad B , Das H S
Published: June 2024

This paper attempts to present a comprehensive analysis of the photopolarimetric properties of asteroids. In light of the limitations identified in several previously employed empirical formulae, this paper introduces a new formula that offers a reliable fit for the phase-polarization curve of asteroids. The validity of the new empirical formula is confirmed by analysing polarimetric data for lunar soil samples across a wide range of phase angles and various spectral bands. Notably, this investigation reveals a strong negative correlation between $P_{\mathrm{ max}}$ and wavelength ($\lambda$) for lunar soil samples. Furthermore, the examination of key features of the phase-polarization curve of asteroids, such as the polarization minimum ($P_{\mathrm{ min}}$), polarization maximum ($P_{\mathrm{ max}}$), and the slope (h) at the inversion angle, allows us to explore their correlations with the geometric albedo (A) of asteroids. We have investigated whether our photopolarimetric studies could corroborate the existing classification scheme for asteroids, which divides them into three major composition classes: Chondrite (C), Metallic (M), and Stony (S)-types, based on spectral analysis. Our findings have revealed a good agreement with the existing classification. Each class is characterized by a specific combination of geometric albedo (A) and polarimetric properties ($P_{\mathrm{ min}}$, $P_{\mathrm{ max}}$, and h) observed in asteroids, represented by four distinct regions. Interestingly, besides the three main types (C-, M-, and S-), we have found an overlapping region containing both M- and S-type asteroids.
rescuer: cosmological K-corrections for star clusters
Authors: Reina-Campos Marta , Harris William E
Published: June 2024

The advent of JWST now allows entire star cluster populations to be imaged in galaxies at cosmologically significant redshifts, bringing with it the need to apply K-corrections to their magnitudes and colour indices. Since the stellar populations within star clusters can be well approximated by a single age and metallicity, their spectral energy distributions are very different from those of galaxies or supernovae, and their K-corrections behave differently. We derive the photometric K-corrections versus redshift for model star clusters that cover a wide range of ages and metallicities, illustrating the results particularly for the broad-band filters on the Hubble Space Telescope/Advanced Camera for Surveys and the JWST/Near-Infrared Camera that are most commonly being used for imaging of populations of star clusters in distant galaxies. In an appendix, we introduce a webtool called rescuer (REdshifted Star ClUstERs) that can generate K-values and their uncertainties for any user-defined combination of cluster properties.
AuriDESI: mock catalogues for the DESI Milky Way Survey
Authors: Kizhuprakkat Namitha , Cooper Andrew P , Riley Alexander H , Koposov Sergey E , Aguilar Jessica Nicole , Ahlen Steven , Allende Prieto Carlos , Brooks David , Claybaugh Todd , Dawson Kyle , de la Macorra Axel , Doel Peter , Forero-Romero Jaime E , Frenk Carlos , Gaztañaga Enrique , Gnedin Oleg Y , Grand Robert J J , Gontcho A Gontcho Satya , Honscheid Klaus , Kehoe Robert , Landriau Martin , Manera Marc , Meisner Aaron , Miquel Ramon , Nie Jundan , Prada Francisco , Rezaie Mehdi , Rossi Graziano , Sanchez Eusebio , Schubnell Michael , Seo Hee-Jong , Tarlé Gregory , Valluri Monica , Zhou Zhimin
Published: June 2024

The Dark Energy Spectroscopic Instrument Milky Way Survey (DESI MWS) will explore the assembly history of the Milky Way by characterizing remnants of ancient dwarf galaxy accretion events and improving constraints on the distribution of dark matter in the outer halo. We present mock catalogues that reproduce the selection criteria of MWS and the format of the final MWS data set. These catalogues can be used to test methods for quantifying the properties of stellar halo substructure and reconstructing the Milky Way’s accretion history with the MWS data, including the effects of halo-to-halo variance. The mock catalogues are based on a phase-space kernel expansion technique applied to star particles in the Auriga suite of six high-resolution lambda-cold dark matter magnetohydrodynamic zoom-in simulations. They include photometric properties (and associated errors) used in DESI target selection and the outputs of the MWS spectral analysis pipeline (radial velocity, metallicity, surface gravity, and temperature). They also include information from the underlying simulation, such as the total gravitational potential and information on the progenitors of accreted halo stars. We discuss how the subset of halo stars observable by MWS in these simulations corresponds to their true content and properties. These mock Milky Ways have rich accretion histories, resulting in a large number of substructures that span the whole stellar halo out to large distances and have substantial overlap in the space of orbital energy and angular momentum.
Revisiting the accretion disc spectra of dwarf novae and nova-like variables: implications for the standard disc model
Authors: Zsidi Gabriella , Nixon C J , Naylor T , Pringle J E
Published: June 2024

Accretion discs are fundamental to much of astronomy. They can occur around stars, both young and old, around compact objects they provide a window into the extremes of physics, and around supermassive black holes in galaxy centres, they generate spectacular luminosities that can outshine the entire galaxy. However, our understanding of the inner workings of accretion discs remains far from complete. Here, we revisit a conundrum in the observations of some of the simplest accreting systems: the cataclysmic variables (CVs). The high-accretion-rate states of (non-magnetic) CVs can be divided into the short-lived outbursts (∼a week), typical of dwarf novae (DNe), and the long-lived (and sometimes perpetual) high states of nova-like (NL) CVs. Since both sorts of high-state occur in approximately steady-state accretion discs with similar properties and accretors, we would expect them to display similar spectral energy distributions. However, previous analyses based on UV spectra from the International Ultraviolet Explorer have shown that their spectral energy distributions are different. We perform a re-analysis of the data using up to date calibrations and distance (and thus dereddening) estimates to test whether this difference persists and whether it is statistically significant over the sample. We find that it does persist, and it is statistically significant. We propose routes to investigating this discrepancy further and discuss the implications this has for other accreting systems, such as X-ray binaries, active galactic nuclei, and protoplanetary discs.
A mock redshift catalogue of the dusty star-forming galaxy population with intrinsic clustering and lensing for deep millimetre surveys
Authors: Nava-Moreno Norma Araceli , Montaña Alfredo , Aretxaga Itziar , Rodríguez-Puebla Aldo , Avila-Reese Vladimir , Peralta Edgar
Published: June 2024

We present a new cosmologically motivated mock redshift survey of the dusty star-forming galaxy population. Our mock survey is based on the Bolshoi–Planck dark matter halo simulation and covers an area of 5.3 deg2. Using a semi-empirical approach, we generate a light-cone and populate the dark matter haloes with galaxies. Infrared properties are assigned to the galaxies based on theoretical and empirical relations from the literature. Additionally, background galaxies are gravitationally lensed by dark matter haloes along the line of sight assuming a point-mass model approximation. We characterize the mock survey by measuring the star formation rate density, integrated number counts, redshift distribution, and infrared luminosity function. When compared with single-dish and interferometric observations, the predictions from our mock survey closely follow the compiled results from the literature. We have also directed this study towards characterizing one of the extragalactic legacy surveys to be observed with the TolTEC camera at the Large Millimeter Telescope: the 0.8 sq. degree Ultra Deep Survey, with expected depths of 0.025, 0.018, and 0.012 mJy beam−1 at 1.1, 1.4, and 2.0 mm. Exploiting the clustering information in our mock survey, we investigate its impact on the effect of flux boosting by the fainter population of dusty galaxies, finding that clustering can increase the median boosting by 0.5  per cent at 1.1 mm, 0.8  per cent at 1.4 mm, and 2.0  per cent at 2.0 mm, and with higher dispersion.
Variable patterns of retrotransposition in different HeLa strains provide mechanistic insights into SINE RNA mobilization processes
Authors: Moldovan John B , Kopera Huira C , Liu Ying , Garcia-Canadas Marta , Catalina Purificacion , Leone Paola E , Sanchez Laura , Kitzman Jacob O , Kidd Jeffrey M , Garcia-Perez Jose Luis , Moran John V
Published: June 2024

Alu elements are non-autonomous Short INterspersed Elements (SINEs) derived from the 7SL RNA gene that are present at over one million copies in human genomic DNA. Alu mobilizes by a mechanism known as retrotransposition, which requires the Long INterspersed Element-1 (LINE-1) ORF2-encoded protein (ORF2p). Here, we demonstrate that HeLa strains differ in their capacity to support Alu retrotransposition. Human Alu elements retrotranspose efficiently in HeLa-HA and HeLa-CCL2 (Alu-permissive) strains, but not in HeLa-JVM or HeLa-H1 (Alu-nonpermissive) strains. A similar pattern of retrotransposition was observed for other 7SL RNA-derived SINEs and tRNA-derived SINEs. In contrast, mammalian LINE-1s, a zebrafish LINE, a human SINE-VNTR-Alu (SVA) element, and an L1 ORF1-containing mRNA can retrotranspose in all four HeLa strains. Using an in vitro reverse transcriptase-based assay, we show that Alu RNAs associate with ORF2p and are converted into cDNAs in both Alu-permissive and Alu-nonpermissive HeLa strains, suggesting that 7SL- and tRNA-derived SINEs use strategies to ‘hijack′ L1 ORF2p that are distinct from those used by SVA elements and ORF1-containing mRNAs. These data further suggest ORF2p associates with the Alu RNA poly(A) tract in both Alu-permissive and Alu-nonpermissive HeLa strains, but that Alu retrotransposition is blocked after this critical step in Alu-nonpermissive HeLa strains.
Principles of miRNA/miRNA* function in plant MIRNA processing
Authors: Rosatti Santiago , Rojas Arantxa M L , Moro Belén , Suarez Irina P , Bologna Nicolas G , Chorostecki Uciel , Palatnik Javier F
Published: June 2024

MicroRNAs (miRNAs) are essential regulators of gene expression, defined by their unique biogenesis, which requires the precise excision of the small RNA from an imperfect fold-back precursor. Unlike their animal counterparts, plant miRNA precursors exhibit variations in sizes and shapes. Plant MIRNAs can undergo processing in a base-to-loop or loop-to-base direction, with DICER-LIKE1 (DCL1) releasing the miRNA after two cuts (two-step MIRNAs) or more (sequential MIRNAs). In this study, we demonstrate the critical role of the miRNA/miRNA* duplex region in the processing of miRNA precursors. We observed that endogenous MIRNAs frequently experience suboptimal processing in vivo due to mismatches in the miRNA/miRNA* duplex, a key region that fine-tunes miRNA levels. Enhancing the interaction energy of the miRNA/miRNA* duplex in two-step MIRNAs results in a substantial increase in miRNA levels. Conversely, sequential MIRNAs display distinct and specific requirements for the miRNA/miRNA* duplexes along their foldback structure. Our work establishes a connection between the miRNA/miRNA* structure and precursor processing mechanisms. Furthermore, we reveal a link between the biological function of miRNAs and the processing mechanism of their precursors with the evolution of plant miRNA/miRNA* duplex structures.
Induro-RT mediated circRNA-sequencing (IMCR-seq) enables comprehensive profiling of full-length and long circular RNAs from low input total RNA
Authors: Unlu Irem , Maguire Sean , Guan Shengxi , Sun Zhiyi
Published: June 2024

Circular RNA (circRNA) has recently gained attention for its emerging biological activities, relevance to disease, potential as biomarkers, and promising an alternative modality for RNA vaccines. Nevertheless, sequencing circRNAs has presented challenges. In this context, we introduce a novel circRNA sequencing method called Induro-RT mediated circRNA-sequencing (IMCR-seq), which relies on a group II intron reverse transcriptase with robust rolling circle reverse transcription activity. The IMCR-seq protocol eliminates the need for conventional circRNA enrichment methods such as rRNA depletion and RNaseR digestion yet achieved the highest circRNA enrichment and detected 6–1000 times more circRNAs for the benchmarked human samples compared to other methods. IMCR-seq is applicable to any organism, capable of detecting circRNAs of longer than 7000 nucleotides, and is effective on samples as small as 10 ng of total RNA. These enhancements render IMCR-seq suitable for clinical samples, including disease tissues and liquid biopsies. We demonstrated the clinical relevance of IMCR-seq by detecting cancer-specific circRNAs as potential biomarkers from IMCR-seq results on lung tumor tissues together with blood plasma samples from both a healthy individual and a lung cancer patient. In summary, IMCR-seq presents an efficient and versatile circRNA sequencing method with high potential for research and clinical applications.
iSuRe-HadCre is an essential tool for effective conditional genetics
Authors: Garcia-Gonzalez Irene , Rocha Susana F , Hamidi Anahita , Garcia-Ortega Lourdes , Regano Alvaro , Sanchez-Muñoz Maria S , Lytvyn Mariya , Garcia-Cabero Aroa , Roig-Soucase Sergi , Schoofs Hans , Castro Marco , Sabata Helena , Potente Michael , Graupera Mariona , Makinen Taija , Benedito Rui
Published: June 2024

Methods for modifying gene function at high spatiotemporal resolution in mice have revolutionized biomedical research, with Cre-loxP being the most widely used technology. However, the Cre-loxP technology has several drawbacks, including weak activity, leakiness, toxicity, and low reliability of existing Cre-reporters. This is mainly because different genes flanked by loxP sites (floxed) vary widely in their sensitivity to Cre-mediated recombination. Here, we report the generation, validation, and utility of iSuRe-HadCre, a new dual Cre-reporter and deleter mouse line that avoids these drawbacks. iSuRe-HadCre achieves this through a novel inducible dual-recombinase genetic cascade that ensures that cells expressing a fluorescent reporter had only transient Cre activity, that is nonetheless sufficient to effectively delete floxed genes. iSuRe-HadCre worked reliably in all cell types and for the 13 floxed genes tested. This new tool will enable the precise, efficient, and trustworthy analysis of gene function in entire mouse tissues or in single cells.
The relationship between nanoscale genome organization and gene expression in mouse embryonic stem cells during pluripotency transition
Authors: Garate Ximena , Gómez-García Pablo Aurelio , Merino Manuel Fernández , Angles Marta Cadevall , Zhu Chenggan , Castells-García Alvaro , Ed-daoui Ilyas , Martin Laura , Ochiai Hiroshi , Neguembor Maria Victoria , Cosma Maria Pia
Published: June 2024

During early development, gene expression is tightly regulated. However, how genome organization controls gene expression during the transition from naïve embryonic stem cells to epiblast stem cells is still poorly understood. Using single-molecule microscopy approaches to reach nanoscale resolution, we show that genome remodeling affects gene transcription during pluripotency transition. Specifically, after exit from the naïve pluripotency state, chromatin becomes less compacted, and the OCT4 transcription factor has lower mobility and is more bound to its cognate sites. In epiblast cells, the active transcription hallmark, H3K9ac, decreases within the Oct4 locus, correlating with reduced accessibility of OCT4 and, in turn, with reduced expression of Oct4 nascent RNAs. Despite the high variability in the distances between active pluripotency genes, distances between Nodal and Oct4 decrease during epiblast specification. In particular, highly expressed Oct4 alleles are closer to nuclear speckles during all stages of the pluripotency transition, while only a distinct group of highly expressed Nodal alleles are in close proximity to Oct4 when associated with a nuclear speckle in epiblast cells. Overall, our results provide new insights into the role of the spatiotemporal genome remodeling during mouse pluripotency transition and its correlation with the expression of key pluripotency genes.
CAbiNet: joint clustering and visualization of cells and genes for single-cell transcriptomics
Authors: Zhao Yan , Kohl Clemens , Rosebrock Daniel , Hu Qinan , Hu Yuhui , Vingron Martin
Published: June 2024

A fundamental analysis task for single-cell transcriptomics data is clustering with subsequent visualization of cell clusters. The genes responsible for the clustering are only inferred in a subsequent step. Clustering cells and genes together would be the remit of biclustering algorithms, which are often bogged down by the size of single-cell data. Here we present ‘Correspondence Analysis based Biclustering on Networks’ (CAbiNet) for joint clustering and visualization of single-cell RNA-sequencing data. CAbiNet performs efficient co-clustering of cells and their respective marker genes and jointly visualizes the biclusters in a non-linear embedding for easy and interactive visual exploration of the data.
KDM6A–SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance
Authors: Wu Jian , Jiang Yixin , Zhang Qin , Mao Xiaobing , Wu Tong , Hao Mengqiu , Zhang Su , Meng Yang , Wan Xiaowen , Qiu Lei , Han Junhong
Published: June 2024

Genomic instability is one of the hallmarks of cancer. While loss of histone demethylase KDM6A increases the risk of tumorigenesis, its specific role in maintaining genomic stability remains poorly understood. Here, we propose a mechanism in which KDM6A maintains genomic stability independently on its demethylase activity. This occurs through its interaction with SND1, resulting in the establishment of a protective chromatin state that prevents replication fork collapse by recruiting of RPA and Ku70 to nascent DNA strand. Notably, KDM6A–SND1 interaction is up-regulated by KDM6A SUMOylation, while KDM6AK90A mutation almost abolish the interaction. Loss of KDM6A or SND1 leads to increased enrichment of H3K9ac and H4K8ac but attenuates the enrichment of Ku70 and H3K4me3 at nascent DNA strand. This subsequently results in enhanced cellular sensitivity to genotoxins and genomic instability. Consistent with these findings, knockdown of KDM6A and SND1 in esophageal squamous cell carcinoma (ESCC) cells increases genotoxin sensitivity. Intriguingly, KDM6A H101D & P110S, N1156T and D1216N mutations identified in ESCC patients promote genotoxin resistance via increased SND1 association. Our finding provides novel insights into the pivotal role of KDM6A–SND1 in genomic stability and chemoresistance, implying that targeting KDM6A and/or its interaction with SND1 may be a promising strategy to overcome the chemoresistance.
Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs
Authors: Gadgil Rujuta Yashodhan , Rider S Dean , Shrestha Resha , Alhawach Venicia , Hitch David C , Leffak Michael
Published: June 2024

Extrachromosomal circular DNAs (eccDNAs) are produced from all regions of the eucaryotic genome. We used inverse PCR of non-B microsatellites capable of forming hairpin, triplex, quadruplex and AT-rich structures integrated at a common ectopic chromosomal site to show that these non-B DNAs generate highly mutagenized eccDNAs by replication-dependent mechanisms. Mutagenesis occurs within the non-B DNAs and extends several kilobases bidirectionally into flanking and nonallelic DNA. Each non-B DNA exhibits a different pattern of mutagenesis, while sister clones containing the same non-B DNA also display distinct patterns of recombination, microhomology-mediated template switching and base substitutions. Mutations include mismatches, short duplications, long nontemplated insertions, large deletions and template switches to sister chromatids and nonallelic chromosomes. Drug-induced replication stress or the depletion of DNA repair factors Rad51, the COPS2 signalosome subunit or POLη change the pattern of template switching and alter the eccDNA mutagenic profiles. We propose an asynchronous capture model based on break-induced replication from microsatellite-induced DNA double strand breaks to account for the generation and circularization of mutagenized eccDNAs and the appearance of genomic homologous recombination deficiency (HRD) scars. These results may help to explain the appearance of tumor eccDNAS and their roles in neoantigen production, oncogenesis and resistance to chemotherapy.
Improved selection of canonical proteins for reference proteomes
Authors: Insana Giuseppe , Martin Maria J , Pearson William R
Published: June 2024

The ‘canonical’ protein sets distributed by UniProt are widely used for similarity searching, and functional and structural annotation. For many investigators, canonical sequences are the only version of a protein examined. However, higher eukaryotes often encode multiple isoforms of a protein from a single gene. For unreviewed (UniProtKB/TrEMBL) protein sequences, the longest sequence in a Gene-Centric group is chosen as canonical. This choice can create inconsistencies, selecting >95% identical orthologs with dramatically different lengths, which is biologically unlikely. We describe the ortho2tree pipeline, which examines Reference Proteome canonical and isoform sequences from sets of orthologous proteins, builds multiple alignments, constructs gap-distance trees, and identifies low-cost clades of isoforms with similar lengths. After examining 140 000 proteins from eight mammals in UniProtKB release 2022_05, ortho2tree proposed 7804 canonical changes for release 2023_01, while confirming 53 434 canonicals. Gap distributions for isoforms selected by ortho2tree are similar to those in bacterial and yeast alignments, organisms unaffected by isoform selection, suggesting ortho2tree canonicals more accurately reflect genuine biological variation. 82% of ortho2tree proposed-changes agreed with MANE; for confirmed canonicals, 92% agreed with MANE. Ortho2tree can improve canonical assignment among orthologous sequences that are >60% identical, a group that includes vertebrates and higher plants.
Evidence for inflammation in normal-appearing brain regions in patients with growing sporadic vestibular schwannoma: A PET study
Authors: Alfaifi Bandar , Hinz Rainer , Jackson Alan , Wadeson Andrea , Pathmanaban Omar N , Hammerbeck-Ward Charlotte , Rutherford Scott A , King Andrew T , Lewis Daniel , Coope David J
Published: June 2024

Background

Nonauditory symptoms can be a prominent feature in patients with sporadic vestibular schwannoma (VS), but the cause of these symptoms is unknown. Inflammation is hypothesized to play a key role in the growth and symptomatic presentation of sporadic VS, and in this study, we investigated through translocator protein (TSPO) positron emission tomography (PET) whether inflammation occurred within the “normal appearing” brain of such patients and its association with tumor growth.

Methods

Dynamic PET datasets from 15 patients with sporadic VS (8 static and 7 growing) who had been previously imaged using the TSPO tracer [11C](R)-PK11195 were included. Parametric images of [11C](R)-PK11195 binding potential (BPND) and the distribution volume ratio (DVR) were derived and compared across VS growth groups within both contralateral and ipsilateral gray (GM) and white matter (WM) regions. Voxel-wise cluster analysis was additionally performed to identify anatomical regions of increased [11C](R)-PK11195 binding.

Results

Compared with static tumors, growing VS demonstrated significantly higher cortical (GM, 1.070 vs. 1.031, P = .03) and whole brain (GM & WM, 1.045 vs. 1.006, P = .03) [11C](R)-PK11195 DVR values. The voxel-wise analysis supported the region-based analysis and revealed clusters of high TSPO binding within the precentral, postcentral, and prefrontal cortex in patients with growing VS.

Conclusions

We present the first in vivo evidence of increased TSPO expression and inflammation within the brains of patients with growing sporadic VS. These results provide a potential mechanistic insight into the development of nonauditory symptoms in these patients and highlight the need for further studies interrogating the role of neuroinflammation in driving VS symptomatology.
Local-strain-induced CO2 adsorption geometries and electrochemical reduction pathway shift
Authors: Liu Chuhao , Bu Yifan , Xu Yifei , Mahmood Azhar , Xie Jisheng , Fu Yifan , Li Shiyun , Peng Cheng , Wu Yue , Liang Xiao , Zong Ruilong , Li Wan-Lu , Zhou Jihan , Xu Bingjun , Niu Li , Li Mufan
Published: June 2024

Unravelling the influence of strain and geometric effects on the electrochemical reduction of carbon dioxide (CO2RR) on Cu-based (or Pd-based) alloys remains challenging due to complex local microenvironment variables. Herein, we employ two PdCu alloys (nanoparticles and nanodendrites) to demonstrate how CO2RR selectivity can shift from CO to HCOO−. Despite sharing consistent phases, exposed crystal facets, and overall oxidative states, these alloys exhibit different local strain profiles due to their distinct geometries. By integrating experimental data, in-situ spectroscopy, and density functional theory calculations, we revealed that CO2 prefers adsorption on tensile-strained areas with carbon-side geometry, following a *COOH-to-CO pathway. Conversely, on some compressive-strained regions induced by the dendrite-like morphology, CO2 adopts an oxygen-side geometry, favoring an *OCHO-to-HCOO pathway due to the downshift of the d-band center. Notably, our findings elucidate a dominant *OCHO-to-HCOO− pathway in catalysts when featuring both adsorption geometries. This research provides a comprehensive model for local environment of bimetallic alloys, and establishes a clear relationship between the CO2RR pathway shift and variation in local strain environments of PdCu alloys.