ResearchPad - biological-sciences https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells]]> https://www.researchpad.co/article/elastic_article_10134 Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

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<![CDATA[Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians]]> https://www.researchpad.co/article/elastic_article_10132 The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

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<![CDATA[Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults]]> https://www.researchpad.co/article/elastic_article_10131 We aimed to investigate the association between baseline levels of total serum glutathione (tGSH) and rate of chronic disease accumulation over time. The study population (n = 2,596) was derived from a population-based longitudinal study on ≥60-year-olds living in Stockholm. Participants were clinically assessed at baseline, 3- and 6-year follow-ups. Multimorbidity was measured as the number of chronic conditions from a previously built list of 60 diseases. Linear mixed models were applied to analyze the association between baseline tGSH levels and the rate of multimorbidity development over 6 years. We found that at baseline, participants with ≥4 diseases had lower tGSH levels than participants with no chronic conditions (3.3 vs 3.6 µmol/L; p < .001). At follow-up, baseline levels of tGSH were inversely associated with the rate of multimorbidity development (β * time: −0.044, p < .001) after adjusting for age, sex, education, levels of serum creatinine, C-reactive protein, albumin, body mass index, smoking, and time of dropout or death. In conclusion, serum levels of tGSH are inversely associated with multimorbidity development; the association exists above and beyond the link between tGSH and specific chronic conditions. Our findings support the hypothesis that tGSH is a biomarker of multisystem dysregulation that eventually leads to multimorbidity.

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<![CDATA[K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells]]> https://www.researchpad.co/article/elastic_article_8307 Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.

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<![CDATA[Understanding the computation of time using neural network models]]> https://www.researchpad.co/article/elastic_article_8305 To maximize future rewards in this ever-changing world, animals must be able to discover the temporal structure of stimuli and then anticipate or act correctly at the right time. How do animals perceive, maintain, and use time intervals ranging from hundreds of milliseconds to multiseconds in working memory? How is temporal information processed concurrently with spatial information and decision making? Why are there strong neuronal temporal signals in tasks in which temporal information is not required? A systematic understanding of the underlying neural mechanisms is still lacking. Here, we addressed these problems using supervised training of recurrent neural network models. We revealed that neural networks perceive elapsed time through state evolution along stereotypical trajectory, maintain time intervals in working memory in the monotonic increase or decrease of the firing rates of interval-tuned neurons, and compare or produce time intervals by scaling state evolution speed. Temporal and nontemporal information is coded in subspaces orthogonal with each other, and the state trajectories with time at different nontemporal information are quasiparallel and isomorphic. Such coding geometry facilitates the decoding generalizability of temporal and nontemporal information across each other. The network structure exhibits multiple feedforward sequences that mutually excite or inhibit depending on whether their preferences of nontemporal information are similar or not. We identified four factors that facilitate strong temporal signals in nontiming tasks, including the anticipation of coming events. Our work discloses fundamental computational principles of temporal processing, and it is supported by and gives predictions to a number of experimental phenomena.

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<![CDATA[Ligand-dependent downregulation of MR1 cell surface expression]]> https://www.researchpad.co/article/elastic_article_8302 The antigen-presenting molecule MR1 presents riboflavin-based metabolites to Mucosal-Associated Invariant T (MAIT) cells. While MR1 egress to the cell surface is ligand-dependent, the ability of small-molecule ligands to impact on MR1 cellular trafficking remains unknown. Arising from an in silico screen of the MR1 ligand-binding pocket, we identify one ligand, 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoic acid, DB28, as well as an analog, methyl 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoate, NV18.1, that down-regulate MR1 from the cell surface and retain MR1 molecules in the endoplasmic reticulum (ER) in an immature form. DB28 and NV18.1 compete with the known MR1 ligands, 5-OP-RU and acetyl-6-FP, for MR1 binding and inhibit MR1-dependent MAIT cell activation. Crystal structures of the MAIT T cell receptor (TCR) complexed with MR1-DB28 and MR1-NV18.1, show that these two ligands reside within the A′-pocket of MR1. Neither ligand forms a Schiff base with MR1 molecules; both are nevertheless sequestered by a network of hydrophobic and polar contacts. Accordingly, we define a class of compounds that inhibits MR1 cellular trafficking.

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<![CDATA[Spread and dynamics of the COVID-19 epidemic in Italy: Effects of emergency containment measures]]> https://www.researchpad.co/article/elastic_article_8299 The spread of coronavirus disease 2019 (COVID-19) in Italy prompted drastic measures for transmission containment. We examine the effects of these interventions, based on modeling of the unfolding epidemic. We test modeling options of the spatially explicit type, suggested by the wave of infections spreading from the initial foci to the rest of Italy. We estimate parameters of a metacommunity Susceptible–Exposed–Infected–Recovered (SEIR)-like transmission model that includes a network of 107 provinces connected by mobility at high resolution, and the critical contribution of presymptomatic and asymptomatic transmission. We estimate a generalized reproduction number (R0 = 3.60 [3.49 to 3.84]), the spectral radius of a suitable next-generation matrix that measures the potential spread in the absence of containment interventions. The model includes the implementation of progressive restrictions after the first case confirmed in Italy (February 21, 2020) and runs until March 25, 2020. We account for uncertainty in epidemiological reporting, and time dependence of human mobility matrices and awareness-dependent exposure probabilities. We draw scenarios of different containment measures and their impact. Results suggest that the sequence of restrictions posed to mobility and human-to-human interactions have reduced transmission by 45% (42 to 49%). Averted hospitalizations are measured by running scenarios obtained by selectively relaxing the imposed restrictions and total about 200,000 individuals (as of March 25, 2020). Although a number of assumptions need to be reexamined, like age structure in social mixing patterns and in the distribution of mobility, hospitalization, and fatality, we conclude that verifiable evidence exists to support the planning of emergency measures.

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<![CDATA[Colloidal stability of the living cell]]> https://www.researchpad.co/article/elastic_article_8295 Cellular function is generally depicted at the level of functional pathways and detailed structural mechanisms, based on the identification of specific protein–protein interactions. For an individual protein searching for its partner, however, the perspective is quite different: The functional task is challenged by a dense crowd of nonpartners obstructing the way. Adding to the challenge, there is little information about how to navigate the search, since the encountered surrounding is composed of protein surfaces that are predominantly “nonconserved” or, at least, highly variable across organisms. In this study, we demonstrate from a colloidal standpoint that such a blindfolded intracellular search is indeed favored and has more fundamental impact on the cellular organization than previously anticipated. Basically, the unique polyion composition of cellular systems renders the electrostatic interactions different from those in physiological buffer, leading to a situation where the protein net-charge density balances the attractive dispersion force and surface heterogeneity at close range. Inspection of naturally occurring proteomes and in-cell NMR data show further that the “nonconserved” protein surfaces are by no means passive but chemically biased to varying degree of net-negative repulsion across organisms. Finally, this electrostatic control explains how protein crowding is spontaneously maintained at a constant level through the intracellular osmotic pressure and leads to the prediction that the “extreme” in halophilic adaptation is not the ionic-liquid conditions per se but the evolutionary barrier of crossing its physicochemical boundaries.

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<![CDATA[NORs on human acrocentric chromosome p-arms are active by default and can associate with nucleoli independently of rDNA]]> https://www.researchpad.co/article/elastic_article_8291 Nucleoli, the sites of ribosome biogenesis and the largest structures in human nuclei, form around nucleolar organizer regions (NORs) comprising ribosomal DNA (rDNA) arrays. NORs are located on the p-arms of the five human acrocentric chromosomes. Defining the rules of engagement between these p-arms and nucleoli takes on added significance as describing the three-dimensional organization of the human genome represents a major research goal. Here we used fluorescent in situ hybridization (FISH) and immuno-FISH on metaphase chromosomes from karyotypically normal primary and hTERT-immortalized human cell lines to catalog NORs in terms of their relative rDNA content and activity status. We demonstrate that a proportion of acrocentric p-arms in cell lines and from normal human donors have no detectable rDNA. Surprisingly, we found that all NORs with detectable rDNA are active, as defined by upstream binding factor loading. We determined the nucleolar association status of all NORs during interphase, and found that nucleolar association of acrocentric p-arms can occur independently of rDNA content, suggesting that sequences elsewhere on these chromosome arms drive nucleolar association. In established cancer lines, we characterize a variety of chromosomal rearrangements involving acrocentric p-arms and observe silent, rDNA-containing NORs that are dissociated from nucleoli. In conclusion, our findings indicate that within human nuclei, positioning of all 10 acrocentric chromosomes is dictated by nucleolar association. Furthermore, these nucleolar associations are buffered against interindividual variation in the distribution of rDNA.

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<![CDATA[A widespread toxin−antitoxin system exploiting growth control via alarmone signaling]]> https://www.researchpad.co/article/elastic_article_8289 Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and, at high concentrations, inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single-domain small alarmone synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA, and SpoT. We asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin−antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS–antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.

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<![CDATA[Conjunctive representations that integrate stimuli, responses, and rules are critical for action selection]]> https://www.researchpad.co/article/elastic_article_8286 People can use abstract rules to flexibly configure and select actions for specific situations, yet how exactly rules shape actions toward specific sensory and/or motor requirements remains unclear. Both research from animal models and human-level theories of action control point to the role of highly integrated, conjunctive representations, sometimes referred to as event files. These representations are thought to combine rules with other, goal-relevant sensory and motor features in a nonlinear manner and represent a necessary condition for action selection. However, so far, no methods exist to track such representations in humans during action selection with adequate temporal resolution. Here, we applied time-resolved representational similarity analysis to the spectral-temporal profiles of electroencephalography signals while participants performed a cued, rule-based action selection task. In two experiments, we found that conjunctive representations were active throughout the entire selection period and were functionally dissociable from the representation of constituent features. Specifically, the strength of conjunctions was a highly robust predictor of trial-by-trial variability in response times and was selectively related to an important behavioral indicator of conjunctive representations, the so-called partial-overlap priming pattern. These results provide direct evidence for conjunctive representations as critical precursors of action selection in humans.

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<![CDATA[Noise-driven cellular heterogeneity in circadian periodicity]]> https://www.researchpad.co/article/elastic_article_8283 Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.

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<![CDATA[Collective decision-making by rational agents with differing preferences]]> https://www.researchpad.co/article/elastic_article_8281 Collective decisions can emerge from individual-level interactions between members of a group. These interactions are often seen as social feedback rules, whereby individuals copy the decisions they observe others making, creating a coherent group decision. The benefit of these behavioral rules to the individual agent can be understood as a transfer of information, whereby a focal individual learns about the world by gaining access to the information possessed by others. Previous studies have analyzed this exchange of information by assuming that all agents share common goals. While differences in information and differences in preferences have often been conflated, little is known about how differences between agents’ underlying preferences affect the use and efficacy of social information. In this paper, I develop a model of social information use by rational agents with differing preferences, and demonstrate that the resulting collective behavior is strongly dependent on the structure of preference sharing within the group, as well as the quality of information in the environment. In particular, I show that strong social responses are expected by individuals that are habituated to noisy, uncertain environments where private information about the world is relatively weak. Furthermore, by investigating heterogeneous group structures, I demonstrate a potential influence of cryptic minority subgroups that may illuminate the empirical link between personality and leadership.

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<![CDATA[The Great Oxidation Event expanded the genetic repertoire of arsenic metabolism and cycling]]> https://www.researchpad.co/article/elastic_article_8279 The rise of oxygen on the early Earth about 2.4 billion years ago reorganized the redox cycle of harmful metal(loids), including that of arsenic, which doubtlessly imposed substantial barriers to the physiology and diversification of life. Evaluating the adaptive biological responses to these environmental challenges is inherently difficult because of the paucity of fossil records. Here we applied molecular clock analyses to 13 gene families participating in principal pathways of arsenic resistance and cycling, to explore the nature of early arsenic biogeocycles and decipher feedbacks associated with planetary oxygenation. Our results reveal the advent of nascent arsenic resistance systems under the anoxic environment predating the Great Oxidation Event (GOE), with the primary function of detoxifying reduced arsenic compounds that were abundant in Archean environments. To cope with the increased toxicity of oxidized arsenic species that occurred as oxygen built up in Earth’s atmosphere, we found that parts of preexisting detoxification systems for trivalent arsenicals were merged with newly emerged pathways that originated via convergent evolution. Further expansion of arsenic resistance systems was made feasible by incorporation of oxygen-dependent enzymatic pathways into the detoxification network. These genetic innovations, together with adaptive responses to other redox-sensitive metals, provided organisms with novel mechanisms for adaption to changes in global biogeocycles that emerged as a consequence of the GOE.

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<![CDATA[Honey-bee–associated prokaryotic viral communities reveal wide viral diversity and a profound metabolic coding potential]]> https://www.researchpad.co/article/elastic_article_8277 Honey bees (Apis mellifera) produce an enormous economic value through their pollination activities and play a central role in the biodiversity of entire ecosystems. Recent efforts have revealed the substantial influence that the gut microbiota exert on bee development, food digestion, and homeostasis in general. In this study, deep sequencing was used to characterize prokaryotic viral communities associated with honey bees, which was a blind spot in research up until now. The vast majority of the prokaryotic viral populations are novel at the genus level, and most of the encoded proteins comprise unknown functions. Nevertheless, genomes of bacteriophages were predicted to infect nearly every major bee-gut bacterium, and functional annotation and auxiliary metabolic gene discovery imply the potential to influence microbial metabolism. Furthermore, undiscovered genes involved in the synthesis of secondary metabolic biosynthetic gene clusters reflect a wealth of previously untapped enzymatic resources hidden in the bee bacteriophage community.

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<![CDATA[Machine learning predicts the functional composition of the protein corona and the cellular recognition of nanoparticles]]> https://www.researchpad.co/article/elastic_article_8275 Protein corona formation is critical for the design of ideal and safe nanoparticles (NPs) for nanomedicine, biosensing, organ targeting, and other applications, but methods to quantitatively predict the formation of the protein corona, especially for functional compositions, remain unavailable. The traditional linear regression model performs poorly for the protein corona, as measured by R2 (less than 0.40). Here, the performance with R2 over 0.75 in the prediction of the protein corona was achieved by integrating a machine learning model and meta-analysis. NPs without modification and surface modification were identified as the two most important factors determining protein corona formation. According to experimental verification, the functional protein compositions (e.g., immune proteins, complement proteins, and apolipoproteins) in complex coronas were precisely predicted with good R2 (most over 0.80). Moreover, the method successfully predicted the cellular recognition (e.g., cellular uptake by macrophages and cytokine release) mediated by functional corona proteins. This workflow provides a method to accurately and quantitatively predict the functional composition of the protein corona that determines cellular recognition and nanotoxicity to guide the synthesis and applications of a wide range of NPs by overcoming limitations and uncertainty.

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<![CDATA[Stressed DNA replication generates stressed DNA]]> https://www.researchpad.co/article/elastic_article_8271 <![CDATA[Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain]]> https://www.researchpad.co/article/elastic_article_8269 Genetic variants in PKD2 which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding of the genetic basis of ADPKD, we do not know how most variants impact channel function. Polycystin-2 is found in organelle membranes, including the primary cilium—an antennae-like structure on the luminal side of the collecting duct. In this study, we focus on the structural and mechanistic regulation of polycystin-2 by its TOP domain—a site with unknown function that is commonly altered by missense variants. We use direct cilia electrophysiology, cryogenic electron microscopy, and superresolution imaging to determine that variants of the TOP domain finger 1 motif destabilizes the channel structure and impairs channel opening without altering cilia localization and channel assembly. Our findings support the channelopathy classification of PKD2 variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.

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<![CDATA[Heart–brain interactions shape somatosensory perception and evoked potentials]]> https://www.researchpad.co/article/elastic_article_8267 Even though humans are mostly not aware of their heartbeats, several heartbeat-related effects have been reported to influence conscious perception. It is not clear whether these effects are distinct or related phenomena, or whether they are early sensory effects or late decisional processes. Combining electroencephalography and electrocardiography, along with signal detection theory analyses, we identify two distinct heartbeat-related influences on conscious perception differentially related to early vs. late somatosensory processing. First, an effect on early sensory processing was found for the heartbeat-evoked potential (HEP), a marker of cardiac interoception. The amplitude of the prestimulus HEP negatively correlated with localization and detection of somatosensory stimuli, reflecting a more conservative detection bias (criterion). Importantly, higher HEP amplitudes were followed by decreases in early (P50) as well as late (N140, P300) somatosensory-evoked potential (SEP) amplitudes. Second, stimulus timing along the cardiac cycle also affected perception. During systole, stimuli were detected and correctly localized less frequently, relating to a shift in perceptual sensitivity. This perceptual attenuation was accompanied by the suppression of only late SEP components (P300) and was stronger for individuals with a more stable heart rate. Both heart-related effects were independent of alpha oscillations’ influence on somatosensory processing. We explain cardiac cycle timing effects in a predictive coding account and suggest that HEP-related effects might reflect spontaneous shifts between interoception and exteroception or modulations of general attentional resources. Thus, our results provide a general conceptual framework to explain how internal signals can be integrated into our conscious perception of the world.

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<![CDATA[Fibroblast rejuvenation by mechanical reprogramming and redifferentiation]]> https://www.researchpad.co/article/elastic_article_8266 Over the course of the aging process, fibroblasts lose contractility, leading to reduced connective-tissue stiffness. A promising therapeutic avenue for functional rejuvenation of connective tissue is reprogrammed fibroblast replacement, although major hurdles still remain. Toward this, we recently demonstrated that the laterally confined growth of fibroblasts on micropatterned substrates induces stem-cell-like spheroids. In this study, we embedded these partially reprogrammed spheroids in collagen-I matrices of varying densities, mimicking different three-dimensional (3D) tissue constraints. In response to such matrix constraints, these spheroids regained their fibroblastic properties and sprouted to form 3D connective-tissue networks. Interestingly, we found that these differentiated fibroblasts exhibit reduced DNA damage, enhanced cytoskeletal gene expression, and actomyosin contractility. In addition, the rejuvenated fibroblasts show increased matrix protein (fibronectin and laminin) deposition and collagen remodeling compared to the parental fibroblast tissue network. Furthermore, we show that the partially reprogrammed cells have comparatively open chromatin compaction states and may be more poised to redifferentiate into contractile fibroblasts in 3D-collagen matrix. Collectively, our results highlight efficient fibroblast rejuvenation through laterally confined reprogramming, which has important implications in regenerative medicine.

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