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Oncogenic IDH1 <sup>mut</sup> drives robust loss of histone acetylation and increases chromatin heterogeneity
Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2 mut ) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDH mut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.
Association between abdominal obesity and nutritional supplement use among Iranian adults in the Shahedieh cohort study
AbstractThe relationship between the use of supplements and the presence of abdominal obesity is a topic that is currently being debated. The purpose of the present study was to evaluate the existence of such an association. The current cross-sectional investigation included a population of 9878 individuals who were the focus of the study’s initial phase in the Shahedieh cohort study, conducted in Yazd, Iran. Waist circumference was measured with the help of an inflexible tape measure. In addition, the data regarding the consumption of various supplements, including multivitamins, folic acid, ferric compounds, omega 3, calcium, vitamin D, zinc, and other supplements, were collected through interviews conducted by trained interviewers. Among the entire sample, 4785 individuals (50.6%) were found to have abdominal obesity, while 4093 individuals (43.3%) reported using at least one type of supplements. In the simple regression analysis, all of the supplements, except for multivitamins and zinc, were identified as adverse factors for abdominal obesity. However, in the multivariable regression analysis, only ferric compounds remained significant as a protective factor (OR = 0.73, 95%CI: 0.57‒0.94). The findings of this study suggest that dietary supplements, particularly ferric compounds, may have implications for managing abdominal obesity. These findings could inform public health strategies by incorporating ferric compound supplementation into dietary interventions aimed at reducing abdominal obesity prevalence. Furthermore, the potential clinical application of ferric compounds highlights the need for integrating nutritional approaches in obesity management programs. However, longitudinal studies are needed to establish causal relationships and confirm the long-term effectiveness and safety of such interventions.
US Corn Belt enhances regional precipitation recycling
Precipitation recycling, where evapotranspiration (ET) from the land surface contributes to precipitation within the same region, is a critical component of the water cycle. This process is especially important for the US Corn Belt, where extensive cropland expansions and irrigation activities have significantly transformed the landscape and affected the regional climate. Previous studies investigating precipitation recycling typically relied on analytical models with simplifying assumptions, overlooking the complex interactions between groundwater hydrology and agricultural management. In this study, we use high-resolution climate models coupled with an explicit water vapor tracer algorithm to quantify the impacts of shallow groundwater, dynamic crop growth, and irrigation on regional precipitation recycling in the US Corn Belt. We find that these coupled groundwater–crop–irrigation processes reduce surface temperatures and increase the growing season precipitation. The increase in precipitation is attributed to a significant enhancement of the precipitation recycling ratio from 14 to 18%. This enhanced precipitation recycling is stronger in a dry year than normal and wet years, depending on both large-scale moisture transport and local ET. Our study underscores the critical role of groundwater hydrology and agricultural management in altering the regional water cycle, with important implications for regional climate predictions and food and water security.
A case study on using a large language model to analyze continuous glucose monitoring data
Abstract Continuous glucose monitors (CGM) provide valuable insights about glycemic control that aid in diabetes management. However, interpreting metrics and charts and synthesizing them into linguistic summaries is often non-trivial for patients and providers. The advent of large language models (LLMs) has enabled real-time text generation and summarization of medical data. The objective of this study was to assess the strengths and limitations of using an LLM to analyze raw CGM data and produce summaries of 14 days of data for patients with type 1 diabetes. We first evaluated the ability of GPT-4 to compute quantitative metrics specific to diabetes found in an Ambulatory Glucose Profile (AGP). Then, using two independent clinician graders, we evaluated the accuracy, completeness, safety, and suitability of qualitative descriptions produced by GPT-4 across five different CGM analysis tasks. GPT-4 performed 9 out of the 10 quantitative metrics tasks with perfect accuracy across all 10 cases. The clinician-evaluated CGM analysis tasks had good performance across measures of accuracy [lowest task mean score 8/10, highest task mean score 10/10], completeness [lowest task mean score 7.5/10, highest task mean score 10/10], and safety [lowest task mean score 9.5/10, highest task mean score 10/10]. Our work serves as a preliminary study on how generative language models can be integrated into diabetes care through data summarization and, more broadly, the potential to leverage LLMs for streamlined medical time series analysis.
Deciphering the artificial evolution of domesticated plants within dynamic habitats
Vertical wind profile distribution within canopy layer based on representative geometry model using wind tunnel experiment
AbstractThis study examined the mean and turbulent wind speed distribution within the canopy height of a tropical urban campus based on a representative geometry model via wind tunnel experiments. The vertical wind profiles were analysed around two high-rise buildings, Menara Razak (MR) and Residensi Tower (RT) at both wind directions (22.5° and 202.5°). To examine the influence of high-rise buildings on strong wind, the collected data of mean wind speed (u), root mean square (urms), and skewness (SK) were analysed. Effects of the wind direction, building layout or arrangement and building geometry under the canopy height were also examined. The results show that the building layout influenced the wind distribution within the target site, and the approaching wind flow direction also influenced the wind flow interaction with the building. The height of the target building (H) influenced the distance traveled by the vortices in the wake flow. For the MR and RT cases, the vortices could be affected up to a minimum distance of H and 1.5H, respectively. The study demonstrates that the building layout significantly influences the distribution of wind speeds within the canopy height of a tropical urban campus.
Development of precision medicine approaches to advance clinical trials for autism and social behavior: A research imperative
Optimization of betulinic and ursolic acids and phenolics extraction from endemic Rosa pisiformis using Box-Behnken design in relation to cytotoxic activities
The return of stagnant slab recorded by intraplate volcanism
Subducted plates often stagnate in the mantle transition zone (MTZ), and the fate of the stagnant slabs is still debatable. They may sink into the lower mantle, or remain partially trapped in the MTZ, but it is uncertain whether they can return to the upper mantle. We report geochemical evidence of late-Miocene (~6 Ma) basalts from, and upper mantle seismic evidence beneath Shuangyashan, an area above the slab tear of the stagnant Pacific plate in eastern Asia, to show how the slab returns to the upper mantle from the MTZ. Remarkably high δ 57 Fe, Gd/Yb and low δ 26 Mg, Ti/Eu, CaO/Al 2 O 3 values of Shuangyashan basalts suggest that the subducted Pacific oceanic crust had been entrained to their upper mantle source. Therefore, the return of oceanic crust from the MTZ to the upper mantle appears to have been driven by upwelling triggered by tearing of the stagnant slab right beneath this area. Meanwhile, local shear splitting measurements reveal a circular pattern of anisotropy in the upper mantle with delay times diminishing toward the slab tear, suggesting that the slab-fragment-bearing upwelling subsequently turned into lateral flows in the upper mantle, and contributed to a wider intraplate magmatism above the stagnant slab. This finding, together with other widespread intraplate volcanism from eastern Asia, extending for approximately 6,000 km, demonstrates that a subduction-induced tear can lead to the destruction and partial return of stagnant slab material, and thus lead to the cycling of subducted crustal materials and the generation of subduction-induced intraplate magmatism.
Bathymetry of the Antarctic continental shelf and ice shelf cavities from circumpolar gravity anomalies and other data
AbstractBathymetry critically influences the intrusion of warm Circumpolar Deep Water onto the continental shelf and under ice shelf cavities in Antarctica, thereby forcing ice melting, grounding line retreat, and sea level rise. We present a novel and comprehensive bathymetry of Antarctica that includes all ice shelf cavities and previously unmeasured continental shelf areas. The new bathymetry is based on a 3D inversion of a circumpolar compilation of gravity anomalies constrained by measurements from the International Bathymetric Chart of the Southern Ocean, BedMachine Antarctica, and discrete seafloor measurements from seismic and ocean robotic probes. Previously unknown troughs with thicker ice shelf cavities are revealed in many parts of Antarctica, especially East Antarctica. The greater depths of troughs on the continental shelf and ice shelf cavities imply that many glaciers are more vulnerable to ocean subsurface warming than previously thought, which may increase the projections of sea level rise from Antarctica.
Metastable state preceding shear zone instability: Implications for earthquake-accelerated landslides and dynamic triggering
Understanding the dynamic response of granular shear zones under cyclic loading is fundamental to elucidating the mechanisms triggering earthquake-induced landslides, with implications for broader fields such as seismology and granular physics. Existing prediction methods struggle to accurately predict many experimental and in situ landslide observations due to inadequate consideration of the underlying physical mechanisms. The mechanisms that influence landslide dynamic triggering, a transition from static (or extremely slow creeping) to rapid runout, remain elusive. Herein, we focus on the inherent physics of granular shear zones under dynamic loading using ring shear experiments. Except for coseismic slip caused by the dynamic load, varying magnitudes of postseismic creep with increasing cycles of dynamic loading are observed, highlighting the effects of coseismic weakening (shear zone fatigue) and subsequent postseismic healing. A metastable state, characterized by a significant increase in postseismic creep, typically precedes shear zone instability. The metastable state may arise as weakened shear resistance approaches the applied shear stress, demonstrating a phase transition from a solid-like state to a fluid state (plastic granular flow). The metastable state may potentially indicate the shear zone’s stress state and serve as a precursor to impending instability. Furthermore, the proposed mechanisms offer a compelling explanation for the widespread postseismic landslide movement following earthquakes. Incorporating these mechanisms into the Newmark method has the potential to improve the prediction of earthquake-induced landslide displacement and enhance our understanding of dynamic triggering.
Genome-wide identification, characterization, and functional analysis of the CHX, SOS, and RLK genes in Solanum lycopersicum under salt stress
Abstract The cation/proton exchanger ( CHX ), salt overly sensitive ( SOS ), and receptor-like kinase ( RLK ) genes play significant roles in the response to salt stress in plants. This study is the first to identify the SOS gene in Solanum lycopersicum (tomato) through genome-wide analysis under salt stress conditions. Quantitative reverse transcription PCR (qRT-PCR) results indicated that the expression levels of CHX , SOS , and RLK genes were upregulated, with fold changes of 1.83, 1.49, and 1.55, respectively, after 12 h of exposure to salt stress. Genome-wide analysis revealed 21 CHX , 5 SOS , and 86 RLK genes in S. lycopersicum . CHX genes were found on chromosomes 2, 3, 4, 5, 6, 7, 8, 9, 11, and 12 of S. lycopersicum . SOS genes were found on chromosomes 1, 4, 6, and 10. RLK genes were found on all chromosomes of S. lycopersicum . The Ka/Ks ratios indicate that the CHX , SOS , and RLK genes have been primarily influenced by purifying selection. This suggests that these genes have faced strong environmental pressures throughout their evolution. Purifying selection typically results in a decrease in genetic diversity. The estimated duplication time for CHX paralogous gene pairs ranged from approximately 26.965 to 245.413 million years ago (Mya), while the duplication time for SOS paralogous gene pairs ranged from around 116.682 to 275.631 Mya. For RLK paralogous gene pairs, the duplication time varied from approximately 27.689 to 239.376 Mya. Synteny analysis of the CHX , SOS , and RLK genes demonstrated collinear relationships with orthologous genes in Arabidopsis thaliana , but no collinearity orthologous relationships in Oryza sativa (rice). Furthermore, the analysis revealed that there were 6 orthologous SlCHX genes, 2 orthologous SlSOS genes, and 44 orthologous SlRLK genes paired with those in A. thaliana. The results of the present study may help to elucidate the role of the CHX , SOS , and RLK genes in salt stress in S. lycopersicum .
How and why funders support engaged research
Research that better aligns policy, practice, and research communities is gaining momentum around the world. This includes engaged research strategies that bring partners, and their diverse perspectives and kinds of knowledge, together to shape research agendas with on-the-ground-needs and to create dynamic problem-solving processes. These approaches aim to generate more equitable and effective solutions to societal challenges. Although many of these partnered strategies have a longstanding history, entrenched research cultures, practices, and institutional structures stand in the way of scaling them. Given the outsized role funders play in shaping research efforts, funders are a critical lever for change. This perspective describes the efforts of a global collaborative of philanthropic and public funders who are adapting their practices, supporting the development of infrastructure (e.g., capacity-strengthening, facilitation expertise, processes to guide relational work, etc.), and targeting system-level challenges to enable engaged research to maximize its potential. The authors integrate insights from different issue areas, geographies, and funding areas to provide concrete examples of funder activities that support engaged research and to suggest areas for further action. Recommendations include scaling changes in funding practices, deepening understanding of how and when engaged research leads to improved outcomes, and reshaping how success is defined and measured.
Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis
Evidence for a metal–bosonic insulator–superconductor transition in compressed sulfur
The abrupt drop of resistance to zero at a critical temperature is a key signature of the current paradigm of the metal–superconductor transition. However, the emergence of an intermediate bosonic insulating state characterized by a resistance peak preceding the onset of the superconducting transition has challenged this traditional understanding. Notably, this phenomenon has been predominantly observed in disordered or chemically doped low-dimensional systems, raising intriguing questions about the generality of the effect and its underlying fundamental physics. Here, we present a systematic experimental study of compressed elemental sulfur, an undoped three-dimensional (3D) high-pressure superconductor, with detailed measurements of electrical resistance as a function of temperature, magnetic field, and current. The anomalous resistance peak observed in this 3D system is interpreted based on an empirical model of a metal–bosonic insulator–superconductor transition, potentially driven by vortex dynamics under magnetic field and energy dissipation processes. These findings offer a fresh platform for theoretical analysis of the decades-long enigmatic of the underlying mechanism of this phenomenon.
Optimising detector readout settings for the detection of spatial correlations between SPDC photon-pairs
AbstractSPDC photon-pairs exhibit spatial correlations which can be measured using detector arrays sensitive to single photons. However, these detector arrays have multiple readout modes and in order to optimise detection it is important to select the optimum mode to detect the correlations against a background of optical and electronic noise. These quantum correlations enable applications in imaging, sensing, communication, and optical processing. Here we compare the measurement of spatial correlations for a broad range of readout modes of an EMCCD camera and attempt to characterise the optimal readout mode for our purposes. This assessment is important for the use of detector arrays of different types for use in quantum, low-light, enhanced resolution, imaging systems.
Comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and Tibetan highlanders during ascent to 4,300 m
With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid–base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid–base acclimatization (PCO 2 , [HCO 3 − ], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO 2 ( P <0.0001) and [HCO 3 − ] ( P <0.0001), and higher pH ( P = 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO 2 ( P < 0.0001) and [HCO 3 − ] ( P < 0.0001), but unchanged pH ( P = 0.1), suggesting full renal compensation, with significantly lower PCO 2 ( P = 0.01), [HCO 3 − ] ( P < 0.0001) and pH ( P = 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization.
Structural, magnetic, and optical characteristics of undoped and chromium, iron, cobalt, copper, and zinc doped nickel oxide nanopowders
Integration of basal and apical embryo lineage regulators controls F-actin cable integrity and zygote asymmetry in <i>Arabidopsis</i>
In many plants, the asymmetric division of the zygote sets up the apical–basal body axis. In the cress Arabidopsis , the zygote coexpresses regulators of the apical and basal embryo lineages, the transcription factors WOX2 and WRKY2/WOX8, respectively. WRKY2/WOX8 activity promotes nuclear migration, cellular polarity, and mitotic asymmetry of the zygote, which are hallmarks of axis formation in many plant species. However, the role of WOX2 and how the antagonistic WOX2 and WRKY2/WOX8 functions are integrated in the zygote have remained a long-standing question. Here, we report that WOX2 loss-of-function completely suppresses the reduced zygote asymmetry of wrky2 mutants and that WOX2 overexpression mimics the wrky2 phenotype. At the molecular level, WRKY2 downregulates WOX2 transcription in the zygote and the basal embryo lineage, in addition to promoting WOX8 expression. WOX2 antagonizes WRKY2 function by repressing WOX8 transcription. As a physiological readout, the WRKY2/WOX8-WOX2 balance regulates the integrity of F-actin cables in the zygote, providing a mechanistic framework for the role of WRKY2/WOX8-WOX2-mediated zygote asymmetry.