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Bulk tissue stiffness has been correlated with regulation of cellular processes and conversely cells have been shown to remodel their pericellular tissue according to a complex feedback mechanism critical to development, homeostasis, and disease. However, bulk rheological methods mask the dynamics within a heterogeneous fibrous extracellular matrix (ECM) in the region proximal to a cell (pericellular region). Here, we use optical tweezers active microrheology (AMR) to probe the distribution of the complex material response function (α=α'+α″, in units of µm/nN) within a type I collagen ECM, a biomaterial commonly used in tissue engineering. We discovered cells both elastically and plastically deformed the pericellular material. α' is wildly heterogeneous, with 1/α' values spanning three orders of magnitude around a single cell. This was observed in gels having a cell-free 1/α' of approximately 0.5nN/µm. We also found that inhibition of cell contractility instantaneously softens the pericellular space and reduces stiffness heterogeneity, suggesting the system was strain hardened and not only plastically remodeled. The remaining regions of high stiffness suggest cellular remodeling of the surrounding matrix. To test this hypothesis, cells were incubated within the type I collagen gel for 24-h in a media containing a broad-spectrum matrix metalloproteinase (MMP) inhibitor. While pericellular material maintained stiffness asymmetry, stiffness magnitudes were reduced. Dual inhibition demonstrates that the combination of MMP activity and contractility is necessary to establish the pericellular stiffness landscape. This heterogeneity in stiffness suggests the distribution of pericellular stiffness, and not bulk stiffness alone, must be considered in the study of cell-ECM interactions and design of complex biomaterial scaffolds.Statement of significanceCollagen is a fibrous extracellular matrix (ECM) protein widely used to study cell-ECM interactions. Stiffness of ECM has been shown to instruct cells, which can in turn modify their ECM, as has been shown in the study of cancer and regenerative medicine. Here we measure the stiffness of the collagen microenvironment surrounding cells and quantitatively measure the dependence of pericellular stiffness on MMP activity and cytoskeletal contractility. Competent cell-mediated stiffening results in a wildly heterogeneous micromechanical topography, with values spanning orders of magnitude around a single cell. We speculate studies must consider this notable heterogeneity generated by cells when testing theories regarding the role of ECM mechanics in health and disease.

Both human immunodeficiency virus (HIV)-1 infection and illicit stimulant use can adversely impact neurocognitive functioning, and these effects can be additive. However, significant variability exists such that as-of-yet unidentified exogenous and endogenous factors affect one's risk for neurocognitive impairment. Literature on both HIV and stimulant use indicates that host genetic variants in immunologic and dopamine-related genes are one such factor. In this study, the individual and interactive effects of HIV status, stimulant use, and genotype upon neurocognitive functioning were examined longitudinally over a 10-year period. Nine hundred fifty-two Caucasian HIV+ and HIV- cases from the Multicenter AIDS Cohort Study were included. All cases had at least two comprehensive neurocognitive evaluations between 1985 and 1995. Pre-highly active antiretroviral therapy (HAART) data were examined in order to avoid the confounding effect of variable drug regimens. Linear mixed models were used, with neurocognitive domain scores as the outcome variables. No four-way interactions were found, indicating that HIVand stimulant use do not interact over time to affect neurocognitive functioning as a function of genotype. Multiple three-way interactions were found that involved genotype and HIV status. All immunologically related genes found to interact with HIV status affected neurocognitive functioning in the expected direction; however, only C-C chemokine ligand 2 (CCL2) and CCL3 affected HIV+ individuals specifically. Dopamine-related genetic variants generally affected HIV-negative individuals only. Neurocognitive functioning among HIV+ individuals who also used stimulants was not significantly different from those who did not use stimulants. The findings support the role of immunologically related genetic differences in CCL2 and CCL3 in neurocognitive functioning among HIV+ individuals; however, their impact is minor. Being consistent with findings from another cohort, dopamine (DA)-related genetic differences do not appear to impact the longitudinal neurocognitive functioning of HIV+ individuals. © Journal of NeuroVirology, Inc. 2014.

Background: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.Methods: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.Results: Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).Conclusion: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers. [ABSTRACT FROM AUTHOR]

Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although most agree that poor adherence to antiretrovirals is a common problem, relatively few factors have been shown to consistently predict treatment failure. In this study, a theoretical framework encompassing demographic characteristics, health beliefs/attitudes, treatment self-efficacy, and neurocognitive status was examined in relationship to highly active antiretroviral therapy adherence. DESIGN: Prospective, cross-sectional observational design. MAIN OUTCOME MEASURES: Neuropsychological test performance, health beliefs and attitudes, and medication adherence tracked over a 1-month period using electronic monitoring technology (Medication Event Monitoring System caps). RESULTS: The rate of poor adherence was twice as high among younger participants than with older participants (68% and 33%, respectively). Results of binary logistic regression revealed that low self-efficacy and lack of perceived treatment utility predicted poor adherence among younger individuals, whereas decreased levels of neurocognitive functioning remained the sole predictor of poor adherence among older participants. CONCLUSION: These data support components of the health beliefs model in predicting medication adherence among younger HIV-positive individuals. However, risk of adherence failure in those ages 50 years and older appears most related to neurocognitive status. Copyright © 2006 by the American Psychological Association, Inc. [ABSTRACT FROM AUTHOR]

Vitamin D has recently emerged as a potentially protective agent against colorectal neoplasia. We assessed the associations between dietary vitamin D, plasma 25-hydroxyvitamin D [25(OH)D], dietary calcium, and colorectal adenomas in a large screening sigmoidoscopy-based case-control study in Southern California. Because conversion of serum 25(OH)D to serum 1,25-vitamin D is highly regulated by serum calcium, we also assessed modification of the 25(OH)D-adenoma association by calcium intake. Cases were 473 subjects with a primary adenoma, and controls were 507 subjects who had no adenomas at sigmoidoscopy and no history of adenomas. Compared with those in the lowest quartile of intake, those in the highest quartile of dietary vitamin D had an adjusted odds ratio (OR) of 0.83 [95% confidence interval (CI) = 0.49-1.41] and those in the highest quartile of dietary calcium had an OR of 0.82 (95% CI = 0.49-1.25). There was a suggestion that plasma 25(OH)D may be protective in this population (OR for highest vs. lowest quartile = 0.74, 95% CI = 0.51-1.09). A significant protective effect of 25(OH)D was clearly evident only in those with calcium intakes below (OR = 0.40 for highest vs. lowest quartile, 95% CI = 0.22-0.71, p for trend = 0.005) and above (OR = 1.17, 95% CI = 0.69-1.99, p for trend = 0.94) the median calcium intake. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests statement:A.J.L. is a consultant for Chugai Pharmaceutical company. He is a founder, board member and consultant at PMV Pharma, which produces small molecules that reactivate p53 mutant proteins and produce wild type proteins. He is a board member of GeneCentric a cancer RNA diagnostic company. And he consults for ROME (autoimmunity), and WCG (an IRB company).

Major histocompatibility complex (MHC) proteins present peptides on the cell surface for T cell surveillance. Reliable in silico prediction of which peptides would be presented and which T cell receptors would recognize them is an important problem in structural immunology. Here, we introduce an AlphaFold-based pipeline for predicting the three-dimensional structures of peptide-MHC complexes for class I and class II MHC molecules. Our method demonstrates high accuracy, outperforming existing tools in class I modeling accuracy and class II peptide register prediction. We validate its performance and utility with new experimental data on a recently described cancer neoantigen/wild-type peptide pair and explore applications toward improving peptide-MHC binding prediction., Competing Interests: Declaration of interests A.J.L. is a founder, director, and shareholder and receives fees for these activities of PMV Pharma. He also is a consultant for Chugai Pharma and receives a fee for that position. Neither company works in the topic of this manuscript. V.M. is an employee and shareholder of BioNTech US, Inc., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young adult pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n = 613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain, liver, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n = 1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers, behavioral responses encompassing cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging., (© 2023. The Author(s).)

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants was conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB. These estimates were calculated after excluding related individuals and accounting for the potential impact of clonal hematopoiesis by excluding heterozygotes who ever developed a hematologic cancer. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance., Competing Interests: Declaration of interests K.C.A., J.N.H., M.N.F., and S.A.S. are unpaid members of the ClinGen TP53 Variant Curation Expert Panel. M.N.F. is a co-developer of CancerGene Connect. A.J.L. is a director of PMV Pharma., (Published by Elsevier Inc.)

Multiple Myeloma is a typical example of a neoplasm that shows significant differences in incidence, age of onset, type, and frequency of genetic alterations between patients of African and European ancestry. This perspective explores the hypothesis that both genetic polymorphisms and spontaneous somatic mutations in the TP53 tumor suppressor gene are determinants of these differences. In the US, the rates of occurrence of MM are at least twice as high in African Americans (AA) as in Caucasian Americans (CA). Strikingly, somatic TP53 mutations occur in large excess (at least 4-6-fold) in CA versus AA. On the other hand, TP53 contains polymorphisms specifying amino-acid differences that are under natural selection by the latitude of a population and have evolved during the migrations of humans over several hundred thousand years. The p53 protein plays important roles in DNA strand break repair and, therefore, in the surveillance of aberrant DNA recombination, leading to the B-cell translocations that are causal in the pathogenesis of MM. We posit that polymorphisms in one region of the TP53 gene (introns 2 and 3, and the proline-rich domain) specify a concentration of the p53 protein with a higher capacity to repress translocations in CA than AA patients. This, in turn, results in a higher risk of acquiring inactivating, somatic mutations in a different region of the TP53 gene (DNA binding domain) in CA than in AA patients. Such a mechanism, by which the polymorphic status of a gene influencing its own "spontaneous" mutation frequency, may provide a genetic basis to address ethnicity-related differences in the incidence and phenotypes of many different forms of cancer., (© 2023. The Author(s).)

We examined whether cognitive reserve moderated the relationship between neurodegeneration and cognition in 67 postmortem persons with HIV (PWH) who were cognitively assessed within 1 year of death. Cognitive reserve was measured via the Wide Range Achievement Test-4 reading subtest (WRAT4). Synaptodendritic neurodegeneration was based on densities of synaptophysin and microtubule-associated protein 2 immunohistochemical reactivity in frontal cortex, and categorized as minimal, moderate, or severe (tertile-split). T-Scores from 15 cognitive tests were averaged into a global cognitive T-score. Among those with low cognitive reserve (based on WRAT4 median split), the moderate neurodegeneration group showed cognition that was poorer than the minimal neurodegeneration group and comparable to the severe neurodegeneration group. Among those with high cognitive reserve, the moderate neurodegeneration group showed cognition comparable to the minimal neurodegeneration group and better than the severe neurodegeneration group. High cognitive reserve may buffer against cognitive impairment among PWH with moderate, but not severe, neurodegeneration., (© 2023. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

In November 2022 the first Dark Genome Symposium was held in Boston, USA. The meeting was hosted by Rome Therapeutics and Enara Bio, two biotechnology companies working on translating our growing understanding of this vast genetic landscape into therapies for human disease. The spirit and ambition of the meeting was one of shared knowledge, looking to strengthen the network of researchers engaged in the field. The meeting opened with a welcome from Rosana Kapeller and Kevin Pojasek followed by a first session of field defining talks from key academics in the space. A series of panels, bringing together academia and industry views, were then convened covering a wide range of pertinent topics. Finally, Richard Young and David Ting gave their views on the future direction and promise for patient impact inherent in the growing understanding of the Dark Genome., (© 2023. The Author(s).)

To understand how the spinal cord enacts complex sensorimotor functions, researchers have studied, classified, and functionally probed it's many neuronal populations for over a century. Recent developments in single-cell RNA-sequencing can characterize the gene expression signatures of the entire set of spinal neuron types and can simultaneously provide an unbiased view of their relationships to each other. This approach has revealed that the location of neurons predicts transcriptomic variability, as dorsal spinal neurons become highly distinct over development as ventral spinal neurons become less so. Temporal specification is also a major source of gene expression variation, subdividing many of the canonical embryonic lineage domains. Together, birthdate and cell body location are fundamental organizing features of spinal neuron diversity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

The use of organic amendments to enhance soil health is increasingly being identified as a strategy to improve residential landscapes while also reducing the need for external inputs (e.g., fertilizers, irrigation). Composted biosolids are a re-purposed waste product that can be used in organic amendments to improve the overall sustainability of a municipality by enhancing residential soil carbon content while simultaneously reducing waste materials. However, the biosolids-based feedstock of these compost products has the potential to be a source of organic contaminants. We conducted a laboratory-based soil column experiment to evaluate the potential for different commercially available compost products to act as a source of emerging organic contaminants in residential landscapes. We compared two biosolids-based compost products, a manure-based compost product, and a control (no compost) treatment by irrigating soil columns for 30 days and collecting daily leachate samples to quantify leaching rates of six hormones, eight pharmaceuticals, and seven per- and polyfluoroalkyl substances (PFAS). Detection of hormones and pharmaceuticals was rare, suggesting that compost amendments are likely not a major source of these contaminants to groundwater resources. In contrast, we detected three of the seven PFAS compounds in leachate samples throughout the study. Perfluorohexanoic acid (PFHxA) was more likely to leach from biosolids-based compost treatments than other treatments (p < 0.05) and perfluorobutane sulfonate (PFBS) was only detected in biosolids-based treatments (although PFBS concentrations did not significantly differ among treatments). In contrast, perfluorooctanoic acid (PFOA) was commonly detected across all treatments (including controls), suggesting potential PFOA experimental contamination. Overall, these results demonstrate that commercially available composted biosolids amendments are likely not a major source of hormone and pharmaceutical contamination. The detection of PFHxA at significantly higher concentrations in biosolids treatments suggests that biosolids-based composts may act as sources of PFHxA to the environment. However, concentrations of multiple PFAS compounds found in leachate in this study were lower than concentrations found in known PFAS hotspots. Therefore, there is potential for environmental contamination from PFAS leaching from composted biosolids, but leachate concentrations are low which should be considered in risk-benefit analyses when considering whether or not to use composted biosolids as an organic amendment to enhance residential soil health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals., (© 2023. The Author(s).)

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

We have previously shown accelerated ageing in adolescents perinatally infected with HIV (PHIV +), based on discrepancies between epigenetic and chronological age. The current study examines follow-up longitudinal patterns of epigenetic ageing and the association of epigenetic ageing with cognition as well as whole brain structure changes in PHIV + and healthy controls enrolled in the Cape Town Adolescent Antiretroviral Cohort Study (CTAAC). The Illumina EPIC array was used to generate blood DNA methylation data from 60 PHIV + adolescents and 36 age-matched controls aged 9-12 years old at baseline and again at a 36-month follow-up. Epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated ageing (EEAA) and age acceleration difference (AAD) at both time points. At follow-up, each participant completed neuropsychological testing, structural magnetic resonance imaging, and diffusion tensor imaging. At follow-up, PHIV infection remains associated with increased EEAA and AAD. Accelerated epigenetic ageing remained positively associated with viral load and negatively associated with CD4 ratio. EEAA was positively associated with whole brain grey matter volume and alterations in whole brain white matter integrity. AAD and EEAA were not associated with cognitive function within the PHIV + group. Measures of epigenetic ageing, as detected in DNA methylation patterns, remain increased in PHIV + adolescents across a 36-month period. Associations between epigenetic ageing measures, viral biomarkers, and alterations in brain micro- and macrostructure also persist at 36-month follow-up. Further study should determine if epigenetic age acceleration is associated with cognitive functional changes due to brain alterations in later life., (© 2023. The Author(s).)

The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remain unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes in the mouse brain. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of the thalamus yielded novel insight into the PVT's connectivity with the cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations., Competing Interests: CG, CG, YL, JM, DG, AL, MP No competing interests declared

Radiation exposure of healthy cells can halt cell cycle temporarily or permanently. In this work, we analyze the time evolution of p21 and p53 from two single cell datasets of retinal pigment epithelial cells exposed to several levels of radiation, and in particular, the effect of radiation on cell cycle arrest. Employing various quantification methods from signal processing, we show how p21 levels, and to a lesser extent p53 levels, dictate whether the cells are arrested in their cell cycle and how frequently these mitosis events are likely to occur. We observed that single cells exposed to the same dose of DNA damage exhibit heterogeneity in cellular outcomes and that the frequency of cell division is a more accurate monitor of cell damage rather than just radiation level. Finally, we show how heterogeneity in DNA damage signaling is manifested early in the response to radiation exposure level and has potential to predict long-term fate., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)