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BACKGROUND:Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS:In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS:A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS:Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).
The Indian Summer Monsoon Rainfall (ISMR) and its extremes exhibit substantial complexity due to the region’s intricate land–ocean distribution and diverse topography, and remain crucial for the livelihoods of billions across the Indian subcontinent. This study examines the influence of increased horizontal resolution on persistent dry biases over India and associated physical mechanisms, using the High-Resolution Model Intercomparison Project (HighResMIP) data under the PRIMAVERA framework. The analysis demonstrates that higher-resolution models show marked improvements in reproducing the mean ISMR and its extremes, with rainfall distributions more consistent with observations. Enhanced resolution also contributes to a more realistic simulation of intraseasonal variability, particularly the active and break phases of the monsoon. However, considerable inter-model spread remains even at finer resolutions, highlighting the ongoing role of model physics and parameterization schemes in determining simulation fidelity. These findings underscore the added value of increased horizontal resolution in reducing systematic biases and enhancing the representation of monsoon variability, while emphasizing the need for continued improvements in the physical representation of key processes within climate models. This figure summarizes the study, which investigates the role of enhanced horizontal resolution in simulating Indian Summer Monsoon (ISM) extremes and intraseasonal variability. Rainfall data from the India Meteorological Department (IMD) and 850 hPa wind data from ERA5 are used to evaluate the performance of models participating in HighResMIP, listed in the blue box. The study conducts extreme rainfall analyses using both observed and model datasets, and Kernel Density Estimation (KDE) is applied to examine rainfall distribution. The results confirm that finer-resolution models reproduce the observed distribution more accurately and capture extreme rainfall events over the Indian landmass. Spatial bias maps are analyzed to understand regional variability, revealing that coarser models exhibit notable dry biases over northern India, which are reduced in most high-resolution models, except for NorESM2-MM, where biases remain pronounced. Performance gains are assessed not only for mean rainfall but also for extremes, and the ETCCDI indices demonstrate that finer-resolution models are more skillful in representing extreme rainfall events. The study further examines intraseasonal variability, including active and break spells during July–August over the core monsoon zone, and evaluates the models’ ability to depict the low-level jet (LLJ) at 850 hPa, a key feature of ISM circulation. The results highlight that high-resolution models consistently outperform their coarser counterparts, capturing mean rainfall, extremes, intraseasonal variability, and seasonal wind patterns more realistically. Overall, the findings demonstrate that high-resolution models offer substantial improvements for monsoon simulation, providing better representation of mean and extreme rainfall as well as LLJ dynamics. However, model physics and parameterization schemes continue to play a critical role in modulating model performance, indicating that resolution alone is not sufficient for achieving optimal skill. Lower-resolution models exhibit larger dry biases and poorer representation of monsoon mean and extreme rainfall. High-resolution models better simulate the rainfall intensity and distribution over the Indian landmass. Intraseasonal variability is more realistically represented in high-resolution models than in their coarser counterparts. High-resolution models skilfully represent the large-scale dynamics and fine-scale features as compared to the coarser ones. Despite the improvements in the high-resolution model, physics and parameterization schemes remain critical in modulating the skill of monsoon simulations.
We report the refined dark-photon exclusion bound from Dark SRF's pathfinder run. Our new result is driven by improved theoretical modeling of frequency instability in high-quality resonant experiments. Our analysis leads to a constraint that is an order of magnitude stronger than previously reported (corresponding to a signal-to-noise ratio that is 4 orders of magnitude larger). This result represents the world-leading constraint on non-dark-matter dark photons over a wide range of masses below 6 μeV and translates to the best laboratory-based limit on the photon mass m_{γ}<2.9×10^{-48} g.
We present recommendations to improve reproducibility and replicability in condensed matter physics. This area of physics has consistently produced both fundamental insights into the workings of matter and transformative inventions. Our recommendations result from a collaboration that includes researchers from academia and government laboratories, scientific journalists, legal professionals, representatives of publishers, professional societies, and other experts. The group met in person in May 2024 at a conference at the University of Pittsburgh to discuss the growing challenges related to research reproducibility and replicability in condensed matter physics. In this report, we discuss best practices and policies at all stages of the scientific process to safeguard the value of condensed matter. We hope this report will lay the groundwork for a broader conversation to develop subfield-specific recommendations.
The South Tibetan Detachment (STD) is parallel to the east–west-trending axis of the Himalayan range over >1500 km and represents an untapped source of information for understanding the coupling between multi-scale deformation processes, fluid flow, exhumation of high-grade rocks and topography. Here, we present hydrogen isotope ( δ 2 H) geochemistry, quartz c -axis fabric deformation thermometry and electron microprobe micro-analyser data from a strand of the STD exposed in NW India (the Zanskar Detachment). Our data document intense meteoric fluid–rock–deformation interactions within the upper part of the hot (>400°C) mylonitic footwall to the detachment, which was active at 22–20 Ma. Calculated δ 2 H water values ranging from −115 to −95‰ suggest that the Zanskar area was standing at least above 2500–3000 m mean topographic elevation during the early Miocene. When compared with previous data obtained from Mt Everest, our results suggest that high topography along the Himalayan range was diachronous, occurring at c . 20 Ma in the western Himalaya (>3000) and at c . 15 Ma in the Central Himalaya (>5000 m). This study highlights the close relationships between topography, meteoric fluid flow, high heat flux and exhumation of the Himalayan Crystalline Core.
