Signaling Pathways Associated with Cancer Stem Cells Play a Significant Role in Immunotherapy Resistance

Cancer stem cells (CSCs) are a subpopulation of tumor cells with properties of self-renewal, pluripotency, plasticity, and differentiation, and are associated with various aberrantly stimulated signaling pathways. They are responsible for tumor recurrence, distant metastasis, and drug resistance, thus inducing poor prognosis. Immunotherapy has achieved encouraging results. However, the resistance associated with its clinical application is a persistent problem in clinical and scientific researches. Increasing evidence shows that signaling pathways associated with CSCs mediate immunotherapy resistance. This review highlights the link between them, and focuses on the underlying mechanism so as to provide potential strategies and approaches for the development of new targets against the immune resistance challenge

Effects of correlation between merging steps on the global halo formation

The excursion set theory of halo formation is modified by adopting the fractional Brownian motion, to account for possible correlation between merging steps. We worked out analytically the conditional mass function, halo merging rate and formation time distribution in the spherical collapse model. We also developed an approximation for the ellipsoidal collapse model and applied it to the calculation of the conditional mass function and the halo formation time distribution. For models in which the steps are positively correlated, the halo merger rate is enhanced when the accreted mass is less than $\sim 25M^*$, while for the negatively correlated case this rate is reduced. Compared with the standard model in which the steps are uncorrelated, the models with positively correlated steps produce more aged population in small mass halos and more younger population in large mass halos, while for the models with negatively correlated steps the opposite is true. An examination of simulation results shows that a weakly positive correlation between successive merging steps appears to fit best. We have also found a systematic effect in the measured mass function due to the finite volume of simulations. In future work, this will be included in the halo model to accurately predict the three point correlation function estimated from simulations.Comment: 8 pages, submitted to MNRA

Surface passivation for highly active, selective, stable, and scalable CO2 electroreduction

Electrochemical conversion of CO2 to formic acid using Bismuth catalysts is one the most promising pathways for industrialization. However, it is still difficult to achieve high formic acid production at wide voltage intervals and industrial current densities because the Bi catalysts are often poisoned by oxygenated species. Herein, we report a Bi3S2 nanowire-ascorbic acid hybrid catalyst that simultaneously improves formic acid selectivity, activity, and stability at high applied voltages. Specifically, a more than 95% faraday efficiency was achieved for the formate formation over a wide potential range above 1.0 V and at ampere-level current densities. The observed excellent catalytic performance was attributable to a unique reconstruction mechanism to form more defective sites while the ascorbic acid layer further stabilized the defective sites by trapping the poisoning hydroxyl groups. When used in an all-solid-state reactor system, the newly developed catalyst achieved efficient production of pure formic acid over 120 hours at 50 mA cm–2 (200 mA cell current)

Safety and Efficacy of Low-Dose Tirofiban Combined With Intravenous Thrombolysis and Mechanical Thrombectomy in Acute Ischemic Stroke: A Matched-Control Analysis From a Nationwide Registry

Purpose: Tirofiban administration to acute ischemic stroke patients undergoing mechanical thrombectomy with preceding intravenous thrombolysis remains controversial. The aim of the current study was to evaluate the safety and efficacy of low-dose tirofiban during mechanical thrombectomy in patients with preceding intravenous thrombolysis.Methods: Patients with acute ischemic stroke undergoing mechanical thrombectomy and preceding intravenous thrombolysis were derived from “ANGEL-ACT,” a multicenter, prospective registry study. The patients were dichotomized into tirofiban and non-tirofiban groups based on whether tirofiban was administered. Propensity score matching was used to minimize case bias. The primary safety endpoint was symptomatic intracerebral hemorrhage (sICH), defined as an intracerebral hemorrhage (ICH) associated with clinical deterioration as determined by the Heidelberg Bleeding Classification. All ICHs and hemorrhage types were recorded. Clinical outcomes included successful recanalization, dramatic clinical improvement, functional independence, and mortality at the 3-month follow-up timepoint. Successful recanalization was defined as a modified Thrombolysis in Cerebral Ischemia score of 2b or 3. Dramatic clinical improvement at 24 h was defined as a reduction in NIH stroke score of ≥10 points compared with admission, or a score ≤1. Functional independence was defined as a Modified Rankin Scale (mRS) score of 0–2 at 3-months.Results: The study included 201 patients, 81 in the tirofiban group and 120 in the non-tirofiban group, and each group included 68 patients after propensity score matching. Of the 201 patients, 52 (25.9%) suffered ICH, 15 (7.5%) suffered sICH, and 18 (9.0%) died within 3-months. The median mRS was 3 (0–4), 99 (49.3%) achieved functional independence. There were no statistically significant differences in safety outcomes, efficacy outcomes on successful recanalization, dramatic clinical improvement, or 3-month mRS between the tirofiban and non-tirofiban groups (all p > 0.05). Similar results were obtained after propensity score matching.Conclusion: In acute ischemic stroke patients who underwent mechanical thrombectomy and preceding intravenous thrombolysis, low-dose tirofiban was not associated with increased risk of sICH or ICH. Further randomized clinical trials are needed to confirm the effects of tirofiban in patients undergoing bridging therapy

A sheep pangenome reveals the spectrum of structural variations and their effects on tail phenotypes

Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here we generated high-quality genome assemblies for 15 individuals from genetically diverse sheep breeds using Pacific Biosciences (PacBio) high-fidelity sequencing, discovering 130.3 Mb nonreference sequences, from which 588 genes were annotated. A total of 149,158 biallelic insertions/deletions, 6531 divergent alleles, and 14,707 multiallelic variations with precise breakpoints were discovered. The SV spectrum is characterized by an excess of derived insertions compared to deletions (94,422 vs. 33,571), suggesting recent active LINE expansions in sheep. Nearly half of the SVs display low to moderate linkage disequilibrium with surrounding single-nucleotide polymorphisms (SNPs) and most SVs cannot be tagged by SNP probes from the widely used ovine 50K SNP chip. We identified 865 population-stratified SVs including 122 SVs possibly derived in the domestication process among 690 individuals from sheep breeds worldwide. A novel 168-bp insertion in the 5' untranslated region (5' UTR) of HOXB13 is found at high frequency in long-tailed sheep. Further genome-wide association study and gene expression analyses suggest that this mutation is causative for the long-tail trait. In summary, we have developed a panel of high-quality de novo assemblies and present a catalog of structural variations in sheep. Our data capture abundant candidate functional variations that were previously unexplored and provide a fundamental resource for understanding trait biology in sheep

Similarity Criterion of Freezing Model Test considering Nonlinear Variation of Thermal Parameters with Temperature

The significant differences in specific heat and thermal conductivity of ice and water lead to the changes of specific heat and thermal conductivity of soil during the freezing process. This makes it hard for the temperature field similarity criterion based on constant thermal parameters to accurately reflect the temperature field evolution of soil mass caused by nonlinearity of thermal parameters in the process. Based on heat conduction differential equation considering nonlinear changes of thermal parameters, this paper uses similarity transformation method to derive the similarity criterion of the temperature field in the frozen soil model test and arrives at the conclusion that the prototype soil and model soil should meet when the original soil is used for the model test. At the same time, given the impact of the third boundary condition on the similarity criterion, the thermal physical similarity conditions for the model soil are derived. On this basis, ABAQUS finite element software is used to numerically simulate the linear and nonlinear prototype and model temperature fields. The third boundary condition considered the temperature evolution of the characteristic points during the freezing process is analyzed. The calculation results indicate that the nonlinear thermal conductivity similarity criterion established herein can correctly reflect the evolution process of the prototype frozen soil temperature field. It is also suggested that the model soil thermal parameters are reasonably calculated. At the same time, it shows that the nonlinear freezing similarity criterion of the soil, when the third boundary condition is satisfied, has clear physical meaning and higher practical value. The research results provide a practical and reasonable parameter calculation method for the model soil preparation in the frozen soil model test and a theoretical basis and technical support for the design and implementation of the water-heat-force coupling model test on frozen soil

Research on the Ground Subsidence Mechanism of Cross Passage Caused by Freezing Method Construction

At present, the built or newly built underground structures are mostly concentrated in developed areas along the coast, lakes, and rivers, while deep soft soil is widely distributed in these areas. The cold heat treatment method is one of the advanced foundation treatments and has broad application prospect. However, geothermal exchange and temperature field change are complex Stefan problems with mobile boundaries, internal heat sources, and phase changes. It is important to determine the freezing area and freezing temperature reasonably under the premise of ensuring the safety of the frozen construction. Therefore, this paper summarizes the research methods of freezing method construction of cross passage and introduces the research on the constitutive model of freezing undisturbed soil, the theory of freezing wall calculation, and the evolution mechanism of the temperature field. Then, a brief evaluation is made in view of the lack of research, and the development direction of this field is put forward with the research characteristics. It is to deepen the understanding of the deformation mechanism of cross passage embedded in soft soil caused by the freezing and melting

Spatiotemporal variability of suspended sediment concentration in the coastal waters of Yellow River Delta: Driving mechanism and geomorphic implications

Satellite images have revealed a significant decline in the suspended sediment concentration (SSC) near surface in the coastal waters of Yellow River Delta (YRD) in recent years. However, there is limited information on the spatial disparity in SSC distributions and its dynamic mechanism. In this study, we utilize a well-calibrated SSC retrieval algorithm and a depth-averaged numerical modeling approach to investigate the delta and sub-delta scale variation trends and driving mechanisms of SSC in the coastal waters of YRD over the past few decades. The results of this study demonstrate the existence of high turbidity zones in coastal waters of the northern abandoned delta and the active lobe of the YRD. These zones have experienced general decreasing trends of SSC at the interannual timescale. Additionally, the distribution of SSC is significantly higher in dry seasons compared to that in wet seasons. The magnitude and varying trends of SSC are strongly influenced by the total bottom shear stress (BSS) caused by combined effects of waves and currents, although the wave-induced BSS is found to be less significant that the current-induced one, but vary more significantly due to wind forcing in the Bohai Sea. Furthermore, the grain size of seabed sediments plays a dominant role in the sediment mobilization and resuspension processes over interannual and longer timescales. The distribution of high BSS and sediment mobility zones align with the active areas for morphological changes with the YRD exhibiting net accretion in the active river mouth and erosion in the abandoned delta lobes. These findings highlight the multiscale variations and the close relationship between SSC and BSS, providing valuable insights into sediment dynamics with geomorphic evolution in highly human-interfered deltaic systems