Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of CD44 as a Cell-Surface Marker for Kit Negative Interstitial Cells of Cajal in Adult Mouse Colon

Loss of Kit protein expression is proven to influence the plasticity of interstitial cells of Cajal (ICCs) and may contribute to gastrointestinal (GI) dysfunctions. The role and fate of Kit negative ICCs are unclear, and cell-specific markers for the Kit ICCs are unknown. In this study, we treated adult mice with imatinib (a Kit signaling blocker) for 8 or 16 days and investigated whether CD44 is a specific marker for the Kit negative ICCs in the adult mouse colon. We aimed at examining the protein and mRNA level of CD44 and Kit by using Western blot and real-time RT-PCR, respectively. Our results indicated that Kit expression was downregulated for both protein and mRNA levels after imatinib treatment for 8 or 16 days as compared to the vehicle-treated mice. Interestingly, CD44 expression remained unchanged throughout the treatment. Immunostaining on whole-mount preparations for Kit and CD44 showed that CD44 was exclusively co-localized with Kit in the ICCs of the vehicle-treated mouse colon. After imatinib treatment, a number of CD44+/Kit– cells with elaborated processes were observed with an evident decrease of Kit+ cell number within the muscular layers (ICC-IM) and around the myenteric nerve plexus (ICC-MY) as compared to vehicle-treated mice. After discontinuing imatinib for 16 days, Kit+ ICC-MY and ICC-IM were completely co-localized with normalization of CD44 and Kit+ cell numbers. Overall, our results identify CD44 as a cell-specific surface marker for Kit–ICCs and may be useful to understand the role and fate of Kit– ICCs in GI disorders.
Cost effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the United States

Abstract Aims To assess from a US payer perspective the cost-effectiveness of the chimeric antigen receptor T (CAR T)-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) to treat relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following ≥2 systemic therapy lines. Methods A three-state (i.e. pre-progression, post-progression, and death) partitioned survival model was used to estimate the quality-adjusted life-years (QALYs) and costs for patients on each treatment over a lifetime horizon. Progression-free survival (PFS) and overall survival (OS) were based on a matching-adjusted indirect treatment comparison (MAIC) that accounted for differences in trial population baseline characteristics. Mixture cure models (MCMs) were used to account for long-term survivors. Costs included drug acquisition and administration for the CAR T-cell therapies and conditioning chemotherapy, apheresis, CAR T-specific monitoring, transplant, hospitalization, adverse events, routine care, and terminal care. Health state utilities were derived from trial and published data. Sensitivity analyses included probabilistic sensitivity analyses (PSAs) and an analysis of extremes that assessed the results across a vast array of combinations of parametric OS and PFS curves across the two therapies. Results Compared to tisa-cel, axi-cel resulted in 2.31 QALYs gained and a cost reduction of $1,407 in the base case. In the PSA, the cost per QALY gained was ≤$31,500 in 95% of the 1,000 simulations. In the analysis of extremes, the cost per QALY gained was ≤$7,500 in 99% of the 1,296 combinations of MCMs and ≤$40,000 in 95% of the 1,296 combinations of standard models. Limitations In absence of head-to-head comparative data, we relied on a MAIC, which cannot account for all possible confounders. Moreover, some outcomes (i.e. transplantations, hospitalizations, adverse events (AEs)) were not adjusted in the MAIC. Conclusions In this simulation, axi-cel was a superior treatment option as it is predicted to achieve better outcomes at lower or minimal incremental costs versus tisa-cel.
Single nucleotide polymorphisms in matrix metalloproteinase 2 (MMP2) enhance BRAFV600E mutation-mediated oncogenicity and invasiveness of papillary thyroid cancer cells.

Thyroid cancer is a common endocrine neoplasm. Despite its good prognosis, it can lead to significant mortality due to metastasis and recurrence. However, the factors involved in metastasis are not well studied. Therefore, we selected matrix metalloproteinases 2 (MMP2) and determined whether it has any role in thyroid cancer. We sequenced the exons of MMP2 in 211 samples including 16 multi-nodular goiters and 195 differentiated thyroid cancers. We identified four non-synonymous single nucleotide polymorphisms (SNPs) of the MMP2 gene in 3.06% (6/195) thyroid cancers. Of the 4 MMP2 SNPs, 3 (75%) concomitantly had BRAFV600E. Hence, we speculated that the MMP2 SNPs may likely cooperate with BRAFV600E in promoting tumor aggressiveness. Overexpression of two MMP2 SNPs (P38L and T458I) exhibited markedly enhanced gelatinase activity with an intact dimerization and induced strong cortactin foci formation in HEK293T cells. Stable expression of the two MMP2 SNPs in BRAFV600E positive BCPAP cells dramatically enhanced cell proliferation, colony formation, and focus formation. Analysis of the morphology of MMP2 SNP bearing BCPAPV600E cells exhibited highly invasive phenotypes characterized by a high rate of wound healing and enhanced cell invasion compared with parental BCPAPV600E cells bearing vector. We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAFV600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup can benefit from BRAF-mediated therapeutic interventions.
Chronic overload of concentration-dependent iron exerts different effects on ovarian function in C57BL/6J mice†

Abstract Overloaded iron can deposit in the reproductive system and impair ovarian function. But few studies have identified the exact effect of overloaded iron on the endocrine function and fertility capacity in female mice. Here, we established iron-overloaded mouse models by intraperitoneal injection of iron dextran to adult female C57BL/6J mice at 0.1 g/kg (LF group), 0.5 g/kg (MF group), and 1.0 g/kg (HF group) concentrations once a week for eight consecutive weeks. We found that overloaded iron resulted in smaller ovaries, as well as accumulated oxidative damages. The endocrine function and follicle development were also impeded in the MF and HF groups. The 10-month breeding trial indicated that (1) Low concentration of iron (0.1 g/kg) wasn't detrimental to the ovary; (2) Middle concentration of iron (0.5 g/kg) impeded the childbearing process, though it could be recovered following the iron excretion; and (3) High concentration of iron (1.0 g/kg) damaged the fertility, even gave rise to sterility. Yet for those fertile mice, litter number and litter size were smaller and the ovarian reserve of their offspring was impaired. Transcriptome profiling results indicated that overloaded iron could compromise ovarian function by disrupting ovarian steroidogenesis, interfering with ovarian microenvironment, and inhibiting Wnt signaling. Taken together, we have demonstrated the effect that chronic concentration-dependent iron overload exerted on mouse ovarian function, which may act as a preliminary basis for further mechanism and intervention investigations. Graphical Abstract
Cohesin Subunit Rad21 Binds to the Herpes Simplex Virus 1 Genome near CTCF Insulator Sites during Latency In Vivo

CTCF insulators are important for transcriptional control, and increasing evidence suggests that CTCF insulators, together with the cohesin complex, regulate viral transcription in DNA viruses. The CTCF-cohesin interaction is important for the formation of chromatin loops, structures that orient distance-separated elements in close spatial proximity for transcriptional control. ABSTRACT Herpes simplex virus 1 (HSV-1) is a human pathogen that can establish a lifelong infection in the host. During latency, HSV-1 genomes are chromatinized and are abundantly associated with histones in sensory neurons, yet the mechanisms that govern the latent-lytic transition remain unclear. We hypothesize that the latent-lytic switch is controlled by CTCF insulators, positioned within the HSV-1 latent genome. CTCF insulators, together with the cohesin complex, can establish and maintain chromatin loops that allow distance-separated gene regions to be spatially oriented for transcriptional control. In the current study, we demonstrated that the cohesin subunit Rad21 was recruited to latent HSV-1 genomes near four of the CTCF insulators during latency. We showed that the CTCF insulator known as CTRS1/2, positioned downstream from the essential transactivating immediate-early (IE) region of ICP4, was only enriched in Rad21 prior to but not during latency, suggesting that the CTRS1/2 insulator is not required for the maintenance of latency. Further, deletion of the CTRL2 insulator, positioned downstream from the latency-associated transcript (LAT) enhancer, resulted in a loss of Rad21 enrichment at insulators flanking the ICP4 region at early times postinfection in mouse ganglia, suggesting that these insulators are interdependent. Finally, deletion of the CTRL2 insulator resulted in a loss of Rad21 enrichment at the CTRL2 insulator in a cell type-specific manner, and this loss of Rad21 enrichment was correlated with decreased LAT expression, suggesting that Rad21 recruitment to viral genomes is important for efficient gene expression. IMPORTANCE CTCF insulators are important for transcriptional control, and increasing evidence suggests that CTCF insulators, together with the cohesin complex, regulate viral transcription in DNA viruses. The CTCF-cohesin interaction is important for the formation of chromatin loops, structures that orient distance-separated elements in close spatial proximity for transcriptional control. Herpes simplex virus 1 (HSV-1) has seven putative CTCF insulators that flank the LAT and the IE, indicating that CTCF insulators play a role in the transition from latency to reactivation. Contributions from the work presented here include the finding that CTCF insulators in HSV-1 genomes are differentially enriched in the cohesin subunit Rad21, suggesting that CTCF-cohesin interactions are establishing and anchoring chromatin loop structures to control viral transcription.
Dielectric Relaxation and the Internal Field

The paper discusses the relation of the relaxation time τ of a dielectric to the measured decay time of polarization T and proposes a new expression for the internal field in a dielectric subjected to an alternating field. It is found for this expression that 1<T/τ<32 and that in most instances no serious error is incurred in using T instead of τ. Application to the case of several distinct relaxation times shows that the new expression gives relations between the complex dielectric constant and frequency which are observed experimentally.
Deep etching of silicon carbide for micromachining applications: Etch rates and etch mechanisms

The etch rate of 4H–SiC in a SF6 helicon plasma has been investigated as a function of pressure, rf power, bias voltage and distance between the substrate holder and the helicon source. Very high etch rates of 1.35 μm/min were achieved when this distance is minimum. Good uniformity on 2 in. SiC substrates and smooth etched surfaces free of micromasking have been obtained when using a nickel mask. The selectivity SiC/Ni was found to be about 50 in high etch rate conditions. Via holes have been etched to a depth of 330 μm in 4H–SiC substrates. Etch mechanisms were also studied in a parallel-plate capacitively coupled reactor. We have detected by laser-induced fluorescence (LIF), the radicals SiF2, CF, and CF2 produced during the reactive ion etching of SiC in a pure SF6 plasma. Spatially and temporally resolved LIF measurements were used to distinguish between gas phase and etched surface production of these species. Whereas CF and CF2 are primary etch products (i.e., mainly produced at the etched surface),.
Computer simulation of a twisted nematic liquid crystal

We have performed the first computer simulation of a twisted nematic liquid crystal using non-spherical hard particles in modified periodic boundary conditions. The director profiles are stable, suggesting that the technique may usefully complement conventional simulations of unperturbed liquid crystals. We make preliminary calculations of the twist elastic constant K 2 by measurement of intermolecular torques: the results are in moderately good agreement with those obtained from fluctuation expressions.
Characterization of a pericentric inversion in plateau fence lizards (Sceloporus tristichus): evidence from chromosome-scale genomes

Abstract Spiny lizards in the genus Sceloporus are a model system among squamate reptiles for studies of chromosomal evolution. While most pleurodont iguanians retain an ancestral karyotype formula of 2n = 36 chromosomes, Sceloporus exhibits substantial karyotype variation ranging from 2n = 22 to 46 chromosomes. We present two annotated chromosome-scale genome assemblies for the Plateau Fence Lizard (Sceloporus tristichus) to facilitate research on the role of pericentric inversion polymorphisms on adaptation and speciation. Based on previous karyotype work using conventional staining, the S. tristichus genome is characterized as 2n = 22 with six pairs of macrochromosomes and five pairs of microchromosomes and a pericentric inversion polymorphism on chromosome 7 that is geographically variable. We provide annotated, chromosome-scale genomes for two lizards located at opposite ends of a dynamic hybrid zone that are each fixed for different inversion polymorphisms. The assembled genomes are 1.84–1.87 Gb (1.72 Gb for scaffolds mapping to chromosomes) with a scaffold N50 of 267.5 Mb. Functional annotation of the genomes resulted in ∼15K predicted gene models. Our assemblies confirmed the presence of a 4.62-Mb pericentric inversion on chromosome 7, which contains 62 annotated coding genes with known functions. In addition, we collected population genomics data using double digest RAD-sequencing for 44 S. tristichus to estimate population structure and phylogeny across the Colorado Plateau. These new genomic resources provide opportunities to perform genomic scans and investigate the formation and spread of pericentric inversions in a naturally occurring hybrid zone.
Activation of Nrf2 signaling pathway by natural and synthetic chalcones: a therapeutic road map for oxidative stress

ABSTRACT Introduction: Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. Chalcones with a common chemical scaffold of 1,3-diaryl-2- propen-1-one, are abundantly present in nature with a wide variety of pharmacological properties. This review will discuss the interactions of natural and synthetic chalcones with Nrf2 signaling. Areas covered: Chalcones are reportedly found to activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins. Chalcones being soft electrophiles are less prone to hostile off-target effects and unlikely to induce carcinogenicity and mutagenicity. Furthermore, their low toxicity, structural diversity, feasibility in structural reorganization and the presence of α,β-unsaturated carbonyl group which makes them suitable drug candidates targeting Nrf2-dependent diseases. Expert opinion: Nrf2-Keap1 signaling pathway plays a central role in redox signaling. However, available therapeutic agents for Nrf2 activation have limited practical applications due to their associated risks, relatively low efficacy and bioavailability. The designing and fabrication of new chemical entities with chalcone scaffold-based Michael acceptor mechanism should be aimed as potential therapeutic Nrf2 activators to target oxidative stress and inflammation-mediated diseases such as atherosclerosis, Parkinson’s disease and many more.
Galactose-Modified PH-Sensitive Niosomes for Controlled Release and Hepatocellular Carcinoma Target Delivery of Tanshinone IIA

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.
Effectiveness of community face mask use on COVID-19 epidemiological trends and patterns in Italy: evidence from a “translational” study

Effectiveness of community face mask use on COVID-19 epidemiological trends and patterns in Italy: evidence from a “translational” study Nicola Luigi Bragazzi, Naim Mahroum, Giovanni Damiani, Jude Dzevela Kong & Jianhong Wu To cite this article: Nicola Luigi Bragazzi, Naim Mahroum, Giovanni Damiani, Jude Dzevela Kong & Jianhong Wu (2021) Effectiveness of community face mask use on COVID-19 epidemiological trends and patterns in Italy: evidence from a “translational” study, Infectious Diseases, 53:4, 252-254, DOI: 10.1080/23744235.2021. 1883731 To link to this article: https://doi.org/10.1080/23744235.2021. 1883731
The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3

Oculopharyngodistal myopathy (OPDM) is associated with trinucleotide repeat expansions in LRP12 or GIPC1, but the genetic basis of many cases remains unknown. Yu et al. identify GGC repeat expansions in NOTCH2NLC in Chinese patients with OPDM, and provide evidence for possible underlying pathogenic mechanisms.
Bioremediation of diesel-contaminated soil using Bacillus sp. (strain TMY-2) in soil by uniform and non- uniform electro kinetic technology field

Selected biomakers, Cholinesterase (ChE) and phagocytic activities have been investigated with the exposed green mussel Perna viridis in Indonesian coastal waters. An operative effect-based monitoring on two polluted sites and one reference area were investigated for aquaculture enterprises and human health aspects. Between two heavily polluted sites, green mussels from Cilincing indicated a lower level of the ChE activity than those from Kamal Muara. The phagocytic activity of green mussels from the polluted sites demonstrated significant higher activity than that of green mussels from the pristine site, Pangkep. However, there were no significant differences of phagocytic activities between the polluted sites. This might indicate that the existing pollutants in Jakarta Bay were more neurotoxic rather than immonotoxic substances. The results showed clearly that both selected biomarkers were potential valuable tools for effect-based monitoring and pollution impacts in coastal zones of Indonesia. Key words: Green mussel, biomarkers, coastal zone management, Indonesia.
Respiratory Motion Mitigation and Repeatability of Two Diffusion-Weighted MRI Methods Applied to a Murine Model of Spontaneous Pancreatic Cancer

Respiratory motion and increased susceptibility effects at high magnetic fields pose challenges for quantitative diffusion-weighted MRI (DWI) of a mouse abdomen on preclinical MRI systems. We demonstrate the first application of radial k-space-sampled (RAD) DWI of a mouse abdomen using a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) on a 4.7 T preclinical scanner equipped with moderate gradient capability. RAD DWI was compared with the echo-planar imaging (EPI)-based DWI method with similar voxel volumes and acquisition times over a wide range of b-values (0.64, 535, 1071, 1478, and 2141 mm2/s). The repeatability metrics are assessed in a rigorous test–retest study (n = 10 for each DWI protocol). The four-shot EPI DWI protocol leads to higher signal-to-noise ratio (SNR) in diffusion-weighted images with persisting ghosting artifacts, whereas the RAD DWI protocol produces relatively artifact-free images over all b-values examined. Despite different degrees of motion mitigation, both RAD DWI and EPI DWI allow parametric maps of apparent diffusion coefficients (ADC) to be produced, and the ADC of the PDAC tumor estimated by the two methods are 1.3 ± 0.24 and 1.5 ± 0.28 × 10−3 mm2/s, respectively (p = 0.075, n = 10), and those of a water phantom are 3.2 ± 0.29 and 2.8 ± 0.15 × 10−3 mm2/s, respectively (p = 0.001, n = 10). Bland-Altman plots and probability density function reveal good repeatability for both protocols, whose repeatability metrics do not differ significantly. In conclusion, RAD DWI enables a more effective respiratory motion mitigation but lower SNR, while the performance of EPI DWI is expected to improve with more advanced gradient hardware.
AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9. We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients or immune regulators, and this has an impact on tumorigenesis potential.