Immortality Research Articles

Advanced Materials Methods Driving New Life in Critical Infrastructure

Fatigue damage is a major threat to many hydraulic steel structures (HSS). HSS experience fatigue loading during operation and are exposed to harsh environmental conditions that reduce fatigue life. The common methods to inspect and repair HSS is time-consuming and costly. Studies investigating the use of bonded Carbon and Basalt fiber reinforced polymer (CFRP, BFRP) to repair fatigue cracks in HSS are lacking. The main objectives of this study was to increase the bonding of FRP, investigate the effectiveness of different fiber-reinforced polymers, and perform experiments on different retrofitting configurations. In this study, eight large-scale center-cracked panels were tested under mode I loading under different environmental conditions, repair materials, and retrofitting configurations. Results indicated that the use of both CFRP and BFRP are both effective at extending fatigue life. Steel retrofitted with full patches of BFRP that cover the crack can reached infinite fatigue life. This article will conclude with several examples where FRP’s have been used to repair lock gates.

Combatting cellular immortality in cancers by targeting the shelterin protein complex

Shelterin proteins (TERF1, TERF2, TPP1, TINF2, POT1) protect telomeres, prevent unwarranted repair activation, and regulate telomerase activity. Alterations in these proteins can lead to cancer progression. This study uses an in-silico approach to examine shelterin in tumour samples across various cancers, employing mutation plots, phylogenetic trees, and sequence alignments. Network pharmacology identified TERF1 as an essential shelterin protein and transcription factors RUNX1, CTCF, and KDM2B as potential biomarkers due to their interactions with miRNAs and shelterin proteins. We performed MCODE analysis to identify subnetworks of ncRNAs interacting with the shelterin proteins. Shelterin expression predicted patient survival in 24 cancer types, with TERF1, TERF2, TINF2, and POT1 significantly expressed in testicular, AML, prostate, breast and renal cancers, respectively, and TPP1 in AML and skin cancer. Spearman and Pearson's analyses showed significant correlations of TERF1 across cancers, with near-significant correlations for all five proteins in different cancer datasets like breast cancer, kidney renal papillary and lung squamous cell carcinoma, skin cutaneous melanoma, etc.,. Shelterin expression correlated with patient survival in breast, renal, lung, skin, uterine, and gastric cancers. Insights into TPP1-associated glycans highlighted glycosylated sites contributing to tumorigenesis. This study provides molecular signatures for further functional and therapeutic research on shelterin, highlighting its potential as a target for anti-cancer therapies and promising prospects for cancer prognosis and prediction.

Fatigue fracture mechanism and life prediction of steel-aluminium clinched joints under different stress ratios

Vehicle bodies are subject to complex random loads during travelling, making it imperative to investigate the effects of different stress ratios on the body joining structure. To investigate the fatigue performance of steel-aluminium clinched joints under different stress ratios, fatigue experiments were conducted on these joints subjected to different load levels at stress ratios of -0.4, 0.1, and 0.4. The fracture mechanism of steel-aluminium clinched joints under different stress ratios was investigated through analysis of the joint's fracture morphology and the composition of abrasive chips using Scanning Electron Microscope and Energy Dispersive Spectroscopy. A fatigue life prediction model for steel-aluminium clinched joints was developed by employing the modified Paris formulation of the Wallker equation. The results indicate that joint failure can be classified into three main forms: lower sheet fracture, upper sheet pull-off accompanied by lower sheet fracture and reaching infinite life (2 million times). The lower sheet of a fatigue failure specimen in a steel-aluminium clinched joint exhibited a novel form of fretting damage known as lower sheet inter-plate fretting wear. Furthermore, the application of Walker's improved Paris formula proved to be highly effective in accurately predicting the fatigue life of steel-aluminium clinched joints under different stress ratios, with the predicted results demonstrating excellent agreement with experimental findings.

An Advanced Sine-Hyperbolic Creep-Damage Model Incorporating Threshold Strength

Abstract This study aims at improving the classic sine-hyperbolic (Sinh) creep-damage model to predict minimum-creep-strain-rate (MCSR), rupture, damage, and creep deformation. The Sinh model employs a continuum-damage-mechanics-based framework to model secondary and tertiary creep regimes. In Sinh, the creep strain and damage rate equations exhibit an implicit threshold stress that arises during numerical optimization. Herein, the Sinh model is modified to include an explicit threshold strength as a material property and the tensile strength. Threshold strength is defined as the lower limit for creep activation at a given temperature. Stresses are applied below the threshold, resulting in infinite life. The advanced Sinh offers several advantages including a physical significance of stress ratios where the onset of creep is defined by threshold strength, a closed-form solution where the rate equations remain finite at any combination of stress and temperature, and adaptability in finite element analysis where the solution space remains numerically stable. Experimental creep data of 304 SS at multiple isotherms are gathered from prior literature. The advanced Sinh is calibrated to the MCSR and SR data of 304 SS. The calibration of threshold strength follows a standard procedure from literature and is observed to be realistic for stainless steel at elevated temperatures. The MCSR and SR predictions illustrate the Sigmoidal bend and demonstrate zero creep rate and infinite life at or below threshold strength. The creep deformation and damage predictions exhibit agreement with experimental data. The advanced Sinh is validated by employing finite element simulation to ensure the applicability of the model across a range of applications. The advanced Sinh improved creep response prediction and added physical realism to the model's framework.

Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated invitro, invivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Research on size effects in fracture properties and residual life prediction for high-speed train axles

As critical load-bearing components of high-speed trains, the design and evaluation of axles primarily adhere to the principle of infinite life, supplemented by systematic flaw detection to ensure their operational safety. The establishment of detection intervals heavily depends on damage tolerance analysis informed by fracture mechanics. The size effect has a great influence on the fracture mechanical properties of materials, and how to accurately assess the remaining life considering the dimensional effects has been an open question in terms of safety in the railroad industry. Consequently, this research focuses on full-scale axle crack propagation tests, exploring the fracture mechanics properties critical to the life analysis of full-scale axle cracks under very high cycle fatigue (VHCF) condition. The findings demonstrate that size effects profoundly affect the fatigue fracture properties of high-speed train axles, especially regarding fatigue crack growth thresholds. Importantly, within the stable growth region, variations in fatigue crack growth rates across different scales prove to be minimal. Subsequently, a finite element model of the full-scale axle was established using the fatigue crack growth rate curve derived from experimental data. The validity of this FEA model was confirmed through bench test results, and predictions of the residual life for axles with cracks were formulated. This comprehensive analysis provides the foundation for developing an ultrasonic detection interval schedule for axles.

TERRA G-quadruplex stabilization behind the anti-multiple myeloma activity: Novel insights about resveratrol pleiotropic effects.

Resveratrol (RSV) is a nutraceutical compound belonging to the nonflavonoid polyphenol family, whose antioxidants, anti-inflammatory, and antitumoral properties have been widely investigated. The ability of RSV to provide beneficial effects for neurological, cardiovascular, and cancer disorders rekindled the interest to explore the molecular mechanisms behind its pleiotropic effects, which are due to the modulation of coding and noncoding genes involved in many key biological pathways. With a computational approach, including docking studies and thermodynamics calculations followed by 200-ns-long molecular dynamics and a clustering analysis, we hypothesized the stabilizing binding between RSV and G4 structures of telomeric repeat-containing RNA (TERRA), which is a tumor-suppressive long noncoding RNAs (lncRNA) involved in the regulation of telomere maintenance. In vitro studies performed on cellular models of multiple myeloma (MM) strengthened our hypothesis by highlighting that the antiproliferative and apoptotic effect induced by the treatment with RSV is associated with an increase of TERRA transcript and with upregulation of telomeric heterochromatin markers, such as H3K27Me3 and H4K20Me3, and of the hallmark of apoptosis, cleaved-poly(ADP-ribose) polymerase-1. Our results propose innovative insights underlying the multifaceted role of RSV in MM, by pointing out the role of this natural compound in an lncRNA-mediated regulation to counteract cellular immortality.

Transcriptome-wide profiling for melanocytes derived from newborn and adult human epidermis with enhanced proliferation.

The senescence-associated protein p16INK4A acts as a limiter element in cell-cycle progression. The loss of p16INK4A function is causally related to cellular immortalization. The increase in p16INK4A levels with advancing age was demonstrated in melanocytes. However, the characteristic difference between young and senescent melanocytes affecting immortalization of melanocytes remains unclear. In this study, we generated 10 different cell lines in total from newborn (NB) and adult (AD) primary normal human epidermal melanocytes (NHEM) using four different methods, transduction of CDK4R24C and cyclin D1 (K4D), K4D with TERT (K4DT), SV40 T-antigen (SV40T), and HPV16 E6 and E7 (E6/E7) and performed whole transcriptome sequencing analysis (RNA-Seq) to elucidate the differences of genome-wide expression profiles among cell lines. The analysis data revealed distinct differences in expression pattern between cell lines from NB and AD although no distinct biological differences were detected in analyses such as comparison of cell morphology, evaluation of cell proliferation, and cell cycle profiles. This study may provide useful in vitro models to benefit the understanding of skin-related diseases.

TERT upregulation promotes cell proliferation via degradation of p21 and increases carcinogenic potential.

Telomerase reverse transcriptase (TERT) gene aberration is detectable in >80% of cases with hepatocellular carcinoma (HCC). TERT reactivation is essential for cellular immortalization because it stabilizes telomere length, although the role of TERT in hepatocarcinogenesis remains unelucidated. To elucidate the significance of aberrant TERT expression in hepatocytes in inflammation-associated hepatocarcinogenesis, we generated Alb-Cre;TertTg mice, which overexpress TERT in the liver and examined their phenotype during chronic inflammation. Based on transcriptome data from the liver tissue of Alb-Cre;TertTg mice, we examined the role of TERT in hepatocarcinogenesis in vitro. We also evaluated the relationship between TERT and cell-cycle-related molecules, including p21, in HCC samples. The liver tumor development rate was increased by TERT overexpression during chronic inflammation, especially in the absence of p53 function. Gene set enrichment analysis of liver tissues revealed that gene sets related to TNF-NFκB signaling, cell cycle, and apoptosis were upregulated in Alb-Cre;TertTg liver. A luciferase reporter assay and immunoprecipitation revealed that TERT interacted with NFκB p65 and enhanced NFκB promoter activity. On the other hand, TERT formed protein complexes with p21, cyclin A2, and cyclin E and promoted ubiquitin-mediated degradation of p21, specifically in the G1 phase. In the clinical HCC samples, TERT was highly expressed but p21 was conversely downregulated, and TERT expression was associated with the upregulation of molecules related to the cell cycle. Taken together, the aberrant upregulation of TERT increased NFκB promoter activity and promoted cell cycle progression via p21 ubiquitination, leading to hepatocarcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Fatigue research of metro car body based on operational loads

PurposeThe principle of infinite life design currently directs fatigue resistance strategies for metro car bodies. However, this principle might not fully account for the dynamic influence of operational loads and the inevitable presence of defects. This study aims to integrate methods of service life estimation and residual life assessment, which are based on operational loads, into the existing infinite life verification framework to further ensure the operational safety of subway trains.Design/methodology/approachOperational loads and fatigue loading spectra were determined through the field test. The material test was conducted to investigate characteristics of the fracture toughness and the crack growth rate. The fatigue strength of the metro car body was first verified using the finite element method and Moore–Kommers–Japer diagrams. The service life was then estimated by applying the Miner rule and high-cycle fatigue curves in a modified form of the Basquin equation. Finally, the residual life was assessed utilizing a fracture assessment diagram and a fitted curve of crack growth rate adhered to the Paris formula.FindingsNeither the maximum utilization factor nor the cumulative damage exceeds the threshold value of 1.0, the metro car body could meet the design life requirement of 30 years or 6.6 million km. However, three out of five fatigue key points were significantly influenced by the operational loads, which indicates that a single fatigue strength verification cannot achieve the infinite life design objective of the metro car body. For a projected design life of 30 years, the tolerance depth is 12.2 mm, which can underscore a relatively robust damage tolerance capability.Originality/valueThe influence of operational loads on fatigue life was presented by the discrepancy analysis between fatigue strength verification results and service life estimation results. The fracture properties of butt-welded joints were tested and used for the damage tolerance assessment. The damage tolerance life can be effectively related by a newly developed equation in this study. It can be a valuable tool to provide the theoretical guidance and technical support for the structural improvements and maintenance decisions of the metro car body.

Influence of infill pattern and layer height on surface characteristics and fatigue behavior of FFF‐printed PEEK

AbstractPolyEther Ether Ketone (PEEK) is a leading thermoplastic biomaterial renowned for its exceptional overall properties and suitability for processing via Fused Filament Fabrication (FFF) Additive Manufacturing (AM). Despite its widespread use in industries, its fatigue behavior remains a critically underexplored aspect. This study aims to investigate the fatigue behavior of FFF‐produced PEEK, considering variations in infill pattern (triangular or rectilinear) and layer height (0.15 mm or 0.25 mm). Fatigue tests revealed a significant influence of the infill pattern on fatigue behavior, with the rectilinear pattern outperforming the triangular one. Layer height had a negligible effect when paired with rectilinear infill. Specimens with rectilinear patterns exhibited superior fatigue performance, achieving infinite fatigue life at maximum applied stress around 70% of ultimate tensile stress. Surface roughness assessment and fracture surface analysis at scanning electron microscope enhanced the interpretation of the results. This pioneering study lays the groundwork for future research in design for AM.

Gambogic acid impairs the maintenance and therapeutic resistance of glioma stem cells by targeting B-cell-specific Moloney leukemia virus insert site 1

BackgroundGlioblastoma (GBM) is the most common and lethal primary brain tumor with low effectiveness of available treatments. The tumor heterogeneity and therapeutic resistance are largely due to the presence of glioma stem cells (GSCs). Therefore, eliminating GSCs can overcome the progression, relapse, and resistance of GBM. Previous studies have shown that gambogic acid (GA), a natural active ingredient, has anti-glioma properties. Nonetheless, it is still unclear whether it has an inhibitory effect on GSCs and what its target might be. This study aimed to investigate the anti-tumor effects of GA on GSCs. In addition, this study found the target of GA in GSCs and elucidated the potential specific mechanisms by conducting both in vitro and in vivo experiments.B-cell-specific Moloney leukemia virus insert site 1 (BMI1) is a key stem cell factor of the polycomb group (PcG) family with important effects on the development, recurrence, and chemoresistance of several cancers. In both normal and cancer stem cells, BMI1 maintains stem cell self-renewal by regulating the cell cycle, cellular immortalization, and senescence. Its high expression in a variety of cancers correlates with poor clinical prognosis and chemoresistance. These mechanisms of BMI1 make it a potential therapeutic target for cancer therapy, and future studies may further reveal the specific roles of BMI1 mechanism and provide a basis for the development of new cancer therapeutic strategies. PurposeThis study investigated the in vitro and in vivo effects of GA in inducing apoptosis in GSCs and inhibiting GSCs self-renewal, as well as its underlying mechanisms. MethodsThis study synthesized biotinylated gambogic acid for the first time and angled for the target of gambogic acid using LC-MS/MS analysis, which has not been reported previously. Human-derived glioma stem cells GSC123 and GSC111 were used for in vitro studies, analyzing functions and mechanisms via microscale thermophoresis (MST), Annexin V/PI staining, Western blotting, immunofluorescence, and co-immunoprecipitation. The orthotopic glioma mouse model was used to assess the anti-tumor effects of GA in vivo. ResultsThis study demonstrated that GA is a specific inhibitor of BMI1, a key regulator controlling stem cell growth and self-renewal. GA binds to BMI1′s RING domain, accelerating K51-dependent degradation and suppressing H2A ubiquitination. Importantly, GA induces apoptosis, and inhibits GSC self-renewal, but minimally impacts neural progenitor cells (NPCs). GA can also be combined effectively with temozolomide and radiotherapy to increase their sensitivities in resistant cells. Furthermore, exogenous induction of BMI1 expression significantly hinders the disruption of GSCs by GA. In vivo, GA inhibits tumorigenicity, enhances the effect of temozolomide, and reduces BMI1 expression. ConclusionThese findings suggest that GA is a potential candidate for targeting GSCs and therefore be used to treat GBM.

Effects of plasma electrolytic polishing on the surface and mechanical properties of Ti-6.5Al-3.5Mo-1.5Zr-0.3Si specimen fabricated by laser powder bed fusion

The high roughness of titanium alloy specimen fabricated by laser powder bed fusion (LPBF) may limit the application of LPBF technology. Plasma electrolytic polishing (PEP) can effectively reduce the surface roughness of metal samples. In this study, an orthogonal test was designed to investigate the effects of polishing time, voltage and electrolyte temperature on the reduction of roughness and wall thickness of Ti-6.5Al-3.5Mo-1.5Zr-0.3Si specimens fabricated by LPBF. The surface roughness of the specimen decreased from Ra = 49.1 μm to Ra = 9.1 μm and the thickness decreased from 1.72 mm to 1.38 mm after the PEP. Due to the recoil pressure induced by rupture of vapor-gaseous envelope (VGE) and the annealing effect caused by electron impact, the width of α/α' grains on the surface of TC11 specimen decreased from 0.51 μm to 0.46 μm; the mean value of geometrically necessary dislocations (GND) increased by 9.8 %; the proportion of high angle grain boundaries (HAGBs) increased from 75.2 % to 80.8 %; the proportion of twin grain boundary length increased from 2.9 % to 11.9 %, and the activated twin variant type increased from 2 to 4. The number of pores in the samples reduced from 85 to 2 after PEP, which resulted in the improvement of tensile and fatigue properties. The ultimate strength and elongation of the tensile specimens increased by 6.2 % and 53.5 % respectively. The infinite fatigue life maximum stress of the high cycle fatigue specimen increased by 62.5 %. Another reason for the improvement of mechanical properties may be the self-healing of microcracks and the electroplasticity in the specimens.

Discovery of telomerase inhibitors: existing strategies and emerging innovations.

Telomerase, crucial for maintaining telomere length, is an attractive target for cancer therapy due to its role in cellular immortality. Despite three decades of research efforts, no small-molecule telomerase inhibitors have been clinically approved, highlighting the extensive challenges in developing effective telomerase-based therapeutics. This review examines conventional and emerging methods to measure telomerase activity and discusses existing inhibitors, including oligonucleotides and small molecules. Furthermore, this review highlights recent breakthroughs in structural studies of telomerase using cryo-electron microscopy, which can facilitate improved structure-based drug design. Altogether, advancements in structural methodologies and high-throughput screening offer promising prospects for telomerase-based cancer therapeutic development.

Promoter mutation-independent TERT expression is related to the immune-enriched milieu in papillary thyroid cancer.

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors.

Topology optimization for fatigue reserve factors

This paper describes a topology optimization approach that applies the common fatigue analysis practices of rainflow cycle counting and critical plane searches to cover both proportional and non-proportional fatigue loading conditions of metals. The existing literature on topology optimization has so far mainly considered fatigue damage under proportional loading conditions and typically uses continuous damage models to avoid the discontinuous nature of fatigue rainflow cycle counting and critical plane searches. Furthermore, previous publications often introduced heuristic schemes to scale the fatigue damage and set the move limits for the design variables rather low to avoid oscillations in the design variables and damage responses during the optimization iterations, because fatigue damage is typically highly localized. Therefore, these approaches cause many optimization iterations. Contrarily, our present approach applies the fatigue reserve factor (FRF) directly in the optimization formulation instead of the fatigue damage where FRF is a fatigue reserve factor for infinite fatigue life. The inverse FRF scales nearly linearly with the stresses. Therefore, the present approach needs no heuristic scaling for the fatigue topology optimization. The numerical implementation applies the semi-analytic adjoint sensitivity method for multiple load cases. Numerically, FRF shows more stable optimization convergence using less optimization iterations. Different FRF topology-optimized designs for a variety of fatigue damage types are validated and compared. Additionally, the optimized FRF designs are compared to both strictly stiffness optimized designs and stress strength optimized designs.

Comparison of fatigue lifetime of new generation CAD/CAM crown materials on zirconia and titanium abutments in implant-supported crowns: a 3D finite element analysis.

Due to the dynamic character of the stomatognathic system, fatigue life experiments simulating the cyclic loading experienced by implant-supported restorations are critical consideration. The aim of this study was to examine the effect of different crown and abutment materials on fatigue failure of single implant-supported crowns. Models were created for 10 different designs of implant-supported single crowns including two zirconia-reinforced lithium silicates (crystallized and precrystallized), monolithic lithium disilicate, polymer-infiltrated ceramic networks, and polyetheretherketone supported by zirconia and titanium abutments. A cyclic load of 179 N with a frequency of 1 Hz was applied on palatal cusp of a maxillary first premolar at a 30° angle in a buccolingual direction. In the models with titanium abutments, the polymer-infiltrated ceramic network model had a lower number of cycles to fatigue failure values in the implant (5.07), abutment (2.30), and screw (1.07) compared to others. In the models with zirconia abutments, the crystallized zirconia-reinforced lithium silicate model had a higher number of cycles to fatigue failure values in the abutment (8.52) compared to others. Depending on the fatigue criteria, polyetheretherketone implant crown could fail in less than five year while the other implant crowns exhibits an infinite life on all models. The type of abutment material had an effect on the number of cycles to fatigue failure values for implants, abutments, and screws, but had no effect on crown materials. The zirconia abutment proved longer fatigue lifetime, and should thus be considered for implant-supported single crowns.

Development and validation of novel keloid-derived immortalized fibroblast cell lines.

Keloids are a common connective tissue disorder with an ill-understood etiopathogenesis and no effective treatment. This is exacerbated because of the absence of an animal model. Patient-derived primary keloid cells are insufficient as they age through passaging and have a limited supply. Therefore, there is an unmet need for development of a cellular model that can consistently and faithfully represent keloid's pathognomic features. In view of this, we developed keloid-derived immortalized fibroblast (KDIF) cell lines from primary keloid fibroblasts (PKF) by transfecting the human telomerase reverse transcriptase (hTERT) gene. The TERT gene encodes the catalytic subunit of the telomerase enzyme, which is responsible for maintaining the cellular replicative potential (cellular immortalization). Primary fibroblasts from keloid-specific lesional (peripheral, middle, and top) as well as extralesional sites were isolated and evaluated for cell line development and comparative cellular characteristics by employing qRT-PCR and immunofluorescence staining. Moreover, the immortalized behavior of KDIF cell lines was evaluated by comparing with cutaneous fibrosarcoma and dermatofibrosarcoma protuberans cell lines. Stable KDIF cell lines with elevated expression of hTERT exhibited the cellular characteristics of site-specific keloid fibroblasts. Histochemical staining for β-galactosidase revealed a significantly lower number of β-gal-positive cells in all three KDIF cell lines compared with that in PKFs. The cell growth curve pattern was studied over 10 passages for all three KDIF cell lines and was compared with the control groups. The results showed that all three KDIF cell lines grew significantly faster and obtained a fast growing characteristic as compared to primary keloid and normal fibroblasts. Phenotypic behavior in growth potential is an indication of hTERT-mediated immortalized transformation. Cell migration analysis revealed that the top and middle KDIF cell lines exhibited similar migration trend as site-specific PKFs. Notably, peripheral KDIF cell line showed significantly enhanced cell migration in comparison to the primary peripheral fibroblasts. All KDIF cell lines expressed Collagen I protein as a keloid-associated fibrotic marker. Functional testing with triamcinolone inhibited cell migration in KDIF. ATCC short tandem repeat profiling validated the KDIF as keloid representative cell line. In summary, we provide the first novel KDIF cell lines. These cell lines overcome the limitations related to primary cell passaging and tissue supply due to immortalized features and present an accessible and consistent experimental model for keloid research.

The Human Being as the Image of God

Abstract This is a theological exposition of the biblical statement that the human being is created in the image of God (Genesis 1:26). The treatment concludes that this affirmation is the clal gadol, the foundational principle of the whole Torah (as Ben Azzai says, Talmud Yerushalmi, Nedarim, ch. 9, h. 4). There are four dimensions to the image of God: (1) Intrinsic dignities—that all human beings (no matter gender, skin color, race, religion) are endowed by their Creator with three intrinsic dignities: infinite value, equality, and uniqueness; (2) Capabilities—God has infinite consciousness, power, relationship (=love), freedom, and life. Humans have these capabilities in a finite but remarkable, i.e., Godlike, form. According to Rabbi Joseph B. Soloveitchik, humans fulfill the commandment of Imitatio Dei (v’halachta b’drachav) by developing these capabilities. God bestows these capabilities on humans to use in fulfilling a mission to perfect God’s Creation in partnership with the Divine (=covenant); (3) These dignities are rooted in love. That all humans possess these dignities reflects the fact that God loves all life, especially humans (the most advanced form of life); (4) Prophetic messianism envisions this planet turned into a Garden of Eden (paradise). This is a reality worthy of an image of God, i.e., the enemies of life (poverty, hunger, oppression, war, sickness) are overcome and the fullness of human dignity (infinite value, equality, uniqueness) is honored, in actual practice, in daily life.

A continuum approach to multiaxial high-cycle fatigue modeling for ductile metallic materials

In this work we propose a generalization of the endurance function employed in the continuum approach to high-cycle fatigue modeling by Ottosen et al. (2008). The von Mises-type backstress-modified effective stress term of the original formulation is replaced by the non-quadratic Hershey-Hosford function, which introduces flexibility with respect to the predicted fatigue limit in pure shear. While the original model assumes a fixed ratio between the fatigue limits in fully reversed torsion and fully reversed bending of 0.5774 for all materials, the modification enables the ratio to take on values on the interval from 0.5 to 0.5852 by calibration to experimental data that is readily available in the literature. Like the original formulation simplifies to the invariant-based Mises-Sines fatigue limit criterion for proportional stress histories, the current proposal can be written as a Hershey-Hosford-Sines criterion. A systematic validation to experimental multiaxial infinite fatigue life data from eight different mild and semi-hard metals with fully reversed torsion and bending fatigue limit ratios lower than 0.6 demonstrates that the proposed modification increases the accuracy and reduces the number of non-conservative predictions.