Effects of macro vs. micro initialization and ocean initial-condition memory on the evolution of ensemble spread in the CESM2 large ensemble.

Unlabelled: "Single Model initial-condition Large Ensembles" (SMILEs) conducted with Earth system models have transformed our ability to quantify internal climate variability and forced climate change at local and regional scales. An important consideration in their experimental design is the choice of initialization procedure as this influences the duration of initial-condition memory, with implications for interpreting the temporal evolution of both the ensemble-mean and ensemble-spread. Here we leverage the strategic design of the 100-member Community Earth System Model version 2 (CESM2) SMILE to investigate the dependence of ensemble spread on the method of initialization (micro- vs.

Discovery of (2,4)-4-(()-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.

Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor () that was potent but had low oral bioavailability in rat.

Synesthesia is linked to large and extensive differences in brain structure and function as determined by whole-brain biomarkers derived from the HCP (Human Connectome Project) cortical parcellation approach.

There is considerable interest in understanding the developmental origins and health implications of individual differences in brain structure and function. In this pre-registered study we demonstrate that a hidden subgroup within the general population-people with synesthesia (e.g.

Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.

Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2.

The role of dissolved organic carbon in Great Smoky Mountains National Park streams impacted by long-term acid deposition.

Following reductions in acid deposition in the Great Smoky Mountains National Park (GRSM) since the 2000s, many streams remain acidic and the role of organic acids (OA) remains unknown due to limited OA data. This study investigated dissolved organic carbon (DOC) concentrations as a surrogate for OA across GRSM and its relationships with watershed characteristics, seasons, flow, and stream chemistry. Baseflow water samples were collected from seven watersheds for 2 years and stormflow samples from three watersheds for 1 year.

The pace of change of summertime temperature extremes.

Summer temperature extremes can have large impacts on humans and the biosphere, and an increase in heat extremes is one of the most visible symptoms of climate change. Multiple mechanisms have been proposed that would predict faster warming of heat extremes than typical summer days, but it is unclear whether this is occurring. Here, we show that, in both observations and historical climate model simulations, the hottest summer days have warmed at the same pace as the median globally, in each hemisphere, and in the tropics from 1959 to 2023.

Controlling images and standards of beauty shapes body image: using a relational cultural approach to improve Black American women's well-being.

Objectives: Controlling images and racialized stereotypical myths inform Eurocentric and cultural standards of beauty that shape Black American women's body image and well-being. Cultural responsiveness is crucial in understanding the lived experiences of Black American women, the systemic oppressive factors that subjugate them, and the impacts on their mental health.

Design: An integrative review was conducted on controlling images and racialized stereotypes, standards of beauty, and body image to assess the contribution of these factors on Black American women's mental health, specifically, disordered eating, depression, and anxiety.

Cognitive stimulation in socioeconomically disadvantaged children with neurodevelopmental disorders: a case series.

Introduction: Research shows how conditions in socio-economically disadvantaged environments can be a risk factor for children's cognitive development. Consequently, children with neurodevelopmental disorders growing up in such environments face a double challenge. This study analyzed the effect of a comprehensive cognitive stimulation program on 4 single case studies comprising children with neurodevelopmental disorders from Guatemala.

Gastric intestinal metaplasia: Prevalence in a large Australian center and nationwide survey of endoscopic practice.

Background And Aim: Atrophic gastritis (AG) and gastric intestinal metaplasia (GIM) are early changes in the stepwise progression to gastric adenocarcinoma. There is heterogeneity in international guidelines regarding the endoscopic diagnosis and surveillance of AG and GIM. This study aims to determine the prevalence of GIM in an Australian center and assess the approach of Australian endoscopists for these two conditions.

A standardized approach to measuring gender transparency in languages.

Languages can express grammatical gender through different ortho-phonological regularities present in nouns (e.g., the cues "-o" and "-a" for the masculine and the feminine respectively in Italian, Portuguese, or Spanish).

Neuropsychological Stimulation Program for Children from Low Socioeconomic Backgrounds: Study Protocol for a Randomized Controlled Trial.

Background: Guatemala remains one of the poorest countries in Central America and suffers from high rates of social inequality and violence. In addition to the negative impact that two years without attending school has had on Guatemalan children due to the consequences of the COVID-19 pandemic, this unfavourable socioeconomic context poses a risk to children's emotional and cognitive development. This work presents a protocol for implementing a cognitive and emotional stimulation program aimed at increasing the academic performance of these children and consequently improving their quality of life.

Observed humidity trends in dry regions contradict climate models.

Arid and semi-arid regions of the world are particularly vulnerable to greenhouse gas-driven hydroclimate change. Climate models are our primary tool for projecting the future hydroclimate that society in these regions must adapt to, but here, we present a concerning discrepancy between observed and model-based historical hydroclimate trends. Over the arid/semi-arid regions of the world, the predominant signal in all model simulations is an increase in atmospheric water vapor, on average, over the last four decades, in association with the increased water vapor-holding capacity of a warmer atmosphere.

Brain iron acquisition depends on age and sex in iron-deficient mice.

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin-bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H-ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1- and Tf-bound iron.

An Open Science MRI Database of over 100 Synaesthetic Brains and Accompanying Deep Phenotypic Information.

We provide a neuroimaging database consisting of 102 synaesthetic brains using state-of-the-art 3 T MRI protocols from the Human Connectome Project (HCP) which is freely available to researchers. This database consists of structural (T1- and T2-weighted) images together with approximately 24 minutes of resting state data per participant. These protocols are designed to be inter-operable and reproducible so that others can add to the dataset or directly compare it against other normative or special samples.

Amyloid-β exposed astrocytes induce iron transport from endothelial cells at the blood-brain barrier by altering the ratio of apo- and holo-transferrin.

Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport.

Environmental regulations in the United States lead to improvements in untreated stormwater quality over four decades.

Identifying sources of pollutants in watersheds is critical to accurately predicting stormwater quality. Many existing software used to model stormwater quality rely on decades-old data sets which may not represent current runoff quality in the United States. Because of environmental regulations promulgated at the federal level over previous decades, there is a need to understand long-term trends (and potential shifts) in runoff quality to better parameterize models.

VAEs with structured image covariance applied to compressed sensing MRI.

This paper investigates how generative models, trained on ground-truth images, can be used as priors for inverse problems, penalizing reconstructions far from images the generator can produce. The aim is that learned regularization will provide complex data-driven priors to inverse problems while still retaining the control and insight of a variational regularization method. Moreover, unsupervised learning, without paired training data, allows the learned regularizer to remain flexible to changes in the forward problem such as noise level, sampling pattern or coil sensitivities in MRI.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4747, a clinical development candidate for the treatment of KRAS-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK.

Amyloid-β exposed astrocytes induce iron transport from endothelial cells at the blood-brain barrier by altering the ratio of apo- and holo-transferrin.

Unlabelled: Excessive brain iron accumulation is observed in early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport.

Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation.

Background: Apo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood-brain barrier. Apo-Tf indicates an iron-deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process.

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability.

Benralizumab: A novel treatment for the cutaneous features of paediatric eosinophilic granulomatosis with polyangiitis (pEGPA).

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis presenting primarily with pulmonary and cutaneous features. The disease is typically seen in the fifth or sixth decade of life (1, 2). We report a case of EGPA in an adolescent who was successfully treated with the interleukin-5 (IL-5) receptor inhibitor, benralizumab.

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation.

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H-ferritin is critical.