Deciphering the potential role of PGRN in regulating CD8+ T cell antitumor immunity.

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8+ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8+ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8+ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8+ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8+ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN-/- mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8+ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.

Low-Cost Photoelectric Flow Rate Sensors Based on a Flexible Planar Curved Beam Structure for Clinical Treatments.

In clinical treatments, reliable flow rate measurements ensure accurate drug delivery during infusions, precise gas delivery during artificial ventilations, etc., thereby reducing patient morbidity and mortality. However, precise flow rate sensors are costly, so medical devices with limited budgets choose cheaper but unsatisfactory flow rate measurement approaches, leading to increased medical risks. Here, a photoelectric flow rate sensor based on a flexible planar curved beam structure (FPCBS) is proposed. The FPCBS ensures low out-of-plane stiffness of the sensitive sheet and allows large deformation in the elastic range, enabling the flow rate sensor to measure the flow rate with high sensitivity over a wide range. Meanwhile, the flow rate sensor can be mass-produced using mature materials and manufacturing technology at less than $5 each. The flow rate sensors are integrated into a commercial infusion pump to measure drug infusion and a home ventilator to monitor respiration. The results are comparable to those measured by a commercial flow rate sensor, demonstrating the applicability of the sensor. Considering its proven outstanding performance at low cost, the flow rate sensor shows great potential in clinical treatment, medical diagnosis, and other medical fields.

Outdoor artificial light at night and reproductive endocrine and glucose homeostasis and polycystic ovary syndrome in women of reproductive age.

BACKGROUND: Artificial light at night, a well-recognized circadian clock disrupter, causes disturbances in endocrine homeostasis. However, the association of artificial light at night with polycystic ovary syndrome (PCOS) is still unknown. This study examines the effects of outdoor artificial light at night on sex hormones, glucose homeostasis markers, and PCOS prevalence in Anhui Province, China. METHODS: We recruited 20633 women of reproductive age from Anhui Medical University Reproductive Medicine Center. PCOS was diagnosed according to Rotterdam criteria. We estimated long-term (previous year) and short-term (previous month) artificial light at night values for residential addresses using 500-meter resolution satellite imagery. We fitted multivariable models, using both linear and logistic regression, to estimate the association of artificial light at night with sex hormones, glucose homeostasis markers, and PCOS prevalence. RESULTS: Both long-term and short-term exposure to outdoor artificial light at night were negatively associated with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, while positively associated with testosterone, fasting insulin, HOMA-IR, and HOMA-ß levels. The second-highest quintile of artificial light at night was associated with increased PCOS prevalence (OR long-term =1.4, 95% CI: 1.2,1.6); OR short-term =1.3, 95% CI: 1.1,1.5) compared to the lowest quintile. In addition, prevalence of PCOS was linearly associated with long-term exposure to artificial light at night, but non-linearly associated with short-term exposure. This association was more evident in younger, obese or overweight, moderately educated, rural women, and for the summer and fall seasons. CONCLUSIONS: Outdoor artificial light at night may be a novel risk factor for PCOS.

The impact of short-term exposure to meteorological factors on the risk of death from hypertension and its major complications: a time series analysis based on Hefei, China.

OBJECTIVES: This study aimed to reveal the short-term impact of meteorological factors on the mortality risk in hypertensive patients, providing a scientific foundation for formulating pertinent prevention and control policies. METHODS: In this research, meteorological factor data and daily death data of hypertensive patients in Hefei City from 2015 to 2018 were integrated. Time series analysis was performed using distributed lag nonlinear model (DLNM) and generalized additive model (GAM). Furthermore, we conducted stratified analysis based on gender and age. Relative risk (RR) combined with 95% confidence interval (95% CI) was used to represent the mortality risk of single day and cumulative day in hypertensive patients. RESULTS: Single-day lag results indicated that high daily mean temperature (T mean) (75th percentile, 24.9 °C) and low diurnal temperature range (DTR) (25th percentile, 4.20 °C) levels were identified as risk factors for death in hypertensive patients (maximum effective RR values were 1.144 and 1.122, respectively). Extremely high levels of relative humidity (RH) (95th percentile, 94.29%) reduced the risk of death (RR value was 0.893). The stratified results showed that the elderly and female populations are more susceptible to low DTR levels, whereas extremely high levels of RH have a more significant protective effect on both populations. CONCLUSION: Overall, we found that exposure to low DTR and high T mean environments increases the risk of death for hypertensive patients, while exposure to extremely high RH environments significantly reduces the risk of death for hypertensive patients. These findings contribute valuable insights for shaping targeted prevention and control strategies.

Prussian Blue Analogue-Derived Co3O4 as Catalysts for Enhanced Selective Oxidation of Cyclohexane Using Molecular Oxygen.

Selective conversion of inert C-H bonds in alkanes into high-value-added functional groups (alcohols, ketones, carboxylic acids, etc.) plays a vital role in establishing a green and sustainable chemical industry. Catalytic selective oxidation of cyclohexane to KA oil (cyclohexanol and cyclohexanone) is a typical representative of alkane functionalization. In this work, hollow cage-like Co3O4 (Co3O4-C) and particle Co3O4 (Co3O4-P) were synthesized by calcining two types of Prussian blue analogues (PBAs), which were used to catalyze the selective oxidation of cyclohexane. The Co3O4-C predominantly exposed (311) crystal plane is easier to adsorb cyclohexane than Co3O4-P, which is beneficial to shorten the induction period, accelerate the reaction rate, and improve the conversion. Consequently, Co3O4-C displayed a 10% conversion of cyclohexane within 1 h, and the KA oil selectivity reached 90%. The Co3O4-P exposed (220) crystal plane has a higher molar percentage of oxygen vacancies and more active oxygen species, as well as a strong cyclohexanone adsorption capacity, which is conducive to the deep oxidation of cyclohexanone to adipic acid and other diacid products. The mechanism analysis of cyclohexane oxidation catalyzed by PBA-based Co3O4 shows that it exemplifies the feasibility to tailor the surface of catalysts by modulating the PBAs, which ultimately influences their reaction performance for accelerating the reaction and maintaining high cyclohexane conversion and KA oil selectivity.

Chimeric nanobody-decorated liposomes by self-assembly.

Liposomes as drug vehicles have advantages, such as payload protection, tunable carrying capacity and improved biodistribution. However, due to the dysfunction of targeting moieties and payload loss during preparation, immunoliposomes have yet to be favoured in commercial manufacturing. Here we report a chemical modification-free biophysical approach for producing immunoliposomes in one step through the self-assembly of a chimeric nanobody (cNB) into liposome bilayers. cNB consists of a nanobody against human epidermal growth factor receptor 2 (HER2), a flexible peptide linker and a hydrophobic single transmembrane domain. We determined that 64% of therapeutic compounds can be encapsulated into 100-nm liposomes, and up to 2,500 cNBs can be anchored on liposomal membranes without steric hindrance under facile conditions. Subsequently, we demonstrate that drug-loaded immunoliposomes increase cytotoxicity on HER2-overexpressing cancer cell lines by 10- to 20-fold, inhibit the growth of xenograft tumours by 3.4-fold and improve survival by more than twofold.

MYC expression and fatty acid oxidation in EGFR-TKI acquired resistance.

This report expands on our previous research, highlighting a unique inverse correlation between MYC expression in tumor cells and immune cells during the development of EGFR-TKI resistance. It is observed that MYC expression and fatty acid oxidation (FAO) metabolism in tissue-resident memory (TRM) CD8 + T cells are significantly impaired. These findings offer new insights into the mechanisms of TKI resistance. Although the study is preliminary, it suggests caution when interpreting the effectiveness of MYC inhibitors in reversing TKI resistance, especially when immune factors are not considered.

Regulating the Oxygen Vacancy and Electronic Structure of NiCo Layered Double Hydroxides by Molybdenum Doping for High-Power Hybrid Supercapacitors.

Amelioration of nickel-cobalt layered double hydroxides (NiCo-LDH) with a high specific theoretical capacitance is of great desire for high-power supercapacitors. Herein, a molybdenum (Mo) doping strategy is proposed to improve the charge-storage performance of NiCo-LDH nanosheets growing on carbon cloth (CC) via a rapid microwave process. The regulation of the electronic structure and oxygen vacancy of the LDH is consolidated by the density functional theory (DFT) calculation, which demonstrates that Mo doping narrows the band gap, reduces the formation energy of hydroxyl vacancies, and promotes ionic and charge transfer as well as electrolyte adsorption on the electrode surface. The optimal Mo-doped NiCo-LDH electrode (MoNiCo-LDH-0.05/CC) has an amazing specific capacity of 471.1 mA h g-1 at 1 A g-1 , and excellent capacity retention of 84.8% at 32 A g-1 , far superior to NiCo-LDH/CC (258.3 mA h g-1 and 76.4%). The constructed hybrid supercapacitor delivers an energy density of 103.3 W h kg-1 at a power density of 750 W kg-1 and retains the cycle retention of 85.2% after 5000 cycles. Two assembled devices in series can drive thirty LED lamps, revealing a potential application prospect of the rationally synthesized MoNiCo-LDH/CC as an energy-storage electrode material.

Weighted gene co-expression network analysis for hub genes in colorectal cancer.

BACKGROUND: This study is designed to explore hub genes participating in colorectal cancer (CRC) development through weighted gene co-expression network analysis (WGCNA). METHODS: Expression profiles of CRC and normal samples were retrieved from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA), and were subjected to WGCNA to filter differentially expressed genes with significant association with CRC. Functional enrichment analysis and protein-protein interaction (PPI) analysis were carried out to filter the candidate genes, further and survival analysis was performed for the candidate genes to obtain potential regulatory hub genes in CRC. Expression analysis was conducted for the candidate genes and a multifactor model was established. RESULTS: After differential analysis and WGCNA, 289 candidate genes were filtered from the GEO and TCGA. Further functional enrichment analysis demonstrated possible regulatory pathways and functions. PPI analysis filtered 15 hub genes and survival analysis indicated a significant correlation of CLCA1, CLCA4, and CPT1A with prognosis of patients with CRC. The multifactor Cox risk model established based on the three genes revealed that if the three genes were a gene set, they had well predictive capacity for the prognosis of patients with CRC. CONCLUSIONS: CLCA1, CLCA4, and CPT1A express at low levels in CRC and function as core anti-tumor genes. As a gene set, they can predict prognosis well.

Ecological restoration affects the dynamic response of alkaline minerals dissolution in bauxite residue.

Regulating alkalinity is the key process to eliminating environmental risk and implementing sustainable management of bauxite residue. Nevertheless, continuous release of free alkali from the solid phase (mainly sodalite and cancrinite) is a major challenge for long-term stability of alkalinity in amended bauxite residue. In order to understand the dissolution behavior of sodalite and cancrinite, their dissolution kinetics under simulated pH conditions of 8, 9 and 10 were investigated. Additionally, PHREEQC software and shrinking core model (SCM) were employed to analyze the release pattern of saline ions. The results revealed that the ratio of Na/Si and Na/Al values exhibited greater stability in sodalite than in cancrinite. The dissolution of elemental Na, Si, and Al in sodalite and cancrinite was matched with non-chemometric characteristics. The kinetic calculations by the shrinking core model (SCM) suggested that both sodalite and cancrinite exhibited slow dissolution kinetics, and their dissolution processes belong to internal diffusion control and external diffusion control, respectively. pH controlled the dissolution kinetic rates of sodalite and cancrinite mainly by changing their coupled dissolution-precipitation processes. More importantly, these findings can predict the change of alkaline components accurately, thus facilitating the implementation of efficient alkalinity regulation strategies for the ecological restoration of bauxite residue disposal areas.

Efficacy and safety of telitacicept in patients with systemic lupus erythematosus: a multicentre, retrospective, real-world study.

OBJECTIVE: To examine the efficacy and safety of telitacicept in the treatment of patients with SLE in everyday clinical practice. METHODS: Seventy-two patients with active SLE who received telitacicept for more than 24 weeks at multiple centres in China between 2019 and 2022 were retrospectively identified. Twenty-one of these patients received 52 continuous weeks of treatment with telitacicept. Treatment outcomes were analysed separately according to whether patients had renal or haematological abnormalities. Trajectory analysis was performed to identify patients with a limited response. Factors contributing to a limited response were explored by multivariable logistic regression analysis. RESULTS: After treatment with telitacicept for 4, 12, 24 and 52 weeks, 22.22%, 54.17%, 72.22% and 80.95% of patients, respectively, achieved an SLE Responder Index 4; 8.33%, 26.39%, 34.72% and 47.62% achieved a Lupus Low Disease Activity State; and 0%, 4.17%, 8.33% and 23.81% achieved remission. Significant decreases in serum IgA, IgG and IgM levels were observed at 4 weeks and showed a downward trend at 12, 24 and 52 weeks. The median 24-hour urinary protein declined from 1323.5 mg to 224.0 mg in patients with lupus nephritis after treatment with telitacicept for 52 weeks. Furthermore, a large proportion of patients (10 of 13) with haematological abnormalities recovered after 52 weeks of treatment with telitacicept. No severe adverse events were reported during the observation period. Age appeared to have a negative impact on treatment efficacy. CONCLUSIONS: Telitacicept demonstrated favourable efficacy and safety in patients with active SLE and improved the renal and haematological manifestations of the disease.

Association between exposure to mixture of heavy metals and hyperlipidemia risk among U.S. adults: A cross-sectional study.

Previous studies have suggested that exposure to heavy metals might increase the risk of hyperlipidemia. However, limited research has investigated the association between exposure to mixture of heavy metals and hyperlipidemia risk. To explore the independent and combined effects of heavy metal exposure on hyperlipidemia risk, this study involved 3293 participants from the National Health and Nutrition Examination Survey (NHANES), including 2327 with hyperlipidemia and the remaining without. In the individual metal analysis, the logistic regression model confirmed the positive effects of barium (Ba), cadmium (Cd), mercury (Hg), Lead (Pb), and uranium (U) on hyperlipidemia risk, Ba, Cd, Hg and Pb were further validated in restricted cubic splines (RCS) regression model and identified as positive linear relationships. In the metal mixture analysis, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile-based g computation (qgcomp) models consistently revealed a positive correlation between exposure to metal mixture and hyperlipidemia risk, with Ba, Cd, Hg, Pb, and U having significant positive driving roles in the overall effects. These associations were more prominent in young/middle-aged individuals. Moreover, the BKMR model uncovered some interactions between specific heavy metals. In conclusion, this study offers new evidence supporting the link between combined exposure to multiple heavy metals and hyperlipidemia risk, but considering the limitations of this study, further prospective research is required.

Single-cell transcriptome profiling reveals immune and stromal cell heterogeneity in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by lymphocytic infiltration and exocrine dysfunction, particularly affecting the salivary gland (SG). We employed single-cell RNA sequencing to investigate cellular heterogeneity in 11 patients with pSS and 5 non-SS controls. Notably, patients with pSS exhibited downregulated SOX9 in myoepithelial cells, potentially associated with impaired epithelial regeneration. An expanded ACKR1+ endothelial subpopulation in patients with pSS suggested a role in facilitating lymphocyte transendothelial migration. Our analysis of immune cells revealed expanded IGHD+ naive B cells in peripheral blood from patients with pSS. Pseudotime trajectory analysis outlined a bifurcated differentiation pathway for peripheral B cells, enriching three subtypes (VPREB3+ B, BANK1+ B, CD83+ B cells) within SGs in patients with pSS. Fibroblasts emerged as pivotal components in a stromal-immune interaction network, potentially driving extracellular matrix disruption, epithelial regeneration impairment, and inflammation. Our study illuminates immune and stromal cell heterogeneity in patients with pSS, offering insights into therapeutic strategies.

In Situ Fabrication of SnS2/SnO2 Heterostructures for Boosting Formaldehyde-Sensing Properties at Room Temperature.

Formaldehyde, as a harmful gas produced by materials used for decorative purposes, has a serious impact on human health, and is also the focus and difficulty of indoor environmental polution prevention; hence, designing and developing gas sensors for the selective measurement of formaldehyde at room temperature is an urgent task. Herein, a series of SnS2/SnO2 composites with hollow spherical structures were prepared by a facile hydrothermal approach for the purpose of formaldehyde sensing at room temperature. These novel hierarchical structured SnS2/SnO2 composites-based gas sensors demonstrate remarkable selectivity towards formaldehyde within the concentration range of sub-ppm (0.1 ppm) to ppm (10 ppm) at room temperature. Notably, the SnS2/SnO2-2 sensor exhibits an exceptional formaldehyde-sensing performance, featuring an ultra-high response (1.93, 0.1 ppm and 17.51, 10 ppm), as well as good repeatability, long-term stability, and an outstanding theoretical detection limit. The superior sensing capabilities of the SnS2/SnO2 composites can be attributed to multiple factors, including enhanced formaldehyde adsorption, larger specific surface area and porosity of the hollow structure, as well as the synergistic interfacial incorporation of the SnS2/SnO2 heterojunction. Overall, the excellent gas sensing performance of SnS2/SnO2 hollow spheres has opened up a new way for their detection of trace formaldehyde at room temperature.

Associations of long-term exposure to air pollution and green space with reproductive hormones among women undergoing assisted reproductive technology: A longitudinal study.

Studies investigating the association between long-term exposure to air pollution (AP)/green space and female reproductive hormones are still limited. Furthermore, their interactive effects remain unclear. Our study sought to explore the separate and interactive impacts of AP/green space on reproductive hormones among women undergoing assisted reproductive technology. We measured estradiol (E2), progesterone (P), testosterone (T), and follicle-stimulating hormone (FSH) from the longitudinal assisted reproduction cohort in Anhui, China. The annual mean concentrations of air pollutants were calculated at the residential level. Normalized Difference Vegetation Index (NDVI) within 500-m represented green space exposure. To assess the effect of AP/green space on hormones, we employed multivariable linear mixed-effect models. Our results showed that each one-interquartile range (IQR) increment in particulate matter (PM2.5 and PM10) and sulfur dioxide (SO2) was associated with -0.03[-0.05, -0.01], -0.03[-0.05, -0.02], and -0.03[-0.05, -0.01] decrease in P. An IQR increase in PM2.5, PM10, SO2, and carbon monoxide (CO) was associated with a -0.16[-0.17, -0.15], -0.15[-0.16, -0.14], -0.15[-0.16, -0.14], and -0.12[-0.13, -0.11] decrease in T and a -0.31[-0.35, -0.27], -0.30[-0.34, -0.26], -0.26[-0.30, -0.22], and -0.21[-0.25, -0.17] decrease in FSH. Conversely, NDVI500-m was associated with higher levels of P, T, and FSH, with ß of 0.05[0.02, 0.08], 0.06[0.04, 0.08], and 0.07[0.00, 0.14]. Moreover, we observed the "U" or "J" exposure-response curves between PM2.5, PM10, and SO2 concentrations and E2 and P levels, as well as "inverted-J" curves between NDVI500-m and T and FSH levels. Furthermore, we found statistically significant interactions of SO2 and NDVI500-m on E2 and P as well as CO and NDVI500-m on E2. These findings indicated that green space might mitigate the negative effects of SO2 on E2 and P, as well as the effect of CO on E2. Future research is needed to determine these findings and underlying mechanisms.

Associations of exposure to heavy metal mixtures with kidney stone among U.S. adults: A cross-sectional study.

Assessing the effects of heavy metals (HMs) on kidney stone is often limited to analyzing individual metal exposures, with studies on the effects of exposure to mixtures of HMs being scarce. To comprehensively evaluate the relationship between exposure to mixed HMs and kidney stones, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2016, which included 7809 adults. We used multiple statistical methods, including multiple logistic regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp) and bayesian kernel machine regression (BKMR), to assess the association between single HM and mixed exposure to HMs and kidney stones. Firstly, in single exposure analysis, urinary cadmium (Cd) and cobalt (Co) demonstrated a positive association with the risk of kidney stones. Secondly, various other approaches consistently revealed that mixed exposure to HMs exhibited a positive association with kidney stone risk, primarily driven by Cd, Co, and barium (Ba) in urine, with these associations being particularly notable among the elderly population. Finally, both BKMR and survey-weighted generalized linear models consistently demonstrated a significant synergistic effect between urinary Co and urinary uranium (Ur) in elevating the risk of kidney stones. Overall, this study provides new epidemiological evidence that mixed exposure to HMs is associated with an increased risk of kidney stones. Further prospectively designed studies are needed to confirm these findings.

Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles.

Cell-derived small extracellular vesicles have been exploited as potent drug vehicles. However, significant challenges hamper their clinical translation, including inefficient cytosolic delivery, poor target-specificity, low yield, and inconsistency in production. Here, we report a bioinspired material, engineered fusogen and targeting moiety co-functionalized cell-derived nanovesicle (CNV) called eFT-CNV, as a drug vehicle. We show that universal eFT-CNVs can be produced by extrusion of genetically modified donor cells with high yield and consistency. We demonstrate that bioinspired eFT-CNVs can efficiently and selectively bind to targets and trigger membrane fusion, fulfilling endo-lysosomal escape and cytosolic drug delivery. We find that, compared to counterparts, eFT-CNVs significantly improve the treatment efficacy of drugs acting on cytosolic targets. We believe that our bioinspired eFT-CNVs will be promising and powerful tools for nanomedicine and precision medicine.

Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.

Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 µM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome.

The quantitative profiling of residue reactivity in proteins promotes the discovery of covalent druggable targets for precise therapy. Histidine (His) residues, accounting for more than 20% of the active sites in enzymes, have not been systematically characterized for their reactivity, due to lack of labeling probes. Herein, we report a chemical proteomics platform for the site-specific quantitative analysis of His reactivity by combination of acrolein (ACR) labeling and reversible hydrazine chemistry enrichment. Based on this platform, in-depth characterization of His residues was conducted for the human proteome, in which the rich content of His residues (>8200) was quantified, including 317 His hyper-reactive residues. Intriguingly, it was observed that the hyper-reactive residues were less likely to be the sites for phosphorylation, and the possible mechanism of this antagonistic effect still needs to be evaluated in further research. Based on the first comprehensive map of His residue reactivity, many more residues could be adopted as the bindable sites to disrupt the activities of a diverse number of proteins; meanwhile, ACR derivatives could also be used as a novel reactive warhead in the development of covalent inhibitors.