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Neuropilin-1 acts as a coreceptor with vascular endothelial growth factor receptors to facilitate binding of its ligand, vascular endothelial growth factor. Neuropilin-1 also binds to heparan sulfate, but the functional significance of this interaction has not been established. A combinatorial library screening using heparin oligosaccharides followed by molecular dynamics simulations of a heparin tetradecasaccharide suggested a highly conserved binding site composed of amino acid residues extending across the b1 and b2 domains of murine neuropilin-1. Mutagenesis studies established the importance of arginine513 and lysine514 for binding of heparin to a recombinant form of Nrp1 composed of the a1, a2, b1, and b2 domains. Recombinant Nrp1 protein bearing R513A,K514A mutations showed a significant loss of heparin-binding, heparin-induced dimerization, and heparin-dependent thermal stabilization. Isothermal calorimetry experiments suggested a 1:2 complex of heparin tetradecasaccharide:Nrp1. To study the impact of altered heparin binding in vivo, a mutant allele of Nrp1 bearing the R513A,K514A mutations was created in mice (Nrp1D) and crossbred to Nrp1+/- mice to examine the impact of altered heparan sulfate binding. Analysis of tumor formation showed variable effects on tumor growth in Nrp1D/D mice, resulting in a frank reduction in tumor growth in Nrp1D/- mice. Expression of mutant Nrp1D protein was normal in tissues, suggesting that the reduction in tumor growth was due to the altered binding of heparin/heparan sulfate to neuropilin-1. These findings suggest that the interaction of neuropilin-1 with heparan sulfate modulates its stability and its role in tumor formation and growth.

Wetlands are responsible for 20%–31% of global methane (CH4) emissions and account for a large source of uncertainty in the global CH4 budget. Data-driven upscaling of CH4 fluxes from eddy covariance measurements can provide new and independent bottom-up estimates of wetland CH4 emissions. Here, we develop a six-predictor random forest upscaling model (UpCH4), trained on 119 site-years of eddy covariance CH4 flux data from 43 freshwater wetland sites in the FLUXNET-CH4 Community Product. Network patterns in site-level annual means and mean seasonal cycles of CH4 fluxes were reproduced accurately in tundra, boreal, and temperate regions (Nash-Sutcliffe Efficiency ∼0.52–0.63 and 0.53). UpCH4 estimated annual global wetland CH4 emissions of 146 ± 43 TgCH4 y−1 for 2001–2018 which agrees closely with current bottom-up land surface models (102–181 TgCH4 y−1) and overlaps with top-down atmospheric inversion models (155–200 TgCH4 y−1). However, UpCH4 diverged from both types of models in the spatial pattern and seasonal dynamics of tropical wetland emissions. We conclude that upscaling of eddy covariance CH4 fluxes has the potential to produce realistic extra-tropical wetland CH4 emissions estimates which will improve with more flux data. To reduce uncertainty in upscaled estimates, researchers could prioritize new wetland flux sites along humid-to-arid tropical climate gradients, from major rainforest basins (Congo, Amazon, and SE Asia), into monsoon (Bangladesh and India) and savannah regions (African Sahel) and be paired with improved knowledge of wetland extent seasonal dynamics in these regions. The monthly wetland methane products gridded at 0.25° from UpCH4 are available via ORNL DAAC (https://doi.org/10.3334/ORNLDAAC/2253).

Telemedicine emerged as an alternative care delivery system used to offer effective long-term management to patients with chronic, inflammatory conditions such as psoriatic disease. Teledermatology can provide reliable clinical information through thorough history-taking and virtual evaluations that include patient-provided images and disease activity assessment tools that may help accurately diagnose and manage patients with psoriasis. The integration of validated screening tools for psoriatic arthritis and effective teledermatology practices may improve access to specialists, thus avoiding preventable delays in the diagnosis and treatment of patients with psoriatic arthritis. Although the provision of telehealthcare should not completely replace high quality, in-person dermatologic or rheumatologic visits, the convenience and collaborative nature of teledermatology may lead to expanded access and expedited care in the appropriate setting, whether it be in a virtual or in-person visit.

AimsContemporary patterns of care of patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D) and the adoption of finerenone are not known. The FINE-REAL study (NCT05348733) is a prospective observational study in patients with CKD and T2D to provide insights into the use of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in clinical practice.MethodsFINE-REAL is an international, prospective, multicenter, single-arm study enrolling approximately 5500 adults with CKD and T2D in an estimated 200 sites across 22 countries. The study is anticipated to be ongoing until 2027.ResultsThe primary objective is to describe treatment patterns in patients with CKD and T2D treated with finerenone in routine clinical practice. Secondary objectives include assessment of safety with finerenone. Other endpoints include characterization of healthcare resource utilization and occurrence of newly diagnosed diabetic retinopathy or its progression from baseline in patients with existing disease. A biobank is being organized for future explorative analyses with inclusion of participants from the United States.ConclusionsFINE-REAL is the first prospective observational study with a nonsteroidal MRA in a population with CKD and T2D and is expected to provide meaningful insights into the treatment of CKD associated with T2D. FINE-REAL will inform decision-making with respect to initiation of finerenone in patients with CKD and T2D.

Wetland CH₄ emissions are among the most uncertain components of the global CH₄ budget. The complex nature of wetland CH₄ processes makes it challenging to identify causal relationships for improving our understanding and predictability of CH₄ emissions. In this study, we used the flux measurements of CH₄ from eddy covariance towers (30 sites from 4 wetlands types: bog, fen, marsh, and wet tundra) to construct a causality-constrained machine learning (ML) framework to explain the regulative factors and to capture CH₄ emissions at sub-seasonal scale. We found that soil temperature is the dominant factor for CH₄ emissions in all studied wetland types. Ecosystem respiration (CO₂) and gross primary productivity exert controls at bog, fen, and marsh sites with lagged responses of days to weeks. Integrating these asynchronous environmental and biological causal relationships in predictive models significantly improved model performance. More importantly, modeled CH₄ emissions differed by up to a factor of 4 under a +1°C warming scenario when causality constraints were considered. These results highlight the significant role of causality in modeling wetland CH₄ emissions especially under future warming conditions, while traditional data-driven ML models may reproduce observations for the wrong reasons. Our proposed causality-guided model could benefit predictive modeling, large-scale upscaling, data gap-filling, and surrogate modeling of wetland CH₄ emissions within earth system land models.

Due to the current COVID-19 reality and the protests supporting the #BlackLivesMatter Movement following the killings of Ahmaud Arbery, Breonna Taylor, and George Floyd, seeking diversified and innovative educational solutions like ethnic studies (ES) and adapting to the everchanging needs of students by creating supportive healing spaces of learning are more important than ever. These events have resulted in demands for educational systems that have the potential to address the wounds of racial violence that marginalized students have faced for centuries. More importantly, in light of the current environment, educational institutions must collaborate with their communities to provide teachers with culturally and community responsive strategies, trainings, and resources that promote healing and wellness. The purpose of this paper is to celebrate the classroom victories of these ES teachers and explore the ways that they connect their curriculum and learning experiences to their students' lived realities. These ES teachers utilize holistic pedagogies that help their students move toward social change while cultivating the spiritual well-being of their students. Using the framework "Body-Soul Rooted Pedagogy" (Desai et al., 2019), the authors' findings discuss the five major categories that emerged: (1) connecting the past to the present, (2) privileging identity, (3) addressing everyday struggles, (4) classroom rituals, and (5) social action. Amidst a global pandemic, social unrest, and the struggle to achieve social justice within broader society, the authors seek to highlight how these practices can be road maps for humanizing educational change.