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White matter damage and subsequent demyelination significantly contribute to long-term functional impairment after ischaemic stroke. Identifying novel pharmacological targets to restore myelin integrity by promoting the maturation of oligodendrocyte precursor cells (OPCs) into new myelinating oligodendrocytes may open new perspectives for ischaemic stroke treatment. In this respect, previous studies highlighted the role of the G protein-coupled membrane receptor 17 (GPR17) as a key regulator of OPC differentiation in experimental models of brain injury, including ischaemic stroke. To determine the translational value of GPR17 as a possible target in the context of human disease, we exploited immunohistochemistry to characterise the distribution of GPR17-expressing cells in brain tissue samples from ischaemic stroke cases and correlated it with the reactive state of neighbouring glial cells. The results showed that GPR17 specifically decorates a subpopulation of differentiation-committed OPCs, labelled by the peculiar marker breast carcinoma-amplified sequence 1 (BCAS1), that accumulates in the peri-infarct region in the later stages after the ischaemic event. Interestingly, the response of GPR17-expressing cells appears to be paralleled by the switch of reactive microglia/macrophages from a phagocytic to a dystrophic phenotype and by astrocytic scar formation. A negative correlation was found between GPR17-expressing OPCs and reactive microglia/macrophages and astrocytes surrounding chronic ischaemic lesions in female subjects, while the same relationship was less pronounced in males. These results were reinforced by bioinformatic analysis of a publicly available transcriptomic dataset, which implicated a possible role of inflammation and defective neuron-to-OPC communication in remyelination failure after ischaemic damage. Hence, these data strengthen the relevance of GPR17-based remyelinating therapies for the treatment of ischaemic stroke. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background: The hemibiotrophic fungus Zymoseptoria tritici causing Septoria tritici blotch (STB), is a devastating foliar pathogen of wheat worldwide. A common group of fungicides used to control STB are the demethylation inhibitors (DMIs). DMI fungicides restrict fungal growth by inhibiting the sterol 14-α-demethylase, a protein encoded by CYP51 gene and essential for maintaining fungal cell permeability. However, the adaptation of Z. tritici populations in response to intensive and prolonged DMI usage has resulted in a gradual shift towards reduced sensitivity to this group of fungicides. In this study, 311 isolates were collected pre-treatment from nine wheat-growing regions in Europe in 2019. These isolates were analysed by high-throughput amplicon-based sequencing of nine housekeeping genes and the CYP51 gene.

Results: Analyses based on housekeeping genes and the CYP51 gene revealed a lack of population structure in Z. tritici samples irrespective of geographical origin. Minimum spanning network (MSN) analysis showed clustering of multilocus genotypes (MLGs) based on CYP51 haplotypes, indicating an effect of selection due to DMI fungicide use. The majority of the haplotypes identified in this study have been reported previously. The diversity and frequencies of mutations varied across regions.

Conclusion: Using a high-throughput amplicon-sequencing approach, we found several mutations in the CYP51 gene combined in different haplotypes that are likely to cause fungicide resistance. These mutations occurred irrespective of genetic background or geographical origin. Overall, these results contribute to the development of effective and sustainable risk monitoring for DMI fungicide resistance. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Although chronic kidney disease (CKD) is associated with obesity, few studies have used visceral adipose tissue (VAT) as an indicator to investigate its causal effect on CKD. Therefore, Mendelian randomization (MR) was employed to study the causal effects of VAT on CKD and its potential mediation by hypertension. Genome-wide association study (GWAS) statistics on VAT exposure were obtained from the UK Biobank, while GWAS datasets of CKD outcomes were obtained from CKDGen and FinnGen (validation study). Furthermore, VAT was considered the exposure, with the estimated glomerular filtration rate based on creatinine (eGFR (crea)), estimated glomerular filtration rate based on cystatin C (eGFR(cys)), and blood urea nitrogen (BUN) employed to assess the causal effect of VAT on kidney test indicators. Lastly, a two-step MR method was used to study the mediating role of hypertension in the pathogenesis of VAT among patients with CKD. VAT exhibited a positive causal association with CKD, irrespective of whether the GWAS datasets from CKDGen (odds ratio [OR] = 1.18, 95% CI: 1.08 to 1.29, P = 1.433140e-04) or FinnGen (1.47, 1.30 to 1.67, p = 2.500000e-09). VAT was not causally associated with eGFR (crea) (1.00, 0.99 to 1.00, p = 0.53), was negatively associated with eGFR (cys) (0.95, 0.93 to 0.97, P = 5.070000e-10), and was positively associated with BUN (1.02,1.01 to 1.02, P = 7.824860e-04). The mediating effect of VAT on CKD via hypertension was 45.8% (95% CI: 26.4 65.1). VAT has a positive causal effect on CKD, with hypertension playing a significant role. However, the effects of VAT on renal function indicators require further investigation.

Tumour content plays a pivotal role in directing the bioinformatic analysis of molecular profiles such as copy number variation (CNV). In clinical application, tumour purity estimation (TPE) is achieved either through visual pathological review [conventional pathology (CP)] or the deconvolution of molecular data. While CP provides a direct measurement, it demonstrates modest reproducibility and lacks standardisation. Conversely, deconvolution methods offer an indirect assessment with uncertain accuracy, underscoring the necessity for innovative approaches. SoftCTM is an open-source, multiorgan deep-learning (DL) model for the detection of tumour and non-tumour cells in H&E-stained slides, developed within the Overlapped Cell on Tissue Dataset for Histopathology (OCELOT) Challenge 2023. Here, using three large multicentre colorectal cancer (CRC) cohorts (N = 1,097 patients) with digital pathology and multi-omic data, we compare the utility and accuracy of TPE with SoftCTM versus CP and bioinformatic deconvolution methods (RNA expression, DNA methylation) for downstream molecular analysis, including CNV profiling. SoftCTM showed technical repeatability when applied twice on the same slide (r = 1.0) and excellent correlations in paired H&E slides (r > 0.9). TPEs profiled by SoftCTM correlated highly with RNA expression (r = 0.59) and DNA methylation (r = 0.40), while TPEs by CP showed a lower correlation with RNA expression (r = 0.41) and DNA methylation (r = 0.29). We show that CP and deconvolution methods respectively underestimate and overestimate tumour content compared to SoftCTM, resulting in 6-13% differing CNV calls. In summary, TPE with SoftCTM enables reproducibility, automation, and standardisation at single-cell resolution. SoftCTM estimates (M = 58.9%, SD ±16.3%) reconcile the overestimation by molecular data extrapolation (RNA expression: M = 79.2%, SD ±10.5, DNA methylation: M = 62.7%, SD ±11.8%) and underestimation by CP (M = 35.9%, SD ±13.1%), providing a more reliable middle ground. A fully integrated computational pathology solution could therefore be used to improve downstream molecular analyses for research and clinics. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The lack of standardization in patient-reported outcome measures (PROMs) has made measurement and comparison of quality of life (QoL) outcomes in research focused on obesity treatment challenging. This study reports on the results of the second and third global multidisciplinary Standardizing Quality of life measures in Obesity Treatment (S.Q.O.T.) consensus meetings, where a core set of PROMs to measure nine previously selected patient-reported outcomes (PROs) in obesity treatment research was established. The S.Q.O.T. II online and S.Q.O.T. III face-to-face hybrid consensus meetings were held in October 2021 and May 2022. The meetings were led by an independent moderator specializing in PRO measurement. Nominal group techniques, Delphi exercises, and anonymous voting were used to select the most suitable PROMs by consensus. The meetings were attended by 28 and 27 participants, respectively, including a geographically diverse selection of people living with obesity (PLWO) and experts from various disciplines. Out of 24 PROs and 16 PROMs identified in the first S.Q.O.T. consensus meeting, the following nine PROs and three PROMs were selected via consensus: BODY-Q (physical function, physical symptoms, psychological function, social function, eating behavior, and body image), IWQOL-Lite (self-esteem), and QOLOS (excess skin). No PROM was selected to measure stigma as existing PROMs deemed to be inadequate. A core set of PROMs to measure QoL in research focused on obesity treatment has been selected incorporating patients' and experts' opinions. This core set should serve as a minimum to use in obesity research studies and can be combined with clinical parameters.

Insects have evolved a spectrum of strategies that facilitate survival in the face of adverse environmental conditions and bottom-up or top-down pressures. The egg is the first stage in the life cycle of most insects. It is not only immobile but in many insects is the stage that survives unfavourable seasons when food resources are unavailable. Eggs are targeted by oophagous natural enemies and also are subject to abiotic stresses. In response to these diverse stresses, insects have developed various egg protection strategies. Females of many insects lay eggs in clusters and then use their own body resources to cover them to provide protection from harsh environments and biotic attack. Such egg protection strategies have allowed some herbivorous insects to thrive in new environments and become serious invasive pests. Females of many insects protect their eggs in other ways (e.g. laying eggs in concealed places, direct parental care) while others do not provide protection at all. Here, we review various egg protective strategies in insects. Our focus is on adaptive ecological mechanisms and temporal variation as well as the benefits and costs of egg coverings. We highlight several case studies on how these egg protective traits might impede biological control of globally important agricultural and forest pests and propose a framework for incorporating egg protective traits into biological control programs especially for invasive insect pests.

Background: Fusarium head blight (FHB), mainly caused by Fusarium graminearum (F. graminearum), remains a devastating disease worldwide. The histone acetyltransferase Gcn5 plays a crucial role in epigenetic regulation. Aberrant Gcn5 acetylation activity can result in serious impacts such as impaired growth and development in organisms. The secondary metabolite phenazine-1-carboxamide (PCN) inhibits F. graminearum by blocking the acetylation process of Gcn5 (FgGcn5), and is currently used to control FHB. However, the molecular basis of acetylation inhibition by PCN remains to be further explored.

Results: Our molecular dynamics simulations revealed that PCN binds to the cleft in FgGcn5 where histone H3 is bound, with key amino acid residues including Leu96 (L96), Arg121 (R121), Phe133 (F133), Tyr169 (Y169), and Tyr201 (Y201), preventing FgGcn5 from binding to histone H3 and affecting histone H3 from being acetylated. Experimental validation of key amino acid mutations further confirmed the impact of these mutations on the interaction of FgGcn5 with PCN and histone H3 peptide.

Conclusion: In summary, our study sheds light on the mechanism by which PCN inhibits the acetylation function of FgGcn5, providing a foundation for the development of drugs or fungicides targeting histone acetyltransferases. © 2024 Society of Chemical Industry.

Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an important role in the maturation of PCs. Since there is an intimate interaction between PCs and ISCs, we speculated that the loss of Mist1 could impact these two neighboring cell types. Here, we report that mice lacking Mist1 had fewer but larger PCs with shrunken secretory granules, accompanied by an increase in goblet cells and tuft cells. Mist1 loss significantly decreased the number of proliferative crypt cells, especially columnar basal cells (CBCs). In addition, Mist1-deficient enteroids needed supplemental Wnt3a to support their growth. Results from RNA sequencing (RNA-seq) demonstrated an apparent deficiency of innate immunity in Mist1-knockout mice. Intriguingly, Mist1 loss increased the survival rate of mice subjected to whole abdominal irradiation (WAI). Moreover, radiation injury was ameliorated in Mist1-knockout mice compared with their wild-type littermates based on histological analysis and enteroid culture, which might be a consequence of increased contents of the endoplasmic reticulum (ER) and the increased activity of mTORC1 in Paneth cells. In summary, our data uncover that Mist1 plays an important functional role in PCs and regulates the maintenance of ISCs and their response to radiation injury. © 2025 The Pathological Society of Great Britain and Ireland.

Background and aim: In 2018, the country of Georgia legalized cannabis for recreational use and decriminalized limited possession. This study aimed to assess whether cannabis use increased among young adults (ages 18-29 years) in Georgia after national policy changes and to evaluate whether perceived access became easier after legalization and current risk factors of young adult cannabis use.

Methods: We used data from the Georgian nationally representative survey administered in 2015 (n = 1308) and 2022 (n = 758), before and after decriminalization. We performed appropriate bivariate analyses and multivariable linear and logistic regressions to assess the following: legalization's impact on cannabis use; perceived difficulty to obtain cannabis; age of first use; differences in use between females and males; and factors associated with current use.

Findings: Among young adults lifetime prevalence of cannabis use was similar in 2015 (17.3%) and 2022 (18.1%) [Odds Ratio (95% confidence interval) = 1.1 [0.7, 1.6], P = 0.726). Annual prevalence (7% in 2015 vs 7.7% in 2022) was also similar (1.1 [0.7, 2.0], P = 0.650). In 2022 it was less difficult to obtain cannabis than in 2015 (0.5 [0.4, 0.8], P = 0.021). The age of first use increased statistically significantly (18.1 years in 2015 vs 19.1 in 2022, P = 0.003). In 2022, annual prevalence of use was lower among females (1.9% vs 13.1%; OR = 0.1 [0.0, 0.3], P < 0.0001) and higher among those who gambled (11.7% vs 4.4%; OR = 3.2 [1.5, 6.8], P < 0.003). Males initiated cannabis use at an earlier age (19.1 years vs 20.6 for females, P = 0.03), and could obtain cannabis easier than females (P < 0.0001).

Conclusion: There was a minimal shift of cannabis use in young adults following implementation of recreational cannabis use legalization in Georgia. Males and people who gambled were at higher risk of cannabis use.