DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring ...aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp
3
-bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl
2
-promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials.
DNA-encoded compound libraries are widely used in drug discovery. Screening of catalysts for compatibility with solid phase-coupled DNA sequences guided the selection of encoded reactions, exemplified by a Zn(II)-mediated aza-Diels-Alder reaction.
Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus ...RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX
CD8
T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.
Juvenile Osteochondritis Dissecans (JOCD) is a common reason for knee pain among children. The aim of this case study was to report on clinical and radiographic outcomes after fixation of an ...osteochondral fragment with bioabsorbable pins in children with open growth plates. We hypothesized that surgical treatment with this technique will result in good function, high rates of radiographic healing and high return to sport rates. A total of 13 knees in 12 patients (6 male, 6 female) with a median of 13 years (11, 17) were evaluated retrospectively at a minimum clinical follow-up of 24 months. Inclusion criteria were defined as open growth plates and an unstable osteochondral lesion grade III or IV. The clinical outcome was evaluated utilizing three standardized patient-reported outcome scores (Tegner Activity Scale TAS, Knee Injury and Osteoarthritis Outcome Score KOOS, Lysholm Score). All patients underwent magnetic resonance imaging 15 months (3, 34) after surgical treatment and defect healing was evaluated utilizing a modified version of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. Due to the small sample size, the data was reported descriptively. The interobserver variability was calculated with the Spearman rank correlation coefficient. Comparisons were made with Wilcoxon sign rank test (or sign test). At final follow-up the median KOOS Score was 98% (79.2%, 100%) and the median Lysholm Score was 94 (69, 100) points. The Tegner Activity Scale was 7 (4, 10) points preoperatively and 7 (4,10) points postoperatively (
= 0.5). Complete bony ingrowth occurred in 9 knees (69%), complete cartilage defect repair in 10 knees (77%) and integration to the border zone was found in 11 knees (85%) 15 (3, 34) months following surgical treatment. Fixation of osteochondral fragments with bioabsorbable pins resulted in good functional and radiographic outcomes, a high return to sport- and a low complication rate among children with open growth plates.
Stroke is a leading cause of severe disability in the United States, but there is no effective method for patients to accurately detect the signs of stroke at home. We developed a mobile app, ...Destroke, that allows remote performance of a modified NIH stroke scale (NIHSS) by patients.
To assess the feasibility of a mobile app for stroke monitoring and education by patients with a history of stroke.
We enrolled 25 patients with a history of stroke in a prospective open-label study to evaluate the feasibility of the Destroke app in patients with stroke. Nineteen patients completed all study assessments, with a median time from stroke onset to enrollment of 5.6 years (range 0.1–12 years). We designed a modified NIHSS that assessed 12 out of 16 tasks on the NIHSS. Patients completed this test eight times over a 28-day period. We conducted pre-study surveys that assessed demographic information, stroke and cardiovascular history, baseline NIHSS, and experience using mobile technologies, and mid- and post-study surveys that assessed patient satisfaction on app usage and confidence in stroke detection.
Ten men and nine women participated in this study (median age of 64 (33–76)), representing ten US states and Washington D.C. Median baseline NIHSS was 0 (0–4). 15 patients reported using health apps. On a 5-point Likert scale, patients rated the app as 4.2 on being able to understand and use the app and 4.3 on using the app when instructed by their doctor. For eight patients with poor confidence in detecting the signs of a stroke before the study, six showed higher confidence after the study.
The use of an at-home stroke monitoring app is feasible by patients with a history of stroke and improves confidence in detecting the signs of stroke.
Almost every meteorite impact occurs at an oblique angle of incidence, yet the effect of impact angle on crater size or formation mechanism is only poorly understood. This is, in large part, due to ...the difficulty of inferring impactor properties, such as size, velocity and trajectory, from observations of natural craters, and the expense and complexity of simulating oblique impacts using numerical models. Laboratory oblique impact experiments and previous numerical models have shown that the portion of the projectile’s kinetic energy that is involved in crater excavation decreases significantly with impact angle. However, a thorough quantification of planetary-scale oblique impact cratering does not exist and the effect of impact angle on crater size is not considered by current scaling laws. To address this gap in understanding, we developed iSALE-3D, a three-dimensional multi-rheology hydrocode, which is efficient enough to perform a large number of well-resolved oblique impact simulations within a reasonable time. Here we present the results of a comprehensive numerical study containing more than 200 three-dimensional hydrocode-simulations covering a broad range of projectile sizes, impact angles and friction coefficients. We show that existing scaling laws in principle describe oblique planetary-scale impact events at angles greater than 30° measured from horizontal. The displaced mass of a crater decreases with impact angle in a sinusoidal manner. However, our results indicate that the assumption that crater size scales with the vertical component of the impact velocity does not hold for materials with a friction coefficient significantly lower than 0.7 (sand). We found that increasing coefficients of friction result in smaller craters and a formation process more controlled by impactor momentum than by energy.
We report results of an interdisciplinary project devoted to the 26 km‐diameter Ries crater and to the genesis of suevite. Recent laboratory analyses of “crater suevite” occurring within the central ...crater basin and of “outer suevite” on top of the continuous ejecta blanket, as well as data accumulated during the past 50 years, are interpreted within the boundary conditions imposed by a comprehensive new effort to model the crater formation and its ejecta deposits by computer code calculations (Artemieva et al. 2013). The properties of suevite are considered on all scales from megascopic to submicroscopic in the context of its geological setting. In a new approach, we reconstruct the minimum/maximum volumes of all allochthonous impact formations (108/116 km3), of suevite (14/22 km3), and the total volume of impact melt (4.9/8.0 km3) produced by the Ries impact event prior to erosion. These volumes are reasonably compatible with corresponding values obtained by numerical modeling. Taking all data on modal composition, texture, chemistry, and shock metamorphism of suevite, and the results of modeling into account, we arrive at a new empirical model implying five main consecutive phases of crater formation and ejecta emplacement. Numerical modeling indicates that only a very small fraction of suevite can be derived from the “primary ejecta plume,” which is possibly represented by the fine‐grained basal layer of outer suevite. The main mass of suevite was deposited from a “secondary plume” induced by an explosive reaction (“fuel‐coolant interaction”) of impact melt with water and volatile‐rich sedimentary rocks within a clast‐laden temporary melt pool. Both melt pool and plume appear to be heterogeneous in space and time. Outer suevite appears to be derived from an early formed, melt‐rich and clast‐poor plume region rich in strongly shocked components (melt ≫ clasts) and originating from an upper, more marginal zone of the melt pool. Crater suevite is obviously deposited from later formed, clast‐rich and melt‐poor plumes dominated by unshocked and weakly shocked clasts and derived from a deeper, central zone of the melt pool. Genetically, we distinguish between “primary suevite” which includes dike suevite, the lower sublayer of crater suevite, and possibly a basal layer of outer suevite, and “secondary suevite” represented by the massive upper sublayer of crater suevite and the main mass of outer suevite.
Palaeoclimate reconstruction on the northern Tibetan Plateau resulted in a large spectrum of different and partly divergent interpretations for the climate evolution during the late glacial and the ...Holocene. In some cases this is caused by incomplete understanding of the geomorphological processes influencing the different proxies used. To overcome these limitations and to enhance the understanding of the complex process interactions in a sensitive and highly dynamical environment a detailed analysis of different members of the sedimentary system at Lake Heihai on the northern Tibetan Plateau was conducted. Lake level variations during the late Pleistocene were influenced by sediment supply to an alluvial fan. This sediment surplus resulted in the temporary blocking of the outflow of Lake Heihai. High sediment supply presumably occurred during or shortly after large glaciations in the Kunlun Shan. The spatial distribution of aeolian sediments revealed a strong relationship to possible source areas. This resulted in a spatially heterogeneous distribution of the aeolian sediments. Furthermore, topographic effects have an important influence on the preservation of the sediments. Aeolian sediments deposited in sheltered positions might not be comparable with other archives with a similar grain size. Nevertheless, deposition of loess during the mid-Holocene indicates a shift to wetter climate conditions on the northern Tibetan Plateau. This might be caused by the intrusion of the East Asian Summer monsoon into the area. During the late Holocene, the Asian summer monsoon retreated and aeolian sediments were reactivated.
•Factors influencing the formation of a high altitude lake were reconstructed.•Different source areas of aeolian sediments were identified.•Timing of aeolian sediment deposition was constrained by OSL dating.•During the mid-Holocene highest moisture conditions occurred.
•The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA in school-aged children with CF.•After therapy initiation with ELX/TEZ/IVA in school-aged children with CF, the prevalence ...and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased.•The strength in reduction of mucopyoceles and CRS-MRI sum score was independent of a pretreatment with LUM/IVA.
Introduction: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied.
Methods: 30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6–16y). MRI were evaluated using the CRS-MRI score.
Results: After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275–0.999).
Conclusions: ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.
Abstract
The Double Asteroid Redirection Test (DART) spacecraft will impact into the asteroid Dimorphos on 2022 September 26 as a test of the kinetic impactor technique for planetary defense. The ...efficiency of the deflection following a kinetic impactor can be represented using the momentum enhancement factor,
β
, which is dependent on factors such as impact geometry and the specific target material properties. Currently, very little is known about Dimorphos and its material properties, which introduces uncertainty in the results of the deflection efficiency observables, including crater formation, ejecta distribution, and
β
. The DART Impact Modeling Working Group (IWG) is responsible for using impact simulations to better understand the results of the DART impact. Pre-impact simulation studies also provide considerable insight into how different properties and impact scenarios affect momentum enhancement following a kinetic impact. This insight provides a basis for predicting the effects of the DART impact and the first understanding of how to interpret results following the encounter. Following the DART impact, the knowledge gained from these studies will inform the initial simulations that will recreate the impact conditions, including providing estimates for potential material properties of Dimorphos and
β
resulting from DART’s impact. This paper summarizes, at a high level, what has been learned from the IWG simulations and experiments in preparation for the DART impact. While unknown, estimates for reasonable potential material properties of Dimorphos provide predictions for
β
of 1–5, depending on end-member cases in the strength regime.
•End-member modeling of the grain size distribution in Hala Lake allowed the discrimination between lacustrine, eolian and fluvial sediments.•Dominant clay sedimentation (slack water type) during the ...global Last Glacial Maximum (LGM) reflects ice interceptions in long cold periods.•Eolian input is attributed to abrupt cold events (Heinrich Event I, Younger Dryas, 8.2ka event).•Transportation and depositional processes are affected by the extratropical Westwind system.
Profundal lake sediment cores are often interpreted in line with diverse and detailed sedimentological processes to infer paleoenvironmental conditions. The effects of frozen lake surfaces on terrigenous sediment deposition and how climate changes on the Tibetan Plateau are reflected in these lakes, however, is seldom discussed. A lake sediment core from Hala Lake (590km2), northeastern Tibetan Plateau spanning the time interval from the Last Glacial Maximum to the present was investigated using high-resolution grain-size composition of lacustrine deposits. Seismic analysis along a north–south profile across the lake was used to infer the sedimentary setting within the lake basin. Periods of freezing and melting processes on the lake surface were identified by MODIS (MOD10A1) satellite data. End-member modeling of the grain size distribution allowed the discrimination between lacustrine, eolian and fluvial sediments. The dominant clay sedimentation (slack water type) during the global Last Glacial Maximum (LGM) reflects ice interceptions in long cold periods, in contrast to abundant eolian input during abrupt cold events. Therefore, fluvial and slack water sedimentation processes can indicate changes in the local paleoclimate during periods of the lake being frozen, when eolian input was minor. Inferred warm (i.e., ∼22.7 and 19.5cal.ka BP) and cold (i.e., ∼11–9 and 3–1.5cal.ka BP) spells have significant environmental impacts, not only in the regional realm, but they are also coherent with global-scale climate events. The eolian input generally follows the trend of the mid-latitude westerly wind dynamics in winter, contributing medium-sized sand to the lake center, deposited within the ice cover during icing and melting phases. Enhanced input was dominant during the Younger Dryas, Heinrich Event 1 and at around 8.2ka, equivalent to the well-known events of the North Atlantic realm.
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