Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.

The Hippo pathway plays a central role in tissue development and homeostasis. However, the function of Hippo in pancreatic endocrine development remains obscure. Here, we generated novel conditional genetically engineered mouse models to examine the roles of Hippo pathway-mediated YAP1/TAZ inhibition in the development stages of endocrine specification and differentiation. While YAP1 protein was localized to the nuclei in bipotent progenitor cells, Neurogenin 3 expressing endocrine progenitors completely lost YAP1 expression. Using genetically engineered mouse models, we found that inactivation of YAP1 requires both an intact Hippo pathway and Neurogenin 3 protein. Gene deletion of Lats1 and 2 kinases (Lats1&2) in endocrine progenitor cells of developing mouse pancreas using Neurog3Cre blocked endocrine progenitor cell differentiation and specification, resulting in reduced islets size and a disorganized pancreas at birth. Loss of Lats1&2 in Neurogenin 3 expressing cells activated YAP1/TAZ transcriptional activity and recruited macrophages to the developing pancreas. These defects were rescued by deletion of Yap1/Wwtr1 genes, suggesting that tight regulation of YAP1/TAZ by Hippo signaling is crucial for pancreatic endocrine specification. In contrast, deletion of Lats1&2 using ß-cell-specific Ins1CreER resulted in a phenotypically normal pancreas, indicating that Lats1&2 are indispensable for differentiation of endocrine progenitors but not for that of ß-cells. Our results demonstrate that loss of YAP1/TAZ expression in the pancreatic endocrine compartment is not a passive consequence of endocrine specification. Rather, Hippo pathway-mediated inhibition of YAP1/TAZ in endocrine progenitors is a prerequisite for endocrine specification and differentiation.

The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.

Unveiling the mechanisms of Moso bamboo's motor function and internal growth stress.

Bamboo, a renewable resource with rapid growth and an impressive height-to-diameter ratio, faces mechanical instability due to its slender structure. Despite this, bamboo maintains its posture without breaking in its battle against environmental and gravitational forces. But what drives this motor function in bamboo? This study subjected Moso bamboo (Phyllostachys edulis) to gravitational stimulation, compelling it to grow at a 45° angle instead of upright. Remarkably, the artificially inclined bamboo exhibited astonishing shape control and adjustment capabilities. The growth strain was detected at both macroscopic and microscopic levels, providing evidence for the presence of internal stress, namely growth stress. The high longitudinal tensile stress on the upper side, along with a significant asymmetry in stress distribution in tilted bamboo, plays a pivotal role in maintaining its mechanical stability. Drawing upon experimental findings, it can be deduced that the growth stress primarily originates from the broad layers of fiber cells. Bamboo could potentially regulate the magnitude of growth stress by modifying the number of fiber cell layers during its maturation process. Additionally, the microfibril angle and lignin disposition may decisively influence the generation of growth stress.

Crebanine, an aporphine alkaloid, induces cancer cell apoptosis through PI3K-Akt pathway in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is one of the most prevalent and lethal primary central nervous system malignancies. GBM is notorious for its high rates of recurrence and therapy resistance and the PI3K/Akt pathway plays a pivotal role in its malignant behavior. Crebanine (CB), an alkaloid capable of penetrating the blood-brain barrier (BBB), has been shown to have inhibitory effects on proinflammatory molecules and multiple cancer cell lines via pathways such as PI3K/Akt. This study aims to investigate the efficacy and mechanisms of CB treatment on GBM. It is the first study to elucidate the anti-tumor role of CB in GBM, providing new possibilities for GBM therapy. Through a series of experiments, we demonstrate the significant anti-survival, anti-clonogenicity, and proapoptotic effects of CB treatment on GBM cell lines. Next-generation sequencing (NGS) is also conducted and provides a complete list of significant changes in gene expression after treatment, including genes related to apoptosis, the cell cycle, FoxO, and autophagy. The subsequent protein expressions of the upregulation of apoptosis and downregulation of PI3K/Akt are further proved. The clinical applicability of CB to GBM treatment could be high for its BBB-penetrating feature, significant induction of apoptosis, and blockage of the PI3K/Akt pathway. Future research is needed using in vivo experiments and other therapeutic pathways shown in NGS for further clinical or in vivo studies.

A review on micro- and nanoplastics in humans: Implication for their translocation of barriers and potential health effects.

As emerging contaminants, micro- and nanoplastics (MNPs) can absorb and leach various toxic chemicals and ultimately endanger the health of the ecological environment and humans. With extensive research on MNPs, knowledge about MNPs in humans, especially their translocation of barriers and potential health effects, is of utmost importance. In this review, we collected literature published from 2000 to 2023, focusing on MNPs on their occurrence in humans, penetrating characteristics in the placental, blood-brain, and blood-testis barriers, and exposure effects on mammalian health. The characteristics and distributions of MNPs in human samples were analyzed, and the results demonstrated that MNPs were ubiquitous in most human samples, except for kidneys and cerebrospinal fluid. In addition, the phenomenon of MNPs crossing barriers and their underlying mechanisms were discussed. We also summarized the potential factors that may affect the barrier crossing and health effects of MNPs, including characteristics of MNPs, exposure doses, administration routes, exposure durations, co-exposure to other pollutants, and genetic predisposition. Exposure to MNPs may cause cytotoxicity, neurotoxicity, and developmental and reproductive toxicity in mammals. People are encouraged to reduce their exposure to MNPs to prevent these adverse health effects. Finally, we discussed the shortcomings of current research on MNPs in humans, providing a valuable reference for understanding and evaluating the potential health risks from MNP exposure in mammals, including humans.

Ruthenium-Catalyzed Difunctionalization of Vinyl Cyclopropanes for Double m-C(sp2)-H/C-5(sp3)-H Functionalization.

With in-depth research on 1,2-difunctionalization, remote difunctionalization has garnered widespread attention for achieving multifunctionality. Herein, we report a strategy for achieving remote difunctionalization under mild conditions. This strategy exhibited good substrate suitability and functional group tolerance. In addition, the significance of this method is further evidenced by its successful application in scaling up and conducting additional transformations of target compounds. Mechanistic studies showed that a radical might be involved in this process.

Exposure to per- and polyfluoroalkyl substances in lung cancer patients and their associations with clinical health indicators.

Per- and polyfluoroalkyl substances (PFASs) have potential carcinogenicity, immunotoxicity, and hepatotoxicity. Research has been conducted on PFAS exposure in people to discuss their potential health effects, excluding lung cancer. In this study, we recruited participants (n = 282) with lung cancer from Heilongjiang Province, northeast China. The PFAS concentrations were measured in their serum to fill the data gap of exposure, and relationships were explored in levels between PFASs and clinical indicators of tumor, immune and liver function. Ten PFASs were found in over 80 % of samples and their total concentrations were 5.27-152 ng/mL, with the highest level for perfluorooctanesulfonate (median: 12.4 ng/mL). Long-chain PFASs were the main congeners and their median concentration (20.5 ng/mL) was nearly three times to that of short-chain PFASs (7.61 ng/mL). Significantly higher concentrations of perfluorobutanoic acid, perfluorononanoic acid and perfluorohexanesulfonate were found in males than in females (p < 0.05). Serum levels of neuro-specific enolase were positively associated with perfluoropentanoic acid in all participants and were negatively associated with perfluorononanesulfonate in females (p < 0.05, multiple linear regression models). Exposure to PFAS mixture was significantly positively associated with the lymphocytic absolute value (difference: 0.224, 95% CI: 0.018, 0.470; p < 0.05, quantile g-computation models) and serum total bilirubin (difference: 2.177, 95% CI: 0.0335, 4.33; p < 0.05). Moreover, PFAS exposure can affect γ-glutamyl transpeptidase through several immune markers (p < 0.05, mediating test). Our results suggest that exposure to certain PFASs could interfere with clinical indicators in lung cancer patients. To our knowledge, this is the first study to detect serum PFAS occurrence and check their associations with clinical indicators in lung cancer patients.

DNA-functionalized cryogel based colorimetric biosensor for sensitive on-site detection of aflatoxin B1 in food samples.

Hydrogel biosensors present numerous advantages in food safety analysis owing to their remarkable biocompatibility, cargo-loading capabilities and optical properties. However, the current drawbacks (slow target responsiveness and poor mechanical strength) restricted their further utilization at on-site detection of targets. To address these challenges, a DNA-functionalized cryogel with hierarchical pore structures is constructed to improve the reaction rate and the robustness of hydrogel biosensor. During cryogel preparation, ice crystals serve as templates, shaping interconnected hierarchical microporous structures to enhance mass transfer for faster responses. Meanwhile, in the non-freezing zone, concentrated monomers create a dense cross-linked network, strengthening cryogel matrix strength. Accordingly, a colorimetric biosensor based on DNA cryogel has been developed as a proof of concept for rapid detection of aflatoxin B1 (AFB1) in food samples, and an excellent analytical performance was obtained under the optimized conditions with a low detection limit (1 nM), broad detection range (5-100 nM), satisfactory accuracy and precision (recoveries, 81.2-112.6 %; CV, 2.75-5.53 %). Furthermore, by integrating with a smartphone sensing platform, a portable device was created for rapid on-site measurement of target within 45 min, which provided some insight for hydrogel biosensors design.

General anesthesia is not associated with dementia in older adults with osteoarthritis for hip/knee replacements, a national population-based nested case-control study.

BACKGROUND: Dementia is a prevalent neurological condition, yet the relationship between dementia and general anesthesia remains uncertain. The study aimed to explore the association between general anesthesia and dementia using a nationwide population-based database. METHODS: The study extracted data from Taiwan's national health insurance, which encompassed the records of one million insured residents. A total of 59,817 patients aged 65 years and above, diagnosed with osteoarthritis between 2002 and 2010, were included. Among these patients, 3277 individuals with an initial diagnosis of dementia between 2004 and 2013 were matched with non-dementia patients based on age, gender, and the date of osteoarthritis diagnosis. Following a 1:2 random matching, the case group included 2171 patients with dementia, while the control group consisted of 4342 patients without dementia. The data was analyzed using conditional and unconditional logistic regressions. RESULTS: No significant differences in the odds of dementia were found between individuals exposed to general and regional anesthesia during hip/knee replacement surgeries (OR = 1.11; 95%CI: 0.73-1.70), after adjusting for age, sex, and co-morbidities. Similarly, there were no significant differences in the odds of dementia based on different durations of anesthesia exposure (General: <2 h: OR = 0.91, 95%CI = 0.43-1.92; 2-4 h: OR = 1.21, 95%CI = 0.82-1.79; >4 h: OR = 0.39, 95%CI = 0.15-1.01; compared to no exposure. Regional: <2 h: OR = 1.18, 95%CI = 0.85-1.62; 2-4 h: OR = 0.9, 95%CI = 0.64-1.27; >4 h: OR = 0.55, 95%CI = 0.15-1.96; compared to no exposure). Likewise, no significant differences were observed in the odds of dementia based on the number of replacement surgeries (twice: OR = 0.74, 95%CI = 0.44-1.23, compared to once). CONCLUSION: Neither general anesthesia nor regional anesthesia in hip/knee surgery was associated with dementia. Different numbers and durations of anesthesia exposure showed no significant differences in the odds for dementia.

scENCORE: leveraging single-cell epigenetic data to predict chromatin conformation using graph embedding.

Dynamic compartmentalization of eukaryotic DNA into active and repressed states enables diverse transcriptional programs to arise from a single genetic blueprint, whereas its dysregulation can be strongly linked to a broad spectrum of diseases. While single-cell Hi-C experiments allow for chromosome conformation profiling across many cells, they are still expensive and not widely available for most labs. Here, we propose an alternate approach, scENCORE, to computationally reconstruct chromatin compartments from the more affordable and widely accessible single-cell epigenetic data. First, scENCORE constructs a long-range epigenetic correlation graph to mimic chromatin interaction frequencies, where nodes and edges represent genome bins and their correlations. Then, it learns the node embeddings to cluster genome regions into A/B compartments and aligns different graphs to quantify chromatin conformation changes across conditions. Benchmarking using cell-type-matched Hi-C experiments demonstrates that scENCORE can robustly reconstruct A/B compartments in a cell-type-specific manner. Furthermore, our chromatin confirmation switching studies highlight substantial compartment-switching events that may introduce substantial regulatory and transcriptional changes in psychiatric disease. In summary, scENCORE allows accurate and cost-effective A/B compartment reconstruction to delineate higher-order chromatin structure heterogeneity in complex tissues.

Molecular characterization, antibacterial and immunoregulatory activities of liver-expressed antimicrobial peptide 2 in black rockfish, Sebastes schlegelii.

LEAP2 (liver expression antimicrobial peptide 2), is an antimicrobial peptide widely found in vertebrates and mainly expressed in liver. LEAP2 plays a vital role in host innate immunity. In teleosts, a number of LEAP2 homologs have been reported, but their in vivo effects on host defense are still limited. In this study, a LEAP2 homolog (SsLEAP2) was identified from black rockfish, Sebastes schlegelii, and its structure, expression as well as biological functions were analyzed. The results showed that the open reading frame of SsLEAP2 is 300 bp, with a 5'- untranslated region (UTR) of 375 bp and a 3' - UTR of 238 bp. The deduced amino acid sequence of SsLEAP2 shares the highest overall identity (96.97%) with LEAP2 of Sebastes umbrosus. SsLEAP2 possesses conserved LEAP2 features, including a signal peptide sequence, a prodomain and a mature peptide, in which four well-conserved cysteines formed two intrachain disulphide domain. The expression of SsLEAP2 was highest in liver and could be induced by experimental infection with Listonella anguillarum, Edwardsiealla piscicida and Rock bream iridovirus C1 (RBIV-C1). Recombinant SsLEAP2 (rSsLEAP2) purified from Escherichia coli was able to bind with various Gram-positive and Gram-negative bacteria. Further analysis showed that rSsLEAP2 could enhance the respiratory burst activity, and induce the expression of immune genes including interleukin 1-ß (IL-1ß) and serum amyloid A (SAA) in macrophages; additionally, rSsLEAP2 could also promote the proliferation and chemotactic of peripheral blood lymphocytes (PBLs). In vivo experiments indicated that overexpression of SsLEAP2 could inhibit bacterial infection, and increase the expression level of immune genes including IL-1ß, tumor necrosis factor ligand superfamily member 13B (TNF13B) and haptoglobin (HP); conversely, knock down of SsLEAP2 promoted bacterial infection and decreased the expression level of above genes. Taken together, these results suggest that SsLEAP2 is a novel LEAP2 homolog that possesses apparent antibacterial activity and immunoregulatory property, thus plays a critical role in host defense against pathogens invasion.

The lncRNA20718-miR6022-RLPs module regulates tomato resistance to Phytophthora infestans.

KEY MESSAGE: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding.

The impact of sodium-glucose cotransporter-2 inhibitors on outcome of patients with diabetes mellitus and colorectal cancer.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.

Silver-Enabled Dearomative Trifluoromethoxylation of Indoles.

The only known method for the dearomative trifluoromethoxylation of indoles is preliminary, with only one substrate successfully undergoing the reaction. In this study, we not only developed a broadly applicable method for indole dearomative trifluoromethoxylation but also achieved divergent trifluoromethoxylation by fine-tuning the reaction conditions. Under optimized conditions, with a silver salt and an easily handled OCF3 reagent, various indoles smoothly underwent dearomatization to afford a diverse array of ditrifluoromethoxylated indolines in 50-84% isolated yields with up to 37:1 diastereoselectivity, and fluorinated trifluoromethoxylated indolines were obtained with exclusive trans selectivity. In addition, the reaction conditions were compatible with other heteroaromatic rings as well as styrene moieties.

The process of solid-state fermentation of soybean meal: antimicrobial activity, fermentation heat generation and nitrogen solubility index.

BACKGROUND: Bacillus amyloliquefaciens has excellent protease production ability and holds great prospects for application in the solid-state fermentation of soybean meal (SBM). RESULTS: Among eight strains of bacteria, Bacillus amyloliquefaciens subsp. plantarum CICC 10265, which exhibited higher protease production, was selected as the fermentation strain. The protease activity secreted by this strain reached 106.41 U mL-1 . The microbial community structure differed significantly between natural fermentation and inoculation-enhanced fermented soybean meal (FSBM), with the latter showing greater stability and inhibition of miscellaneous bacterial growth. During fermentation, the temperature inside the soybean meal increased, and the optimal environmental temperature for FSBM was found to be between 35 and 40 °C. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and nitrogen solubility index (NSI) results demonstrated that solid-state fermentation had a degrading effect on highly denatured proteins in SBM, resulting in an NSI of 67.1%. CONCLUSION: Bacillus amyloliquefaciens subsp. plantarum CICC 10265 can enhance the NSI of SBM in solid-state fermentation and inhibit the growth of miscellaneous bacteria. © 2023 Society of Chemical Industry.

Visible-Light-Mediated Synthesis of C-Alkyl Glycosides via Glycosyl Radical Addition and Aryl Migration.

A visible-light-induced glycoarylation of activated olefins has been accomplished. Glycosyl radicals are generated via radical transfer strategies between (TMS)3SiOH and glycosyl bromides. Subsequent radical translocation and rapid 1,4-aryl migration form ß-sugar amide derivatives, and eight types of sugars are compatible with this reaction. Further, the cascade reaction produced a quaternary carbon center with good functional group adaptability and high regioselectivity in mild conditions.

Application of Hyperspectral Imaging as a Nondestructive Technology for Identifying Tomato Maturity and Quantitatively Predicting Lycopene Content.

Maturity is a crucial indicator in assessing the quality of tomatoes, and it is closely related to lycopene content. Using hyperspectral imaging, this study aimed to monitor tomato maturity and predict its lycopene content at different maturity stages. Standard normal variable (SNV) transformation was applied to preprocess the hyperspectral data. Then, using competitive adaptive reweighted sampling (CARS), the characteristic wavelengths were selected to simplify the calibration models. Based on the full and characteristic wavelengths, a support vector classifier (SVC) model was developed to determine tomato maturity qualitatively. The results demonstrated that the classification accuracy using the characteristic wavelength led to the obtention of better results with an accuracy of 95.83%. In addition, the support vector regression (SVR) and partial least squares regression (PLSR) models were utilized to predict lycopene content. With a coefficient of determination for prediction (R2P) of 0.9652 and a root mean square error for prediction (RMSEP) of 0.0166 mg/kg, the SVR model exhibited the best quantitative prediction capacity based on the characteristic wavelengths. Following this, a visual distribution map was created to evaluate the lycopene content in tomato fruit intuitively. The results demonstrated the viability of hyperspectral imaging for detecting tomato maturity and quantitatively predicting the lycopene content during storage.

Stereoselective Synthesis of Multisubstituted Alkenes via Ruthenium-Catalyzed Remote Migration Arylation of Nonactivated Olefins.

Polysubstituted alkenes are an important class of organic intermediates that widely exist in various natural products and drug molecules. Herein, we reported a stereoselective synthesis of multisubstituted alkenes via ruthenium-catalyzed remote migration arylation of nonactivated olefins. This strategy exhibited wide substrate suitability and excellent functional group tolerance. In addition, we demonstrated the indispensable role of two types of ruthenium through mechanism experiments.

Photoredox-Catalyzed N-Directed Regioselective Difluoroalkylation of Unactivated C(sp3)-H Bonds.

We report a redox-neutral, visible-light-mediated difluoroalkylation of unactivated C(sp3)-H bonds in amides via nitrogen-centered radicals triggered intramolecular hydrogen atom transfer. Notably, all types (tertiary, secondary, and primary) of γ-C(sp3)-H bonds displayed excellent reactivity. This methodology presents a facile route for the regioselective introduction of α,α-difluoroketone fragments into organic molecules. Moreover, the resulting gem-difluoroketones can be readily converted to structurally diverse difluoro-containing molecules, offering broad potential applications in medicinal chemistry and chemical biology.