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PubMed2026

Proteome-level evidence that tebuconazole, both alone and in interaction with thiacloprid, affects epigenetic events in bumblebee heads.

Tebuconazole, a widely used ergosterol biosynthesis-inhibiting fungicide, can affect nontargets, especially when combined with insecticides. We employed label-free quantitative proteomics to investigate the effects of long-term exposure to sublethal concentrations (100 μg/L) of tebuconazole, either by itself or alongside the neonicotinoid thiacloprid (100 μg/L), on the heads of Bombus terrestris workers. A Bayesian factor power analysis revealed that the experiment produced conclusive proteomic results. Tebuconazole treatment revealed eleven differentially abundant proteins, which increased elevenfold with thiacloprid. The proteins that changed in the same direction in both treatments suggest the occurrence of epigenetic events because they are involved in histone trimethylation (H3K4me3), pre-mRNA processing, and folate (vitamin B9) metabolism. Following co-exposure, the abundance of histone H2A.V and its associated proteins was affected. Two important detoxification-related proteins, CYP6BE1 and CYP6AQ1 (honey bee homologs), were identified, as well as proteins that suggest hormonal and neurotoxic effects. Overall, this study suggests that tebuconazole affects key epigenetic processes in bumblebee heads at the proteome level, though this was not confirmed at the biological level or through orthogonal methods. The tested chemicals were previously found to affect trimethylations, but not H3K4me3. We suggest analyzing the different trimethylations, their interplay, and associated hallmarks, such as folate levels. SIGNIFICANCE: The effects of pesticides and their combinations on organisms can be unexpected until they are examined using modern, complex methods. High-throughput proteomics can provide data on important biochemical processes affected by pesticides, offering a different perspective to that at the expression level. Despite their low acute toxicity, a group of fungicides that inhibit (ergo)sterol biosynthesis (EBI or SBI) are considered dangerous to pollinators, including bumblebees. This is due to the increasing toxicity of insecticides through the inhibition of cytochrome P450 detoxification enzymes. We found that tebuconazole had a similar effect on epigenetic events when used alone or in combination with the insecticide thiacloprid. Key proteins suggest that H3K4 histone trimethylation (H3K4me3) was impacted. To our knowledge, this expands the existing evidence suggesting that tebuconazole/triazole fungicides affect histone trimethylation H3K27me3. Since literature shows that thiacloprid affects H3K9me3, it is possible that thiacloprid and tebuconazole interact in these epigenetic events that affect each other. Overall, our results suggest that tebuconazole affects proteins involved in histone trimethylation, pre-mRNA processing, and folate metabolism. These are all hallmarks of epigenetic processes and were further extended by the co-exposure of tebuconazole and thiacloprid to more differently abundant proteins. Additionally, the results provide data on cytochrome P450s of the CYP6 family, which act as detoxifying proteins, as well as proteins that indicate hormonal and neurotoxic effects in bumblebee heads. Finally, the results of the Bayesian power analysis confirmed the meaningfulness of the proteomic data analyzed in this study. If the new findings obtained at the proteome level are verified by different methods, the full extent of the side effects of tebuconazole can be revealed.

Animals↗
PubMed2026

Impacts of climate-driven yield changes on the affordability of healthy diets: a modelling study.

BACKGROUND: Food security is central to global nutrition improvement and public health goals, and healthy diets represent a higher-level aspiration beyond merely avoiding hunger. Climate change poses an increasing threat to food systems by affecting crop yields and food prices. Although climate change-driven risks to hunger have been widely studied, the extent to which climate change undermines the affordability of healthy diets while accounting for socioeconomic responses and regional inequalities remains insufficiently understood. This study aimed to quantify the effects of climate change on the future affordability of healthy diets under alternative socioeconomic and climate scenarios. METHODS: We developed an integrated modelling framework that explicitly couples multimodel crop-yield projections with an integrated assessment model (Global Change Analysis Model [GCAM]). Yield responses from six global gridded crop models driven by four climate models were integrated into GCAM, allowing endogenous socioeconomic adjustments such as land-use shifts, production reallocation, and price responses to emerge under shared socioeconomic pathways (SSPs). Diet affordability was then assessed using the Food and Agriculture Organization of the UN's Cost and Affordability of a Healthy Diet framework across three socioeconomic-climate scenarios (SSP1-2.6, SSP2-4.5, and SSP3-6.0). FINDINGS: Under a high-emissions pathway (ie, SSP3-6.0), climate change was projected to render healthy diets unaffordable for a model-mean of 119 million people globally by 2100, even when CO2 fertilisation effects are included, with the upper end of the model ensemble reaching about 1·6 billion people. In contrast, climate-induced affordability losses were found to be negligible under both a low-emissions pathway (ie, SSP1-2.6; -0·3 million) and a medium-emission pathway (SSP2-4.5; +0·2 million). Under a high-emission pathway, model-mean projections indicated that diet costs could increase by up to 12% in the most affected regions by the end of the century. Under medium emissions, cost increases were projected to remain below 4%, whereas under low emissions, affordability changes were projected to be minimum across regions (within approximately 0·5%). Substantial regional disparities emerged, with the largest and most consistent affordability losses concentrated in low-income regions that contributed least to historical greenhouse gas emissions. Under SSP3-6.0, these disparities persisted particularly in regions of Africa and Asia despite projected three-to-five-fold increases in income over the century, with climate-induced disruptions to food systems increasing the number of people unable to afford a healthy diet through mid-century. INTERPRETATION: Climate change is likely to exacerbate global nutritional inequalities by disproportionately increasing the affordability risks of healthy diets in regions that have contributed least to historical greenhouse gas emissions. Under high-warming scenarios, socioeconomic development alone is insufficient to fully offset these risks, highlighting the structural vulnerability of low-income food systems to climate-driven price shocks. These findings suggest that in the absence of targeted interventions, climate change could continue to undermine progress towards equitable and health-oriented nutrition outcomes. FUNDING: Ministry of Science and Technology of the People's Republic of China; National Natural Science Foundation of China; National Aeronautics and Space Administration Goddard Institute for Space Studies Climate Impacts Group; Future of Life Institute; and Global Alliance for Improved Nutrition.

Journal Article↗
PubMed2026

APOL1 kidney disease: a critical narrative review of molecular mechanisms, clinical heterogeneity, and the emerging therapeutic landscape.

BACKGROUND: The G1 and G2 variants of the APOL1 gene represent significant genetic risk factors for APOL1 kidney disease and contribute substantially to the excess burden of renal disease observed in individuals of African ancestry. Importantly, both variants exhibit incomplete penetrance, with only approximately 15-20% of high-risk genotype carriers ultimately developing overt nephropathy. OBJECTIVE: To provide a critically appraised, clinically oriented narrative synthesis of APOL1 kidney disease that (i) assigns an explicit certainty rating to each major mechanistic and clinical claim, (ii) identifies where published estimates diverge, where associations remain contested, and where conclusions have been overstated in the secondary literature, and (iii) aligns terminology, testing guidance and therapeutic expectations with the conclusions of the 2025 KDIGO Controversies Conference and with clinical trial data available to August 2026. METHODS: This literature narrative review was performed using a literature search of PubMed and Scopus focusing on APOL1-related nephropathy. Mainly studies published from 2010 to 2026 were considered; however, some selected historical papers from 2005 to 2010 were used for better understanding of the underlying mechanisms and history. Used search terms were "APOL1," "APOL1 risk variants," "chronic kidney disease," AMPLITUDE trial, MZE829, HORIZON trial, "focal segmental glomerulosclerosis," "HIV-associated nephropathy," "podocyte injury," "inaxaplin," "VX-147," KDIGO 2025, and "antisense oligonucleotides." Trial status and topline results for agents in development were additionally verified against ClinicalTrials.gov registrations and sponsor disclosures. The literature search was last updated on 10 August 2026. The inclusion criteria of the study were peer-reviewed original articles, genome-wide association studies, randomised controlled trials, translational studies, mechanistic investigations, and high-quality review articles published in the English language. Exclusion criteria included conference abstracts without peer review, duplicate papers, non-English publications with unreliable translation, and case reports with no relevance to the underlying mechanisms. More attention was paid to studies focusing on molecular pathogenesis of APOL1 nephropathy, second-hit pathophysiology, genotypes/phenotypes, and new therapies (e.g. inhibitors such as Inaxaplin). The review method and design have been prepared according to SANRA (Scale for the Assessment of Narrative Review Articles) criteria. Among eligible articles, priority was given to studies with larger sample sizes, more recent publication dates, higher-impact peer-reviewed journals, and direct clinical or mechanistic relevance to APOL1-associated nephropathy; where multiple studies addressed the same question, the most methodologically rigorous and most recent source was preferentially cited. To move beyond description, each principal claim carried forward into this review was assigned a qualitative certainty rating (high, moderate, low or very low) on the basis of study design, consistency across independent cohorts, directness of the evidence to human disease, and precision of the estimate. These ratings, together with the study design that would be required to resolve each remaining uncertainty, are presented in Table 5. This grading represents a structured judgement by the authors and is not a formal GRADE assessment. RESULTS: Pathogenic actions of APOL1 risk alleles depend on toxic gain-of-function activities that result from the disruption of ion channels. Mitochondrial dysfunction, endoplasmic reticulum stress, and inflammasome activation play roles as secondary downstream modulators of podocyte damage. The existence of incomplete penetrance and lack of symptoms in people with high-risk alleles highlights the need for secondary triggers, including environmental, infectious, and inflammatory factors, for disease onset and progression. High-risk APOL1 genotypes increase the likelihood of rapidly progressing kidney diseases like FSGS, which amplify susceptibility in HIVAN when accompanied by secondary causes like HIV infection. Management is mainly through renin-angiotensin antagonists, but recent treatments include antisense oligonucleotides, immunomodulators, and small molecule inhibitors like inaxaplin. Although promising, inaxaplin (VX-147) showed a ~47% reduction in urine protein/creatinine ratio (UPCR) in Phase 2a trial; however, these findings are based on a relatively small sample size, an open-label study design, and short-term follow-up, and therefore require confirmation in ongoing Phase 3 studies. As this is a narrative review rather than a primary study, no new patient-level data are reported. Across the studies synthesised, high-risk APOL1 genotypes were consistently associated with podocyte injury and with a faster decline in kidney function than low-risk genotypes; however, the magnitude of this association varied substantially with how cohorts were ascertained. The association is robust and reproducible for focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-attributed kidney failure, and remains inconsistent for diabetic kidney disease. Therapeutic development has accelerated, but the supporting clinical evidence remains early phase. Inaxaplin (VX-147) reduced the urine protein-to-creatinine ratio by approximately 47.6% at week 13 in a 16-participant, single-group, open-label Phase 2a study, and is now being evaluated in the randomised, double-blind, placebo-controlled Phase 2/3 AMPLITUDE trial (NCT05312879), whose pre-specified week 48 interim analysis is anticipated in early 2027. MZE829, an orally administered APOL1 inhibitor, produced a mean 35.6% reduction in the urine albumin-to-creatinine ratio at 12 weeks in the Phase 2 HORIZON study; because HORIZON was a small, open-label, single-arm basket study (15 participants enrolled, 12 evaluable) whose primary endpoints were safety and tolerability, this reduction is neither placebo adjusted nor the result of a formal test of efficacy. To date, no APOL1-targeted agent has demonstrated benefit on a hard kidney endpoint. CONCLUSION: APOL1 is the clearest current example of a genetically defined, mechanism-targetable kidney disease, but its evidence base is uneven. The genetic association is firmly established; whereas much of the mechanistic literature derives from overexpression systems, several downstream pathways remain contested, and every APOL1-targeted therapy is so far supported only by short-term, surrogate-endpoint data. The principal unresolved issues are the determinants of incomplete penetrance, the absence of a validated progression biomarker and of any model reproducing the common slowly progressive phenotype, and the long-term efficacy and safety of APOL1-directed therapy. Genotype-guided risk stratification is therefore best regarded as clinically reasonable but not yet proven, and routine population-level screening is not currently supported.

AMPLITUDE trial↗