Wiley最新文献

Conifers exhibit distinct age-related transitions in wood development, yet the molecular mechanisms governing these changes remain poorly characterized. Here, we integrate multi-omics and functional analyses to unravel a transcriptional regulatory network underlying age-related wood formation in Chinese pine (Pinus tabuliformis). Cross-sectional and Raman microspectroscopy analyses revealed age-dependent enhancement of lignification and carbohydrate deposition in secondary xylem, coinciding with increased pith proportion. Temporal transcriptome profiling identified PtARN (AGE-RELATED NAC TRANSCRIPTION FACTOR) as a key age-correlated regulator, whose expression is directly activated by the conserved age timer PtDAL1 through promoter binding. We conducted a genome-wide identification of secondary cell wall biosynthesis pathway genes in P. tabuliformis, and genome-wide DNA affinity purification analysis uncovered that PtARN direct binding to promoters of 189 secondary cell wall biosynthesis genes. Strikingly, PtARN represses PtMYB162, a lignin biosynthesis suppressor, forming a regulatory cascade to fine-tune lignification. Collectively, our work establishes PtARN as a master regulator orchestrating age-dependent secondary cell wall deposition and lignification in the secondary xylem of Chinese pine, and delineates a previously uncharacterized PtDAL1-PtARN-mediated molecular regulatory network in P. tabuliformis. These findings significantly advance our understanding of the molecular regulatory network underlying wood formation in conifers, and bridging developmental timing with cell wall remodelling, and provide a robust framework for conifer-specific wood formation studies.

In climacteric fruits, ripening is triggered by a shift from auto-inhibitory to auto-catalytic ethylene production, but the activation of system II autocatalytic burst remains unclear. Here, we identified two MADS-box transcription factors, PpMADS2 and PpMADS4, as key positive regulators in peach (Prunus persica L. Batsch) ripening. Their expression increased during maturation and was induced by ethylene. Overexpression in pre-ripening fruit accelerated ethylene production, colour change, sugar accumulation and softening, while silencing delayed these processes. PpMADS2 interacts with PpMADS4 to form a functional complex which potentiates their activity, and they act by directly binding to and activating the promoters of ethylene biosynthetic genes PpACS1 and PpACO1, thereby promoting peach ethylene biosynthesis. Conversely, synthesis of ethylene in turn promotes the expression of PpMADS2/4 for positive feedback, amplifying ethylene production, contributing to the system II autocatalytic burst, ultimately leading to the maturation of peach fruit. This study provides a new insight into the MADS-box-ethylene regulatory network controlling climacteric fruit ripening.

Background: Real-world glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies face substantial attrition rates in commercial digital weight loss services (DWLSs). Conversational artificial intelligence (AI) has been proposed to enhance patient support at production scale, but robust evidence of its effectiveness in improving medication retention is scarce.

Objectives: To evaluate the effect of integrating an asynchronous AI patient support agent (Junebot) into a commercial DWLS on 6-month medication adherence and to assess the independent relationship of digital engagement on retention.

Methods: This retrospective analysis evaluated 16 556 adults prescribed semaglutide within an Australian DWLS between May 2024 and October 2025. The primary endpoint was 6-month medication adherence (≥ 6 orders fulfilled within 183 days). Analytical protocols featured a multivariate binary logistic regression on the full intention-to-treat cohort and three distinct 1:1 propensity score matching (PSM) sensitivity analyses to isolate era-based and tier-specific engagement effects.

Results: Six-month adherence was higher post-Junebot than in the pre-Junebot control (53.2% vs. 47.3%; p < 0.001). However, the full cohort model (R ² = 0.2236) revealed that the post-Junebot operational era was independently associated with an increase in the odds of attrition (OR: 1.178; 95% CI [1.052-1.318]; p = 0.004), a trend corroborated by the era-matched PSM model (OR of attrition: 1.309; p = 0.038). Non-automation factors dominated retention trajectories: high-intensity tracking during month 1 (> 25 tracks) dramatically predicted attrition (OR: 15.753; p < 0.001), alongside program pauses (OR: 2.508; p < 0.001) and higher program cost (OR: 2.458; p < 0.001). Within-cohort analysis demonstrated a profound, linear curve for active interaction; structured digital engagement spanning 50%-74.99% of weeks significantly optimised adherence odds across both medication-only (OR: 32.016) and medication plus health coaching cohorts (OR: 13.311).

Conclusion: Integrating an AI digital assistant did not independently improve medication adherence; programmatic costs, program pauses and initial tracking anxiety were stronger predictors of long-term retention. After matching post-Junebot cohorts, moderate, active digital engagement appeared to correlate with 6-month retention. Digital providers should prioritise proactive behavioural risk screening and financial accessibility over baseline AI integration.

Aims: To quantify the extent to which cardiac autonomic markers account for the associations between adiposity and liver enzyme levels in non-diabetic adults with overweight or obesity.

Materials and methods: The clinical discovery cohort included 432 non-diabetic adults with overweight or obesity. Body mass index (BMI) and waist-to-height ratio (WHtR) were exposures; alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) were outcomes. Resting mean heart rate and heart rate variability (HRV) were assessed as cardiac autonomic markers. Multivariable regression and mediation analyses were performed. Supportive analyses included 21 383 UK Biobank participants.

Results: Higher BMI and WHtR were associated with higher liver enzyme levels, higher resting mean heart rate and lower HRV in the clinical cohort. Resting mean heart rate was the most consistent cardiac autonomic mediator, accounting for 16.6%-27.5% of the associations between BMI and liver enzyme levels and 17.8%-36.9% of those for WHtR. HRV indices accounted for 10.1%-28.2% and 8.8%-29.9% of the corresponding associations, respectively. After inclusion of the homeostatic model assessment of insulin resistance (HOMA-IR) as a parallel mediator, indirect effects through cardiac autonomic markers remained statistically significant, particularly for ALT. In UK Biobank, resting pulse rate accounted for 5.83%-9.47% of the associations between adiposity and liver enzyme levels.

Conclusions: Higher resting heart rate and lower HRV partly accounted for cross-sectional associations between adiposity and liver enzyme levels. Cardiac autonomic markers warrant further evaluation as complementary physiological measures in studies of obesity-related liver enzyme variation.

Aim: We aimed to examine the association between glucagon-like peptide-1 receptor agonists (GLP1-RA) use and diabetic retinopathy and non-arteritic anterior ischemic optic neuropathy (NAION), using dipeptidyl peptidase-4 inhibitors (DPP4i) as active comparators.

Methods: We created a retrospective propensity score (PS)-matched cohort study of patients who initiated either GLP1-RA or DPP4i (years 2006-2021). Using new-users, we created two PS-matched cohorts: patients with diabetes (overall cohort) and patients with diabetes and chronic kidney disease (CKD-cohort); the latter represents patients at higher likelihood of diabetes microvascular complications. Primary outcomes were non-vision-threatening diabetic retinopathy (NVTDR), vision-threatening diabetic retinopathy and diabetic macular edema (VTDR/DME), and NAION. Secondary outcomes included vision impairment or blindness and occurrence of retinopathy procedures.

Results: PS-matched overall cohort included 98 082 pairs of GLP1-RA or DPP4i users. GLP1-RA users had higher risk of NVTDR (11.05% vs. 9.98%; odds ratio [OR] 1.12, 95% confidence interval [95% CI]: 1.09-1.15), VTDR/DME (2.17% vs. 1.98%; OR 1.09, 95% CI: 1.03-1.16), and occurrence of retinopathy procedures (4.16% vs. 3.68%, OR 1.14, 95% CI: 1.09-1.19). There was no significant difference in risk of NAION (OR 1.11, 95% CI: 0.96-1.29) or vision impairment or blindness (OR 1.04, 95% CI: 0.97-1.11). In the CKD cohort (15 440 matched pairs), GLP1-RA was associated with high risk of NVTDR (OR 1.10, 95% CI: 1.03-1.18), and occurrence of retinopathy procedures (OR 1.14, 95% CI: 1.03-1.26), but not other outcomes.

Conclusions: GLP1-RA use was associated with a modest increase in risk of diabetic retinopathy and retinopathy-related procedures, independent of the presence of retinopathy at baseline. However, GLP1-RA use was not associated with vision impairment or blindness, although administrative codes notably have low validity for blindness diagnosis.

Aims: Financial constraints often limit healthy eating among individuals with Type 2 diabetes (T2D) and lower socioeconomic status (SES). Produce Prescription Programs (PRx), which provide financial support for healthy foods, have shown promise in the United States but remain understudied in Europe. This study assessed the feasibility of a 3-month PRx intervention among adults with T2D and low SES, and explored its potential effects on dietary intake, metabolic outcomes and quality of life.

Materials and methods: In this 3-month RCT, conducted in primary care in Rotterdam, the Netherlands, adults with T2D, BMI > 25 kg/m² and low SES were assigned to either PRx or usual care. Both groups received three dietitian consultations and were advised to follow a Mediterranean diet. PRx additionally provided weekly plant-based food boxes, cooking workshops and educational support. Feasibility outcomes included recruitment, retention, adherence and acceptability. Exploratory efficacy outcomes included nutritional intake, anthropometric measures, metabolic outcomes and quality of life at three and 6 months.

Results: Seventy-seven individuals were screened and 35 participants (57.3 ± 11.8 years; 74% female; BMI 32.6 ± 6.0 kg/m²) were included, of whom 17 were allocated to PRx. Participants collected an average of 10.9 out of 12 food boxes (91%) and attended 1.8 out of 3 workshops (59%). Among the 11 participants (69%) who completed the evaluation questionnaire, satisfaction scores ranged from 4.3 to 4.7 out of 5. Exploratory between-group comparisons favoured the PRx group for dietary intake, weight, BMI and physical quality of life, while no clear differences were observed for glycaemic outcomes. These findings were supported by favourable within-group changes in dietary and anthropometric outcomes in the PRx group, several of which appeared to be maintained at 6-month follow-up.

Conclusions: This pilot RCT demonstrates that a 3-month PRx intervention providing plant-based food boxes is feasible and acceptable among adults with T2D and low SES. As the first European RCT evaluating a PRx intervention in this population, it provides preliminary evidence of potential benefits for dietary, anthropometric and quality of life outcomes, warranting further investigation in adequately powered trials.

Trial registration: OMON: NL-OMON57037; 8 October 2024.

Aims: Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved in the US for the treatment of Type 2 diabetes (T2D), weight loss and obstructive sleep apnoea. This study aimed to assess the utilisation and effectiveness of tirzepatide among individuals in a large US commercially insured population.

Materials and methods: This retrospective, observational study used administrative claims and electronic health records from the Healthcare Integrated Research Database (HIRD). Adults with ≥ 1 prescription claim for tirzepatide (for obesity/overweight, without T2D), between November 2023-June 2024 and continuous medical/pharmacy enrollment for ≥ 12 months pre-index and ≥ 6 months post-index were included. Descriptive analyses included baseline demographic and clinical characteristics, treatment patterns and tirzepatide effectiveness (change from baseline in weight, BMI, cardiometabolic risk factors evaluated among persistent individuals) and were stratified by individuals who were GLP-1 RA naïve and individuals who switched to tirzepatide from a GLP-1 RA obesity medication.

Results: Of the 22 512 individuals who initiated tirzepatide (mean age: 46 years, 73% female), 55% (n = 12 292) were adherent (PDC ≥ 80%) and 68% (n = 15 208) were persistent during the 6-month follow-up period. Of the overall population, 91% (n = 20 554) had ≥ 1 obesity-related complication at baseline, with dyslipidaemia, hypertension and anxiety being the most frequent complications. Clinically meaningful mean weight reduction (10.5%; n = 808) and numerical reductions in most cardiometabolic risk factors were observed among persistent individuals with available pre- and post-index measurements, including 12.0% body weight reduction in the GLP-naïve subgroup.

Conclusions: Over half of US adults with obesity or overweight who initiated tirzepatide were adherent (PDC ≥ 80%) and had a favourable persistence profile during a 6-month follow-up period. Persistent users achieved clinically meaningful weight reduction and numerical reductions in most cardiometabolic risk factors.

Among various plant defence strategies, trichomes are tiny hair-like structures on the epidermis that aid in defence, environmental adaptation and the production of valuable secondary metabolites. This review features trichomes as frontline guards for plant survival, integrating their structural, physiological and metabolic roles in safeguarding against environmental adversity. We explore the developmental biology of trichomes, emphasising a multilayered regulatory network governed by transcriptional hierarchies, hormonal crosstalk, epigenetic remodelling and post-transcriptional modulation. Trichomes, divided into glandular and non-glandular types, function as physical shields and dynamic chemical interfaces, mediating defence against herbivores, pathogens, UV radiation and abiotic stresses such as drought and heavy metal exposure. Notably, glandular trichomes serve as specialised biosynthetic centres, producing high-value secondary metabolites, such as terpenoids, alkaloids and phenolics, which are increasingly harnessed in sustainable agriculture and green biotechnologies. Considering the broader context of climate resilience and bioeconomic innovation, this review describes trichomes as multifunctional and evolvable units of plant adaptation. It also highlights emerging research avenues such as single-cell omics, chromatin dynamics, metabolic and genetic engineering, which offer promising strategies for exploiting trichomes as a foundation for next-generation crop improvement and sustainable metabolic engineering.

Background: Genetic clusters related to Type 2 diabetes (T2D) have differential impact on cardiovascular diseases (CVDs), although the underlying mechanisms, such as proteomic perturbation, remain unexplored. We conducted a network Mendelian randomisation (MR) study to identify proteomic mediators linking T2D genetic clusters and CVDs.

Methods: We assessed the associations between genetic liability to T2D and eight genetic clusters (N = 2 535 601) with 12 CVDs (N ≤ 1 946 349). For significant pairs, we performed a two-step MR (mediation) to identify proteins mediating these associations. Inverse-variance weighted method was the main analysis, with sensitivity analyses including genetic colocalisation. Robustness was evaluated in European-specific analyses as well as using Olink-measured proteomic data. False discovery rate (FDR) was used to correct for multiple comparisons.

Results: Obesity cluster was linked to most CVDs (except haemorrhage strokes), with similar patterns for body fat, metabolic syndrome and lipodystrophy clusters. Majority of the protein signals (2739 out of 4907) were related to obesity cluster although glycemia-related clusters were only associated with a few proteomic signals (≤ 13). Amongst 16 proteins supported by genetic colocalisation (PP_H4 > 0.8), the proportion mediated ranged from 1.2% to 36.8%. APOC3, ADH1B, F11 and KLKB1 appeared to be shared across the different genetic clusters, implicating their shared role in CVDs risk. Sensitivity and replication analyses gave similar estimates.

Conclusion: This proteogenomic MR study delineates protein-mediated pathways linking cluster-stratified T2D genetic predisposition to cardiovascular risk, which can inform preventive strategies by stratifying individuals based on distinct biological pathways represented by these genetic clusters.