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Background Objective Methods Results Conclusions Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene.The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age‐matched healthy subjects (n = 87).LTL was measured by real‐time polymerase chain reaction quantitative analysis (qPCR).The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)‐like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair.Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Telomere biology disorders (TBD) are a complex set of inherited illnesses characterized by short telomeres. Dyskeratosis congenita (DC), which is now considered a severe TBD phenotype, is characterized by reticulated pigmentary changes, nail dystrophy, premalignant oral leukoplakia, and systemic involvement. This case describes a 2‐year‐old female with reticulated pigmentary changes and Terry's nails who was found to have a TERT variant and short telomeres; she lacked other mucocutaneous and systemic features of TBD. This report describes a unique clinical presentation of TBD and highlights the importance of upholding suspicion for TBD in individuals with limited or subtle features of classic DC. [ABSTRACT FROM AUTHOR]

Lettuce (Lactuca sativa L., Asteraceae) is one of the most important vegetable crops, known for its various horticultural types and significant morphological variation. The first reference genome of lettuce, a crisphead type (L. sativa var. capitata cv. Salinas), was previously released. Here, we reported a near-complete chromosome-level reference genome for looseleaf lettuce (L. sativa var. crispa). PacBio high-fidelity sequencing, Oxford Nanopore, and Hi-C technologies were employed to produce genome assembly. The final assembly is 2.59 Gb in length with a contig N50 of 205.47 Mb, anchored onto nine chromosomes, containing 14 recognizable telomeres and only 11 gaps. Repetitive sequences account for 77.11% of the genome, and 41,375 protein-coding genes were predicted, with 99.10% of these assigned functional annotations. This chromosome-level genome enriched genomic resources for various horticultural types of lettuce and will facilitate the characterization of morphological variation and genetic improvement in lettuce. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA). Methods: Summary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bidirectional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established. Results: Telomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers. Conclusion: We found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA [ABSTRACT FROM AUTHOR]

Introduction: Alternative lengthening of telomeres (ALT) occurs in sarcomas and ALT cancers share common mechanisms of therapy resistance or sensitivity. Telomeric DNA C-circles are self-primed circular telomeric repeats detected with a PCR assay that provide a sensitive and specific biomarker exclusive to ALT cancers. We have previously shown that 23% of high-risk neuroblastomas are of the ALT phenotype. Here, we investigate the frequency of ALT in Ewing's family sarcoma (EFS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) by analyzing DNA from fresh frozen primary tumor samples utilizing the real-time PCR C-circle Assay (CCA). Methods: We reviewed prior publications on ALT detection in pediatric sarcomas. DNA was extracted from fresh frozen primary tumors, fluorometrically quantified, C-circles were selectively enriched by isothermal rolling cycle amplification and detected by real-time PCR. Results: The sample cohort consisted of DNA from 95 EFS, 191 RMS, and 87 OS primary tumors. One EFS and 4 RMS samples were inevaluable. Using C-circle positive (CC+) cutoffs previously defined for high-risk neuroblastoma, we observed 0 of 94 EFS, 5 of 187 RMS, and 62 of 87 OS CC+ tumors. Conclusions: Utilizing the ALT-specific CCA we observed ALT in 0% of EFS, 2.7% of RMS, and 71% of OS. These data are comparable to prior studies in EFS and OS using less specific ALT markers. The CCA can provide a robust and sensitive means of identifying ALT in sarcomas and has potential as a companion diagnostic for ALT targeted therapeutics. [ABSTRACT FROM AUTHOR]

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments. Mechanisms of action of miRNAs in regulating the hTERT complex and their impact on the tumor cells phenotypes. [ABSTRACT FROM AUTHOR]

An established technology to create cloned animals is through the use of somatic cell nuclear transfer (SCNT), in which reprogramming the somatic cell nucleus to a totipotent state by enucleated oocyte cytoplasm is a necessary process, including telomere length reprogramming. The limitation of this technology; however, is that the live birth rate of offspring produced through SCNT is significantly lower than that of IVF. Whether and how telomere length play a role in the development of cloned animals is not well understood. Only a few studies have evaluated this association in cloned mice, and fewer still in cloned cows. In this study, we investigated the difference in telomere length as well as the abundance of some selected molecules between newborn deceased cloned calves and normal cows of different ages either produced by SCNT or via natural conception, in order to evaluate the association between telomere length and abnormal development of cloned cows. The absolute telomere length and relative mitochondrial DNA (mtDNA) copy number were determined by real-time quantitative PCR (qPCR), telomere related gene abundance by reverse-transcription quantitative PCR (RT-qPCR), and senescence-associated β-galactosidase (SA-β-gal) expression by SA-β-gal staining. The results demonstrate that the newborn deceased SCNT calves had significantly shortened telomere lengths compared to newborn naturally conceived calves and newborn normal SCNT calves. Significantly lower mtDNA copy number, and significantly lower relative abundance of LMNB1 and TERT , higher relative abundance of CDKN1A , and aberrant SA-β-gal expression were observed in the newborn deceased SCNT calves, consistent with the change in telomere length. These results demonstrate that abnormal telomere shortening, lower mtDNA copy number and abnormal abundance of related genes were specific to newborn deceased SCNT calves, suggesting that abnormally short telomere length may be associated with abnormal development in the cloned calves. • The association of telomere length and related genes with developmental abnormalities in cloned calves was investigated. • Shortened telomere length and reduced mtDNA copy number were specific to newborn deceased SCNT calves. • Abnormal telomere shortening may be associated with abnormal development in cloned cows. • To help further understand the role of telomeres in developmental barriers to cloned calves. • Telomeres and related genes may be able to serve as molecular targets to enhance live birth rates in cloned calves. [ABSTRACT FROM AUTHOR]

Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC). Men with AUD (n = 108, mean age = 52.4, SD = 8.6) were recruited in a detoxification unit, and HC (n = 80, mean age = 50.04, SD = 9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR. Telomere length did not differ between individuals with AUD and HC (p = 0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p = 0.018) or without comorbidity (p = 0.018). Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age. • Telomere length is a marker of ageing. • Telomere length did not differ between individuals with AUD and controls. • Individuals with externalizing disorders have longer telomere length. [ABSTRACT FROM AUTHOR]

• Recent evidence suggests that pregnancy accelerates biologic aging. • Little is known about how mode of delivery affects markers of biologic aging. • Leukocyte telomere length, a marker of biologic aging, was shorter after cesarean. • Telomere shortening persisted at an average of 6 weeks postpartum. • Other differences in multiomics by mode of delivery were not appreciated. Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging. Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma). Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta −496.1, 95 % confidence interval [CI] −891.1, −101.1, p = 0.01) and beyond (adjusted beta −396.8; 95 % CI −727.2, −66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction. Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted. [ABSTRACT FROM AUTHOR]

Context.--Pancreatic neuroendocrine neoplasms (Pan- NENs) represent a heterogeneous group of epithelial tumors of the pancreas showing neuroendocrine differentiation. These neoplasms are classified into well-differentiated pancreatic neuroendocrine tumors (PanNETs), which include G1, G2, and G3 tumors, and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs), which are G3 by definition. This classification mirrors clinical, histologic, and behavioral differences and is also supported by robust molecular evidence. Objective.--To summarize and discuss the state of the art regarding neoplastic progression of PanNENs. A better comprehension of the mechanisms underpinning neoplas- tic evolution and progression of these neoplasms may open new horizons for expanding biologic knowledge and ultimately for addressing new therapeutic strategies for patients with PanNENs. Data Sources.--Literature review of published studies and the authors' own work. Conclusions.--PanNETs can be seen as a unique category, where G1-G2 tumors may progress to G3 tumors mainly driven by DAXX/ATRX mutations and alternative lengthening of telomeres. Conversely, PanNECs display totally different histomolecular features more closely related to pancreatic ductal adenocarcinoma, including TP53 and Rb alterations. They seem to derive from a nonneuroendocrine cell of origin. Even the study of PanNEN precursor lesions corroborates the rationale of considering PanNETs and PanNECs as separate and distinct entities. Improving the knowledge regarding this dichotomous distinction, which guides tumor evolution and progression, will represent a critical basis for PanNEN precision oncology. [ABSTRACT FROM AUTHOR]

Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD. A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested. Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group. Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns. • There is a non-linear association between telomere length and cognitive performance. • Longer telomeres are associated with higher episodic memory scores. • The association between telomeres and cognitive performance might be sex-specific. [ABSTRACT FROM AUTHOR]

The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF–TP53–MDM2 pathway and amplification of MDM2 and CDK4. [ABSTRACT FROM AUTHOR]

Meiotic progression requires coordinated assembly and disassembly of protein complexes involved in chromosome synapsis and meiotic recombination. Mouse TRIP13 and its ortholog Pch2 are instrumental in remodeling HORMA domain proteins. HORMAD proteins are associated with unsynapsed chromosome axes but depleted from the synaptonemal complex (SC) of synapsed homologs. Here we report that TRIP13 localizes to the synapsed SC in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. Loss of TRIP13 leads to meiotic arrest and thus sterility in both sexes. Trip13-null meiocytes exhibit abnormal persistence of HORMAD1 and HOMRAD2 on synapsed SC and chromosome asynapsis that preferentially affects XY and centromeric ends. These major phenotypes are consistent with reported phenotypes of Trip13 hypomorph alleles. Trip13 heterozygous mice exhibit meiotic defects that are less severe than the Trip13-null mice, showing that TRIP13 is a dosage-sensitive regulator of meiosis. Localization of TRIP13 to the synapsed SC is independent of SC axial element proteins such as REC8 and SYCP2/ SYCP3. Terminal FLAG-tagged TRIP13 proteins are functional and recapitulate the localization of native TRIP13 to SC and telomeres. Therefore, the evolutionarily conserved localization of TRIP13/ Pch2 to the synapsed chromosomes provides an explanation for dissociation of HORMA domain proteins upon synapsis in diverse organisms. [ABSTRACT FROM AUTHOR]

This study aimed to measure telomere length in healthy children living next to Urmia Lake, Iran, which is exposed to salt dust from a drying lakebed. In this case-control pilot study, we recruited 39 sex- and age-matched healthy children from two different geographic regions to study the relative telomere lengths using qPCR. We categorized the study samples into high-impact and low-impact areas based on wind direction, aerosol particle level, and distance from the lake. Our main results revealed that children living in high-impact areas have shorter telomeres than those living in low-impact areas. Furthermore, according to our statistical model, parental age significantly affected telomere length in children, but inversely. When the father’s age impact was positive, the mother had a negative effect. Based on our results, to prevent Urmia Lake from dying out completely, national and international organizations should implement comprehensive visions and strategies for its restoration. [ABSTRACT FROM AUTHOR]

Telomere lengths and telomere dynamics can correlate with lifespan, behaviour and individual quality. Such relationships have spurred interest in understanding variation in telomere lengths and their dynamics within and between populations. Many studies have identified how environmental processes can influence telomere dynamics, but the role of genetic variation is much less well characterized. To provide a novel perspective on how telomeric variation relates to genetic variability, we longitudinally sampled individuals across a narrow hybrid zone (n = 127 samples), wherein two Manacus species characterized by contrasting genome‐wide heterozygosity interbreed. We measured individual (n = 66) and population (n = 3) differences in genome‐wide heterozygosity and, among hybrids, amount of genetic admixture using RADseq‐generated SNPs. We tested for population differences in telomere lengths and telomere dynamics. We then examined how telomere lengths and telomere dynamics covaried with genome‐wide heterozygosity within populations. Hybrid individuals exhibited longer telomeres, on average, than individuals sampled in the adjacent parental populations. No population differences in telomere dynamics were observed. Within the parental population characterized by relatively low heterozygosity, higher genome‐wide heterozygosity was associated with shorter telomeres and higher rates of telomere shortening—a pattern that was less apparent in the other populations. All of these relationships were independent of sex, despite the contrasting life histories of male and female manakins. Our study highlights how population comparisons can reveal interrelationships between genetic variation and telomeres, and how naturally occurring hybridization and genome‐wide heterozygosity can relate to telomere lengths and telomere dynamics. [ABSTRACT FROM AUTHOR]

Background: Buyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI). Methods: Myocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days. Results: Coronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway. Conclusion: BYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI. [ABSTRACT FROM AUTHOR]

Aging is a complex process influenced by internal and external factors. Oxidative stress damages DNA, leading to 8-hydroxy-2' deoxyguanosine formation (8-OHdG). Telomere shortening is considered a biomarker of aging and oxidative stress may enhance its attrition. The ability to manage and repair oxidative stress varies among species and life histories. Avian species, such as Psittacidae birds, exhibit exceptional lifespans despite their physiological characteristics that might suggest otherwise. This study investigates 8-OHdG levels in serum samples from long- and short-lived birds of the order Psittaciformes, examining their relationship with telomere length and antioxidant capacity based on lifespan strategies. Among 43 individuals analyzed 26 belonged to the "long-lived species" group and 17 belonged to the "short-lived species" one. Relative telomere length (rTL) was measured in DNA isolated from whole blood by qPCR, and oxidative stress markers, such as Total Antioxidant Capacity (TAC) and 8-OHdG, were determined by spectrophotometry in serum samples. Long-lived birds had longer rTL than short-lived ones [1.308 ± 0.11 vs. 0.565 ± 0.13, (p < 0.001)]. On the contrary, short-lived birds showed more DNA damage than their counterparts [3.847 ± 0.351 vs. 2.012 ± 0.308, respectively, (p < 0.001)]. Old birds had shorter rTL than young ones, for both longevity groups (p < 0.001). Although no correlation was found between 8-OHdG levels and age, nor 8-OHdG and telomere length, long-lived birds exhibited 75.42-unit increased TAC levels when increased 8-OHdG concentrations (p = 0.046). These findings highlight distinct patterns of telomere length and oxidative stress influenced by lifespan strategies among avian longevity groups. [ABSTRACT FROM AUTHOR]

Simple Summary: Three-dimensional (3D) telomere analysis using TeloView v 2.2 has shown promise in quantifying genomic instability and predicting therapy response. In a study of 156 Classic Hodgkin's lymphoma (cHL), we identified significant 3D telomere parameters that predict patient outcomes. A predictive model using four 3D telomere parameters, including the proportion of t-stumps (very short telomeres), achieved an area under curve (AUC) of 0.83, with a sensitivity and specificity of 0.82 and 0.78, respectively. Classic Hodgkin's lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15–20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients' response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively. [ABSTRACT FROM AUTHOR]

Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10–1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23–3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a primary CNS tumor that is highly lethal in adults and has limited treatment options. Despite advancements in understanding the GBM biology, the standard treatment for GBM has remained unchanged for more than a decade. Only 6.8% of patients survive beyond five years. Telomerase, particularly the hTERT promoter mutations present in up to 80% of GBM cases, represents a promising therapeutic target due to its role in sustaining telomere length and cancer cell proliferation. This review examines the biology of telomerase in GBM and explores potential telomerase-targeted therapies. We conducted a systematic review following the PRISMA-P guidelines in the MEDLINE/PubMed and Scopus databases, from January 1995 to April 2024. We searched for suitable articles by utilizing the terms "GBM", "high-grade gliomas", "hTERT" and "telomerase". We incorporated studies addressing telomerase-targeted therapies into GBM studies, excluding non-English articles, reviews, and meta-analyses. We evaluated a total of 777 records and 46 full texts, including 36 studies in the final review. Several compounds aimed at inhibiting hTERT transcription demonstrated promising preclinical outcomes; however, they were unsuccessful in clinical trials owing to intricate regulatory pathways and inadequate pharmacokinetics. Direct hTERT inhibitors encountered numerous obstacles, including a prolonged latency for telomere shortening and the activation of the alternative lengthening of telomeres (ALT). The G-quadruplex DNA stabilizers appeared to be potential indirect inhibitors, but further clinical studies are required. Imetelstat, the only telomerase inhibitor that has undergone clinical trials, has demonstrated efficacy in various cancers, but its efficacy in GBM has been limited. Telomerase-targeted therapies in GBM is challenging due to complex hTERT regulation and inadequate inhibitor pharmacokinetics. Our study demonstrates that, despite promising preclinical results, no Telomerase inhibitors have been approved for GBM, and clinical trials have been largely unsuccessful. Future strategies may include Telomerase-based vaccines and multi-target inhibitors, which may provide more effective treatments when combined with a better understanding of telomere dynamics and tumor biology. These treatments have the potential to be integrated with existing ones and to improve the outcomes for patients with GBM. [ABSTRACT FROM AUTHOR]

The number of infertile couples undergoing in vitro fertilisation (IVF) has increased significantly. The efficacy of this procedure is contingent upon a multitude of factors, including gamete quality. One factor influencing gamete quality is oxidative stress, which leads to telomere damage and accelerates cellular ageing. Identifying new biomarkers that can predict the success of assisted reproduction techniques is a current relevant area of research. In this review, we discuss the potential role of SIRT1, a protein known to protect against oxidative stress and telomeres, which are responsible for genome stability, as biomarkers of gamete quality and assisted reproduction technique outcomes. [ABSTRACT FROM AUTHOR]

Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) has been receiving a lot of attention from scientists and clinicians because it is an extremely common clinical condition. Due to its special hemodynamic changes, AF has a high rate of disability and mortality. So far, although AF has some therapeutic means, it is still an incurable disease because of its complex risk factors and pathophysiologic mechanisms, which is a difficult problem for global public health. Age is an important independent risk factor for AF, and the incidence of AF increases with age. To date, there is no comprehensive review on aging‐associated AF. In this review, we systematically discuss the pathophysiologic evidence for aging‐associated AF, and in particular explore the pathophysiologic mechanisms of mitochondrial dysfunction, telomere attrition, cellular senescence, disabled macroautophagy, and gut dysbiosis involved in recent studies with aging‐associated AF. We hope that by exploring the various dimensions of aging‐associated AF, we can better understand the specific relationship between age and AF, which may be crucial for innovative treatments of aging‐associated AF. [ABSTRACT FROM AUTHOR]

A study published in Acta Neuropathologica explores the relationship between chromosome 1p loss and the risk of recurrence in meningioma, a type of brain tumor. The researchers found that losses in chromosome 1p, particularly those exceeding 5%, were associated with an increased risk of recurrence. The study also suggests that even small losses in chromosome 1p may indicate chromosomal instability and increased tumor growth. The findings highlight the importance of considering 1p loss as a marker for increased risk in meningioma, with a proposed clinically relevant cut-off of 5%. [Extracted from the article]

Defects in the splicing machinery are implicated in various diseases, including cancer. We observed a general reduction in the expression of spliceosome components and splicing regulators in human cell lines undergoing replicative, stress‐induced, and telomere uncapping‐induced senescence. Supporting the view that defective splicing contributes to senescence, splicing inhibitors herboxidiene, and pladienolide B induced senescence in normal and cancer cell lines. Furthermore, depleting individual spliceosome components also promoted senescence. All senescence types were associated with an alternative splicing transition from the MDM4‐FL variant to MDM4‐S. The MDM4 splicing shift was reproduced when splicing was inhibited, and spliceosome components were depleted. While decreasing the level of endogenous MDM4 promoted senescence and cell survival independently of the MDM4‐S expression status, cell survival was also improved by increasing MDM4‐S. Overall, our work establishes that splicing defects modulate the alternative splicing of MDM4 to promote senescence and cell survival. [ABSTRACT FROM AUTHOR]

Background: Childhood maltreatment (CM) is linked to long-term adverse health outcomes, including accelerated biological aging and cognitive decline. This study investigates the relationship between CM and various aging biomarkers: telomere length, facial aging, intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, frailty index, and cognitive performance. Methods: We conducted a Mendelian randomization (MR) study using published GWAS summary statistics. Aging biomarkers included telomere length (qPCR), facial aging (subjective evaluation), and epigenetic age markers (HannumAge, IEAA, GrimAge, PhenoAge). The frailty index was calculated from clinical assessments, and cognitive performance was evaluated with standardized tests. Analyses included Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median (WM) methods, adjusted for multiple comparisons. Results: CM was significantly associated with shorter telomere length (IVW: β = − 0.1, 95% CI − 0.18 to − 0.02, pFDR = 0.032) and increased HannumAge (IVW: β = 1.33, 95% CI 0.36 to 2.3, pFDR = 0.028), GrimAge (IVW: β = 1.19, 95% CI 0.19 to 2.2, pFDR = 0.040), and PhenoAge (IVW: β = 1.4, 95% CI 0.12 to 2.68, pFDR = 0.053). A significant association was also found with the frailty index (IVW: β = 0.31, 95% CI 0.13 to 0.49, pFDR = 0.006). No significant associations were found with facial aging, IEAA, or cognitive performance. Conclusions: CM is linked to accelerated biological aging, shown by shorter telomere length and increased epigenetic aging markers. CM was also associated with increased frailty, highlighting the need for early interventions to mitigate long-term effects. Further research should explore mechanisms and prevention strategies. [ABSTRACT FROM AUTHOR]

Summary Severe aplastic anaemia (SAA) is a rare and life‐threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post‐haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2–77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1–99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy‐neutral loss of heterozygosity (6p‐CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = −0.14, p = 0.0002), and possibly genetically predicted TL (r = −0.07, p = 0.06) were noted. The post‐HCT 3‐year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6‐CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p‐log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post‐HCT survival. TL may guide clinical decisions in patients with SAA. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development. Multiple myeloma (MM) is an incurable blood malignancy. Here, the authors report 35 MM risk loci and two causal mechanisms for genetic MM risk: longer telomeres and elevated plasma B-cell maturation antigen (BCMA) and interleukin−5 receptor alpha (IL5RA) levels. [ABSTRACT FROM AUTHOR]

The six-subunit shelterin complex binds to mammalian telomeres and protects them from triggering multiple DNA damage response pathways. The loss of this protective function by shelterin can have detrimental effects on cells. In this review, we first discuss structural studies of shelterin, detailing the contributions of each subunit and inter-subunit interactions in protecting chromosome ends. We then examine the influence of telomeric chromatin dynamics on the function of shelterin at telomeres. These studies provide valuable insights and underscore the challenges that future research must tackle to attain high-resolution structures of shelterin. [ABSTRACT FROM AUTHOR]

Summary Genome assembly projects have grown exponentially due to breakthroughs in sequencing technologies and assembly algorithms. Evaluating the quality of genome assemblies is critical to ensure the reliability of downstream analysis and interpretation. To fulfil this task, we have developed the AssemblyQC pipeline that performs file-format validation, contaminant checking, contiguity measurement, gene- and repeat-space completeness quantification, telomere inspection, taxonomic assignment, synteny alignment, scaffold examination through Hi-C contact-map visualization, and assessments of completeness, consensus quality and phasing through k-mer analysis. It produces a comprehensive HTML report with method descriptions, tables, and visualizations. Availability and implementation The pipeline uses Nextflow for workflow orchestration and adheres to the best-practice established by the nf-core community. This pipeline offers a reproducible, scalable, and portable method to assess the quality of genome assemblies—the code is available online at GitHub: https://github.com/Plant-Food-Research-Open/assemblyqc. [ABSTRACT FROM AUTHOR]

In billion years of evolution, eukaryotes preserved the chromosome ends with arrays of guanine repeats surrounded by thymines and adenines, which can form stacks of four‐stranded planar structure known as G‐quadruplex (G4). The rationale behind the evolutionary conservation of the G4 structure at the telomere remained elusive. Our recent study has shed light on this matter by revealing that telomere G4 undergoes oscillation between at least two distinct folded conformations. Additionally, tumor suppressor BRCA2 exhibits a unique mode of interaction with telomere G4. To elaborate, BRCA2 directly interacts with G‐triplex (G3)‐derived intermediates that form during the interconversion of the two different G4 states. In doing so, BRCA2 remodels the G4, facilitating the restart of stalled replication forks. In this review, we succinctly summarize the findings regarding the dynamicity of telomeric G4, emphasize its importance in maintaining telomere replication homeostasis, and the physiological consequences of losing G4 dynamicity at the telomere. [ABSTRACT FROM AUTHOR]

Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD. [ABSTRACT FROM AUTHOR]

Ageing and chronic stress have been linked to reduced telomere length (TL) in mixed‐age groups. Whether stress response components are linked to TL during the midlife‐to‐late adulthood transition remains unclear. Our study aimed to synthesise evidence on the relationship between psychological and biological components of stress response on TL in middle‐aged and older adults. We conducted a systematic review of studies obtained from six databases (PubMed, CINAHL, EMBASE, PsycINFO, Web of Science, and Scopus) and evaluated by two independent reviewers. Original research measuring psychological and biological components of stress response and TL in human individuals were included. From an initial pool of 614 studies, 15 were included (n = 9446 participants). Synthesis of evidence showed that higher psychological components of the stress response (i.e., global perceived stress or within a specific life domain and cognitive appraisal to social‐evaluative stressors) were linked to shorter TL, specifically in women or under major life stressors. For the biological stress response, cortisol, dehydroepiandrosterone sulphate and IGF‐1/cortisol imbalance, IL‐6, MCP‐1, blood pressure, and heart rate presented a significant association with TL, but this relationship depended on major life stressors and the stress context (manipulated vs. non‐manipulated conditions). This comprehensive review showed that psychological and biological components of the stress response are linked to shorter TL, but mainly in women or those under a major life stressor and stress‐induced conditions. The interaction between stressor attributes and psychological and biological reactions in the transition from middle to late adulthood still needs to be fully understood, and examining it is a critical step to expanding our understanding of stress's impact on ageing trajectories. [ABSTRACT FROM AUTHOR]

Various reviews and meta‐analyses have shown the positive effects of mindfulness‐based interventions (MBIs) on the mental health of cancer patients and survivors. Some studies have also investigated the impact of MBIs on physiological markers of health in oncology, but a systematic review has not been conducted in this field. The current paper aims to fill this gap in the literature. Following preferred reporting items for systematic reviews and meta‐analyses 2020 guidelines, data were obtained from the databases of Pubmed, Scopus, Web of Science in May 2022. Twenty‐five studies were included. Globally, 35 biomarkers were employed in these studies and were categorized 8 groups (cortisol; blood pressure (BP), heart rate, and respiratory rate; C‐reactive protein; telomere length and telomerase activity (TA); genetic signature; cytokines and hormones; leucocyte activation; leucocyte count and cell subpopulation analysis). In seven of these categories of biomarkers, positive effects of MBIs were observed. The most promising results were obtained for cortisol, BP, TA and pro‐inflammatory gene expression. However, the generally low number of studies per single biomarker limits the possibility to draw reliable conclusions. The present review presents a comprehensive state‐of‐the‐art for MBIs in oncology on biomarkers, confirming MBIs' potential for improving physiological health in cancer patients and survivors besides those already shown in literature on psychological well‐being. [ABSTRACT FROM AUTHOR]

Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all‐cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®. 10.9% of the participants died during a mean follow‐up of 13.3 years, with the mean age at death of 70.1 years. The Spearman correlation between PAC proteomic age and chronological age was 0.77. PAC showed robust age‐adjusted associations and predictions for all‐cause mortality and the onset of various diseases in general and disease‐free participants. The proteins associated with PAC proteomic age deviation were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that biological age acceleration, based on PAC, strongly predicts all‐cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease‐free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities. [ABSTRACT FROM AUTHOR]

Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short‐term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length—survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics. [ABSTRACT FROM AUTHOR]

Shortened telomere length (TL) has been associated with lower cognitive performance, different neurological diseases in adults, and certain neurodevelopmental disorders in children. However, the evidence about the association between TL and neuropsychological developmental outcomes in children from the general population is scarce. Therefore, this study aimed to explore the association between TL and neuropsychological function in children 4–5 years of age. We included 686 children from the INMA Project, a population-based birth cohort in Spain. Leucocyte TL was determined by quantitative PCR method, and neuropsychological outcomes were measured using the McCarthy Scales of Children's Abilities (MCSA). Multiple linear regression models were used to estimate associations adjusted for potential confounding variables. Main findings showed that a longer TL was associated with a higher mean working memory score (β = 4.55; 95% CI = 0.39, 8.71). In addition, longer TL was associated with a higher mean global quantitative score (β = 3.85; 95% CI = −0.19, 7.89), although the association was marginally significant. To our knowledge, this is the first study that shows a positive association between TL and better neuropsychological outcomes in children. Although further research is required to confirm these results, this study supports the hypothesis that TL is essential in protecting and maintaining a child's health, including cognitive functions such as working memory. [ABSTRACT FROM AUTHOR]

Understanding the complex dynamics of telomere biology is important in the strong link between aging and cancer. Telomeres, the protective caps at the end of chromosomes, are central players in this connection. While their gradual shortening due to replication limits tumors expansion by triggering DNA repair mechanisms, it also promotes oncogenic changes within chromosomes, thus sustaining tumorigenesis. The enzyme telomerase, responsible for maintaining telomere length, emerges as a central player in this context. Its expression in cancer cells facilitates the preservation of telomeres, allowing them to circumvent the growth-limiting effects of short telomeres. Interestingly, the influence of telomerase extends beyond telomere maintenance, as evidenced by its involvement in promoting cell growth through alternative pathways. In this context, inflammation accelerates telomere shortening, resulting in telomere dysfunction, while telomere elements also play a role in modulating the inflammatory response. The recognition of this interplay has promoted the development of novel therapeutic approaches centered around telomerase inhibition. This review provides a comprehensive overview of the field, emphasizing recent progress in knowledge and the implications in understanding of cancer biology. [ABSTRACT FROM AUTHOR]

Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component—reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately. [ABSTRACT FROM AUTHOR]

Fluorescence in situ hybridization (FISH) with two different probes, the canonical insect telomeric sequence (TTAGG)n and the sequence (TTAGGGATGG)n, was performed on meiotic chromosomes of two members of the true bug family Cimicidae (Cimicomorpha), the common bed bug Cimex lectularius Linnaeus, 1758 and the tropical bed bug C. hemipterus (Fabricius, 1803), whose telomeric motifs were not known. In both species, there were no hybridization signals with the first probe, but strong signals at chromosomal ends were observed with the second probe, indicating the presence of a telomeric motif (TTAGGGATGG)n. This study represents the first FISH confirmation of the presence of a non-canonical telomeric motif not only for the infraorder Cimicomorpha but also for the suborder Heteroptera (Hemiptera) as a whole. The present finding is of key significance for unraveling the evolutionary shifts in the telomeric sequences in this suborder. [ABSTRACT FROM AUTHOR]

The present review has mainly focused on a systematic investigation of the genes responsible for biological ageing. Ageing has been defined as a successive decline in biological functions, leading to age-associated disorders, which have caused death. Cell homeostasis has been disturbed due to multiple factors such as accumulation of DNA damage, decrease in telomeres, replicative senescence, cell division, metabolism, respiration, autophagy, calorie management, and genetic integrity. This imbalance in cell homeostasis has a major impact on the accelerated biological ageing process. Increased risk of age-associated disorders and mortality rates makes it necessary to know the cellular and molecular mechanisms behind it. This current study provides an overview of genes and their functions associated with dysregulation in core cellular functions such as replication, genetic stability, metabolism, respiration, and autophagy. The genes associated with these biological processes have been identified through a comprehensive literature survey and additional genes were included based on the outcome of STRING analysis. These genes were functionally enriched using gene ontology. Finally, a selected set of genes was mapped with 74 biological functions. Then, a correlation map was plotted to bring out genes with maximum impact on the biological processes involved in ageing. This study not only observed the most commonly known players such as mTOR and SIRT1 but also noticed less-reported genes such as ATM, LRRK2, ERCC1, ATG5, and BECN1 which were also found to be highly impacting the process of biological ageing. Additionally, the gerontology of these top five less-reported genes also has been explored. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is associated with the reduction in physical activity and muscular performance, while increasing TL by physical activity may beneficially impact health and longevity. Information on TL changes induced by Qigong exercise is scarce. Thus, this study determined the effects of Qigong training on TL and its relationship with muscle strength and antioxidants in young sedentary females. Using a quasi-experimental design, 36 women were assigned to an 8-week period of Qigong training (Qigong Group, QG, n = 17) or Control observation (Control Group, CG, n = 19). Relative TL was significantly increased after 8 weeks of Qigong training (P < 0.05), but no significant changes were seen in the CG; TL changes between Groups were significantly different (P < 0.05). These changes in relative TL were positively correlated with changes in leg-back muscle strength (r = 0.413, P = 0.012), but negatively with changes in catalase enzyme activity (r = -0.343, P = 0.040). The findings suggest that 8 weeks of Qigong training increased TL in sedentary young females. Also, the positive association between changes in relative TL and leg-back strength and the negative association with changes in antioxidant activity may indicate mechanisms mediating Qigong effects on TL. [ABSTRACT FROM AUTHOR]

This study aimed to examine the association between peripheral leukocyte telomere length and indicators of metabolic abnormalities in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) assessed by magnetic resonance imaging (MRI). This cross-sectional study included adults over 20 years with body mass index (BMI) of over >25 kg/m2 and sonographic evidence of hepatic steatosis. The subjects were evaluated by clinical and biochemical variables, determination of hepatic fat fraction by MRI and relative peripheral leukocyte telomere length by quantitative real-time polymerase chain reaction. Thirty-two subjects (22 men and 10 women) with MASLD were included, with a median age of 40 years, median BMI of 33.75 kg/m2, median HFF 19 %, and median relative T/S ratio of 0.64. Subjects with relative T/S ratio below the median had significantly higher age, lower BMI, higher AST serum levels, higher GGT serum levels, lower serum ferritin levels, and higher FIB4 score. In a multivariable logistic regression model considering relative T/S ratio below or above the median only age was significantly associated with relative T/S ratio. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD. [ABSTRACT FROM AUTHOR]

In humans, DNA methylation (DNAm) based estimators of telomere length (TL) have been shown to better predict TL-associated variables (e.g., age, sex, and mortality) than TL itself. The biological significance of DNAm-based estimators of TL (DNAmTL) is unclear. In vitro DNAmTL shortens with cell replications, even when telomerase is maintaining TL. Telomerase is typically suppressed in humans, except in testes. Accordingly, sperm TL increases with age, and offspring with greater paternal age at conception (PAC) have longer TL. Thus, we expect that PAC associations with DNAmTL can shed light on whether in vivo cell replications in the presence of high telomerase activity (production of sperm) shorten DNAmTL or if PAC-lengthened TL causes lengthened DNAmTL. In a pre-registered analysis, using data from 1733 blood samples from the Philippines, we examined the association between paternal age at conception (PAC) and offspring DNAmTL. We did not find an association between PAC and DNAmTL but found a positive association of paternal grandfather's age at father's conception predicting grandchild's DNAmTL. In post hoc analyses, we examined how DNAmTL versus qPCR-measured TL (qPCR-TL) correlated with measures typically associated with TL. Contrary to previous findings, on almost all measures of external validity (correlations with parental TLs, southern blot TL, and age), qPCR-TL outperformed DNAmTL. The "kilobase" units of DNAm-based estimators of TL showed considerable deviations from southern blot-derived kilobase measures. Our findings suggest that DNAmTL is not a reliable index of inherited aspects of TL and underscores uncertainty about the biological meaning of DNAmTL. [ABSTRACT FROM AUTHOR]

Maintaining the telomere length is decisive for the viability and homeostasis process of all the cells of an organism, including human glial cells. Telomere shortening of microglial cells has been widely associated with the onset and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Additionally, traumatic brain injury appears to have a positive correlation with the telomere-shortening process of microglia, and telomere length can be used as a non-invasive biomarker for the clinical management of these patients. Moreover, telomere involvement through telomerase reactivation and homologous recombination also known as the alternative lengthening of telomeres (ALT) has been described in gliomagenesis pathways, and particular focus has been given in the translational significance of these mechanisms in gliomas diagnosis and prognostic classification. Finally, glia telomere shortening is implicated in some psychiatric diseases. Given that telomere dysfunction of glial cells is involved in the central nervous system (CNS) disease pathogenesis, it represents a promising drug target that could lead to the incorporation of new tools in the medicinal arsenal for the management of so far incurable conditions. [ABSTRACT FROM AUTHOR]

"Cuohu Bazi" (CHBZ) is an ancient sorghum variety collected from the fields of China, known for its agronomic traits like dwarf stature, early maturation. In this study, we present the first telomere-to-telomere (T2T) and gap-free genome assembly of CHBZ using PacBio HiFi reads, Oxford Nanopore Technologies, and Hi-C data. The assembled genome comprises 724.85 Mb, effectively resolving all 3,913 gaps that were present in the previous sorghum BTx623 reference genome. Notably, the T2T assembly captures 10 centromeres and all 20 telomeres, providing strong support for their integrity. This assembly is of high quality in terms of contiguity (contig N50: 71.1 Mb), completeness (BUSCO score: 99.01%, k-mer completeness: 98.88%), and correctness (QV: 61.60). Repetitive sequences accounted for 70.41% of the genome and a total of 32,855 protein-coding genes have been annotated. Furthermore, 161 CHBZ-specific presence/absence variants genes have been identified when comparing to BTx623 genome. This study provides valuable insights for future research on sorghum genetics, genomics, and evolutionary history. [ABSTRACT FROM AUTHOR]

As an element with metalloid properties, arsenic is pervasively present in the environment and is recognized as a potent carcinogen. Consequently, the issue of human arsenic exposure has become a significant concern within the global public health sector. Numerous studies have indicated that arsenic induces cellular senescence through various mechanisms, including triggering epigenetic alterations, inducing the senescence-associated secretory phenotype (SASP), promoting telomere shortening, and causing mitochondrial dysfunction. This article collates and summarizes the latest research advancements on the involvement of cellular senescence in arsenic toxicity and explores the mechanisms of arsenic-induced toxicity. This study aims to provide new perspectives and directions for future research on arsenic toxicity and the development of prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

To assess the immediate responses of the yeast cells to telomere defects, we employed the auxin‐inducible degron (AID) enabling rapid depletion of essential (Rap1, Tbf1, Cdc13, Stn1) and non‐essential (Est1, Est2, Est3) telomeric proteins. Using two variants of AID systems, we show that most of the studied proteins are depleted within 10–30 min after the addition of auxin. As expected, depletion of essential proteins yields nondividing cells, provided that the strains are cultivated in an appropriate carbon source and at temperatures lower than 28°C. Cells with depleted Cdc13 and Stn1 exhibit extension of the single‐stranded overhang as early as 3 h after addition of auxin. Notably, prolonged incubation of strains carrying AID‐tagged essential proteins in the presence of auxin resulted in the appearance of auxin‐resistant clones, caused at least in part by mutations within the OsTIR1 gene. Upon assessing the length of telomeres in strains carrying AID‐tagged non‐essential telomeric proteins, we found that the depletion of Est1 and Est3 leads to auxin‐dependent telomere shortening. However, the EST3‐AID strain had slightly shorter telomeres even in the absence of auxin. Furthermore, a strain with the AID‐tagged version of Est2 (catalytic subunit of telomerase) not only had shorter telomeres in the absence of auxin but also did not exhibit auxin‐dependent telomere shortening. Our results demonstrate that while AID can be useful in assessing immediate cellular responses to telomere deprotection, each strain must be carefully evaluated for the effect of AID‐tag on the properties of the protein of interest. Take‐away: Auxin‐inducible degron (AID) allows rapid depletion of telomere‐associated proteins.The AID system is sensitive to temperature and carbon source.Long‐term cultivation in the presence of auxin causes appearance of auxin‐resistant clones.The C‐terminal AID tag interferes with function of some of the proteins.Changes in telomere status are noticeable within hours after depletion of a telomeric factor. [ABSTRACT FROM AUTHOR]

Background: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD). Summary: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis. Key Messages: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood. [ABSTRACT FROM AUTHOR]