Inherited blood cancer predisposition through altered transcription elongation.

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

Human hematopoietic stem cell vulnerability to ferroptosis.

Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet, the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to the loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illustrating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

Why are some people more attractive to mosquitoes than others?

Mosquitoes rely on their sense of smell to find humans to secure a blood meal, transmitting deadly diseases with their bite. In this issue of Cell, De Obaldía and colleagues examine why mosquitoes bite some people more than others and report an association with the level of carboxylic acids in the human skin odor.

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.

The µ-opioid receptor (µOR) is an important target for pain management1 and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of ß-arrestin-1 with the µOR core binding site appears less specific and occurs with much lower affinity than binding of Gi.

Multispectral 3D DNA Machine Combined with Multimodal Machine Learning for Noninvasive Precise Diagnosis of Bladder Cancer.

Extracellular vesicle (EV) molecular phenotyping offers enormous opportunities for cancer diagnostics. However, the majority of the associated studies adopted biomarker-based unimodal analysis to achieve cancer diagnosis, which has high false positives and low precision. Herein, we report a multimodal platform for the high-precision diagnosis of bladder cancer (BCa) through a multispectral 3D DNA machine in combination with a multimodal machine learning (ML) algorithm. The DNA machine was constructed using magnetic microparticles (MNPs) functionalized with aptamers that specifically identify the target of interest, i.e., five protein markers on bladder-cancer-derived urinary EVs (uEVs). The aptamers were hybridized with DNA-stabilized silver nanoclusters (DNA/AgNCs) and a G-quadruplex/hemin complex to form a sensing module. Such a DNA machine ensured multispectral detection of protein markers by fluorescence (FL), inductively coupled plasma mass spectrometry (ICP-MS), and UV-vis absorption (Abs). The obtained data sets then underwent uni- or multimodal ML for BCa diagnosis to compare the analytical performance. In this study, urine samples were obtained from our prospective cohort (n = 45). Our analytical results showed that the 3D DNA machine provided a detection limit of 9.2 × 103 particles mL-1 with a linear range of 4 × 104 to 5 × 107 particles mL-1 for uEVs. Moreover, the multimodal data fusion model exhibited an accuracy of 95.0%, a precision of 93.1%, and a recall rate of 93.2% on average, while those of the three types of unimodal models were no more than 91%. The elevated diagnosis precision by using the present fusion platform offers a perspective approach to diminishing the rate of misdiagnosis and overtreatment of BCa.

Construction of a three-dimensional inflammation model of human bronchial epithelial cells BEAS-2B by using the self-assembling D-form peptide Sciobio-â ¢.

Human bronchial epithelial cells in the airway system, as the primary barrier between humans and the surrounding environment, assume a crucial function in orchestrating the processes of airway inflammation. Target to develop a new three-dimensional (3D) inflammatory model to airway system, and here we report a strategy by using self-assembling D-form peptide to cover the process. By testing physicochemical properties and biocompatibility of Sciobio-Ⅲ, we confirmed that it can rapidly self-assembles under the trigger of ions to form a 3D nanonetwork-like scaffold, which supports 3D cell culture including the cell strains like BEAS-2B cells. Subsequently, inflammation model was established by lipopolysaccharide (LPS), the expression of some markers of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8), the levels of relevant inflammatory factors were measured by RT-qPCR and the secretion profile of inflammatory cytokines by ELISA, are obtained the quite difference effects in 2D and 3D microenvironment, which suggested Sciobio-Ⅲ hydrogel is an ideal scaffold that create the microenvironment for 3D cell culture. Here we are success to establish a 3D inflammation model for airway system. This innovative model allows for rapid and accurate evaluation of drug metabolism and toxicological side effects, hope to use in drug screening for airway inflammatory diseases and beyond.

Optoelectronic Tweezers Micro-Well System for Highly Efficient Single-Cell Trapping, Dynamic Sorting, and Retrieval.

Single-cell arrays have emerged as a versatile method for executing single-cell manipulations across an array of biological applications. In this paper, an innovative microfluidic platform is unveiled that utilizes optoelectronic tweezers (OETs) to array and sort individual cells at a flow rate of 20 µL min-1. This platform is also adept at executing dielectrophoresis (DEP)-based, light-guided single-cell retrievals from designated micro-wells. This presents a compelling non-contact method for the rapid and straightforward sorting of cells that are hard to distinguish. Within this system, cells are individually confined to micro-wells, achieving an impressive high single-cell capture rate exceeding 91.9%. The roles of illuminating patterns, flow velocities, and applied electrical voltages are delved into in enhancing the single-cell capture rate. By integrating the OET system with the micro-well arrays, the device showcases adaptability and a plethora of functions. It can concurrently trap and segregate specific cells, guided by their dielectric signatures. Experimental results, derived from a mixed sample of HepG2 and L-O2 cells, reveal a sorting accuracy for L-O2 cells surpassing 91%. Fluorescence markers allow for the identification of sequestered, fluorescence-tagged HepG2 cells, which can subsequently be selectively released within the chip. This platform's rapidity in capturing and releasing individual cells augments its potential for future biological research and applications.

Aurora kinase B disruption suppresses pathological retinal angiogenesis by affecting cell cycle progression.

PURPOSE: The detrimental effects of pathological angiogenesis on the visual function are indisputable. Within a prominent role in chromosome segregation and tumor progression, aurora kinase B (AURKB) assumes a prominent role. However, its role in pathological retinal angiogenesis remains unclear. This study explores this latent mechanism. METHODS: To inhibit AURKB expression, we designed specific small interfering RNAs targeting AURKB and transfected them into vascular endothelial cells. Barasertib was selected as the AURKB inhibitor. The anti-angiogenic effects of both AURKB siRNA and barasertib were assessed in vitro by cell proliferation, transwell migration, and tube formation. To evaluate the angiogentic effects of AURKB in vivo, neonatal mice were exposed to 75% oxygen followed by normoxic repositioning to establish an oxygen-induced retinopathy (OIR) model. Subsequently, phosphate-buffered saline and barasertib were administered into OIR mice via intravitreal injection. The effects of AURKB on cell cycle proteins were determined by western blot analysis. RESULTS: We found that AURKB was overexpressed during pathological angiogenesis. AURKB siRNA and barasertib significantly inhibited endothelial cell proliferation, migration, and tube formation in vitro. Furthermore, AURKB inhibition attenuated retinal angiogenesis in the OIR model. A possible mechanism is the disruption of cell cycle by AURKB inhibition. CONCLUSION: In conclusion, AURKB significantly influenced pathological retinal angiogenesis, thereby presenting a promising therapeutic target in ocular neovascular diseases.

Synthesis and Flame Retardant Behavior of Phosphorous- and Nitrogen-Containing Copolymer and Its Application in Polypropylene.

In this study, a 4-(hydroxymethyl)-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide (PEPA)-functionalized acrylate monomer, PEPAA, is designed and utilized for the synthesis of macromolecular flame retardants poly(PEPAA-co-AM) with varying PEPAA/AM ratio through copolymerization with acrylamide (AM). The poly(PEPAA-co-AM) is then incorporated into polypropylene (PP) to prepare PP/poly(PEPAA-co-AM) composites. The flame retardant effect of poly(PEPAA-co-AM) on PP is investigated using cone calorimetric test (CCT), and compared with that of PEPAA homopolymer (P-PEPAA), AM homopolymer (PAM), and blends of P-PEPAA/PAM. The results demonstrate that, in comparison with P-PEPAA, PAM, and blends of P-PEPAA/PAM, the incorporation of poly(PEPAA-co-AM) significantly enhances the flame retardancy of PP. Notably, the best flame retardancy is achieved when the ratio of PEPAA/AM copolymerization in poly(PEPAA-co-AM) is 2/8. The morphology and composition of residual chars from combustion are analyzed using SEM-EDS while the residual graphitization degree is examined through Raman spectroscopy. Additionally, TG-FTIR-MS is utilized to investigate the pyrolysis products in gas phase during thermal decomposition of poly(PEPAA-co-AM). Based on these experimental results, a flame retardant mechanism for poly(PEPAA-co-AM) is proposed. The PP/poly(PEPAA-co-AM) composites not only retain the excellent processing properties of pure PP but also exhibit enhanced mechanical properties.

The role of leptin in ischemic stroke and its subtypes: A Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have suggested a relationship between leptin and risk of stroke. However, evidence for the association remains inconsistent, and whether the association reflects a causal relationship remains to be established. To clarify this relationship, we adopted a two-sample Mendelian randomization (MR) analysis to investigate whether leptin plays a causal role in the risk of stroke and its subtypes. METHODS AND RESULTS: Five independent single-nucleotide polymorphisms (SNPs) associated with the leptin level from genome-wide association studies (GWASs) of European individuals were selected. We performed an MR analysis using the inverse-variance-weighted (IVW) as primary method to examine the causal effects of leptin on ischemic stroke (IS). Moreover, MR-Egger intercept and Cochran's Q statistic were also performed to detect the pleiotropy or heterogeneity of our MR results. Genetically predicted circulating leptin level was not associated with ischemic stroke [odds ratio (OR): 1.48, 95% confidence interval (CI): 0.78-2.8, P = 0.22], large artery stroke (OR: 1.44, 95% CI: 0.39-5.25, P = 0.57), cardioembolic stroke (OR:1.33, 95% CI: 0.55-3.22, P = 0.52), and small vessel stroke (OR: 1.48, 95% CI: 0.39-5.63, P = 0.56) using the IVW method. Likewise, there is no convincing evidence for the associations between leptin levels and cardiovascular diseases (CVD) risk factors. CONCLUSIONS: This study did not provide evidence that leptin levels are associated with increased risk of stroke and its subtypes.

Resveratrol alleviates fumonisin-induced intestinal cytotoxicity by modulating apoptosis, tight junction, and inflammation in IPEC-J2 porcine intestinal epithelial cells.

Fumonisins are common contaminants in the global food and environment, pose a variety of health risks to humans and animals. However, the method of mitigating fumonisin toxicity is still unclear. Resveratrol is a natural compound with antioxidant and anti-inflammatory properties. In this study, the protective effect of resveratrol against fumonisin-induced intestinal toxicity was investigated by the porcine intestinal epithelial cell line (IPEC-J2). The cells were treated with 0-40 µM fumonisin for 24 or 48 h with or without the 24 h resveratrol (15 µM) pretreatment. The data showed that resveratrol could alleviate the fumonisin B1 (FB1)-induced decrease in cell viability and amplify in membrane permeability. At the same time, it could reduce the accumulation of intracellular reactive oxygen species and increase the expression ranges of Nrf2 and downstream genes (SOD1 and NQO-1), thereby counteracting FB1-induced apoptosis. Furthermore, resveratrol was able to reduce the expression levels of inflammatory factors (TNF-α, IL-1ß, and IL-6), increase the expression levels of tight junction proteins (Claudin-1, Occludin, and ZO-1), and the integrity of the IPEC-J2 monolayer. Our data also showed that resveratrol could attenuate the toxicity of the co-occurrence of three fumonisins. It is implied that resveratrol represents a promising protective approach for fumonisin, even other mycotoxins in the future. This provided a new strategy for further blocking and controlling the toxicity of fumonisin, subsequently avoiding adverse effects on the human and animal health.

Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma.

PURPOSE: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC). METHODS: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed. RESULTS: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs ( p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99). CONCLUSIONS: LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.

Development of a diagnostic model for biliary atresia based on MMP7 and serological tests using machine learning.

OBJECTIVE: To develop a machine learning diagnostic model based on MMP7 and other serological testing indicators for early and efficient diagnosis of biliary atresia (BA). METHODS: A retrospective analysis was conducted on patient information from those hospitalized for pathological jaundice at Beijing Children's Hospital between January 1, 2019, and December 31, 2023. Patients with serum MMP7, liver stiffness measurements, and other routine serological tests were included in the study. Six machine learning models were constructed, including logistic regression (LR), random forest (RF), decision tree (DET), support vector machine classifier (SVC), neural network (MLP), and extreme gradient boosting (XGBoost), to diagnose BA. The area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the various models. RESULTS: A total of 98 patients were included in the study, comprising 64 BA patients and 34 patients with other cholestatic liver diseases. Among the six machine learning models, the XGBoost algorithm model and RF algorithm model achieved the best predictive performance, with an AUROC of nearly 100% in both the training and validation sets. In the training set, these two algorithm models achieved an accuracy, precision, recall, F1 score, and AUROC of 1. Through model interpretation analysis, serum MMP7 levels, serum GGT levels, and acholic stools were identified as the most important indicators for diagnosing BA. The nomogram constructed based on the XGBoost algorithm model also demonstrated convenient and efficient diagnostic efficacy. CONCLUSION: Machine learning models, especially the XGBoost algorithm and RF algorithm models, constructed based on preoperative serum MMP7 and serological tests can diagnose BA more efficiently and accurately. The most important influencing factors for diagnosis are serum MMP7, serum GGT, and acholic stools.

A Rapid Self-Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable ß-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Surgical treatment patterns and clinical outcomes of type B aortic dissection involving the aortic arch.

OBJECTIVE: In the present report, we have described the outcomes of endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D). METHODS: Cases of endovascular repair, hybrid arch repair, and open surgical repair performed between January 2015 and December 2019 for aortic dissection designated as B1-2, D by the Society for Vascular Surgery/Society of Thoracic Surgeons classification were retrospectively analyzed. The primary end point was all-cause mortality at follow-up. The secondary end points included early mortality, early morbidities, and aortic-related late events. Kaplan-Meier curves were created to analyze survival from all-cause mortality and freedom from aortic-related late events in the endovascular, hybrid, and open groups. Propensity score matching and stratification (stratified by proximal dissection extension: B1, D and B2, D) were performed as sensitivity analyses to compare the outcomes among the three treatment patterns after controlling for major confounders. RESULTS: The present study included 151 patients (men, 79.5%; mean age, 47.3 ± 10.5 years), with 72 (47.7%) in the endovascular group, 46 (30.5%) in the hybrid group, and 33 (21.8%) in the open group. No significant difference was noted in early mortality between the endovascular, hybrid, and open groups (1.4% vs 2.2% vs 3.0%; P = .791). The incidence of early endoleak was significantly greater (33.3% vs 13.0% vs 6.1%; P = .002) and the incidence of renal function deterioration was less (4.2% vs 26.1% vs 24.2%; P = .001) after endovascular repair vs hybrid arch repair and open surgery. After a median follow-up of 40.0 months (range, 0-84.0 months), no significant differences were found in all-cause mortality (5.6% vs 4.3% vs 3.0%; P = 1.0), aortic-related late events (16.7% vs 15.2% vs 12.1%; P = .834), or late endoleak (9.7% vs 4.3% vs 6.1%; P = .630) after endovascular, hybrid, and open surgery. The propensity score matching and stratification analyses displayed consistent outcomes for early mortality, all-cause mortality, and aortic-related late events among the three groups. CONCLUSIONS: The mid- to long-term outcomes after endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D) were favorable and comparable in selected patients. Extensive experience and multidisciplinary teamwork are prerequisites for individualized strategies for repair of B1-2, D.

The Overview of Cognitive Aging Models.

To understand the cause of the age-related decline in cognitive function and its underlying mechanism, the cognitive aging model can provide us with important insights. In this section, we will introduce behavioral and neural models about age-related cognitive changes. Among behavioral models, several aging theories were discussed from the perspectives of educational, biological, and sociological factors, which could explain parts of the aging process. With the development of imaging technology, many studies have discussed the neural mechanism of aging and successively proposed neural models to explain the aging phenomenon. Behavioral models and neural mechanism models supplement each other, gradually unveiling the mystery of cognitive aging.

Long-term bowel function after single-stage transanal endorectal pull-through in neonatal patients with Hirschsprung disease.

BACKGROUND: The aim of this study was to assess long-term outcomes of neonatal patients with Hirschsprung disease (HD) after single-stage transanal endorectal pull-through (TEPT) and to explore the predictive factors contributing to subnormal bowel function. METHODS: Patients aged > 3 years operated for HD with TEPT during neonatal period between 2007 and 2019 answered the bowel function score (BFS) questionnaire. The patients were retrospectively divided into two groups according to whether they had normal bowel function. The clinical variables were compared between the subnormal and normal BFS groups. Univariate and multivariable logistic regression analysis were performed to identify the predictive factors contributing to subnormal bowel function. RESULTS: A total of 160 children (71.7%) were included in this study, with mean follow-up time of 7.3 years (range 3.0-15.1 years). The level of aganglionosis were determined to be the short-segment (124/160, 77.5%), long-segment (33/160, 20.6%), and TCA (3/160, 1.9%). One hundred and thirty-four patients (83.8%) had a BFS ≥ 17, and 26 patients (16.2%) with subnormal bowel function (BFS < 17). Univariate and multivariate logistic regression analysis showed that level of aganglionosis with long-segment or TCA and postoperative hospital stay > 8.5 days were independent risk factors with OR of 3.213 (1.252, 8.246) and 3.813 (1.371, 10.606) for subnormal BFS, respectively. CONCLUSION: Most HD patients who underwent one-stage TEPT in the neonatal period have favorable long-term results, and the level of aganglionosis with long-segment or TCA and long postoperative hospital stay may be closely related to subnormal bowel function.

Contact-electro-catalysis for Direct Synthesis of H2 O2 under Ambient Conditions.

Hydrogen peroxide (H2 O2 ) is an indispensable basic reagent in various industries, such as textile bleach, chemical synthesis, and environmental protection. However, it is challenging to prepare H2 O2 in a green, safe, simple and efficient way under ambient conditions. Here, we found that H2 O2 could be synthesized using a catalytic pathway only by contact charging a two-phase interface at room temperature and normal pressure. Particularly, under the action of mechanical force, electron transfer occurs during physical contact between polytetrafluoroethylene particles and deionized water/O2 interfaces, inducing the generation of reactive free radicals (⋅OH and ⋅O2 - ), and the free radicals could react to form H2 O2 , yielding as high as 313 µmol L-1 h-1 . In addition, the new reaction device could show long-term stable H2 O2 production. This work provides a novel method for the efficient preparation of H2 O2 , which may also stimulate further explorations on contact-electrification-induced chemistry process.

A novel partially open state of SHP2 points to a "multiple gear" regulation mechanism.

The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.

Remote Raman Detection of Trace Explosives by Laser Beam Focusing and Plasmonic Spray Enhancement Methods.

Remote Raman spectroscopy is a technique that can detect and identify different target molecules through Raman vibrational modes from a remote distance. However, the current remote Raman technique is restricted by poor detection sensitivity, and it is still extremely challenging for trace explosive detection. Here, in order to achieve trace explosive detection from a remote distance, we innovatively propose two enhanced Raman spectroscopy methods by using a plasmonic spray and a laser beam focusing/Raman signal collecting instrument. In brief, a facile convex lens can converge the laser beam and collect Raman scattering signals, and a plasmonic spray can be used for surface-enhanced Raman scattering. Under the combination of the above enhancement methods, we achieve remote Raman detection of a variety of trace explosives with a concentration of ∼1 µg/cm2 from a distance of 30 m. These novel methods demonstrate a simple approach that significantly improves the capability of remote detection of trace chemicals for further applications.