Journals
2026 EN
QuispeCarbajal Mariella · Todd Lauren · Glynn Steven E.
Abstract Yme1 is a conserved ATP‐dependent protease that maintains mitochondrial function by degrading proteins in the intermembrane space. However, how Yme1 selects substrates within the crowded mitochondrial environment is poorly understood. An established substrate of Yme1 in yeast is the Tim10 subunit of the small Tim9‐Tim10 protein chaperone complex, which is degraded following disruption of the subunit's internal disulfide bonds. Here, we use biochemical and biophysical approaches to examine initial substrate binding and degradation of small Tim proteins by Yme1 and shed light on the molecular mechanism of substrate selection. We show that Yme1 preferentially binds Tim10 over other small Tim proteins by forming a strong interaction with the subunit irrespective of the presence of its disulfide bonds. This interaction is primarily mediated by Tim10's flexible N‐terminal “tentacle,” though substrate unfolding exposes additional contact sites that enhance engagement. Notably, the human ortholog TIMM13 is also recognized by yeast Yme1, suggesting conservation of recognition strategy across species. Yme1 also binds to the assembled Tim9‐Tim10 chaperone but independently of the Tim10 N‐terminal tentacle. These findings suggest that Yme1 interacts with both the functional chaperone complex and the disassembled Tim10 monomers but only commits to degradation after disruption of its disulfide bonds.
Journals
2026 EN
Dohmen Rosalie L. · Teeman Sarah M. · Patel Riddhi
+8 more
Abstract The use of specific isotope labeling methods has significantly enhanced structural and kinetic research in protein science using a variety of biophysical techniques. Histidine plays key roles in a wide range of protein functions: enzymatic catalysis, metal ion coordination, protein stability, and redox reactions. In this article, we report a method for optimized histidine‐specific isotopic labeling in proteins overproduced in Escherichia coli . We developed and validated this method using photoactive yellow protein (PYP) from Halorhodospira halophila , a prototype of the Per‐Arnt‐Sim (PAS) domain superfamily that contains only two native histidine residues. We tested both the efficiency of isotope editing of histidine and the degree of isotope scrambling after protein overproduction in E. coli grown in defined growth medium containing the 20 amino acids. Using varied amounts of isotope‐edited histidine in the range of 0, 8, 16, 32, 64, and 128 mg/L of cell culture, we found that 32 mg of histidine per liter of cell culture is sufficient for over 98% of isotope labeling using double ionization mass spectroscopy measurements. Analysis of isotope envelopes of mass spectra of intact PYP are consistent with the absence of isotope scrambling, as are nuclear magnetic resonance spectra that show only resonances from the labeled histidine residues. In addition, we use Fourier transform infrared spectroscopy to demonstrate that these protein samples allow the detection of vibrational modes shifted upon histidine‐specific isotope labeling. This method is widely applicable to histidine‐specific isotope labeling of other proteins upon overexpression in E. coli .
Journals
2026 EN
Bucur Diana E. · Kildea Steven
Abstract BACKGROUND Fusarium head blight (FHB) in oats represents a significant challenge to crop production and food safety, primarily because of mycotoxin contamination. In this study, 286 Fusarium isolates, representing in majority F . langsethiae , and small numbers of F. tricinctum , F. poae and F. sporotrichioides , obtained from commercial Irish oat crops in 2022 were evaluated in vitro for their sensitivity to three azole fungicides: prothioconazole‐desthio (PDZ), tebuconazole (TBZ) and mefentrifluconazole (MFZ). A microtitre plate assay was used to generate dose–response curves and to determine their half‐maximal effective concentrations (EC 50 ) to each of the three fungicides. RESULTS Differences in fungicide sensitivity and evidence of moderate cross‐resistance among the azole fungicides tested, particularly in F. langsethiae , were detected. Specifically, isolates were overall more sensitive to PDZ, while sensitivity differences between fungicides and partial cross‐resistance between MFZ and TBZ were statistically significant. These results were supported by a principal component analysis and a cluster analysis that confirmed F. langsethiae isolates were least sensitive to MFZ, this fungicide being responsible for the highest amount of variability in the population. CONCLUSION Given that oats are used in human consumption and animal feed, these findings underscore the critical need for ongoing resistance monitoring to maintain food safety standards aligned with European Union regulatory requirements. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Journals
2026 EN
Bhagunde Pratik · Penner Natasha · Willis Brian A.
+5 more
ABSTRACT Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid‐beta (Aβ) protein. In clinical studies, lecanemab has been shown to reduce amyloid markers in early symptomatic Alzheimer's disease and slow decline on clinical endpoints of cognition and function. Nonlinear mixed‐effects modeling assessed the correlation between amyloid PET and change in CDR‐SB using data from lecanemab phase 2 study (Study 201) and phase 3 study (Study 301; Clarity AD). Data from placebo‐treated subjects were used to establish a disease‐progression model; the effect of amyloid reduction on disease progression was defined using data from lecanemab‐treated subjects. CDR‐SB scores were used with beta regression to fit a Richard's function parameterized in terms of baseline CDR‐SB, intrinsic rate of disease progression, shape, and precision of the beta distribution. Simulations were conducted to evaluate the impact of lecanemab treatment over 4 years. Baseline CDR‐SB was predicted by diagnosis and baseline mini‐mental state examination (BMMSE) score. Intrinsic rate of disease progression was predicted by amyloid PET and BMMSE. Amyloid PET was a better predictor of drug effect than lecanemab exposure, demonstrating amyloid reduction as a surrogate marker of efficacy. Simulations projected the difference in CDR‐SB between lecanemab and placebo treated subjects continued increasing over 4 years. Patients with low baseline amyloid and less severe disease were projected to have slower disease progression and better outcomes with lecanemab treatment.
Journals
2026 EN
Mseddi Mourad · Nath Christa · Ben Hassine Khalil
+7 more
ABSTRACT Fludarabine (Flu), administered as a prodrug Flu monophosphate, is a lymphodepleting agent used prior to hematopoietic stem cell transplantation (HSCT) which exhibits substantial pharmacokinetics (PK) variability, contributing to suboptimal outcomes. This study developed and validated a physiologically based pharmacokinetic (PBPK) model using literature‐based data and a middle‐out approach for Flu and its two main metabolites in adults and children, and evaluated its performance to predict individual Flu exposures in 28 pediatric HSCT patients using a virtual twin (VT) approach using PK‐Sim software. Different informed models with individual demographic and biological characteristics were assessed by comparing predicted and observed plasma exposures (AUC 0➔24h ) via fold error metrics and regression analyses. The PBPK model accurately reproduced observed Flu and metabolites concentrations in both adults and children. In the VT cohort, informing the model with plasma protein scaling factor and nuclear GFR improved drug exposure predictions in total (mean fold error (MFE) = 0.91) and unbound (MFE = 0.88) compartments with minimal bias in both Deming and Bland–Altman analyses. This model provided superior agreement between observed and predicted exposures, achieving improved agreement across statistical and regression approaches compared to the model with estimated GFR. PBPK‐based VT modeling enables accurate, individualized prediction of Flu PK in pediatric HSCT patients. These results support the implementation of model‐informed precision dosing to achieve personalized pediatric dosing of Flu in HSCT.
Journals
2026 EN
Wang Hao · Vlahos Ross · Bozinovski Steven
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Journals
2026 EN
Harvey Bret C. · White Jason L. · Railsback Steven F.
+2 more
ABSTRACT As attention to valley‐bottom or Stage‐0 restoration increases, direct attempts to evaluate its effects on highly valued salmonid fishes remain rare. We evaluated a valley‐bottom restoration project at Whychus Creek, Oregon, by simulating its effects on the abundance of both resident trout (native Rainbow Trout Oncorhynchus mykiss and introduced Brown Trout Salmo trutta ) that currently occupy the site and anadromous Chinook Salmon O. tshawytscha that historically occupied the site. Specifically, we compared results from a spatially explicit, individual‐based model for pre‐restoration versus post‐restoration conditions in a 650‐m reach of stream within the larger restoration area. For both pre‐ and post‐restoration conditions, we explicitly represented the entire areas inundated by the highest streamflow that occurred during a 15‐year simulation period. The model represented the entire lifecycle of resident trout and the part of the lifecycle of Chinook Salmon that would occur at the study site, from the arrival of adults to the emigration of juvenile fish; simulations concurrently included all three salmonid species. The simulations indicated large benefits of restoration for all three species; model results for trout biomass corresponded with single empirical estimates of abundance before and after restoration. However, simulations also yielded year‐class failures for both species of resident trout under both pre‐ and post‐restoration conditions. This last result highlights the ability of mechanistic individual‐based models to not only estimate the effects of restoration on populations of special concern, but also to place those effects in the context of the broad array of factors affecting populations.
Journals
2026 EN
Hasan Mohammad Rajib · Selvanathan Eliyathamby A. · Bhatia Bhanu
+2 more
ABSTRACT Well‐being transcends the complex and often competing sustainability dimensions. As such, a population's well‐being serves as a bellwether for sustainable development and is an important consideration of development progress. Since the 2015 launch of the UN sustainable development goals (SDGs), well‐being‐focused research has expanded significantly. Sustainable Development is among the few journals consistently contributing to this field. A timely overview of maturing well‐being‐SDG research progresses this contribution, warranting a systematic quantitative literature review (SQLR). The review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) approach. Applying predefined exclusion–inclusion criteria, 50 relevant well‐being development goal‐focused articles were reviewed. A detailed analysis revealed the current state of knowledge, key research themes, methods, trends, and leading contributors. The synthesis of prior studies also identified research gaps and future directions to better support the sustainable development agenda. Finally, the review underscores the central role of promoting long‐term sustainability and human well‐being.
Journals
2026 EN
Hilbert Torey · MacEachern Steven N. · Zhang Yuan
ABSTRACT Recently, there has been growing concern about heavy‐tailed and skewed noise in biological data. We introduce RobustPALMRT, a flexible permutation framework for testing the association of a covariate of interest adjusted for control covariates. RobustPALMRT controls type I error rate for finite‐samples, even in the presence of heavy‐tailed or skewed noise. The new framework expands the scope of state‐of‐the‐art tests in three directions. First, our method applies to robust and quantile regressions, even with the necessary hyper‐parameter tuning. Second, by separating model‐fitting and model‐evaluation, we discover that performance improves when using a robust loss function in the model‐evaluation step, regardless of how the model is fit. Third, we allow fitting multiple models to detect specialized features of interest in a distribution. To demonstrate this, we introduce DispersionPALMRT, which tests for differences in dispersion between treatment and control groups. We establish theoretical guarantees, identify settings where our method has greater power than existing methods, and analyze existing immunological data on Long‐COVID patients. Using RobustPALMRT, we unveil novel differences between Long‐COVID patients and others even in the presence of highly skewed noise.
Journals
2026 EN
De Block Petra · Razafimandimbison Sylvain G. · Rakotonasolo Franck
+1 more
Abstract As presently circumscribed, the Paleotropical genus Tarenna , belonging to the tribe Pavetteae (Rubiaceae), comprises about 200 species and has its centres of diversity in tropical Asia and Africa. Previous molecular phylogenetic studies of the tribe revealed the polyphyly of Tarenna , suggesting that the genus needs to be recircumscribed. However, a robust phylogeny of Pavetteae using a sufficient sampling of Tarenna and a comparative assessment of the morphological variation of its members throughout the entire geographic range of the genus, needed for such a taxonomic adjustment, are currently lacking. In this study, a new phylogeny of Pavetteae was reconstructed based on four plastid markers ( rps16 , trnT‐F , petD , accD‐psa1 ) and two nuclear markers (nrITS, MADS‐box PI). Our objectives were (1) to produce a robust molecular phylogeny based on a large sampling of Tarenna ; (2) to undertake morphological comparisons between the continental African, Madagascan and Asian/Australasian/Pacific Tarenna ; and, (3) to recircumscribe Tarenna so that the genus is less polyphyletic and to transfer the segregated species to their correct placement within the tribe Pavetteae. Our results support the polyphyly of Tarenna as presently delimited, as its sampled species are resolved in five morphologically distinct and geographically segregated lineages: three restricted to continental Africa, one to Madagascar and the Western Indian Ocean islands and one including the type T. asiatica confined to Asia, Australasia and the Pacific. We propose a narrow circumscription of Tarenna to include the Asian/Australasian/Pacific species but excluding the continental African and Madagascan species. Thirty‐eight continental African Tarenna species are transferred to the hitherto small genus Cladoceras , which is characterized by exotestal cells shaped like puzzle pieces in surface view (versus polygonal exotestal cells in Asian/Australasian/Pacific taxa). The new genus Alatostigma is described to accommodate four continental African species ( A. agnata , A. funebris , A. hutchinsonii , A. jolinonii ) characterized by longitudinally winged abaxial stigma surfaces and polygonal exotestal cells. The new genus Sonbridia , sister to the Paleotropical genus Pavetta , is established to accommodate two continental African species ( S. bipindensis , S. warburgiana , the latter previously known as Tarenna precidantenna ), characterized by short anthers born on long filaments, pedicels thickened below the fruit, and exotestal cells shaped like puzzle pieces in surface view. The species from Madagascar, the Comoros and the Seychelles are transferred to the new genus Nesotarenna , characterized by lax inflorescences, long pedicels, bracteoles borne low on the pedicels and polygonal exotestal cells. The new genera are described in detail and the necessary nomenclatural changes are made to transfer the continental African and Madagascan species to the new genera.