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Constructing organic fluorophosphines, vital drug skeletons, through the direct fluorination of readily available alkyl phosphonates has been impeded due to the intrinsic low electrophilicity of P V and the high bond energy of P═O bond. Here, alkyl phosphonates are electrophilically activated with triflic anhydride and N -heteroaromatic bases, enabling nucleophilic fluorination at room temperature to form fluorophosphines via reactive phosphine intermediates. This approach facilitates the late-stage (radio)fluorination of broad dialkyl and monoalkyl phosphonates. Monoalkyl phosphonates derived from targeted drugs, including cyclophosphamide, vortioxetine, and dihydrocholesterol, are effectively fluorinated, achieving notable yields of 47−71%. Radiofluorination of medically significant 18 F-tracers and synthons are completed in radiochemical conversions (radio-TLC) of 51−88% and molar activities up to 251 ± 12 GBq/μmol (initial activity 11.2 GBq) within 10 min at room temperature. Utilizing a phosphonamidic fluoride building block (BFPA), [ 18 F]BFPA-Flurpiridaz and [ 18 F]BFPA-E[c(RGDyK)] 2 demonstrate high-contrast target imaging, excellent pharmacokinetics, and negligible defluorination. Constructing organic fluorophosphines via direct fluorination of alkyl phosphonates is challenging. Herein, the authors show that alkyl phosphonates are electrophilically activated with triflic anhydride and N -heteroaromatic bases, enabling nucleophilic fluorination at room temperature to form fluorophosphines via reactive phosphine intermediates.

Quantitative real-time PCR (q-RT-PCR) is a widely used method for measuring gene expression, but its accuracy depends on the use of stable reference genes for data normalization. In this study, we evaluated the expression stability of seven candidate reference genes ( RPS18 , RPS5 , RPL32 , RPL8 , EF-1α , β-Actin , and GAPDH ) in the small carpenter bee Ceratina calcarata across developmental stages (larvae, pupae, adults) and different landscape environments (conventional farms, organic farms, and roadside sites). Using four analytical algorithms, GeNorm, NormFinder, BestKeeper, and the comparative ΔCt method, we identified RPS18 and RPL8 as the most stable reference genes under varying biological and environmental conditions. These findings were further supported by RefFinder, which integrates results from all algorithms. Our study provides the first validated reference genes for C. calcarata , enabling more accurate and reproducible gene expression analysis in this ecologically important wild bee species. This work will support future research in pollinator biology, environmental stress responses, and conservation genomics.

Abnormal activation of the innate and adaptive immune systems has been observed in inflammatory bowel disease (IBD) patients. Anxiety and depression increase the risk of IBD by activating the adaptive immune system. However, whether anxiety affects innate immunity and its impact on IBD severity remains elusive. This study investigated the mechanism by which anxiety contributes to IBD development in a murine model of acute wrap restraint stress (WRS). Here, we found that anxiety-induced overactivation of group 2 innate lymphoid cells (ILC2) aggravated colonic inflammation. Overactivation of the hypothalamic–pituitary–adrenal (HPA) axis is a hallmark of the physiological change of anxiety. Corticosterone (CORT), a stress hormone, is a marker of HPA axis activation and is mainly secreted by HPA activation. We hypothesized that the overproduction of CORT stimulated by anxiety exacerbated colonic inflammation due to the abnormally elevated function of ILC2. The results showed that ILC2 secreted more IL-5 and IL-13 in the WRS mice than in the control mice. Meanwhile, WRS mice experienced more body weight loss, shorter colon length, higher concentrations of IL-6 and TNF-α, more severely impaired barrier function, and more severe inflammatory cell infiltration. As expected, the serum corticosterone levels were elevated after restraint stress. Dexamethasone (DEX) was then injected to mimic HPA axis activation induced CORT secretion. DEX injection can also stimulate ILC2 to secrete more type II cytokines and exacerbate oxazolone (OXA) induced colitis. Blocking the IL-13/STAT6 signaling pathway alleviated colitis in WRS and DEX-injected mice. In conclusion, the overactivation of ILC2 induced by CORT contributed to the development of OXA-induced colitis in mice.

Activation of p53 may induce apoptosis or cellular senescence in stressed cells. We here report that epidermal growth factor receptor (EGFR) is downregulated by p53 activation in a subset of cancer cell lines, and this EGFR downregulation mediates cellular senescence caused by p53 activation. EGFR confers resistance to senescence by sustaining the ERK signaling. DYRK1A (dual-specificity tyrosine-phosphorylated and tyrosine-regulated kinase 1A), an EGFR-stabilizing kinase, is downregulated by p53 and, when ectopically expressed, can attenuate p53 activation-induced EGFR reduction and cellular senescence. We further showed that the increased degradation of DYRK1A caused by p53 activation was mediated by MDM2. MDM2 was found to physically interact with and ubiquitinate DYRK1A, ultimately leading to its proteosomal degradation. Importantly, administration of Nutlin-3a, which disrupts the binding of MDM2 to p53, but not that of MDM2 to DYRK1A, reduced the levels of DYRK1A and EGFR, induced senescence, and inhibited growth of tumor xenografts formed by U87 glioblastoma cells. Ectopic expression of EGFR in tumor xenografts attenuated senescence and tumor reduction caused by Nultin-3a. Our findings thus established a novel link between p53 and EGFR and may have implications in p53 activation-based therapies.

The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, has evolved resistance to nearly every management tactic utilized in the field. This study investigated the resistance mechanisms in a WCR strain resistant to the Bacillus thuringiensis (Bt) protein eCry3.1Ab using dsRNA to knockdown WCR midgut genes previously documented to be associated with the resistance. ATP-binding cassette transporter (ABCC4), aminopeptidase-N, cadherin, and cathepsin-B were previously found to be differentially expressed in eCry3.1Ab-resistant WCR larvae when compared to susceptible larvae after feeding on maize expressing eCry3.1Ab and its near-isoline. Here we compared the susceptibility of resistant and susceptible WCR larvae to eCry3.1Ab protein in presence or absence of dsRNA targeting the above genes using 10-day diet overlay toxicity assays. Combining ABCC4 dsRNA with eCry3.1Ab protein increased susceptibility to Bt protein in WCR-resistant larvae, but the other three genes had no such effect. Among 65 ABC transport genes identified, several were expressed differently in resistant or susceptible WCR larvae, fed on eCry3.1Ab-expressing maize versus its isoline, that may be involved in Bt resistance. Our findings provide strong evidence that ABCC4 is indirectly involved in WCR resistance to eCry3.1Ab protein by enhancing the effects of Bt-induced toxicity.

Diabrotica virgifera virgifera LeConte, the western corn rootworm (WCR) is one of the most destructive pests in the U.S. Corn Belt. Transgenic maize lines expressing various Cry toxins from Bacillus thuringiensis have been adopted as a management strategy. However, resistance to many Bt toxins has occurred. To investigate the mechanisms of Bt resistance we carried out RNA-seq using Illumina sequencing technology on resistant, eCry3.1Ab-selected and susceptible, unselected, whole WCR neonates which fed on seedling maize with and without eCry3.1Ab for 12 and 24 hours. In a parallel experiment RNA-seq experiments were conducted when only the midgut of neonate WCR was evaluated from the same treatments. After de novo transcriptome assembly we identified differentially expressed genes (DEGs). Results from the assemblies and annotation indicate that WCR neonates from the eCry3.1Ab-selected resistant colony expressed a small number of up and down-regulated genes following Bt intoxication. In contrast, unselected susceptible WCR neonates expressed a large number of up and down-regulated transcripts in response to intoxication. Annotation and pathway analysis of DEGs between susceptible and resistant whole WCR and their midgut tissue revealed genes associated with cell membrane, immune response, detoxification, and potential Bt receptors which are likely related to eCry3.1Ab resistance. This research provides a framework to study the toxicology of Bt toxins and mechanism of resistance in WCR, an economically important coleopteran pest species.

Background and Objective. Serine hydroxymethyltransferase 2 (SHMT2) functions as a key enzyme in serine/glycine biosynthesis and one-carbon metabolism. Recent studies have shown that SHMT2 participated in tumor growth and progression in a variety of cancer types. The objective of the present study is to explore the expression of SHMT2 and evaluate its prognostic value in patients with intrahepatic cholangiocarcinoma (iCCA). Patients and Methods. We retrospectively investigated the expression of SHMT2 in 100 primary iCCA samples through immunohistochemical (IHC) staining on a tissue array. Results. High SHMT2 expression was found in 52 of the 100 specimens. The results indicated that SHMT2 level was upregulated compared to adjacent nontumor intrahepatic bile duct tissue. Furthermore, SHMT2 level was closely associated with tumor T stage (P=0.017) and tumor TNM stage (P=0.041) in patients with iCCA, but not with age, gender, tumor size, tumor number, pathological grade, vascular invasion, or N stage. Moreover, Kaplan-Meier analysis suggested that patients with lower SHMT2 level have longer survival rate than those with high expression (45.8 vs 23.1%, P=0.030). Additionally, the multivariate analysis model indicated SHMT2 is an independent adverse prognosticator in iCCA. Conclusion. High SHMT2 level was correlated with poorer overall survival in patients with iCCA. SHMT2 was proved to be a powerful and independent prognostic factor and a potential therapeutic target for patients with iCCA.

This study presents an efficient method using the local radial basis function finite difference scheme (RBF-FD). The innovative coefficients are derived from the integrals of the multiquadric (MQ) function. Theoretical convergence rates for the coefficients used in function derivative approximation are provided. The proposed scheme utilizes RBF-FD estimations on three-point non-uniform stencils to construct the final approximation on a tensor grid for the 3D Heston–Hull–White (HHW) PDE, which is relevant in economics and mathematical finance. Numerical evidence and comparative analyses validate the results and the proposed scheme.

Increasing evidence suggests a link between Alzheimer′s disease (AD) and diabetes mellitus (DM). However, the precise mechanisms by which DM contributes to AD remain unclear. This study is aimed at elucidating the potential role of DM in the early stages of AD. Accordingly, a streptozotocin (STZ)‐induced diabetic 5 × familial AD (FAD) mouse model was established. Immunohistochemistry and positron emission tomography/computed tomography (PET/CT) scanning were performed to examine amyloid beta (A β ) deposition in the brain. The integrity of the colonic epithelium was assessed using quantitative reverse transcription–polymerase chain reaction (qRT‐PCR) and immunofluorescence staining. Microbial diversity analysis was conducted for 5 × FAD mice with and without STZ‐induced DM to determine shifts in intestinal flora profiles. After oral administration of butyrate to STZ‐treated 5 × FAD mice, we observed that A β deposition in the brain was decreased, and the intestinal flora improved. Immunohistochemistry and PET/CT findings revealed a marked increase in A β formation in the brains of 5 × FAD mice treated with STZ. qRT‐PCR and immunofluorescence staining revealed severe intestinal barrier dysfunction in these mice. Gut microbiota sequencing indicated significant dysbiosis in STZ‐treated 5 × FAD mice, characterized by a reduction in short‐chain fatty acid (SCFA)–producing species. After oral administration of butyrate, A β deposition in the brains of STZ‐treated 5 × FAD mice was significantly reduced, and beneficial changes occurred in the intestinal flora, including increases in bacteria associated with SCFA production and neurological function. Dysregulation of the gut microbiome may exacerbate cerebral amyloidosis during AD pathogenesis. Microbes associated with SCFA production may play a beneficial role in AD treatment, and butyrate supplementation can significantly delay AD progression.

Increasing evidence suggests a link between Alzheimer's disease (AD) and diabetes mellitus (DM). However, the precise mechanisms by which DM contributes to AD remain unclear. This study is aimed at elucidating the potential role of DM in the early stages of AD. Accordingly, a streptozotocin (STZ)-induced diabetic 5 × familial AD (FAD) mouse model was established. Immunohistochemistry and positron emission tomography/computed tomography (PET/CT) scanning were performed to examine amyloid beta (A ) deposition in the brain. The integrity of the colonic epithelium was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence staining. Microbial diversity analysis was conducted for 5 × FAD mice with and without STZ-induced DM to determine shifts in intestinal flora profiles. After oral administration of butyrate to STZ-treated 5 × FAD mice, we observed that A deposition in the brain was decreased, and the intestinal flora improved. Immunohistochemistry and PET/CT findings revealed a marked increase in A formation in the brains of 5 × FAD mice treated with STZ. qRT-PCR and immunofluorescence staining revealed severe intestinal barrier dysfunction in these mice. Gut microbiota sequencing indicated significant dysbiosis in STZ-treated 5 × FAD mice, characterized by a reduction in short-chain fatty acid (SCFA)-producing species. After oral administration of butyrate, A deposition in the brains of STZ-treated 5 × FAD mice was significantly reduced, and beneficial changes occurred in the intestinal flora, including increases in bacteria associated with SCFA production and neurological function. Dysregulation of the gut microbiome may exacerbate cerebral amyloidosis during AD pathogenesis. Microbes associated with SCFA production may play a beneficial role in AD treatment, and butyrate supplementation can significantly delay AD progression.