Activation Signals Research Articles

Relationship between environmental evolution and human activities in the northeastern Qinghai-Xizang Plateau throughout the past millennium and its implications for the onset of the Anthropocene

AbstractIn current research on the Anthropocene, assessing the impact of human activities via stratigraphic records of sediments and demarcating the Anthropocene epoch globally are critical scientific issues that urgently need to be addressed. The northeastern Qinghai-Xizang Plateau (QXP), where humans first settled permanently in large numbers in the QXP, has varying sedimentary environments that are extremely sensitive to human activities. In contrast to other regions of the QXP, the northeastern sector boasts a richer array of climatic and environmental reconstruction sequences. This distinctive feature renders it an exemplary locale for investigating the stratigraphic boundary of the Anthropocene. Through in-depth analysis and integration of existing paleoclimate and paleoenvironment sequences in the northeastern QXP, we draw the following conclusions: (1) Throughout the past millennium, the impact of human activities on the environment of the northeastern QXP has become increasingly significant, especially in the past 200–300 years, gradually overshadowing climatic factors. (2) Since AD 1950, multiple physicochemical indicators related to human activities in the northeastern QXP have shown exponential growth, forming a distinct peak within the past millennium and clearly depicting the global “Great Acceleration” phenomenon and its development process. (3) Intensified human activities have driven swift environmental shifts and “decoupled” the interplay between climatic variations and the ecological environment, propelling the northeastern QXP into the “Early Anthropocene” from the “Late Holocene”. On the basis of the above findings, we construct a model suitable for identifying the stratigraphic boundary of the Anthropocene in the northeastern QXP and note that since the ecological environment in the northeastern QXP has entered the “Early Anthropocene”, the climate signals of certain physicochemical indicators in sediments are gradually becoming weaker, whereas the signals of human activities are becoming stronger.

Automatic motion artifact detection in electrodermal activity signals using 1D U-net architecture

We developed a method for automated detection of motion and noise artifacts (MNA) in electrodermal activity (EDA) signals, based on a one-dimensional U-Net architecture. EDA has been widely employed in diverse applications to assess sympathetic functions. However, EDA signals can be easily corrupted by MNA, which frequently occur in wearable systems, particularly those used for ambulatory recording. MNA can lead to false decisions, resulting in inaccurate assessment and diagnosis. Several approaches have been proposed for MNA detection; however, questions remain regarding the generalizability and the feasibility of implementation of the algorithms in real-time especially those involving deep learning approaches. In this work, we propose a deep learning approach based on a one-dimensional U-Net architecture using spectrograms of EDA for MNA detection. We developed our method using four distinct datasets, including two independent testing datasets, with a total of 9602 128-s EDA segments from 104 subjects. Our proposed scheme, including data augmentation, spectrogram computation, and 1D U-Net, yielded balanced accuracies of 80.0 ± 13.7 % and 75.0 ± 14.0 % for the two independent test datasets; these results are better than or comparable to those of other five state-of-the-art methods. Additionally, the computation time of our feature computation and machine learning classification was significantly lower than that of other methods (p < .001). The model requires only 0.28 MB of memory, which is far smaller than the two deep learning approaches (4.93 and 54.59 MB) which were used as comparisons to our study. Our model can be implemented in real-time in embedded systems, even with limited memory and an inefficient microprocessor, without compromising the accuracy of MNA detection.

A pilot study of chlorambucil in pre-treated metastatic pancreatic adenocarcinoma patients bearing germline BRCA or other DNA damage repair system variants

BackgorundPancreatic adenocarcinoma remains a malignancy with a grim prognosis and scarce personalized treatment options. Pathogenic variants of DNA damage repair (DDR) genes are emerging as molecular targets, as they confer a higher sensitivity to DNA-damaging agents. This study aimed at assessing the activity of chlorambucil as salvage therapy in metastatic pancreatic cancer patients bearing a germline pathogenetic variant or variant of uncertain significance on a DDR-related gene. MethodsPlatinum-pretreated metastatic pancreatic cancer patients harbouring a germline variant on a DDR gene received chlorambucil at a daily oral dose of 6 mg/m2 for 42 every 56 days for the first cycle and for 14 every 28 days for the following cycles, until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival rate (PFS-6). Median progression-free survival (PFS) and overall survival (OS) were secondarily described. ResultsTwenty patients were enrolled between December 2020 and September 2022. PFS-6 was 5%, median PFS and OS were 1.6 months and 3.0 months, respectively. Grade-3 adverse events were observed in 25% of patients, while no Grade-4 toxicity was reported. ConclusionsSingle agent chlorambucil did not show sufficient signal of activity to warrant its further investigation in metastatic pancreatic cancer patients bearing a DDR-related germline alteration.

Overcoming drug resistance of cancer cells by targeting the FGF1/FGFR1 axis with honokiol or FGF ligand trap.

Chemoresistance of cancer cells, resulting from various mechanisms, is a significant obstacle to the effectiveness of modern cancer therapies. Targeting fibroblast growth factors (FGFs) and their receptors (FGFRs) is becoming crucial, as their high activity significantly contributes to cancer development and progression by driving cell proliferation and activating signaling pathways that enhance drug resistance. We investigated the potential of honokiol and FGF ligand trap in blocking the FGF1/FGFR1 axis to counteract drug resistance. Using PEAQ-ITC, we verified direct interaction of honokiol with the FGFR1 kinase domain. We then demonstrated the effect of FGF1/FGFR1 inhibition on taltobulin resistance in cells expressing FGFR1. Finally, we generated drug-resistant clones by prolonged exposure of cells with negligible FGFR levels to taltobulin alone, taltobulin and honokiol, or taltobulin and FGF ligand trap. We demonstrated for the first time a direct interaction of honokiol with the FGFR1 kinase domain, resulting in inhibition of downstream signaling pathways. We revealed that both honokiol and FGF ligand trap prevent FGF1-dependent protection against taltobulin in cancer cells expressing FGFR1. In addition, we showed that cells obtained by long-term exposure to taltobulin are resistant to both taltobulin and other microtubule-targeting drugs, and exhibit elevated levels of FGFR1 and cyclin D. We also found that the presence of FGF-ligand trap prevents the development of long-term resistance to taltobulin. Our results shed light on how blocking the FGF1/FGFR1 axis by honokiol and FGF ligand trap could help develop more effective cancer therapies, potentially preventing the emergence of drug-resistant relapses.

A Cyberphysical Structural Health Monitoring Framework for Threshold-Free Active Signal Detection and Classification on the Edge

A Cyberphysical Structural Health Monitoring Framework for Threshold-Free Active Signal Detection and Classification on the Edge

Axon-like active signal transmission

Any electrical signal propagating in a metallic conductor loses amplitude due to the natural resistance of the metal. Compensating for such losses presently requires repeatedly breaking the conductor and interposing amplifiers that consume and regenerate the signal. This century-old primitive severely constrains the design and performance of modern interconnect-dense chips1. Here we present a fundamentally different primitive based on semi-stable edge of chaos (EOC)2,3, a long-theorized but experimentally elusive regime that underlies active (self-amplifying) transmission in biological axons4,5. By electrically accessing the spin crossover in LaCoO3, we isolate semi-stable EOC, characterized by small-signal negative resistance and amplification of perturbations6,7. In a metallic line atop a medium biased at EOC, a signal input at one end exits the other end amplified, without passing through a separate amplifying component. While superficially resembling superconductivity, active transmission offers controllably amplified time-varying small-signal propagation at normal temperature and pressure, but requires an electrically energized EOC medium. Operando thermal mapping reveals the mechanism of amplification—bias energy of the EOC medium, instead of fully dissipating as heat, is partly used to amplify signals in the metallic line, thereby enabling spatially continuous active transmission, which could transform the design and performance of complex electronic chips.

1/fα noise in the Robin Hood model

Abstract We consider the Robin Hood dynamics, a one-dimensional extremal self-organized critical model that describes the low-temperature creep phenomenon. One of the key quantities is the time evolution of the state variable (force noise). To understand the temporal correlations, we compute the power spectra of the local force fluctuations and apply finite-size scaling to get scaling functions and critical exponents. We find a signature of the 1 / f α noise for the local force with a nontrivial value of the spectral exponent 0 &lt; α &lt; 2 . We also examine temporal fluctuations in the position of the extremal site and a local activity signal. We present results for different local interaction rules of the model.

A high sensing performance piezoresistive sensor based on TPU/c-MWCNTs/ V2CTX-MXene electrospun film for human motion detection

Since wearable pressure sensors have promising applications in the fields of human physiological signal detection and bionic robots, there is an urgent need for wearable pressure sensors with comprehensive attributes such as high sensitivity and wide detection range. Here, we introduce a facile electrospinning process to fabricate a film composed of thermoplastic polyurethane/carboxyl multiwalled carbon nanotube/V2CTX-MXene (TPU/c-MWCNTs/V2C). This film has high sensitivity and great linearity, designed for flexible piezoresistive sensors. To further enhance sensor performance, we applied a spin-coating of polydimethylsiloxane (PDMS) on the sandpaper surface to create a top substrate with intermittent spinosum structures. Additionally, a layer of TPU fibers was electrospun between the conductive film and the interdigitated electrodes. The assembled components form a flexible piezoresistive sensor with a wide detection range of 0–200 kPa, a high sensitivity of 545.2 kPa−1, a low detection limit of 5 Pa, a short response time of 48 ms, and excellent long-term durability after 7000 loading/unloading cycles, making the piezoresistive sensor highly discriminating for detecting complex human movements. Thanks to the great sensing performance and stable structure, we conducted various demonstrations to capture human physiological signals, including signals of muscle activity and pulse. These findings indicate the potential of the designed flexible pressure sensor for applications in electronic skin and smart devices.

Exploring the Mechanism of Modified Zexie Decoction Against Metabolic Associated Fatty Liver Disease Based on Network Pharmacology and Experimental Validation.

The incidence of metabolic-associated fatty liver disease (MAFLD) increases annually. Modified Zexie Decoction (MZXD) can treat this disease; however, their mechanisms of action are uncertain. This study evaluated the mechanisms of MZXD against MAFLD based on network pharmacology, molecular docking, and in vivo experiments. The main active compounds, targets and signaling pathways of MZXD against MAFLD were obtained using network pharmacological analysis. Underlying mechanisms were validated by molecular docking and in vivo assays. Forty-one active ingredients and 197 intersection targets were identified. The main active ingredients include quercetin, luteolin, isorhamnetin, 3-methylhexane, and 3β- acetoxyatractylone. The main targets were TP53, JUN, HSP90AA1, MAPK1, MAPK3, AKT1, NF-κB p65, TNF, ESR1, FOS, and IL-6. The pathway enrichment analysis indicated that MZXD was related to the IL-17, TNF, and PI3K-AKT signaling pathways. Molecular docking suggested that these active ingredients bound strongly to TNF, IL-6, and NF-κB p65, which are integral components of the TNF pathway. In the rat MAFLD model, MZXD attenuated high-fat diet( HFD)-induced liver injury and lipid accumulation, decreased the serum levels of the inflammatory mediators TNF-α, IL6, and IL-1β, and inhibited the protein expression of TNF-α, IL6, p- IKB-α and p-NF-κB p65. Furthermore, immunohistochemistry results showed that MZXD attenuated the F4/80 staining intensity of the liver compared with the model group. Collectively, our results suggested that MZXD could improve MAFLD by downregulating TNF/NF-κB signaling mediated macrophage activation.

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1.

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 in apo. The inactive state exhibited substantially increased structural heterogeneity and plasticity compared to the more rigidified active state in the absence of stabilizing ligands. Transmembrane helices TM3 and TM7 were identified as distinguishing factors modulating the state-dependent dynamics. TM7 displayed amplified fluctuations selectively in the inactive state simulations attributed to disruption of conserved electrostatic contacts anchoring it to surrounding helices in the active state. Additionally, we identified significant reorganizations in key salt bridge and hydrogen bond networks contributing to the CB1 activation/inactivation. For instance, D213-Y224 hydrogen bond and D184-K192 salt bridge showed marked rearrangements between the states. Collectively, these findings reveal the specialized role of TM7 in directing state-dependent CB1 dynamics through electrostatic switch mechanisms. By elucidating the intrinsic enhanced flexibility of inactive CB1, this study provides valuable insights into the conformational landscape enabling functional transitions. Our perspective advances understanding of CB1 activation mechanisms and offers opportunities for structure-based drug discovery targeting the state-specific conformational dynamics of this receptor.

668P First-in-human phase I dose escalation study of ALG.APV-527, a 5T4 tumor antigen-conditional 4-1BB bispecific antibody, in patients with advanced solid tumors, demonstrates positive safety, signals of biological activity and patients with lasting stable disease

668P First-in-human phase I dose escalation study of ALG.APV-527, a 5T4 tumor antigen-conditional 4-1BB bispecific antibody, in patients with advanced solid tumors, demonstrates positive safety, signals of biological activity and patients with lasting stable disease

Bio-inspired target detection method of active sonar based on multi-ping perception

Abstract The performance of the active sonar may degrade severely in real ocean environments, influenced by strong reverberation and multiple clutters. Inspired by the observation that dolphins always utilize a train of clicks when detecting underwater, we proposed an active target detection method by making full use of the multi-ping echo information which encompasses the differences between targets and reverberation/clutters. The detection performance of the click trains with different parameters were analysed first to give an insight on signal choice. Then we achieved apparent reverberation/clutter suppression result by utilizing the correlations and differences between multi-ping echoes. Further, the relative motion status between the target and the sonar platform could be perceived within multiple echoes, which strengthened the detection ability of weak target. We proposed two weighting strategies for multi-ping co-utilization. Either equal weights or unequal weights based on the different envelopes of dolphin echolocation click trains were exerted on multiple echoes, which can achieve different perception results for the relative target motion status. Both simulation and lake trials were conducted to verify the performance of the proposed method. The proposed method effectively suppress reveberaton and noise background by around 2-3 dB and achieve bionic detection of weak targets compared to traditional active sonar signal processing method.

A Radiological Clip Design Using Ultrasound Identification to Improve Localization.

We demonstrate the use of ultrasound to receive an acoustic signal transmitted from a radiological clip designed from a custom circuit. This signal encodes an identification number and is localized and identified wirelessly by the ultrasound imaging system. We designed and constructed the test platform with a Teensy 4.0 microcontroller core to detect ultrasonic imaging pulses received by a transducer embedded in a phantom, which acted as the radiological clip. Ultrasound identification (USID) signals were generated and transmitted as a result. The phantom and clip were imaged using an ultrasonic array (Philips L7-4) connected to a Verasonics™ Vantage 128 system operating in pulse inversion (PI) mode. Cross-correlations were performed to localize and identify the code sequences in the PI images. USID signals were detected and visualized on B-mode images of the phantoms with up to sub-millimeter localization accuracy. The average detection rate across 30,400 frames of ultrasound data was 98.1%. The USID clip produced identifiable, distinguishable, and localizable signals when imaged. Radiological clips are used to mark breast cancer being treated by neoadjuvant chemotherapy (NAC) via implant in or near treated lesions. As NAC progresses, available marking clips can lose visibility in ultrasound, the imaging modality of choice for monitoring NAC-treated lesions. By transmitting an active signal, more accurate and reliable ultrasound localization of these clips could be achieved and multiple clips with different ID values could be imaged in the same field of view.

Exploring the action mechanism of Oxalis corniculata L. decoction in treating osteoarthritis utilizing liquid chromatography-mass spectrometry technology combined with network pharmacology.

This study aimed to identify the chemical constituents of Oxalis corniculata L. decoction. Furthermore, the mechanism of action of O corniculata L. decoction in treating osteoarthritis (OA) was investigated utilizing network pharmacology. The chemical composition of the O corniculata L. decoction was analyzed by employing UHPLC-Q-Exactive-MS/MS. Subsequently, a "compound-target-pathway" network was established through network pharmacology, offering a novel approach to identify the molecular mechanism underlying the treatment of OA with O corniculata L. decoction. Ultimately, the molecular docking technique was employed to validate the binding ability of the active ingredients with therapeutic targets. A total of 539 compounds were identified in O corniculata L. decoction. Topological analysis of the protein-protein interaction network indicated that compounds, including guanosine, naringenin-7-O-beta-D-glucuronide, noroxyhydrastinine, and chrysophanol 8-O-glucoside, have therapeutic potential for OA. In addition, GAPDH, TNF, TP53, epidermal growth factor receptor, and ESR1 may be key targets for the treatment of OA, primarily involving lipid and atherosclerosis, cellular senescence, IL-17 signaling pathway, and epidermal growth factor receptor tyrosine kinase inhibitor resistance signaling pathways. This method preliminarily identified the chemical composition of O corniculata L. decoction and predicted the active ingredients, potential targets, and signaling pathways of O corniculata L. decoction in treating OA. The findings of this research revealed the potential function of O corniculata L. decoction in anti-inflammation, alongside its ability to promote osteoblast proliferation and differentiation, providing new ideas for the processing of O corniculata L. herbs and related drug development.

B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation

B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment.

The GAPS Programme at TNG. LIX. Characterisation study of the ~300 Myr-old multi-planetary system orbiting the star BD+40 2790 (TOI-2076)

The long-term Global Architecture of Planetary Systems (GAPS) programme has been characterising a sample of young systems with transiting planets via spectroscopic and photometric follow-up observations. One of the main goals of GAPS is measuring planets' dynamical masses and bulk densities to help build a picture of how planets evolve in the early stages of their formation via a comparison between the fundamental physical properties of young and mature exoplanets. We collected more than 300 high-resolution spectra of the sim 300 Myr old star BD+40 2790 (TOI-2076) over about three years. This star hosts three transiting planets discovered by TESS, with orbital periods of sim 10, 21, and 35 days. From our determined fundamental planetary physical properties, we investigate the temporal evolution of the planetary atmospheres by calculating the expected mass loss rate due to photo-evaporation up to a system age of 5 Gyr. BD+40 2790 shows an activity-induced scatter larger than 30 ms in the radial velocities. We employed different methods to measure the stellar radial velocities, along with several models to filter out the dominant stellar activity signal to bring to light the planet-induced signals, which are expected to have semi-amplitudes that are lower by one order of magnitude. We evaluated the mass loss rate of the planetary atmospheres using photo-ionisation hydrodynamic modeling, accounting for the temporal evolution of the stellar high-energy flux through the adoption of different models for X-rays and EUV irradiation. The dynamical analysis confirms that the three sub-Neptune-sized companions (with our radius measurements of $R_b$=2.54pm 0.04, $R_c$=3.35pm 0.05, and $R_d$=3.29pm 0.06 have masses that situate them in the planetary regime. We derived 3sigma upper limits below or close to the mass of Neptune for all the planets in our sample: 11--12, 12--13.5, and 14--19 for planets $b$, $c$, and $d$, respectively. In the case of planet $d$, we found promising clues that the mass could be between sim 7 and 8 with a significance level between 2.3--2.5sigma (at best). This result must be further investigated using other analysis methods and techniques or using high-precision near-infrared (nIR) spectrographs to collect new radial velocities, which could be less affected by stellar activity. Atmospheric photo-evaporation simulations predict that BD+40 2790\,b is currently losing its H-He gaseous envelope and that it will be completely lost at an age within 0.5--3\,Gyr if its current mass is lower than 12\,M$_ Furthermore, BD+40 2790\,c could have a lower bulk density than $b$ and might be able to retain its atmosphere up to an age of 5 Gyr. For the outermost object, planet $d$, we predicted an almost negligible evolution of its mass and radius, induced by photo-evaporation.

Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.Graphical

A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

Cross-Priming-Linked Hierarchical Isothermal Amplification Programming Progressive Activating Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a in miRNA Signaling.

Cascade isothermal nucleic acid amplification, which integrates several different amplification protocols to enhance the assay performance, is widely utilized in biosensing, particularly for detecting microRNAs (miRNAs), crucial biomarkers associated with tumor initiation and progression. However, striking a balance between a high amplification efficiency and simplicity in design remains a challenge. Therefore, methods achieving high amplification efficiency without significantly increasing complexity are highly favored. In this study, we propose a novel approach for miRNA detection, employing cross-priming-linked hierarchical isothermal amplification (CP-HIA) to progressively activate the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a system. The CP-HIA method strategically combines nicking-rolling circle amplification (n-RCA) and palindrome-aided circular strand displacement amplification (p-CSDA) for miRNA detection. Remarkably, this method utilizes only two main probes. Its key innovation lies in the interactive cross-priming strategy, wherein the amplification product from n-RCA is recycled to further drive p-CSDA, and vice versa. This interactive process establishes a hierarchical amplification, significantly enriching the activation probes for progressive CRISPR/Cas12a activation and subsequent target signal amplification. Consequently, the method exhibits greatly enhanced analytical performance, including high sensitivity and specificity in detecting low concentrations of miRNA. As low as 1.06 fM miRNA can thus be quantitatively detected, and the linear response of the miRNA is from 10 fM to 10 nM. These features demonstrate its potential for early disease diagnosis and monitoring. We anticipate that the CP-HIA method will serve as a promising platform for developing advanced molecular diagnostic tools for biomedical research.

Genomic alterations in two patients with esophageal carcinosarcoma identified by whole genome sequencing: a case report

BackgroundEsophageal carcinosarcoma (ECS) is a relatively rare malignancy, accounting for < 1% of all esophageal cancers. Its etiopathogenesis remains unknown. This study analyzed the genomic abnormalities in sarcomatous tumors from two patients undergoing subtotal esophagectomy using whole genome sequencing to elucidate the key characteristics of ECS.Case presentationWe identified TP53 driver mutations, copy number gains in 11q13 (including CCND1), and Apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) signature enrichment in both ECS patients. Along with common genetic abnormalities, we identified CDKN2A driver mutations in case 1 and RAC1, NOTCH1, and TTC28 as novel fusion gene partners of MECOM in case 2. Notably, we detected germline pathogenic variant in Fanconi anemia (FA) complementation group I (FANCI) and group G (FANCG), which are involved in repairing DNA double-strand breaks by homologous recombination, for the first time, in ECS blood samples. These germline variants were truncating-type, Lys1221fs of FANCI (rs1567179036) for case 1 and Gln365Ter of FANCG (rs121434426) for case 2. We also identified somatic changes in cancer-associated pathways, such as PI3K/Akt/mTOR, cell cycle, and NOTCH signaling pathways, and structural chromosomal defects such as chromosome doubling.ConclusionsOur findings indicate that therapeutic drugs targeting the activation signal or FA pathway might be effective in treating ECS, however, their therapeutic significance should be elucidated in future studies.