Cold-hot Janus electrochemical aptamer-based sensor for calibration-free determination of biomolecules.

Real-time, high-frequency measurements of pharmaceuticals, metabolites, exogenous antigens, and other biomolecules in biological samples can provide critical information for health management and clinical diagnosis. Electrochemical aptamer-based (EAB) sensor is a promising analytical technique capable of achieving these goals. However, the issues of insufficient sensitivity, frequent calibration and lack of adapted portable electrochemical device limit its practical application in immediate detection. In response we have fabricated an on-chip-integrated, cold-hot Janus EAB (J-EAB) sensor based on the thermoelectric coolers (TECs). Attributed to the Peltier effect, the enhanced/suppressed current response can be generated simultaneously on cold/hot sides of the J-EAB sensor. The ratio of the current responses on the cold and hot sides was used as the detection signal, enabling rapid on-site, calibration-free determination of small molecules (procaine) as well as macromolecules (SARS-CoV-2 spike protein) in single step, with detection limits of 1 µM and 10 nM, respectively. We have further demonstrated that the J-EAB sensor is effective in improving the ease and usability of the actual detection process, and is expected to provide a universal, low-cost, fast and easy potential analytical tool for other clinically important biomarkers, drugs or pharmaceutical small molecules.

SLC2A1 boosts the resistance of non-small cell lung cancer to taxanes by stimulating the formation of EPCAM+ cancer stem-like cells via glycolysis.

BACKGROUND: The mechanisms by which SLC2A1 enhances chemo-resistance of taxanes to non-small cell lung cancer (NSCLC) remains enigmatic. METHODS: An investigation into the SLC2A1 expression pattern and prognosis across diverse datasets, as well as our internally collected samples, was undertaken. Additionally, the biological function of SLC2A1 was further delved into through in vitro experiments. The study also examined the chemo-resistance of NSCLC to taxanes using CCK-8, Annexin-V, and caspase-3 assays. Furthermore, the impact of taxanes on SLC2A1 expression was determined via western blot analysis. The effects of SLC2A1 on the formation of CSCs was examined via flow cytometry and metabolomics techniques. Finally, the impact of SLC2A1 on the tumor microenvironment was analyzed using single-cell sequencing and cellchat. RESULTS: In the present investigation, it was observed that there was an elevated expression of SLC2A1 in NSCLC tumor tissues, which exhibited a significant association with a poorer prognosis. SLC2A1 overexpression in vitro promoted NSCLC cell proliferation, invasion, migration, chemo-resistance, and the formation of CD90+ and EpCAM+ CSCs. NSCLC cells were categorized based on SLC2A1 and EpCAM expression. SLC2A1highEpCAM+ CSCs were more chemo-resistance to taxanes. NSCLC patients with high SLC2A1 and EpCAM expression had poorer prognosis. Mechanically, SLC2A1 promoted the formation of CD90+ and EpCAM+ CSCs via activating glycolysis. Finally, SLC2A1low tumor cells promoted CD8+T cell function via HLA-A, B, C, and suppressed NK cell function via HLA-E. CONCLUSION: Together, SLC2A1 plays an important role in enhancing chemo-resistance of taxanes to NSCLC.

Effects of Progressive and Velocity-Based Autoregulatory Resistance Training on Lower-Limb Movement Ability in Taekwondo Athletes.

BACKGROUND: Both autoregulatory progressive resistance exercise (APRE) and velocity-based resistance training (VBRT) utilize real-time monitoring of athlete physical performance to adjust training loads to provide appropriate training stimuli. However, the monitoring and adjustment approaches differ between both methods. This study aimed to compare the effects of APRE and VBRT on the muscle strength, power, and agility of college taekwondo athletes. HYPOTHESIS: Eight weeks of APRE and VBRT will promote similar results to strength gains in regards maximal strength, but VBRT will be superior to APRE in explosive power and agility. STUDY DESIGN: Clinical trial. LEVEL OF EVIDENCE: Level 3. METHODS: Thirty taekwondo athletes were divided randomly into 2 groups (VBRT/APRE), and all participants completed an 8-week APRE/VBRT intervention. Maximum strength, explosive power, and agility performance were assessed during the squat 1-repetition maximum (1RM), countermovement jump (CMJ), drop jump (DJ), kicking strength test (KST), taekwondo-specific agility test (TSAT), and hexagon test (HT). RESULTS: Highly significant time effects (P < 0.01) were observed for squat 1RM, CMJ, and TSAT in both the APRE and VBRT groups. However, there were no significant group-by-time differences for any of the measured outcomes to intergroup (P > 0.05), but APRE had a small effect size (ES) over VBRT for CMJ (ES = 0.48, η2p = 0.06), TSAT (ES = 0.26, η2p = 0.02), and HT (ES = 0.42, η2p = 0.05). CONCLUSION: An 8-week autoregulatory APRE and VBRT can both effectively improve both the maximal strength, explosive power, and agility performance of taekwondo athletes, with APRE exhibiting potential advantages in improving CMJ, TSAT, and HT. CLINICAL RELEVANCE: These results provide important insights into the selection of suitable resistance training programs by professional coaches, taking into account athlete needs, training efficiency, and safety considerations.

A High-Throughput Method for Accurate Extraction of Intact Rice Panicle Traits.

Rice panicle traits serve as critical indicators of both yield potential and germplasm resource quality. However, traditional manual measurements of these traits, which typically involve threshing, are not only laborious and time-consuming but also prone to introducing measurement errors. This study introduces a high-throughput and nondestructive method, termed extraction of panicle traits (EOPT), along with the software Panicle Analyzer, which is designed to assess unshaped intact rice panicle traits, including the panicle grain number, grain length, grain width, and panicle length. To address the challenge of grain occlusion within an intact panicle, we define a panicle morphology index to quantify the occlusion levels among the rice grains within the panicle. By calibrating the grain number obtained directly from rice panicle images based on the panicle morphology index, we substantially improve the grain number detection accuracy. For measuring grain length and width, the EOPT selects rice grains using an intersection over union threshold of 0.8 and a confidence threshold of 0.7 during the grain detection process. The mean values of these grains were calculated to represent all the panicle grain lengths and widths. In addition, EOPT extracted the main path of the skeleton of the rice panicle using the Astar algorithm to determine panicle lengths. Validation on a dataset of 1,554 panicle images demonstrated the effectiveness of the proposed method, achieving 93.57% accuracy in panicle grain counting with a mean absolute percentage error of 6.62%. High accuracy rates were also recorded for grain length (96.83%) and panicle length (97.13%). Moreover, the utility of EOPT was confirmed across different years and scenes, both indoors and outdoors. A genome-wide association study was conducted, leveraging the phenotypic traits obtained via EOPT and genotypic data. This study identified single-nucleotide polymorphisms associated with grain length, width, number per panicle, and panicle length, further emphasizing the utility and potential of this method in advancing rice breeding.

Two-Dimensional M-Chalcogene Family with Tunable Superconducting, Topological, and Magnetic Properties.

An interesting question is whether chalcogen atoms can emulate the role of carbon or boron elements stabilized between two transition metal layers, as observed in MXenes or MBenes. Here, we predict a new family of two-dimensional ternary compounds M4XY2 (where M = Pd, Y, Zr, etc.; X = S, Se, Te; and Y = Cl, Br, I), named M-chalcogene. Through first-principles calculations, we reveal diverse physical properties in these compounds, including superconducting, topological, and magnetic characteristics, where the bilayer transition metals play crucial roles. Moreover, the expected helical edge states and superconducting transition temperatures in Pd4SCl2 can be finely tuned by strains. Additionally, the Ti4SCl2 is predicted to be a topological insulator and shows promise as a gas sensor candidate for certain exotic gases. Our findings expand two-dimensional material families and provide promising platforms for diverse physical phenomena with efficient tunability by external stimuli for various applications.

Identifying Factors Associated with Fast Visual Field Progression in Patients with Ocular Hypertension Based on Unsupervised Machine Learning.

PURPOSE: To identify ocular hypertension (OHT) subtypes with different trends of visual field (VF) progression based on unsupervised machine learning and to discover factors associated with fast VF progression. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: A total of 3133 eyes of 1568 ocular hypertension treatment study (OHTS) participants with at least five follow-up VF tests were included in the study. METHODS: We used a latent class mixed model (LCMM) to identify OHT subtypes using standard automated perimetry (SAP) mean deviation (MD) trajectories. We characterized the subtypes based on demographic, clinical, ocular, and VF factors at the baseline. We then identified factors driving fast VF progression using generalized estimating equation (GEE) and justified findings qualitatively and quantitatively. MAIN OUTCOME MEASURE: Rates of SAP mean deviation (MD) change. RESULTS: The LCMM model discovered four clusters (subtypes) of eyes with different trajectories of MD worsening. The number of eyes in clusters were 794 (25%), 1675 (54%), 531 (17%) and 133 (4%). We labeled the clusters as Improvers (cluster 1), Stables (cluster 2), Slow progressors (cluster 3), and Fast progressors (cluster 4) based on their mean of MD decline rate, which were 0.08, -0.06, -0.21, and -0.45 dB/year, respectively. Eyes with fast VF progression had higher baseline age, intraocular pressure (IOP), pattern standard deviation (PSD) and refractive error (RE), but lower central corneal thickness (CCT). Fast progression was associated with being male, heart disease history, diabetes history, African American race, and stroke history. CONCLUSION: Unsupervised clustering can objectively identify OHT subtypes including those with fast VF worsening without human expert intervention. Fast VF progression was associated with higher history of stroke, heart disease and diabetes. Fast progressors were more from African American race , males and had higher incidence of glaucoma conversion. Subtyping can provide guidance for adjusting treatment plans to slow vision loss and improve quality of life of patients with a faster progression course.

Novel Stability Criteria of Asynchronously Switched Nonlinear Neutral Time-Delay Systems.

This article investigates the input-to-state stability and integral input-to-state stability for the switched nonlinear neutral systems (SNNSs) with multiple time-varying delays (MTVDs) and asynchronous switching. According to the fact that the switching signals of the controllers and the subsystems are inconsistent, novel stability criteria on the input-to-state stability and integral input-to-state stability properties for SNNSs with MTVDs and the asynchronous switching phenomenon are presented by multiple Lyapunov-Krasovskii functionals, the merging switching signal, and the mode-dependent average dwell time technique. Compared with the existing related works, our results are less conservative. Meanwhile, our proposed works not only investigate the effects of switches and neutral terms on the stability property for SNNSs but also study the case of the systems with MTVDs and asynchronous switching. Finally, two practical examples, including the practical coupled mass-spring-damper-pendulum system, are presented to show the effectiveness of our results.

MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression.

BACKGROUND: The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. METHODS: In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. RESULTS: Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79-87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. CONCLUSIONS: Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Rapid nanomolar detection of cocaine in biofluids by electrochemical aptamer-based sensor with low-temperature effect for drugged driving screening.

Cocaine is one of the most abused illicit drugs, and its abuse damages the central nervous system and can even lead directly to death. Therefore, the development of simple, rapid and highly sensitive detection methods is crucial for the prevention and control of drug abuse, traffic accidents and crime. In this work, an electrochemical aptamer-based (EAB) sensor based on the low-temperature enhancement effect was developed for the direct determination of cocaine in bio-samples. The signal gain of the sensor at 10 °C was greatly improved compared to room temperature, owing to the improved affinity between the aptamer and the target. Additionally, the electroactive area of the gold electrode used to fabricate the EAB sensor was increased 20 times by a simple electrochemical roughening method. The porous electrode possesses more efficient electron transfer and better antifouling properties after roughening. These improvements enabled the sensor to achieve rapid detection of cocaine in complex bio-samples. The low detection limits (LOD) of cocaine in undiluted urine, 50% serum and 50% saliva were 70 nM, 30 nM and 10 nM, respectively, which are below the concentration threshold in drugged driving screening. The aptasensor was simple to construct and reusable, which offers potential for drugged driving screening in the real world.

CsMIKC1 regulates inflorescence development and grain production in Cannabis sativa plants.

Female inflorescence is the primary output of medical Cannabis. It contains hundreds of cannabinoids that accumulate in the glandular trichomes. However, little is known about the genetic mechanisms governing Cannabis inflorescence development. In this study, we reported the map-based cloning of a gene determining the number of inflorescences per branch. We named this gene CsMIKC1 since it encodes a transcription factor that belongs to the MIKC-type MADS subfamily. Constitutive overexpression of CsMIKC1 increases inflorescence number per branch, thereby promoting flower production as well as grain yield in transgenic Cannabis plants. We further identified a plant-specific transcription factor, CsBPC2, promoting the expression of CsMIKC1. CsBPC2 mutants and CsMIKC1 mutants were successfully created using the CRISPR-Cas9 system; they exhibited similar inflorescence degeneration and grain reduction. We also validated the interaction of CsMIKC1 with CsVIP3, which suppressed expression of four inflorescence development-related genes in Cannabis. Our findings establish important roles for CsMIKC1 in Cannabis, which could represent a previously unrecognized mechanism of inflorescence development regulated by ethylene.

Enhanced oral bioavailability of cannabidiol by flexible zein nanoparticles: in vitro and pharmacokinetic studies.

Introduction: Cannabidiol (CBD) has a variety of pharmacological effects including antiepileptic, antispasmodic, anxiolytic and anti-inflammatory among other pharmacological effects. However, since CBD is a terpene-phenolic compound, its clinical application is limited by its poor water solubility, low stability, and low bioavailability. Methods: In this study, we used several strategies to address the above problems. Hydrochloric acid was used to modify zein to improve the molecular flexibility. Flexible zein nanoparticles (FZP-CBD) loaded with CBD was prepared to improve the stability and bioavailability of CBD. The parameters were evaluated in terms of morphology, particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), loading capacity (LC%), and storage stability. Simulated gastrointestinal fluid release experiment and bioavailability assay were applied in the evaluation. Results: The simulated gastrointestinal fluid experiment showed that the release rates of FZP-CBD and natural zein nanoparticles (NZP-CBD) loaded with CBD were 3.57% and 89.88%, respectively, after digestion with gastric fluid for 2 h, 92.12% and 92.56%, respectively, after intestinal fluid digestion for 2 h. Compared with NZP-CBD, the C max of FZP-CBD at 3 different doses of CBD was increased by 1.7, 1.3 and 1.5 times respectively, and AUC0-t was increased by 1.4, 1.1 and 1.7 times respectively, bioavailability (F) was increased by 135.9%, 114.9%, 169.6% respectively. Discussion: The experimental results showed that FZP-CBD could protect most of the CBD from being released in the stomach, and then control its release in the intestines, promote the absorption of CBD in the small intestine, and increase the bioavailability of CBD. Therefore, FZP-CBD could improve the utilization value of CBD and provide a new idea for the application of CBD in medicine and pharmacy.

Record-High Superconducting Transition Temperature in a Ti1-xMnx Alloy with the Rich Magnetic Element Mn.

It is well-known that magnetic moments are very harmful to superconductivity. A typical example is the element Mn, whose compounds usually exhibit strong magnetism. Thus, it is very difficult to achieve superconductivity in materials containing Mn. Here, we report enhanced superconductivity with a superconducting transition temperature (Tc) up to a record-high value of about 26 K in a beta-phase Ti1-xMnx alloy containing the rich magnetic element Mn under high pressures. This is contrary to the intuition that magnetic moments always suppress superconductivity. Under high pressures, we also found that in the middle-pressure regime, the Pauli limit of the upper critical field is surpassed. The synchrotron X-ray diffraction data show an unchanged beta-phase with a continuous contraction of the cell volume, which is well-supported by the first-principles calculations. Although the theoretical results based on electron-phonon coupling can interpret the Tc value in a certain pressure region, the monotonic enhancement of superconductivity by pressure cannot seek support from the theory. Our results show a surprising enhancement of superconductivity in the Ti1-xMnx alloy with a considerable Mn content.

Prevalence and molecular characteristics of intestinal pathogenic Escherichia coli isolated from diarrheal pigs in Southern China.

Intestinal pathogenic Escherichia coli (InPEC) is one of the most common causes of bacterial diarrhea in farm animals, including profuse neonatal diarrhea and post weaning diarrhea (PWD) in piglets. In this study, we investigated the prevalence of InPEC and associated primary virulence factors among 543 non-duplicate E. coli isolates from diarrheal pigs from 15 swine farms in southern China. Six major virulence genes associated with InPEC were identified among 69 (12.71 %) E. coli isolates and included est (6.62 %), K88 (4.79 %), elt (3.68 %), eae (1.47 %), stx2 (0.92 %) and F18 (0.55 %). Three pathotypes of InPEC were identified including ETEC (8.10 %), EPEC (1.29 %) and STEC/ETEC (0.92 %). In particular, K88 was only found in ETEC from breeding farms, whereas F18 was only present in STEC/ETEC hybrid from finishing farms. Whole genome sequence analysis of 37 E. coli isolates revealed that InPEC strains frequently co-carried multiple antibiotic resistance gene (ARG). est, elt and F18 were also found to co-locate with ARGs on a single IncFIB/IncFII plasmid. InPEC isolates from different pathotypes also possessed different profiles of virulence genes and antimicrobial resistance genes. Population structure analysis demonstrated that InPEC isolates from different pathotypes were highly heterogeneous whereas those of the same pathotype were extremely similar. Plasmid analysis revealed that K88 and/or est/elt were found on pGX18-2-like/pGX203-2-like and pGX203-1-like IncFII plasmids, while F18 and elt/est, as well as diverse ARGs were found to co-locate on IncFII/IncFIB plasmids with a non-typical backbone. Moreover, these key virulence genes were flanked by or adjacent to IS elements. Our findings indicated that both clonal expansion and horizontal spread of epidemic IncFII plasmids contributed to the prevalence of InPEC and the specific virulence genes (F4, F18, elt and est) in the tested swine farms.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

The potential of a targeted unilateral compound training program to reduce lower limb strength asymmetry and increase performance: a proof-of-concept in basketball.

Objective: This study investigates the efficacy of training methodologies aimed at mitigating asymmetries in lower limb strength and explosiveness among basketball players. Methods: Thirty male university basketball athletes were enrolled in this research. Initial assessments were made regarding their physical attributes, strength, and explosiveness. Subsequently, the participants were randomly allocated into two groups: an experimental group (EG, n = 15) and a control group (CG, n = 15). Over 10 weeks, the EG engaged in a unilateral compound training regimen, incorporating resistance training exercises such as split squats, Bulgarian split squats, box step-ups, and single-leg calf raises (non-dominant leg: three sets of six repetitions; dominant leg: one set of six repetitions) and plyometric drills including lunge jumps, single-leg hops with back foot raise, single-leg lateral jumps, and single-leg continuous hopping (non-dominant leg: three sets of 12 repetitions; dominant leg: one set of 12 repetitions). The CG continued with their standard training routine. Assessments of limb asymmetry and athletic performance were conducted before and after the intervention to evaluate changes. Results: 1) Body morphology assessments showed limb length and circumference discrepancies of less than 3 cm. The initial average asymmetry percentages in the single-leg countermovement jump (SLCMJ) for jump height, power, and impulse were 15.56%, 12.4%, and 4.48%, respectively. 2) Post-intervention, the EG demonstrated a significant reduction in the asymmetry percentages of SLCMJ height and power (p < 0.01), along with improvements in the isometric mid-thigh pull (IMTP) test metrics (p < 0.05). 3) The EG also showed marked enhancements in the double-leg countermovement jump (CMJ) and standing long jump (SLJ) outcomes compared to the CG (p < 0.01), as well as in squat performance (p < 0.05). Conclusion: The 10-week unilateral compound training program effectively reduced the asymmetry in lower limb strength and explosiveness among elite male university basketball players, contributing to increased maximal strength and explosiveness.

Veno-arterial extracorporeal membrane oxygenation for the treatment of obstructive shock caused by venous air embolism: A case report.

BACKGROUND: Venous air embolism (VAE) is a potentially lethal condition, with a reported incidence rate of about 0.13%, and the true incidence may be higher since many VAE are asymptomatic. The current treatments for VAE include Durant's maneuver, aspiration and removal of air through venous catheters, and hyperbaric oxygen therapy. For critically ill patients, use of cardiotonic drugs and chest compressions remain useful strategies. The wider availability of extracorporeal membrane oxygenation (ECMO) has brought a new option for VAE patients. CASE SUMMARY: A 53-year-old female patient with VAE presented to the emergency clinic due to abdominal pain with fever for 1 d and unconsciousness for 2 h. One day ago, the patient suffered from abdominal pain, fever, and diarrhea. She suddenly became unconscious after going to the toilet during the intravenous infusion of ciprofloxacin 2 h ago, accompanied by nausea and vomiting, during which a small amount of gastric contents were discharged. She was immediately sent to a local hospital, where cranial and chest computed tomography showed bilateral pneumonia as well as accumulated air visible in the right ventricle and pulmonary artery. The condition deteriorated despite endotracheal intubation, rehydration, and other treatments, and the patient was then transferred to our hospital. Veno-arterial ECMO was applied in our hospital, and the patient's condition gradually improved. The patient was successfully weaned from ECMO and extubated after two days. CONCLUSION: ECMO may be an important treatment for patients with VAE in critical condition.

Unraveling the causes of the Seoul Halloween crowd-crush disaster.

As the world steadily recovers from the COVID-19 pandemic, managing large gatherings becomes a critical concern for ensuring crowd safety. The crowd-crush disaster in Seoul in 2022 highlights the need for effective predictive crowd management techniques. In this study, an empirical analysis of this incident is conducted using data from various sources, and model-based simulations are created to replicate hazardous crowd conditions in high-risk areas. In the empirical analysis, mobile device data indicates a significant increase in population above normal levels in the disaster area just hours before the incident occurred. In the simulations, a hydrodynamic model is employed to simulate a bidirectional collision, which quantitatively demonstrates that the average density during the crush reached 7.57 ped/m2 (with a maximum of (9.95)ped/m2). Additionally, the average crowd pressure peaked at 1,063 N/m (with a maximum of 1,961 N/m), and the maximum velocity entropy was 10.99. Based on these findings, it can be concluded that the primary causes of the disaster were the substantial population, bidirectional collision, and escalating panic. The results of controlled simulations under various management strategies are then presented. By implementing effective crowd management techniques, crowd safety can be enhanced through quantitative comparisons of these key indicators.

PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer.

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

Lignin-based Carbon Nanomaterials for Biochemical Sensing Applications.

Lignin-based carbon nanomaterials offer several advantages, including biodegradability, biocompatibility, high specific surface area, ease of functionalization, low toxicity, and cost-effectiveness. These materials show promise in biochemical sensing applications, particularly in the detection of metal ions, organic compounds, and human biosignals. Various methods can be employed to synthesize carbon nanomaterials with different dimensions ranging from 0D to 3D, resulting in diverse structures and physicochemical properties. This study provides an overview of the preparation techniques and characteristics of multidimensional (0-3D) lignin-based carbon nanomaterials, such as carbon dots (CDs), carbon nanotubes (CNTs), graphene, and carbon aerogels (CAs). Additionally, the sensing capabilities of these materials are compared and summarized, followed by a discussion on the potential challenges and future prospects in sensor development.