Immortality Research Articles

Effect of Implantoplasty on Roughness, Fatigue and Corrosion Behavior of Narrow Diameter Dental Implants.

Implantoplasty (IP) is used in dental implants with peri-implantitis and aims to remove threads and polish rough surfaces in order to prevent bacterial colonization. As a result of this procedure, implant strength might be compromised. We tested 20 tapered screw-shaped Ti6Al4V dental implants with a simulated bone loss of 50%. Ten implants underwent IP and 10 served as controls. Surface topography (Sa, Sz, Ssk, and Sdr) was analyzed with a confocal optical microscope. Subsequently, a minimum of four series of cyclic loads were applied with a servo-hydraulic mechanical testing machine (5 × 106 cycles at 15 Hz, between a maximal nominal value-starting at 529 N in the IP group and 735 N in the control group-and 10% of that force). We recorded the number of cycles until failure and the type of failure. Implant failure was analyzed by visual inspection and scanning electron microscopy. Open circuit potential and potenctiodynamic tests were carried out with high precision potentiostat using Hank's solution at 37 °C to evaluate the effect of the implantoplasty on the corrosion resistance. Implantoplasty significantly reduced the surface topography values (median) and interquartile range (IQR); Sa from 1.76 (IQR = 0.11) to 0.49 (IQR = 0.16), Sz from 20.98 (IQR = 8.14) to 8.19 (IQR = 4.16), Ssk from 0.01 (IQR = 0.34) to -0.74 (IQR = 0.53) and Sdr from 18.20 (IQR = 2.26) to 2.67 (IQR = 0.87). The fatigue limits of the control and implantoplasty groups were 551 N and 529 N, respectively. The scanning electron micrographs showed fatigue striations indicating fatigue failure. Besides, the fractographic analysis revealed a typical brittle intergranular fracture mechanism. The infinite life range of the dental implants evaluated was largely above the threshold of usual chewing forces. Implantoplasty seems to render a fairly smooth surface and has a limited impact on fatigue resistance. In addition, implantoplasty produces a decrease in the corrosion resistance of the implant. Corrosion current density from 0.019 μA/cm2 for as-received to 0.069 μA/cm2 in the interface smooth-roughened dental implant. These places between the machining and the rough area of the implant are the most susceptible, with the appearance of pitting.

Modeling and simulation of belt bucket elevator head shaft for safe life operation

This research paper presents a step by step conceptual design and life prediction approach for the design, modeling and simulation of head shaft of a belt bucket elevator, to be used for conveying grains to a height of 33.5 m and at the rate of 200 tons/h. output. For this elevator system, the force and torque acting on the head shaft as well as the bending moment were calculated. Furthermore, the diameter of each cross section of the shaft was determined taking into consideration the geometric and fatigue stress concentration factors, due to shoulders which contribute significantly to most fatigue failures of shafts. The stress induced on the shaft by the force and the factor of safety for each cross section of the shaft was calculated using the DE-Goodman criterion. The model of the shaft was created from the calculated diameters and subjected to static and fatigue analysis using SolidWorks FEA. The results were validated by comparing the values from the FEA and the calculated values for stress and factor of safety of the critical section of the shaft, which showed an equivalent value. The FEA gave a fatigue load factor greater than one, which signifies that the shaft will not go into failure mode within the infinite life cycle of the shaft. The value of the fatigue strength obtained from FEA was higher than the value for the maximum von misses stress of the shaft, this result shows that the head shaft will sustain the loading stresses over a finite life prediction. This research is significant because the stress induced forces on the head shaft from each component of the elevator system were properly identified and analyzed so as to obtain precise results for life prediction.

Complex interaction network revealed by mutation of human telomerase ‘insertion in fingers’ and essential N-terminal domains and the telomere protein TPP1

In the majority of human cancer cells, cellular immortalization depends on the maintenance of telomere length by telomerase. An essential step required for telomerase function is its recruitment to telomeres, which is regulated by the interaction of the telomere protein, TPP1, with the telomerase essential N-terminal (TEN) domain of the human telomerase reverse transcriptase, hTERT. We previously reported that the hTERT 'insertion in fingers domain' (IFD) recruits telomerase to telomeres in a TPP1-dependent manner. Here, we use hTERT truncations and the IFD domain containing mutations in conserved residues or premature aging disease-associated mutations to map the interactions between the IFD and TPP1. We find that the hTERT-IFD domain can interact with TPP1. However, deletion of the IFD motif in hTERT lacking the N-terminus and the C-terminal extension does not abolish interaction with TPP1, suggesting the IFD is not essential for hTERT interaction with TPP1. Several conserved residues in the central IFD-TRAP region that we reported regulate telomerase recruitment to telomeres, and cell immortalization compromise interaction of the hTERT-IFD domain with TPP1 when mutated. Using a similar approach, we find that the IFD domain interacts with the TEN domain but is not essential for intramolecular hTERT interactions with the TEN domain. IFD-TEN interactions are not disrupted by multiple amino acid changes in the IFD or TEN, thus highlighting a complex regulation of IFD-TEN interactions as suggested by recent cryo-EM structures of human telomerase.

Small RNA deep sequencing revealed microRNAs’ involvement in modulating cellular senescence and immortalization state

Unlike rodent cells, spontaneous immortalization of avian cells and human cells is a very rare event. According to patent publications and current literature, there are no more than 4 spontaneously immortalized chicken embryo fibroblast (CEF) cell lines established up to date. One of those cell lines is ADOL (Avian Disease and Oncology Laboratory) ZS-1 cell line, which was established by continuous passaging of the CEFs derived from the specific pathogen free (SPF) 0.TVB*S1 (commonly known as rapid feathering susceptible or RFS) genetic line of chickens. The RFS genetic line of chickens was developed and has been maintained on the SPF chicken farm of USDA-ARS facility, ADOL, in East Lansing, Michigan, which is known as one of a few lines of chickens that are free of any known avian endogenous virus genes. To explore potential roles that epigenetic factors may play in modulating cellular senescence processes and spontaneous immortalization state, total RNAs extracted from samples of the RFS primary CEFs, RFS CEFs reached the 21st passage, and the ZS-1 cells were subjected to small RNA sequencing. Collectively, a total of 531 miRNAs was identified in the 3 types of samples. In contrast to the primary CEF samples, 50 miRNAs were identified with significantly differential expression only in the 21st passage samples; a different subset of 63 differentially expressed miRNAs was identified only in the ZS-1 samples; the majority of differentially expressed miRNAs identified in both the 21st passage CEF and the ZS-1 samples were more or less directionally consistent. Gene Ontology analysis results suggested that the epigenetic factor, miRNAs, plays a role in modulating the cellular senescence and spontaneous immortalization processes through various bioprocesses and key pathways including ErbB and MAPK signaling pathways. These findings provided the experimental and bioinformatic evidence for a better understanding on the epigenetic factor of miRNAs in association with cellular senescence and spontaneous immortalization process in avian cells.

Improved Soil Quality Prediction Model Using Deep Learning for Smart Agriculture Systems

Soil is the major source of infinite lives on Earth and the quality of soil plays significant role on Agriculture practices all around. Hence, the evaluation of soil quality is very important for determining the amount of nutrients that the soil require for proper yield. In present decade, the application of deep learning models in many fields of research has created greater impact. The increasing soil data availability of soil data there is a greater demand for the remotely avail open source model, leads to the incorporation of deep learning method to predict the soil quality. With that concern, this paper proposes a novel model called Improved Soil Quality Prediction Model using Deep Learning (ISQP-DL). The work considers the chemical, physical and biological factors of soil in particular area to estimate the soil quality. Firstly, pH rating of soil samples has been collected from the soil testing laboratory from which the acidic range has been categorized through soil test and the same data has been taken as input to the Deep Neural Network Regression (DNNR) model. Secondly, soil nutrient data has been given as second input to the DNNR model. By utilizing this data set, the DNNR method is used to evaluate the fertility rate by which the soil quality has been estimated. For training and testing, the model uses Deep Neural Network Regression (DNNR), by utilizing the dataset. The results show that the proposed model is effective for SQP (Soil Quality Prediction Model) with efficient good fitting and generality is enhanced with input features with higher rate of classification accuracy. The results show that the proposed model achieves 96.7% of accuracy rate compared with existing models.

The Effect of Periodic Inspection and Safety Criteria on the Service Life of Steel Construction Conveyors

Steel construction structures are seen in many different applications in our country and in the world. However, the periodic maintenance of these steel construction products is explained by national and international laws and regulations. According to the relevant regulation in our country, it is obligatory to carry out periodic inspections of these constructive structures, which are referred to as machinery and equipment, once a year. As in many facilities, it is obvious that these structures are the main elements of the facility and will be used throughout the life of the facility. It is not clear under which conditions these structures, which are generally produced using structural steels and which are connected by welding or bolts, will be examined in the periodic inspections. As a result of the research on the lifetime of general structural steels, it has been proved by many researchers that these structures have an infinite life if they reach the number of million repetitions. However, the life of welding or bolts, which are the connecting elements of the structure, remains uncertain. In this study, accident breaking studies were carried out by detailing the damage due to a tragic accident in a steel construction that has served for about 36 years. By keeping company and personal information confidential, the steel structure and bolt connections of the construction were examined in terms of strength, hardness and microstructure, and the results were detailed.

Fatigue behavior of orthotropic composite bridge decks without cutout at rib-to-floorbeam intersection

The composite bridge panel consisting of an orthotropic steel deck with no extended cutout at the rib-to-floorbeam (RF) intersection and an ultra-high performance concrete (UHPC) rigid layer was proposed, which can simplify the manufacture process and enhance economic benefit. Refined finite element models were established to analyze the stress response of fatigue-prone details, and the approach of variable thickness rib was proposed to achieve an infinite fatigue life. The effect of critical geometric parameters on fatigue performance of RF joint was further investigated, and the parameter combinations with infinite fatigue life were determined. The results show that the rib-to-deck (RD) joint indicates infinite fatigue life, and the stiffness of panel meets the requirements of specification. There is a significant stress raiser at RF joint, and Dong's structural stress reveals that the surface stress at rib side is dominated by bending stress. The effects of the thicknesses of UHPC layer and deck plate on the stress are not significant. Increasing the thickness of the rib belly as well as decreasing the floorbeam thickness and spacing can reduce the stress range of rib side at RF joint, and the 10 mm thick floorbeam is preferable. The UHPC layer can be 50 mm if the rib with variable thickness is utilized, while the UHPC is required to be 60 mm and the floorbeam spacing is 2.5 m if the rib with uniform thickness is adopted.

Evaluation of the reproducibility and positive controls of cellular immortality test for the detection of immortalized cellular impurities in human cell-processed therapeutic products.

Contamination of human cell-processed therapeutic products (hCTPs) with tumorigenic/immortalized cellular impurities is a major concern in the manufacturing and quality control of hCTPs. The cellular immortality test based on cell growth analysis is a method for detecting tumorigenic/immortalized cellular impurities in hCTPs. However, the performance of the cellular immortality test has not yet been well characterized. In this study, we examined the reproducibility of the cellular immortality test in detecting HeLa cells as a model of tumorigenic cellular impurities, as well as the applicability of other models of cellular impurities with different tumorigenicity to the cellular immortality test. Using HeLa cells as a model for cellular impurities, we measured the growth rate of human mesenchymal stem cells (hMSCs) supplemented with HeLa cells at concentrations ranging from 0.01 to 0.0001% at each passage in three laboratories and evaluated the reproducibility of the detection of immortalized cellular impurities. In addition, HEK293cells (another immortalized cell line) and MRC-5cells (a non-immortalized cell line) were employed as cellular impurity models that exhibit different growth characteristics from HeLa cells, and the ability of the cellular immortality test to detect these different impurities when mixed with hMSCs was examined. In the multisite study, the growth rate of hMSCs supplemented with 1 and 10 HeLa cells (0.0001% and 0.001%) significantly increased and reached a plateau in all three laboratories, whereas those of hMSCs alone eventually decreased. Moreover, when hMSCs were supplemented with 10 and 100 HEK293 and MRC-5cells (0.001% and 0.01%), the growth rate significantly increased. The growth rate of hMSCs supplemented with HEK293cells increased with passage and remained high, whereas that of hMSCs supplemented with MRC-5cells eventually decreased, as in the case of hMSCs alone. These results indicate that the cellular immortality test is reproducible and can detect immortalized (i.e., potentially tumorigenic) cells such as HEK293cells with a lower growth rate than HeLa cells by discriminating against normal cells, which could contribute to ensuring the safety and quality of hCTPs.

Abstract IA016: Characterization of the protein-protein interactions involved in hDOT1L epigenetic regulation on biochemical, structural and functional level towards developing new therapeutic intervention

Abstract MLL1 (KMT2a) gene rearrangements underlie the pathogenesis of aggressive MLL-driven acute leukemia. More than 90 different MLL translocation partners have been identified with the most common fusion partners, AF9, ENL, AF4, and AF10. AF9 and ENL are closely related members of the YEATS domain protein family and have been identified as part of several reported complexes including Super Elongation Complex (SEC) and DotCom Complex. AF9 and ENL, through their C-terminal hydrophobic domain, known as ANC1 Homology Domain (AHD), recruit the histone H3K79 methyltransferase hDOT1L to the MLL target genes, constitutively activating transcription of pro-leukemic targets. We have characterized the protein−protein interactions between hDOT1L and MLL fusion oncogenic proteins, AF9 and ENL, on the biochemical, biophysical, and functional level. This study mapped a 10 amino-acid region (aa 865− 874), highly conserved in hDOT1L from a variety of species, as an interacting site with the AHD domain of AF9/ENL proteins and demonstrated that these PPIs are essential for cellular immortalization mediated by MLL-AF9. Applying genetic approach and studying the effects of blocking the AF9-hDOT1L PPIs or hDOT1L enzymatic activity, it was demonstrated complete disruption of hDOT1L recruitment to critical target genes, Hoxa9 and Meis1, in cells expressing hDOT1L mutants with an impaired AF9 binding site. This was followed by significant decrease in H3K79me2 in the promoter regions of these genes, cell differentiation and induction of apoptosis. To identify the potential therapeutic benefits of this novel targeting approach, the effect of these different hDOT1L mutants was investigated on adult murine hematopoiesis. The in vivo studies demonstrated that genetic interventions that result in loss of hDOT1L enzymatic activity rapidly depletes hematopoietic stem and progenitor cells. In contrast, blocking the AF9-hDOT1L PPIs allowed for sustained hematopoiesis. These studies provided an important proof of concept for the potential therapeutic advantage of inhibiting the AF9-hDOT1L interaction and disrupting the integrity of the MLL-fusion complexes. In addition, these results demonstrated that hDOT1L recruitment can be abolished by a single point mutant (I867A), highlighting the crucial role of the hydrophobic interactions and giving insights for further drug discovery. We have reported the first peptidomimetics targeting PPIs between MLL-AF9 and hDOT1L, providing evidence for the druggability assessment of this novel potential therapeutic approach. The AF9/ENL C-terminal domain, is an intrinsically disordered protein, representing a challenge for structural studies. Applying X-ray crystallography, we have successfully determined the 3D structure of the AF9 AHD domain in complex with peptidomimetics establishing a platform for structure-based design of novel, optimized, potent inhibitors, the current focus of our research efforts. Citation Format: Zaneta Nikolovska-Coleska. Characterization of the protein-protein interactions involved in hDOT1L epigenetic regulation on biochemical, structural and functional level towards developing new therapeutic intervention. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA016.

Funerals and Family Care in the South African Local Catholic Church

The importance of funerals in South Africa is emphasized in this essay. Specifically, to rebuild the society that was torn apart as a result of the union of numerous families. Only if the family is rebuilt in accordance with God's plan can this take place. Sadly, there are a number of South African societies where the Catholic Church is not respected. The most common topic of conversation in South Africa in both the church and society is death. In South Africa, funerals may at times serve dubious functions. Many nuclear families come together during funerals. To comfort the grieving family, people of many faiths and denominations thus gather together. Surprisingly, the bulk shows up with empty hands and without any supplies to aid the efforts of the struggling family members. Funerals are therefore costly for bereaved families in South Africa, despite the fact that many family members lament their poverty. The majority of those who comfort a grieving family are not particularly inspired by the Christian funeral service. The funeral attendees in South Africa hold both God and the church responsible for the advice they receive as a result of a death. This is due to the fact that people often tend to place a higher value on material wealth than on the spiritual and everlasting aspects that death carries based on the promise of life everlasting by Jesus Christ. The only solution is to achieve a balance between worldly and spiritual richness, which also necessitates increasing awareness of an individuals' spiritual demands and needs.

Analysis of dynamic fatigue characteristics of critical parts of highly strengthened single cylinder diesel engine

In this paper, the strength analysis and fatigue life calculation of multi-component coupling of crankshaft, connecting rod and engine body of highly strengthened single cylinder diesel engine are carried out. The stress of crankshaft, connecting rod and engine body in two working cycles is calculated by multi-component coupling transient dynamics, and the strength is analyzed based on the third strength theory firstly; Then, the accuracy of the transient calculation results is verified by the strength experiment of the crankshaft and connecting rod reduced scale model and the calculation of the static stress of the body; Finally, according to the stress fatigue life calculation method, the fatigue life of crankshaft, connecting rod and engine body is calculated. The maximum stress of crankshaft, connecting rod and body is less than the yield limit of corresponding materials; The fatigue life calculation results show that the damage accumulation of the engine body is very little, which meets the design requirements of infinite life. The damage accumulation of the crankshaft at the fillet of the main journal and the connecting rod at the side of the rod is 32005.6 hours and 102841.7 hours respectively, which meeting the design requirements of 20000 hours.

Telomerase: A link between cancer and biological immortality

Cancer is a leading cause of death worldwide, with approximately 18.1 million new cases and 9.6 million fatalities annually. Many studies have shown that telomeres and telomerase play crucial roles in the progression of almost all types of cancer. The length of telomeres is reduced with each cell division, and when they become too short, the cells can no longer divide and die. Telomerase is responsible for maintaining the length of the telomere during replication. In healthy cells, telomerase is only active during embryonic development and gamete formation. Telomerase is inactive in most somatic cells and highly active in germ cells, stem cells, and cancer cells. This activity ensures that somatic cells can only divide a finite number of times (Hayflick limit) before they reach senescence and enter apoptosis. However, cancer cells express high levels of telomerase and can divide indefinitely. This makes them immortal, eating away from the host’s resources, and acquiring properties, such as loss of cell adhesion, metastasis, and loss of contact inhibition, which creates tissue lumps wherever the tumor develops. Many recent advances in science and technology have shown the significant role of telomerase in cancer and aging, which also opens a wide door for cancer treatment, hoping for patients back to life. In this review, we discuss the significance of telomerase and its effect on cancer progression and various research and therapeutic aspects of telomerase.

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.

Fatigue assessment of steel-UHPC composite deck with a thin polymer overlay in a long-span suspension bridge under static and random traffic loads

Steel-ultra-high performance concrete (UHPC) composite deck emerges as a novel structure that is promising to improve the fatigue performance of orthotropic steel deck (OSD). However, a long-span suspension bridge has a strict requirement on the self-weight of a steel-UHPC composite deck because it is susceptible to dead load variations. This study evaluates the fatigue performance of the steel-UHPC deck with a thin polymer overlay (TPO) in the Yichang Yangtze River Highway Bridge, a long-span suspension bridge, under static load and random traffic flow. The measured strains at the fatigue-prone details were employed to calculate the equivalent stress ranges and total fatigue life of the steel-UHPC deck. A three-dimensional finite element model was established and validated by experimental measurements to evaluate the steel-UHPC deck’s stiffness and the TPO layer’s crack resistance. The differences between the stress values predicted by the validated model and the experimentally measured ones were around 5%. The results showed that the steel-UHPC deck with TPO significantly reduced fatigue-prone details’ equivalent stress ranges without increasing the dead load. The maximum stress reduction at various details reached 62%, and the total fatigue life at each detail in the steel-UHPC deck reached infinite life. The TPO layer has enough crack resistance in case the deck is overloaded by 50%. Compared with the original deck, the steel-UHPC composite deck improves the OSD’s local stiffness and reduces relative deformation between structural components, thus reducing the stress ranges at fatigue-prone details and improving the bridge deck’s fatigue performance. The results can provide a reference for the design and retrofit of the deck overlay of the long-span suspension bridge with OSD.

The path to immortalization of cells starts by managing stress through gene duplications

The genomes of immortalized cell lines (and cancer cells) are characterized by multiple types of aberrations, ranging from single nucleotide polymorphisms (SNPs) to structural rearrangements that have accumulated over time. Consequently, it is difficult to estimate the relative impact of different aberrations, the order of events, and which gene functions were under selective pressure at the early stage towards cellular immortalization. Here, we have established novel cell cultures derived from Drosophila melanogaster embryos that were sampled at multiple time points over a one-year period. Using short-read DNA sequencing, we show that copy-number gain in preferentially stress-related genes were acquired in a dominant fraction of cells in 300-days old cultures. Furthermore, transposable elements were active in cells of all cultures. Only a few (<1%) SNPs could be followed over time, and these showed no trend to increase or decrease. We conclude that the early cellular responses of a novel culture comprise sequence duplication and transposable element activity. During immortalization, positive selection first occurs on genes that are related to stress response before shifting to genes that are related to growth.

CSIG-05. A GABP DOMINANT NEGATIVE APPROACH TO THE REVERSAL OF TUMOR IMMORTALITY

Abstract Immortality is a fundamental hallmark of human cancer cells and therapeutic reversal is of great interest. Telomerase Reverse Transcriptase promoter (TERTp) mutations reactivate TERT expression, the rate limiting step in telomerase activity and cellular immortality. TERTp mutations are the most common non-coding mutation across all cancer types, including glioblastoma (GBM), oligodendroglioma, medulloblastoma, and high-grade meningioma. While prior telomerase therapies lack tumor selectivity and are poorly tolerated, TERTp mutations and their regulation offer a unique opportunity for tumor specific reversal of cellular immortality. The mutations generate a de novo E26 Transformation Specific (ETS) binding motif that recruits the GA-Binding Protein (GABP) multimeric complex to reactivate TERT expression. Initially we found a GABP tetramer reactivates the mutant TERTp, suggesting targeting only the tetramer may induce telomere shortening and tumor cell death. However, through knocking out this tetramer in cell cultures, we found that the GABP dimer is upregulated and maintains TERT expression. In the absence of both the dimer and one tetramer isoform, many tumor cells senesce or undergo cell death. However, some tumor cells escape this fate via upregulation of a second GABP tetrameric paralogue that maintains TERT expression. Therefore, to block all GABP complexes with a single approach, we devised a transactivation domain null, putative dominant negative GABP subunit that ultimately could be delivered to patients via a replicating retroviral system. Introduction of the construct into TERTp mutant glioma cells significantly reduced TERT expression while not altering expression in TERTp wildtype GBM cells, suggesting tumor selectivity. TERT expression was also reduced in a second TERTp mutant tumor type. We are currently investigating the long-term effects of the dominant negative GABP on telomere length and tumor immortality. Dominant negative GABP is a promising candidate for tumor selective reversal of cellular immortality by inhibiting mutant TERTp activation by all GABP multimeric forms.

Mechanical characterization and fractographic study of the carbon/PEI composite under static and fatigue loading

The fatigue life of carbon fiber reinforced thermoplastic matrix composites is of great interest for many engineering applications. This work evaluated the influence of poly(etherimide) (PEI) on the fatigue life of laminated thermoplastic composites reinforced with carbon fibers. The mechanical characterization of the carbon/PEI composites was performed by static loading (tensile test) and cyclic fatigue. Tensile strength obtained was used to calculate 5 stress levels for cyclic fatigue testing with R = 0.1 and 12 Hz for 85, 80, 70, 60, and 55%, being this last stress level found as the infinite life. These stress levels allowed plotting a well-described SN curve. Seeking to understand the fracture behavior of carbon/PEI composites, a fractographic study by scanning electron microscopy (SEM) was performed. SEM micrographs confirm the good quality of carbon/PEI laminate with good adhesion between fibers and matrix and also confirmed the nature of fatigue life showing in-plane fracture for high loads and explosive fracture for lower loads.

Biogenesis of telomerase RNA from a protein-coding mRNA precursor

Telomerase is a eukaryotic ribonucleoprotein (RNP) enzyme that adds DNA repeats onto chromosome ends to maintain genomic stability and confer cellular immortality in cancer and stem cells. The telomerase RNA (TER) component is essential for telomerase catalytic activity and provides the template for telomeric DNA synthesis. The biogenesis of TERs is extremely divergent across eukaryotic kingdoms, employing distinct types of transcription machinery and processing pathways. In ciliates and plants, TERs are transcribed by RNA polymerase III (Pol III), while animal and ascomycete fungal TERs are transcribed by RNA Pol II and share biogenesis pathways with small nucleolar RNA (snoRNA) and small nuclear RNA (snRNA), respectively. Here, we report an unprecedented messenger RNA (mRNA)-derived biogenesis pathway for the 1,291 nucleotide TER from the basidiomycete fungus Ustilago maydis. The U. maydis TER (UmTER) contains a 5'-monophosphate, distinct from the 5' 2,2,7-trimethylguanosine (TMG) cap common to animal and ascomycete fungal TERs. The mature UmTER is processed from the 3'-untranslated region (3'-UTR) of a larger RNA precursor that possesses characteristics of mRNA including a 5' 7-methyl-guanosine (m7G) cap, alternative splicing of introns, and a poly(A) tail. Moreover, this mRNA transcript encodes a protein called Early meiotic induction protein 1 (Emi1) that is conserved across dikaryotic fungi. A recombinant UmTER precursor expressed from an mRNA promoter is processed correctly to yield mature UmTER, confirming an mRNA-processing pathway for producing TER. Our findings expand the plethora of TER biogenesis mechanisms and demonstrate a pathway for producing a functional long noncoding RNA from a protein-coding mRNA precursor.

Mechanical and fatigue behaviour of polyamide 12 processed via injection moulding and selective laser sintering. Analysis based on Kitagawa-Takahashi diagrams

This work deals with the mechanical and fatigue behaviour of polyamide 12 processed via Selective Laser Sintering and Injection Moulding. Apart from the analysis regarding the influence of the manufacturing technique, the effect of the layer orientation with respect to the direction of the applied load will be also analysed, since the additive manufacturing technique is a layer-wise technology that can induce anisotropy in the material. An extensive experimental program was carried out to determine the tensile, fracture, fatigue life and fatigue crack growth behaviours. The main novelty of this work lies, for the first time in polymers, in the use of the perspective of the Kitagawa-Takahashi diagrams for infinite fatigue life and by analogy their extension to failure.

Evaluation of Stress and Fatigue on Different Implant Lengths in the Rehabilitation of Atrophic Mandibles with Full-Arch Fixed Prosthesis Using Finite Element Method.

This research aimed to evaluate the stress and fatigue generated in short implants compared to regular implants in rehabilitation with fixed full-arch implant-supported prostheses in atrophic mandibles using the finite element method (FEM). Four models were constructed with different implants lengths: 4, 6, 8, and 10 mm. A 100-N oblique load was applied to evaluate the stress on the bone, implant, and prosthetic components. Similar behavior was observed for all groups, except for 4 mm, which showed more discrepant values. During the fatigue test, all the groups exhibited infinite lives except G4. Based on the similarity of all the models, it is suggested that all short implants investigated are seemingly viable alternatives for the rehabilitation of atrophic mandibles. However, the 6-mm-long and 8-mm-long implants evinced more favorable mechanical behavior than the 4-mm-long type.