A vision chip with complementary pathways for open-world sensing.

Image sensors face substantial challenges when dealing with dynamic, diverse and unpredictable scenes in open-world applications. However, the development of image sensors towards high speed, high resolution, large dynamic range and high precision is limited by power and bandwidth. Here we present a complementary sensing paradigm inspired by the human visual system that involves parsing visual information into primitive-based representations and assembling these primitives to form two complementary vision pathways: a cognition-oriented pathway for accurate cognition and an action-oriented pathway for rapid response. To realize this paradigm, a vision chip called Tianmouc is developed, incorporating a hybrid pixel array and a parallel-and-heterogeneous readout architecture. Leveraging the characteristics of the complementary vision pathway, Tianmouc achieves high-speed sensing of up to 10,000 fps, a dynamic range of 130 dB and an advanced figure of merit in terms of spatial resolution, speed and dynamic range. Furthermore, it adaptively reduces bandwidth by 90%. We demonstrate the integration of a Tianmouc chip into an autonomous driving system, showcasing its abilities to enable accurate, fast and robust perception, even in challenging corner cases on open roads. The primitive-based complementary sensing paradigm helps in overcoming fundamental limitations in developing vision systems for diverse open-world applications.

A system hierarchy for brain-inspired computing.

Neuromorphic computing draws inspiration from the brain to provide computing technology and architecture with the potential to drive the next wave of computer engineering1-13. Such brain-inspired computing also provides a promising platform for the development of artificial general intelligence14,15. However, unlike conventional computing systems, which have a well established computer hierarchy built around the concept of Turing completeness and the von Neumann architecture16-18, there is currently no generalized system hierarchy or understanding of completeness for brain-inspired computing. This affects the compatibility between software and hardware, impairing the programming flexibility and development productivity of brain-inspired computing. Here we propose 'neuromorphic completeness', which relaxes the requirement for hardware completeness, and a corresponding system hierarchy, which consists of a Turing-complete software-abstraction model and a versatile abstract neuromorphic architecture. Using this hierarchy, various programs can be described as uniform representations and transformed into the equivalent executable on any neuromorphic complete hardware-that is, it ensures programming-language portability, hardware completeness and compilation feasibility. We implement toolchain software to support the execution of different types of program on various typical hardware platforms, demonstrating the advantage of our system hierarchy, including a new system-design dimension introduced by the neuromorphic completeness. We expect that our study will enable efficient and compatible progress in all aspects of brain-inspired computing systems, facilitating the development of various applications, including artificial general intelligence.

Towards artificial general intelligence with hybrid Tianjic chip architecture.

There are two general approaches to developing artificial general intelligence (AGI)1: computer-science-oriented and neuroscience-oriented. Because of the fundamental differences in their formulations and coding schemes, these two approaches rely on distinct and incompatible platforms2-8, retarding the development of AGI. A general platform that could support the prevailing computer-science-based artificial neural networks as well as neuroscience-inspired models and algorithms is highly desirable. Here we present the Tianjic chip, which integrates the two approaches to provide a hybrid, synergistic platform. The Tianjic chip adopts a many-core architecture, reconfigurable building blocks and a streamlined dataflow with hybrid coding schemes, and can not only accommodate computer-science-based machine-learning algorithms, but also easily implement brain-inspired circuits and several coding schemes. Using just one chip, we demonstrate the simultaneous processing of versatile algorithms and models in an unmanned bicycle system, realizing real-time object detection, tracking, voice control, obstacle avoidance and balance control. Our study is expected to stimulate AGI development by paving the way to more generalized hardware platforms.

Structural and biochemical characterization of Schlafen11 N-terminal domain.

Schlafen11 (SLFN11) is one of the most studied Schlafen proteins that plays vital roles in cancer therapy and virus-host interactions. Herein, we determined the crystal structure of the Sus scrofa SLFN11 N-terminal domain (NTD) to 2.69 Å resolution. sSLFN11-NTD is a pincer-shaped molecule that shares an overall fold with other SLFN-NTDs but exhibits distinct biochemical characteristics. sSLFN11-NTD is a potent RNase cleaving type I and II tRNAs and rRNAs, and with preference to type II tRNAs. Consistent with the codon usage-based translation suppression activity of SLFN11, sSLFN11-NTD cleaves synonymous serine and leucine tRNAs with different efficiencies in vitro. Mutational analysis revealed key determinates of sSLFN11-NTD nucleolytic activity, including the Connection-loop, active site, and key residues essential for substrate recognition, among which E42 constrains sSLFN11-NTD RNase activity, and all nonconservative mutations of E42 stimulated RNase activities. sSLFN11 inhibited the translation of proteins with a low codon adaptation index in cells, which mainly dependent on the RNase activity of the NTD because E42A enhanced the inhibitory effect, but E209A abolished inhibition. Our findings provide structural characterization of an important SLFN11 protein and expand our understanding of the Schlafen family.

Unmodificated stepless regulation of CRISPR/Cas12a multi-performance.

As CRISPR technology is promoted to more fine-divided molecular biology applications, its inherent performance finds it increasingly difficult to cope with diverse needs in these different fields, and how to more accurately control the performance has become a key issue to develop CRISPR technology to a new stage. Herein, we propose a CRISPR/Cas12a regulation strategy based on the powerful programmability of nucleic acid nanotechnology. Unlike previous difficult and rigid regulation of core components Cas nuclease and crRNA, only a simple switch of different external RNA accessories is required to change the reaction kinetics or thermodynamics, thereby finely and almost steplessly regulating multi-performance of CRISPR/Cas12a including activity, speed, specificity, compatibility, programmability and sensitivity. In particular, the significantly improved specificity is expected to mark advance the accuracy of molecular detection and the safety of gene editing. In addition, this strategy was applied to regulate the delayed activation of Cas12a, overcoming the compatibility problem of the one-pot assay without any physical separation or external stimulation, and demonstrating great potential for fine-grained control of CRISPR. This simple but powerful CRISPR regulation strategy without any component modification has pioneering flexibility and versatility, and will unlock the potential for deeper applications of CRISPR technology in many finely divided fields.

The m6A reader IGF2BP2 promotes the progression of esophageal squamous cell carcinoma cells by increasing the stability of OCT4 mRNA.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high morbidity and mortality. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as a reader of RNA m6A (N6 methyladenosine) modification to regulate gene expression at the post-transcriptional level. Emerging evidence suggests that IGF2BP2 plays critical roles in tumorigenesis and malignant development. However, the biological function and molecular mechanism of IGF2BP2 in ESCC are not well understood. Here, we found that IGF2BP2 expression was upregulated in esophageal cancer tissues and ESCC cells, and IGF2BP2 overexpression enhanced proliferation, migration, invasion, and stem cell-like properties of ESCC cells. Conversely, the knockdown of IGF2BP2 expression inhibited malignant phenotype of ESCC cells. Mechanistically, IGF2BP2 upregulated octomer-binding transcription factor 4 (OCT4) mRNA expression, and RNA immunoprecipitation (RIP) assay proved that IGF2BP2 could interact with OCT4 mRNA. Moreover, OCT4 was modified at m6A confirmed by methylated m6A RNA immunoprecipitation (Me-RIP)-qPCR assay, and IGF2BP2 knockdown reduced OCT4 mRNA stability. These results suggested that IGF2BP2 served as a reader for m6A-modified OCT4, thus increased OCT4 mRNA expression by regulating its stability. Furthermore, the knockdown of OCT4 could reverse the effects of IGF2BP2 on ESCC cells. In conclusion, these data indicate that IGF2BP2, as a reader for m6A, plays an oncogenic role by regulating OCT4 expression in ESCC, which provides new insights into targeting IGF2BP2/OCT4 axis for the therapy of ESCC.

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS: The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS: GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.

The conversion of monolignans to sesquilignans and dilignans is closely correlated to the regulation of Arctium lappa seed germination.

MAIN CONCLUSION: The secondary metabolic conversion of monolignans to sesquilignans/dilignans was closely related to seed germination and seedling establishment in Arctium lappa. Arctium lappa plants are used as a kind of traditional Chinese medicines for nearly 1500 years, and so far, only a few studies have put focus on the key secondary metabolic changes during seed germination and seedling establishment. In the current study, a combined approach was used to investigate the correlation among secondary metabolites, plant hormone signaling, and transcriptional profiles at the early critical stages of A. lappa seed germination and seedling establishment. Of 50 metabolites in methonolic extracts of A. lappa samples, 35 metabolites were identified with LC-MS/MS and 15 metabolites were identified with GC-MS. Their qualitative properties were examined according to the predicted chemical structures. The quantitative analysis was performed for deciphering their metabolic profiles, discovering that the secondary metabolic conversion from monolignans to sesquilignans/dilignans was closely correlated to the initiation of A. lappa seed germination and seedling establishment. Furthermore, the critical transcriptional changes in primary metabolisms, translational regulation at different cellular compartments, and multiple plant hormone signaling pathways were revealed. In addition, the combined approach provides unprecedented insights into key regulatory mechanisms in both gene transcription and secondary metabolites besides many known primary metabolites during seed germination of an important traditional Chinese medicinal plant species. The results not only provide new insights to understand the regulation of key medicinal components of 'ARCTII FRUCTUS', arctiin and arctigenin at the stages of seed germination and seedling establishment, but also potentially spur the development of seed-based cultivation in A. lappa plants.

Femtosecond laser direct writing large-area fiber Bragg grating based on diaphragm shaping.

We propose and demonstrate a new method of direct writing large-area fiber Bragg grating by femtosecond laser through the coating. By adding an adjustable diaphragm before the focusing objective, we can precisely control the length of the refractive index modulation line along the femtosecond laser incident direction up to 29.1 µm. In combination with femtosecond laser scanning fabrication technology, a uniform refractive index modulation plane can be inscribed in the fiber in a single scanning. Based on the plane-by-plane inscription method, we have fabricated a high-quality high-reflectivity fiber Bragg grating and a chirped fiber Bragg grating on 20/400 double-clad fiber core. The reflectivity of both gratings is greater than 99%, and the insertion loss is as low as 0.165 dB and 0.162 dB, respectively. The thermal slope of chirped fiber Bragg grating without any refrigeration is 0.088 °C/W and there is no obvious temperature increase when using the water cooling. Therefore, the fabrication method of large-area fiber Bragg grating based on diaphragm shaping can efficiently fabricate high-quality fiber Bragg grating in the large core diameter fiber, which has an important application prospect in high-power all-fiber oscillators, especially all-fiber oscillators in special wavebands.

Evaluating Factors Associated With Telehealth Appropriateness in Outpatient Rheumatoid Arthritis Encounters Using the Encounter Appropriateness Score for You (EASY).

OBJECTIVE: Telehealth has been proposed as a safe and effective alternative to in-person care for rheumatoid arthritis (RA). The purpose of this study was to evaluate factors associated with telehealth appropriateness in outpatient RA encounters. METHODS: A prospective cohort study (January 1, 2021, to August 31, 2021) was conducted using electronic health record data from outpatient RA encounters in a single academic rheumatology practice. Rheumatology providers rated the telehealth appropriateness of their own encounters using the Encounter Appropriateness Score for You (EASY) immediately following each encounter. Robust Poisson regression with generalized estimating equations modeling was used to evaluate the association of telehealth appropriateness with patient demographics, RA clinical characteristics, comorbid noninflammatory causes of joint pain, previous and current encounter characteristics, and provider characteristics. RESULTS: During the study period, 1823 outpatient encounters with 1177 unique patients with RA received an EASY score from 25 rheumatology providers. In the final multivariate model, factors associated with increased telehealth appropriateness included higher average provider preference for telehealth in prior encounters (relative risk [RR] 1.26, 95% CI 1.21-1.31), telehealth as the current encounter modality (RR 2.27, 95% CI 1.95-2.64), and increased patient age (RR 1.05, 95% CI 1.01-1.09). Factors associated with decreased telehealth appropriateness included moderate (RR 0.81, 95% CI 0.68-0.96) and high (RR 0.57, 95% CI 0.46-0.70) RA disease activity and if the previous encounters were conducted by telehealth (RR 0.83, 95% CI 0.73-0.95). CONCLUSION: In this study, telehealth appropriateness was most associated with provider preference, the current and previous encounter modality, and RA disease activity. Other factors like patient demographics, RA medications, and comorbid noninflammatory causes of joint pain were not associated with telehealth appropriateness.

Zwitterion-Modified MXene Quantum Dot as a Nanocarrier for Traditional Chinese Medicine Sanguinarine Delivery and Its Application for Photothermal-Chemotherapy Synergistic Antibacterial and Wound Healing.

The nanomaterialization of traditional Chinese medicine (TCM) has aroused widespread interest among researchers. Sanguinarine (SAN) is a kind of TCM with good antibacterial properties, which has important applications in anti-infection of wounds. Additionally, the combination of photothermal therapy and chemotherapy can overcome bacterial resistance, further improving bactericidal and wound healing efficiency. In this paper, we prepared an antibacterial agent by loading SAN on the zwitterion-modified MXene quantum dot nanocarrier (SAN@AHEP@Ta4C3), realizing pH/NIR controlled drug release and photothermal/chemotherapy synergistic antibacterial and wound healing. The particle size of SAN@AHEP@Ta4C3 is about 120 nm, and it has a good water solubility and stability. In addition, it also has excellent photothermal conversion performance (η = 39.2%), which can effectively convert light energy into heat energy under near-infrared (NIR) laser irradiation, further promoting drug release and achieving bactericidal effects by synergistic chemotherapy and photothermal therapy. The in vitro and in vivo experiments show that SAN@AHEP@Ta4C3 exhibits an excellent antibacterial effect against Staphylococcus aureus and Escherichia coli, and it can effectively promote the wound healing of mice. Moreover, the SAN@AHEP@Ta4C3 also has good biocompatibility and has no side effects on normal tissue and organs. This work introduces a multifunctional antibacterial agent based on TCM and hot-spot material MXene, which will have considerable application prospects in biomedical fields.

LNCHC directly binds and regulates YBX1 stability to ameliorate metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non-coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. METHODS: RNA-binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y-Box binding protein 1 (YBX1) were identified by RNA-seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin-like phospholipase domain containing 3 (PNPLA3) in MASLD progression. RESULTS: Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up-regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction-associated steatohepatitis development. CONCLUSIONS: In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment.

Advances in D-dimer testing: progress in harmonization of clinical assays and innovative detection methods.

The D-dimer is a sensitive indicator of coagulation and fibrinolysis activation, especially valuable as a biomarker of intravascular thrombosis. Measurement of plasma D-dimer levels plays a crucial role in the diagnosis and monitoring of conditions such as deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. A variety of immunoassays, including enzyme-linked immunosorbent assays, latex-enhanced immunoturbidimetric assays, whole-blood aggregation analysis, and immunochromatography assays, are widely used in clinical settings to determine D-dimer levels. However, the results obtained from different D-dimer assays vary significantly. These assays exhibit intra-method coefficients of variation ranging from 6.4% to 17.7%, and the measurement discrepancies among different assays can be as high as 20-fold. The accuracy and reliability of D-dimer testing cannot be guaranteed due to the lack of an internationally endorsed reference measurement system (including reference materials and reference measurement procedures), which may lead to misdiagnosis and underdiagnosis, limiting its full clinical application. In this review, we present an in-depth analysis of clinical D-dimer testing, summarizing the existing challenges, the current state of metrology, and progress towards harmonization. We also review the latest advancements in D-dimer detection techniques, which include mass spectrometry and electrochemical and optical immunoassays. By comparing the basic principles, the definition of the measurand, and analytical performance of these methods, we provide an outlook on the potential improvements in D-dimer clinical testing.

Naringin attenuates Actinobacillus pleuropneumoniae-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway.

Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia (PCP), which is clinically characterized by acute hemorrhagic, necrotizing pneumonia, and chronic fibrinous pneumonia. Although many measures have been taken to prevent the disease, prevention and control of the disease are becoming increasingly difficult due to the abundance of APP sera, weak vaccine cross-protection, and increasing antibiotic resistance in APP. Therefore, there is an urgent need to develop novel drugs against APP infection to prevent the spread of APP. Naringin (NAR) has been reported to have an excellent therapeutic effect on pulmonary diseases, but its therapeutic effect on lung injury caused by APP is not apparent. Our research has shown that NAR was able to alleviate APP-induced weight loss and quantity of food taken and reduce the number of WBCs and NEs in peripheral blood in mice; pathological tissue sections showed that NAR was able to prevent and control APP-induced pathological lung injury effectively; based on the establishment of an in vivo/in vitro model of APP inflammation, it was found that NAR was able to play an anti-inflammatory role through inhibiting the MAPK/NF-κB signaling pathway and exerting anti-inflammatory effects; additionally, NAR activating the Nrf2 signalling pathway, increasing the secretion of antioxidant enzymes Nqo1, CAT, and SOD1, inhibiting the secretion of oxidative damage factors NOS2 and COX2, and enhancing the antioxidant stress ability, thus playing an antioxidant role. In summary, NAR can relieve severe lung injury caused by APP by reducing excessive inflammatory response and improving antioxidant capacity.

The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study.

BACKGROUND: Subclinical hypothyroidism (SCH) is linked to dyslipidaemia and adverse pregnancy outcomes. However, the impact of dyslipidaemia on the outcome of pregnancy in SCH is unclear. METHODS: We enrolled 36,256 pregnant women and evaluated their pregnancy outcomes. The following data was gathered during the first trimester (≤ 13+ 6 weeks of gestation): total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), high-density lipoprotein (HDL-C), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations. The reference ranges for lipids were estimated to range from the 5th to the 95th percentile. Logistic regression assessed the relationships between dyslipidaemia and adverse pregnancy outcomes, including abortion, preeclampsia/eclampsia, low birth weight, foetal growth restriction, premature rupture of foetal membranes, gestational hypertension, preterm birth, macrosomia and gestational diabetes mellitus (GDM). Additionally, the best thresholds for predicting adverse pregnancy outcomes based on TSH, FT4, and lipid levels were determined using receiver operating characteristic curves. RESULTS: In the first trimester, LDL-C > 3.24 mmol/L, TG > 1.92 mmol/L, HDL-C < 1.06 mmol/L, and TC > 5.39 mmol/L were used to define dyslipidaemia. In this cohort, 952 (3.56%) patients were diagnosed with SCH, and those who had dyslipidaemia in the first trimester had higher incidences of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%) than did those without dyslipidaemia. However, after adjusting for prepregnancy body mass index (pre-BMI), dyslipidaemia was no longer related to these risks. Furthermore, elevated TG dyslipidaemia in SCH patients was connected to an enhanced potential of gestational hypertension (odds ratio [OR]: 2.687, 95% confidence interval [CI]: 1.074 ~ 6.722), and elevated LDL-C dyslipidaemia correlated with increased preeclampsia/eclampsia risk (OR: 3.172, 95% CI: 1.204 ~ 8.355) after accounting for age, smoking status, alcohol use, pre-BMI, and levothyroxine use. Additionally, the combination of TC, TG, LDL-C, pre-BMI, and TSH exhibited enhanced predictive capabilities for gestational hypertension, preeclampsia/eclampsia, and GDM. Values of 0.767, 0.704, and 0.706 were obtained from the area under the curve. CONCLUSIONS: Among pregnant women with SCH, dyslipidaemia in early pregnancy was related to elevated risks of adverse pregnancy consequences. The combined consideration of age, pre-BMI, TSH, and lipid levels in the first trimester could be beneficial for monitoring patients and implementing interventions to reduce adverse pregnancy outcomes.

PAM-independent ultra-specific activation of CRISPR-Cas12a via sticky-end dsDNA.

Although CRISPR-Cas12a [clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 12a] combining pre-amplification technology has the advantage of high sensitivity in biosensing, its generality and specificity are insufficient, which greatly restrains its application range. Here, we discovered a new targeting substrate for LbaCas12a (Lachnospiraceae bacterium Cas12a), namely double-stranded DNA (dsDNA) with a sticky-end region (PAM-SE+ dsDNA). We discovered that CRISPR-Cas12a had special enzymatic properties for this substrate DNA, including the ability to recognize and cleave it without needing a protospacer adjacent motif (PAM) sequence and a high sensitivity to single-base mismatches in that substrate. Further mechanism studies revealed that guide RNA (gRNA) formed a triple-stranded flap structure with the substrate dsDNA. We also discovered the property of low-temperature activation of CRISPR-Cas12a and, by coupling with the unique DNA hybridization kinetics at low temperature, we constructed a complete workflow for low-abundance point mutation detection in real samples, which was fast, convenient and free of single-stranded DNA (ssDNA) transformation. The detection limits were 0.005-0.01% for synthesized strands and 0.01-0.05% for plasmid genomic DNA, and the mutation abundances provided by our system for 28 clinical samples were in accordance with next-generation sequencing results. We believe that our work not only reveals novel information about the target recognition mechanism of the CRISPR-Cas12a system, but also greatly broadens its application scenarios.

A PAM-free CRISPR/Cas12a ultra-specific activation mode based on toehold-mediated strand displacement and branch migration.

CRISPR (clustered regularly interspaced short palindromic repeats) technology has achieved great breakthroughs in terms of convenience and sensitivity; it is becoming the most promising molecular tool. However, only two CRISPR activation modes (single and double stranded) are available, and they have specificity and universality bottlenecks that limit the application of CRISPR technology in high-precision molecular recognition. Herein, we proposed a novel CRISPR/Cas12a unrestricted activation mode to greatly improve its performance. The new mode totally eliminates the need for a protospacer adjacent motif and accurately activates Cas12a through toehold-mediated strand displacement and branch migration, which is highly universal and ultra-specific. With this mode, we discriminated all mismatch types and detected the EGFR T790M and L858R mutations in very low abundance. Taken together, our activation mode is deeply incorporated with DNA nanotechnology and extensively broadens the application boundaries of CRISPR technology in biomedical and molecular reaction networks.

Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Moving Object Detection in Freely Moving Camera via Global Motion Compensation and Local Spatial Information Fusion.

Motion object detection (MOD) with freely moving cameras is a challenging task in computer vision. To extract moving objects, most studies have focused on the difference in motion features between foreground and background, which works well for dynamic scenes with relatively regular movements and variations. However, abrupt illumination changes and occlusions often occur in real-world scenes, and the camera may also pan, tilt, rotate, and jitter, etc., resulting in local irregular variations and global discontinuities in motion features. Such complex and changing scenes bring great difficulty in detecting moving objects. To solve this problem, this paper proposes a new MOD method that effectively leverages local and global visual information for foreground/background segmentation. Specifically, on the global side, to support a wider range of camera motion, the relative inter-frame transformations are optimized to absolute transformations referenced to intermediate frames in a global form after enriching the inter-frame matching pairs. The global transformation is fine-tuned using the spatial transformer network (STN). On the local side, to address the problem of dynamic background scenes, foreground object detection is optimized by utilizing the pixel differences between the current frame and the local background model, as well as the consistency of local spatial variations. Then, the spatial information is combined using optical flow segmentation methods, enhancing the precision of the object information. The experimental results show that our method achieves a detection accuracy improvement of over 1.5% compared with the state-of-the-art methods on the datasets of CDNET2014, FBMS-59, and CBD. It demonstrates significant effectiveness in challenging scenarios such as shadows, abrupt changes in illumination, camera jitter, occlusion, and moving backgrounds.

[Determination of 24 elements migration in Yixing clay pottery by inductively coupled plasma mass spectrometry].

OBJECTIVE: To establish an analytical method for determining the migration of 24 elements in Yixing clay pottery in 4% acetic acid simulated solution by inductively coupled plasma mass spectrometry. METHODS: Four types of Yixing clay pottery, including Yixing clay teapot, Yixing clay kettle, Yixing clay pot, and Yixing clay electric stew pot, were immersed in 4% acetic acid as a food simulant for testing. The migration amount of 24 elements in the migration solution was determined using inductively coupled plasma mass spectrometry. RESULTS: Lithium, magnesium, aluminum, iron, and barium elements with a mass concentration of 1000 µg/L; Lead, cadmium, total arsenic, chromium, nickel, copper, vanadium, manganese, antimony, tin, zinc, cobalt, molybdenum, silver, beryllium, thallium, titanium, and strontium elements within 100 µg/L there was a linear relationship within, the r value was between 0.998 739 and 0.999 989. Total mercury at 5.0 µg/L, there was a linear relationship within, the r value of 0.995 056. The detection limit of the elements measured by this method was between 0.5 and 45.0 µg/L, the recovery rate was 80.6%-108.9%, and the relative standard deviation was 1.0%-4.8%(n=6). A total of 32 samples of four types of Yixing clay pottery sold on the market, including teapots, boiling kettles, casseroles, and electric stewing pots, were tested. It was found that the migration of 16 elements, including beryllium, titanium, chromium, nickel, cobalt, zinc, silver, cadmium, antimony, total mercury, thallium, tin, copper, total arsenic, molybdenum, and lead, were lower than the quantitative limit. The element with the highest migration volume teapot was aluminum, magnesium, and barium; The kettle was aluminum and magnesium; Casserole was aluminum, magnesium, and lithium; The electric stew pot was aluminum. CONCLUSION: This method is easy to operate and has high accuracy, providing an effective and feasible detection method for the determination and evaluation of element migration in Yixing clay pottery.