Journals
2026 EN
Nielsen Jace C. · Saito Masako · Wang Xuegong
+4 more
Abstract Fezolinetant is a non‐hormonal, selective neurokinin‐3 receptor antagonist that blocks neurokinin B activation of kisspeptin/neurokinin B/dynorphin neurons to thereby modulate neuronal activity in the thermoregulatory center. Fezolinetant has been approved in many regions, including North America, Europe, Asia, and Australia for the treatment of vasomotor symptoms associated with menopause at a dose of 45 mg once daily (QD). The risk of potential QT prolongation for fezolinetant was assessed prior to the initiation of the phase 3 trials. A concentration–QTc (C–QTc) analysis was performed in accordance with recommendations from ICH E14 Guideline and utilized data from a phase 1 single and multiple ascending dose study, which tested single doses up to 900 mg and multiple daily doses up to 720 mg in healthy male and female participants. The fezolinetant C–QTc relationship indicated no clinically relevant QT prolongation at therapeutic or supra‐therapeutic doses of fezolinetant. Based on these modeling results as well as data from other clinical and non‐clinical studies, no thorough QT/QTc (TQT) study was required for fezolinetant.
Journals
2026 EN
Jafari Eissa A. · Alshahawey Mona · Zaman Muhammad A.
+4 more
Hypertension is a known modifiable risk factor for Alzheimer’s disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013–12/31/2016), to identify apparent treatment‐resistant hypertension (aTRH), and hypertension‐control levels (well‐controlled hypertension, intermediate‐controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD‐9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson–Aalen estimator and log‐rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234–1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time ( P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837–0.956) and fixed‐dose combination medications (OR: 0.804, 95% CI: 0.732–0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.
Journals
2026 EN
Bradford Jessica L. · Neidinger Philipp · Armbruster Marianne
+3 more
Utilizing a fused isoindoline nitroxide‐styrylpyrene system (StyPyNO), this work presents an interrogation into the effects of the radical spin on the [2+2] photocycloaddition of styrlpyrene and explores the photoswitchability of the system. Through irradiation with both broadband lamps and laser light sources, the influence of the nitroxide moiety on photoreactivity was analyzed and compared with both styryl pyrene and diamagnetic controls. The presence of the radical spin prevented the intermolecular [2+2] photocycloaddition observed from the control systems, instead allowing for a trans –cis photoisomerism under identical 420 nm irradiation conditions. Studies into the triplet lifetimes of the radical containing and control systems allowed for deeper understanding around the mechanism of photoreactivity. The system explored presents a means of controlling photo reaction progression not only via wavelength of irradiation, but also via the presence or removal of the unpaired electron within the nitroxide moiety. This in turn presents the potential for a dual gated chemical/photoswitchable system.
Journals
2026 EN
Smith Natalie · Cohen Michael · Tracey Lauren
+11 more
Abstract Globally, regional and remote communities are burdened by both an increased prevalence and worse prognosis of many infectious and chronic diseases. However, largely owing to logistical challenges, these communities are under‐represented in clinical trials and research studies. As individuals from rural communities experience unique environmental exposures and risk factors for disease, immune phenotyping data collected from metropolitan populations may not be broadly generalizable. To address this, we present a workflow that enables the inclusion of resource‐limited sites in high‐parameter mass cytometry studies. In this approach, whole blood (WB) or peripheral blood mononuclear cells (PBMCs) are collected, stained fresh for surface antigens, and cryopreserved at the collection site. Samples are then shipped to the central site for further processing, including neutrophil depletion, fixation, barcoding, intracellular staining, and data acquisition. Importantly, the WB staining approach does not require specialized equipment such as centrifuges and is therefore feasible to perform in a resource‐limited environment. A support protocol details steps for data preprocessing and cleanup. We present example data demonstrating the application of this workflow to determine immune differences between eight patients with late‐stage lung cancer and four healthy blood donors. Overall, this workflow may improve access to underserved communities and facilitate, for the first time, the scalability of immune phenotyping studies to harness geographically dispersed clinical centers. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1 : Preparation and staining of PBMCs for cytometry Basic Protocol 2 : Preparation and staining of whole blood for cytometry Basic Protocol 3 : Fixation, permeabilization, intracellular staining, and data acquisition for blood sample immunophenotyping Support Protocol : Data preprocessing and cleanup
Journals
2026 EN
Boutamine Karim · Casano Gilles · Bassil Patricia
+6 more
The growing transition from fossil fuels to renewable energy sources such as wind and solar requires efficient stationary energy storage systems to ensure grid stability. Among emerging technologies, redox flow batteries (RFBs) offer a promising solution due to their unique decoupling of energy and power capacities, allowing flexible system design. Recent advances in organic RFBs (ORFBs) have highlighted redox‐active organic molecules as sustainable alternatives to conventional vanadium‐based systems, addressing issues of cost and corrosivity. In particular, nitroxide radicals such as tetramethylpiperidinyloxyl (TEMPO) derivatives have demonstrated high reversibility and fast kinetics in aqueous systems, though the stability of their oxidized N‐oxoammonium form remains a challenge for long‐term storage. Isoindoline‐based nitroxides offer potential for enhanced stability but have been limited by complex and low‐yield synthetic routes. Herein, we present a convenient metal‐catalyzed [2 + 2 + 2] intermolecular cycloaddition strategy for the synthesis of isoindoline‐based nitroxides and their aza analogs, including two new candidates, TC‐TMIO and PPO. Electrochemical characterization reveals that PPO, a cationic 2,3‐dihydropyrrolo[3,4‐c]pyridinium nitroxide, exhibits an oxidation potential 220 mV higher than the benchmark 4‐TMA‐TEMPO and achieves solubility exceeding 3 M in 1 M NaCl aqueous solution. Preliminary stability assessments of the PPO and RFB testing using a methyl viologen/PPO system demonstrate its potential as a high‐performance, sustainable posolyte for aqueous ORFBs.
Journals
2026 EN
Huang JyhJaan Steven · Pizer Charlotte · Lin JunTing
+2 more
Abstract Establishing along‐strike correlations of event deposits in deep‐sea environments allows for the reconstruction of spatial and temporal patterns of geological processes, such as seismically triggered turbidites. However, in settings like the ultra‐deep Japan Trench, highly variable seafloor topography and limited chronological tie points pose significant challenges for tracing individual deposits between semi‐isolated trench basins. Using cores from International Ocean Discovery Program (IODP) Expedition 386 at the central Japan Trench, this study examines how non‐destructive X‐ray fluorescence core scanning (XRF‐CS) combined with multivariate statistics can be used to distinguish and correlate individual event deposits across contrasting depositional settings, based on their geochemical fingerprints. The results of the five‐cluster model demonstrate that the XRF‐CS properties of event deposits are clearly distinguishable from background sediments, as well as from one another. The chemostratigraphic cluster sequence can be correlated between cores from basin depocentres—where event deposits are thicker but the record is shorter, and cores from topographic highs—where the record extends further back in time but event deposits are thin and difficult to distinguish using previously applied event correlation methods. The high‐resolution chemostratigraphy enables a more detailed, geochemically‐enhanced stratigraphic interpretation, identifying several previously unrecognised event deposits with unique internal structures that suggest varying depositional processes. Notably, excluding the 2011 event deposit, the three most recent event deposits are allocated to different clusters, implying compositional heterogeneity probably linked to sediment provenance. The results of this study therefore demonstrate a rapid and reproducible technique for using chemostratigraphy to establish high‐resolution event correlations in submarine sediment cores, leading to several working hypotheses for Japan Trench palaeoseismology to be tested with future work.
Journals
2026 EN
Liu ChiaFeng · Leon Steven · Herrig Isabella
+2 more
ABSTRACT Bicaudal C1 (Bicc1) encodes an RNA‐binding protein critical for many organ development and epithelial tissue homeostasis. Bicc1 null mutations have been shown to lead to the development of polycystic kidney disease (PKD) and death at an early prenatal stage. To elucidate the tissue‐specific functions of Bicc1, we engineered two independent conditional knockout (cKO) mouse lines targeting distinct exonic regions of the gene. The first line was generated using a traditional embryonic stem (ES) cell‐based approach, wherein loxP sites were inserted flanking exon 4 (E4), enabling Cre‐mediated excision of a functionally essential coding region. The second line was created using CRISPR/Cas9 genome editing, introducing loxP sites around both exon 4 and exon 5 (E4‐5) in a double‐step zygote injection strategy. Both alleles were validated by PCR genotyping, sequencing, and functional recombination was confirmed via a tissue‐specific Cre driver. These independent cKO models provide a robust platform for dissecting the role of Bicc1 in specific tissues and developmental stages, and offer new avenues for studying the mechanistic basis of PKD and other Bicc1‐related pathologies.
Journals
2026 EN
Coetsee Corli · Kleyn Linda · Vogeler Jody C.
+4 more
Abstract African elephants, whether alone or in combination with other environmental factors such as floods, droughts, fire, and other herbivores, have significant impacts on large savanna trees, often contributing to declines over time. However, their effects on woody vegetation in general remain less well understood. To investigate these dynamics in a southern African savanna, we consulted park personnel in Kruger National Park to identify areas where woody cover loss had been observed and where elephants were believed to be the primary driver. Using a Global Ecosystem Dynamics Investigation (GEDI)‐fusion remote sensing method, we then measured changes in woody cover and height across these areas from 2007 to 2022. Contrary to widespread concerns, GEDI‐fusion data did not indicate a general decline in woody cover across the park. In fact, the overall trend shows an increase in woody vegetation. Nonetheless, some localized areas, which were flagged by park staff, showed declines in both general woody cover and large tree height, particularly along perennial rivers and on fertile soils. While we found no overall correlation between woody losses and increases in dry‐season elephant densities across the study period, certain areas, especially those along perennial rivers, had the most notable increases in local elephant densities. To better isolate the role of fire, we overlaid woody cover losses with areas that experienced no fire during the study period (2.15% of pixels or ~40,000 ha). Notably, 44% of these fire‐free areas overlapped with regions identified by park staff as of concern in terms of elephant‐related impacts. While flood events may have contributed to tree losses in fire‐free areas where these occur along perennial rivers, the findings collectively indicate that elephants—either independently or in combination with other factors—play a substantial role in the observed declines in woody cover and tree height in these areas. This study highlights the value of combining local knowledge and grassroots insights with advanced remote sensing techniques to detect and interpret spatial patterns of change. It also emphasizes the importance of targeted and adaptive management strategies in high‐impact areas to reduce elephant‐driven pressure on vulnerable vegetation and to support resilience across the broader landscape.
Journals
2026 EN
Bell Aaron J. · Paterson Stephen M. A. · Van Wilgenburg Steven L.
+3 more
Abstract Global fire regimes are changing, raising concerns about the ability of fire‐prone ecosystems to maintain biodiversity. We tested whether the pyrodiversity–biodiversity hypothesis (i.e., variation in postfire characteristics promotes biodiversity) or alternative hypotheses better explain patterns of biodiversity in a true island system. Using fixed‐area sampling plots in a chronosequence of 42 boreal lake islands spanning gradients in island area (1–350.4 ha), isolation (0.1–7.9 km from mainland), and fire history (1–231+ year since fire), we tested whether alpha and beta diversity of beetles, plants, and birds increased with spatial (within‐island variation in burn severity) and temporal (variation in time since fire among islands) pyrodiversity, respectively. Species richness of plants and birds increased with spatial pyrodiversity indicating that habitat heterogeneity from localized variation in burn severity supported more species in some groups. Beta diversity of all taxa increased with temporal pyrodiversity, highlighting the importance of conserving age‐class variation within the boreal patch mosaic. In contrast, the habitat amount hypothesis and island biogeography theory were weak predictors of species richness across all taxa, and island area and isolation did not consistently affect beta diversity among the islands. Our findings emphasize the importance of maintaining pyrodiversity in boreal landscapes to combat biodiversity loss in the age of “megafires” and suggest leveraging the fire refugia effects of large lakes within the region to conserve vital components of temporal pyrodiversity such as old‐growth forests.
Journals
2026 EN
Bowles Ella · Henri Dominique A. · Provencher Jennifer F.
+14 more
ABSTRACT There has been a widespread effort to braid multiple knowledge systems in biodiversity research and monitoring, yet there is further need to consider how to do so. We interviewed Indigenous Peoples and representatives of 12 Indigenous communities, completed a systematic review of biodiversity studies that utilized Indigenous knowledges (IK) and Western sciences (WS) in Canada, and then braided the outcomes of the conversations and literature review to address if, when, and how IK and WS can be brought together for biodiversity research and monitoring in Canada. Overall, there was a great deal of support for, and desire to, braid IK and WS among interview participants. A suite of nine pillars and priorities was identified for doing so from participants' responses. These priorities included: (1) build and foster relationships; (2) IK should guide projects; (3) Indigenous communities should lead projects; (4) IK must be respected equally with WS; (5) embrace reciprocity (focus on people) and (6) embrace responsibility (focus on land) to the land and one another; (7) ensure equal gender and age representation; (8) intergenerational knowledge transfer is important; and (9) language revitalization is critical. The extent to which the pillars and priorities for braiding were reflected in the current literature varied, and we identified indicators that may help project leads choose what to prioritize in design to fulfill the pillars. These indicators included engagement, relevance, governance, and accessibility. The stages of projects at which IK and WS were brought together (i.e., design, data collection, analysis, reporting, and decision‐making), the roles for each IK and WS at various project stages, and the methods for IK collation and WS data collection varied extensively across the literature. This work deepens our understanding of the practices of knowledge braiding in biodiversity research and monitoring in Canada and offers a toolkit for doing so.