Wiley最新文献

Binary Optical Computing

The front cover shows a novel binary-weighted optical computing engine with spatial multiplexing and aggregation that achieves high-efficiency and noise robust image sensing. See article 2400936 by Ziwei Li, Qionghai Da and co-workers for more details.

Maleimide core is a broadly used chemical-based scaffold for natural and new compounds synthesis. Several of them show anticancer and multidrug resistance (MDR) reversal activity. A new family of twelve 3,4-substituted N-benzyl and N-methyl maleimides were synthesized in a two-step sequence consisting of bromination and Suzuki cross-coupling or bromination–thiolation. We were able to obtain two groups of maleimide derivatives which were tested and determining their cytotoxicity. Following our previous work, the biological activity of these compounds as MDR reversal agents was tested with a cancerous cell line MCF-7 that has been exposed chronically to etoposide to achieve MDR. MCF-7 cell line resistant to etoposide (MCF-7R), was treated with a combination of etoposide and the synthetized compounds. The results presented strong effects in compounds 20, 21, 22, 23, 24, and 25 in no resistant and resistant cells, the IC₅₀ values for the proliferation inhibition ranged from 1.8–30.8 µM. The combination between etoposide and maleimide shows proliferation increase in most of the compounds except for compound 15 where it was shown a MDR low reversion degree. These findings suggest that maleimides tested in this work can be used in tumorigenic cancer cells before and after acquiring resistance. The combination with etoposide should be evaluated considering that an undesirable effect can be caused due to proliferation increase.

Aims: The goal of this observational, single-cohort, pre-post study was to describe the association of tirzepatide with glycaemic control and weight loss in patients with type 2 diabetes (T2D) in a US commercially insured population.

Materials and methods: Using the Healthcare Integrated Research Database (HIRD®), members ≥18 years, diagnosed with T2D, initiating tirzepatide between 13 May 2022 and 31 January 2023, with ≥1 glycated haemoglobin (HbA1c) result around the index date and the end of the 6-month follow-up period were identified. Baseline demographics and antihyperglycaemic medication use and key outcomes (HbA1c and weight) at 6-month follow-up were assessed overall and in subgroups stratified by baseline glucagon-like peptide-1 (GLP-1) receptor agonist (RA) use and HbA1c (<7% and ≥7%) level.

Results: The cohort of 2247 identified patients was primarily non-Hispanic White, female (58%), 54 years old, 54% had GLP-1 RA at baseline, 59% had an HbA1c ≥7% at baseline and 61% had overweight/obesity. At 6-month follow-up, a majority of the cohort (69%) had an HbA1c <7%, which was higher (77%) in the GLP-1 RA naïve subgroup. Mean change in weight was: -6.3 kg for the overall cohort; -7.1 kg in patients with baseline HbA1c <7%; and -8.1 kg in the GLP-1 RA naïve subgroup.

Conclusion: In this observational, single-cohort study, at 6-month follow-up, patients with T2D initiating tirzepatide showed HbA1c and weight reductions; more pronounced HbA1c reductions occurred in GLP-1 RA naïve patients or those with baseline HbA1c ≥7%, while more weight loss was observed among GLP-1 RA naïve patients or those with baseline HbA1c <7%.

Heat stress is a major factor limiting crop yield, a challenge intensified by climate change. Initial findings indicate that BES1/BZR1 may use heat shock to regulate plant thermal adaptability independently of BIN2-mediated brassinosteroid signalling, although the exact molecular mechanism remains unclear. In this study, we identified TaBZR2, a wheat gene whose expression showed a strong positive correlation with heat stress tolerance, based on transcriptome analysis of heat-tolerant wheat cultivars. Overexpression of TaBZR2 enhanced heat stress tolerance, while RNA interference of TaBZR2 reduced it. Further analysis revealed that TaBZR2 interacts with and is phosphorylated by wheat somatic embryogenesis receptor-like kinase 2 (TaSERL2). Overexpression of TaSERL2 reduced heat stress tolerance by promoting TaBZR2 degradation and inhibiting its regulation of wheat heat stress response genes. However, heat stress reduced the phosphorylation levels of both TaSERL2 and TaBZR2, lessening TaSERL2's inhibitory effect on TaBZR2 and enhancing the stability of TaBZR2. These results reveal that the TaSERL2-TaBZR2 module negatively regulates plant heat stress tolerance. This study expands the current model of heat stress responses and provides evidence for the role of BES1/BZR1 in heat stress regulation independent of brassinosteroid signalling.

Escalating concern regarding the impacts of reduced genetic diversity on the conservation of endangered species has spurred efforts to obtain chromosome-level genomes through consortia such as the Vertebrate Genomes Project. However, assembling reference genomes for many threatened species remains challenging due to difficulties obtaining optimal input samples (e.g., fresh tissue, cell lines) that can characterise long-term conservation collections. Here, we present a pipeline that leverages genome synteny to construct high-quality genomes for species of conservation concern despite less-than-optimal samples and/or sequencing data, demonstrating its use on Hector's and Māui dolphins. These endemic New Zealand dolphins are threatened by human activities due to their coastal habitat and small population sizes. Hector's dolphins are classified as endangered by the IUCN, while the Māui dolphin is among the most critically endangered marine mammals. To assemble reference genomes for these dolphins, we created a pipeline combining de novo assembly tools with reference-guided techniques, utilising chromosome-level genomes of closely related species. The pipeline assembled highly contiguous chromosome-level genomes (scaffold N50: 110 MB, scaffold L50: 9, miniBUSCO completeness scores > 96.35%), despite non-optimal input tissue samples. We demonstrate that these genomes can provide insights relevant for conservation, including historical demography revealing long-term small population sizes, with subspecies divergence occurring ~20 kya, potentially linked to the Last Glacial Maximum. Māui dolphin heterozygosity was 40% lower than Hector's and comparable to other cetacean species noted for reduced genetic diversity. Through these exemplar genomes, we demonstrate that our pipeline can provide high-quality genomic resources to facilitate ongoing conservation genomics research.

At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small-molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropathy; however, the underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation and fibrosis by inhibiting STAT3 activity in mice with diabetic nephropathy. Moreover, STAT3 is a direct molecular target of isoquercitrin, which as corroborated by tight and stable noncovalent binding between them. This interaction is mechanistically supported by the affinity of isoquercitrin for the Ser668-Gln635-Gln633 region within the pY+1 binding pocket of the SH2 domain. This binding obstructs pivotal processes like STAT3 phosphorylation and dimerization, thereby suppressing its transcriptional function. Finally, a kidney-targeted nanocarrier, Iso@PEG-GK, is developed to load isoquercitrin, thus enhancing its therapeutic precision for diabetic nephropathy. Iso@PEG-GK significantly improved the absorption and renal distribution of isoquercitrin. This study is the first to demonstrate that isoquercitrin exerts a significant protective effect against diabetic nephropathy and may provide a novel therapeutic drug for this disease.

Abdominal aortic aneurysm (AAA) is the most common true aneurysm worldwide, and recent studies suggest that dendritic cells (DCs) play a key role in its development, though the specific subtypes and underlying mechanisms remain unclear. In this study, the role of interferon regulatory factor 8 (IRF8) in AAA is investigated by focusing on its effect on the differentiation of DC precursors into conventional type 1 dendritic cells (cDC1s). It is found significant infiltration of HLA-DR⁺ IRF8⁺ cells in human AAA tissue samples. In mice, DC-specific overexpression of Irf8 exacerbates aneurysm expansion following periadventitial elastase application, while DC-specific Irf8 deletion attenuates AAA development. Batf3^-/- mice, which lack cDC1s, exhibit AAA characteristics similar to the Irf8-deleted mice. Additionally, an increased population of activated CD8⁺ T cells is observed in the DC-Irf8 overexpressed mice, while the DC-Irf8 deletion mice show a decrease in these cells. Blocking antigen cross-presentation to CD8⁺ T cells also reduces AAA progression. Tissue microarray analysis of human aortic samples further confirms a correlation between IRF8 expression and AAA development. These findings suggest that IRF8 activation promotes cDC1 differentiation, leading to the recruitment of CD8⁺ T cells, which contribute to aortic wall destruction and AAA formation.