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Long noncoding RNAs (LncRNAs) are key regulators of gene expression and can mediate their effects in both the nucleus and cytoplasm. Some of the best-characterized lncRNAs are localized within the nucleus, where they modulate the nuclear architecture and influence gene expression. In this review, we discuss the role of lncRNAs in nuclear architecture in the context of their gene regulatory functions in innate immunity. Here, we discuss various approaches to functionally characterize nuclear-localized lncRNAs and the challenges faced in the field.

Deoxyribonucleic acid (DNA) represents the main reservoir of genetic information in the cells, which is why it is protected in the nucleus. Entry into the nucleus is, in general, difficult, as the nuclear membrane is a selective barrier to molecules longer than 40 kDa. However, in some cases, the size of certain nanoparticles (NPs) allows their internalization into the nucleus, thus causing a direct effect on the DNA structure. NPs can also induce indirect effects on DNA through reactive oxygen species (ROS) generation. In this context, nanomaterials are emerging as a disruptive tool for the development of novel therapies in a broad range of biomedical fields; although their effect on cell viability is commonly studied, further interactions with DNA or indirect alterations triggered by the internalization of these materials are not always clarified, since the small size of these materials makes them perfectly suitable for interaction with subcellular structures, such as the nucleus. In this context, and using as a reference the predicted interactions presented in a computational model, we describe and discuss the observed direct and indirect effects of the implicated nanomaterials on DNA.

[Background]: The neuronal transdifferentiation of adult bone marrow cells (BMCs) is still considered an artifact based on an alternative explanation of experimental results supporting this phenomenon obtained over decades. However, recent studies have shown that following neural induction, BMCs enter an intermediate cellular state before adopting neural-like morphologies by active neurite extension and that binucleated BMCs can be formed independent of any cell fusion events. These findings provide evidence to reject the idea that BMC neural transdifferentiation is merely an experimental artifact. Therefore, understanding the intermediate states that cells pass through during transdifferentiation is crucial given their potential application in regenerative medicine and disease modelling., [Methods]: In this study, we examined the functional significance of the variety of morphologies and positioning that cell nuclei of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) can adopt during neural-like differentiation using live-cell nuclear fluorescence labelling, time-lapse microscopy, and confocal microscopy analysis., [Results]: Here, we showed that after neural induction, hBM-MSCs enter an intermediate cellular state in which the nuclei are able to move within the cells, switching shapes and positioning and even generating cellular protrusions as they attempt to contact the cells around them. These findings suggest that changes in nuclear positioning occur because human cell nuclei somehow sense their environment. In addition, we showed the process of direct interactions between cell nuclei, which opens the possibility of a new level of intercellular interaction., [Conclusions]: The present study advances the understanding of the intermediate stage through which hBM-MSCs pass during neural transdifferentiation, which may be crucial to understanding the mechanisms of these cell conversion processes and eventually harness them for use in regenerative medicine. Importantly, our study provides for the first time evidence that the nuclei of hBM-MSC-derived intermediate cells somehow sense their environment, generating cellular protrusions to contact other cells. In summary, human mesenchymal stromal cells could not only help to increase our understanding of the mechanisms underlying cellular plasticity but also facilitate the exact significance of nuclear positioning in cellular function and in tissue physiology.

The endosymbiosis of an alpha-proteobacterium that gave rise to mitochondria was one of the key events in eukaryogenesis. One striking outcome of eukaryogenesis was a much more complex cell with a large genome. Despite the existence of many alternative hypotheses for this and other patterns potentially related to endosymbiosis, a constructive evolutionary model in which these hypotheses can be studied is still lacking. Here, we present a theoretical approach in which we focus on the consequences rather than the causes of mitochondrial endosymbiosis. Using a constructive evolutionary model of cell-cycle regulation, we find that genome expansion and genome size asymmetry arise from emergent host–symbiont cell-cycle coordination. We also find that holobionts with large host and small symbiont genomes perform best on long timescales and mimic the outcome of eukaryogenesis. By designing and studying a constructive evolutionary model of obligate endosymbiosis, we uncovered some of the forces that may drive the patterns observed in nature. Our results provide a theoretical foundation for patterns related to mitochondrial endosymbiosis, such as genome size asymmetry, and reveal evolutionary outcomes that have not been considered so far, such as cell-cycle coordination without direct communication.

We present an analysis of the optical and ultraviolet properties of AT 2020wey, a faint and fast tidal disruption event (TDE) at 124.3 Mpc. The light curve of the object peaked at an absolute magnitude of M-g = 17.45 +/- 0.08 mag and a maximum bolometric luminosity of L-peak = (8.74 +/- 0.69) x 10(42) erg s 1, making it comparable to iPTF16fnl, the faintest TDE to date. The time from the last non-detection to the g-band peak is 23 +/- 2 days, and the rise is well described by L proportional to/ t(1.80 +/- 0.22). The decline of the bolometric light curve is described by a sharp exponential decay steeper than the canonical t(-5/3) power law, making AT 2020wey the fastest declining TDE to date. The multi-band light curve analysis shows first a slowly declining blackbody temperature of T-BB similar to 20 000 K around the peak brightness followed by a gradual temperature increase. The blackbody photosphere is found to expand at a constant velocity (similar to 1300 km s(-1)) to a value of R-BB similar to 3.5 x 10(14) cm before contracting rapidly. Multi-wavelength fits to the light curve indicate a complete disruption of a star of M-star = 0.11(-0.0)(+0.05) M-circle dot by a black hole of M-BH = 106(-0.09)(6.46+0.09) M-circle dot. Our spectroscopic dataset reveals broad (similar to 10(4) km s(-1)) Balmer and He II 4686 angstrom lines, with H alpha reaching its peak with a lag of similar to 8.2 days compared to the continuum. In contrast to previous faint and fast TDEs, there are no obvious Bowen fluorescence lines in the spectra of AT 2020wey. There is a strong correlation between the MOSFIT-derived black hole masses of TDEs and their decline rate. However, AT 2020wey is an outlier in this correlation, which could indicate that its fast early decline may be dictated by a different physical mechanism than fallback. After performing a volumetric correction to a sample of 30 TDEs observed between 2018 and 2020, we conclude that faint TDEs are not rare by nature; they should

The endosymbiotic theory posits that ancient eukaryotic cells engulfed O2-consuming prokaryotes, which protected them against O2 toxicity. Previous studies have shown that cells lacking cytochrome c oxidase (COX), required for respiration, have increased DNA damage and reduced proliferation, which could be improved by reducing O2 exposure. With recently developed fluorescence lifetime microscopy-based probes demonstrating that the mitochondrion has lower [O2] than the cytosol, we hypothesized that the perinuclear distribution of mitochondria in cells may create a barrier for O2 to access the nuclear core, potentially affecting cellular physiology and maintaining genomic integrity. To test this hypothesis, we utilized myoglobin-mCherry fluorescence lifetime microscopy O2 sensors without subcellular targeting (cytosol) or with targeting to the mitochondrion or nucleus for measuring their localized O2 homeostasis. Our results showed that, similar to the mitochondria, the nuclear [O2] was reduced by ∼20 to 40% compared with the cytosol under imposed O2 levels of ∼0.5 to 18.6%. Pharmacologically inhibiting respiration increased nuclear O2 levels, and reconstituting O2 consumption by COX reversed this increase. Similarly, genetic disruption of respiration by deleting SCO2, a gene essential for COX assembly, or restoring COX activity in SCO2-/- cells by transducing with SCO2 cDNA replicated these changes in nuclear O2 levels. The results were further supported by the expression of genes known to be affected by cellular O2 availability. Our study reveals the potential for dynamic regulation of nuclear O2 levels by mitochondrial respiratory activity, which in turn could affect oxidative stress and cellular processes such as neurodegeneration and aging.

Mechanosignaling describes processes by which biomechanical stimuli are transduced into cellular responses. External biophysical forces can be transmitted via structural protein networks that span from the cellular membrane to the cytoskeleton and the nucleus, where they can regulate gene expression through a series of biomechanical and/or biochemical mechanosensitive mechanisms, including chromatin remodeling, translocation of transcriptional regulators, and epigenetic factors. Striated muscle cells, including cardiac and skeletal muscle myocytes, utilize these nuclear mechanosignaling mechanisms to respond to changes in their intracellular and extracellular mechanical environment and mediate gene expression and cell remodeling. In this brief review, we highlight and discuss recent experimental work focused on the pathway of biomechanical stimulus propagation at the nucleus-cytoskeleton interface of striated muscles, and the mechanisms by which these pathways regulate gene regulation, muscle structure, and function. Furthermore, we discuss nuclear protein mutations that affect mechanosignaling function in human and animal models of cardiomyopathy. Furthermore, current open questions and future challenges in investigating striated muscle nuclear mechanosignaling are further discussed.

© Amer Physical Soc 2015. Firmado por 26 autores. This work has been funded by FWO-Vlaanderen (Belgium), by GOA/2010/010 (BOF KU Leuven), by the Interuniversity Attraction Poles Programme initiated by the Belgian Science Policy Office (BriX network P7/12), by the European Commission within the Seventh Framework Programme through I3-ENSAR (Contract No. RII3-CT-2010-262010). This material is based upon work supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics under Award No. DE-FG02-94-ER40834, by Spanish MINECO via Project No. FPA2010-17142, by the Slovak grant agency VEGA (Contract No. 2/0121/14), and by the Slovak Research and Development Agency (Contract No. APVV-0177-11)., The low-energy structure of the neutron-rich nucleus Ni-68 has been investigated by measuring the beta decay of the low-spin isomer in Co-68 selectively produced in the decay chain of Mn-68. A revised level scheme has been built based on the clear identification of beta-gamma-E0 delayed coincidences. Transitions between the three lowest-lying 0(+) and 2(+) states are discussed on the basis of measured intensities or their upper limits for unobserved branches and state-of-the-art shell model calculations., Unión Europea. FP7, Spanish MINECO, Interuniversity Attraction Poles Programme, U.S. Department of Energy, Office of Science, Office of Nuclear Physics, Slovak grant agency VEGA, Slovak Research and Development Agency, FWO-Vlaanderen (Belgium), BOF KU Leuven, Depto. de Estructura de la Materia, Física Térmica y Electrónica, Fac. de Ciencias Físicas, TRUE, pub

© Science. This work was also supported by ETH research grant TH 34/043, the Polish MniSzW grant N N203 390834, and the Young Investigators Program of the Helmholtz Gemeinschaft. VERITAS: This research is supported by grants from the U.S. Department of Energy, NSF, the Smithsonian Institution, the Natural Sciences and Engineering Research Council of Canada, Science Foundation Ireland, and the STFC in the U.K. We acknowledge the excellent work of the technical support staff at the Fred Lawrence Whipple Observatory and the collaborating institutions in the construction and operation of the instrument. VLBA: The Very Long Baseline Array is operated by the National Radio Astronomy Observatory, a facility of NSF, operated under cooperative agreement by Associated Universities, Inc., The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10(12) electron volts and are bright sources of very-high-energy (VHE) gamma-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE gamma-ray flares accompanied by a strong increase of the radio flux from its nucleus. These results imply that charged particles are accelerated to very high energies in the immediate vicinity of the black hole., ETH, Polish MniSzW, Young Investigators Program of the Helmholtz Gemeinschaft, U.S. Department of Energy, NSF, Smithsonian Institution, Natural Sciences and Engineering Research Council of Canada, Science Foundation Ireland, STFC, U.K, Depto. de Estructura de la Materia, Física Térmica y Electrónica, Fac. de Ciencias Físicas, TRUE, pub

© 2005 The American Physical Society, We present a theory that accurately describes the counting of excited states of a noninteracting fermionic gas. At high excitation energies the results reproduce Bethe's theory. At low energies oscillatory corrections to the many-body density of states, related to shell effects, are obtained. The fluctuations depend nontrivially on energy and particle number. Universality and connections with Poisson statistics and random matrix theory are established for regular and chaotic single-particle motion., Depto. de Estructura de la Materia, Física Térmica y Electrónica, Fac. de Ciencias Físicas, TRUE, pub

The extracellular environment defines a physical boundary condition with which cells interact. However, to date, cell response to geometrical environmental cues is largely studied in static settings, which fails to capture the spatiotemporally varying cues cells receive in native tissues. Here, a photoresponsive spiropyran-based hydrogel is presented as a dynamic, cell-compatible, and reconfigurable substrate. Local stimulation with blue light (455 nm) alters hydrogel swelling, resulting in on-demand reversible micrometer-scale changes in surface topography within 15 min, allowing investigation into cell response to controlled geometry actuations. At short term (1 h after actuation), fibroblasts respond to multiple rounds of recurring topographical changes by reorganizing their nucleus and focal adhesions (FA). FAs form primarily at the dynamic regions of the hydrogel; however, this propensity is abolished when the topography is reconfigured from grooves to pits, demonstrating that topographical changes dynamically condition fibroblasts. Further, this dynamic conditioning is found to be associated with long-term (72 h) maintenance of focal adhesions and epigenetic modifications. Overall, this study offers a new approach to dissect the dynamic interplay between cells and their microenvironment and shines a new light on the cell's ability to adapt to topographical changes through FA-based mechanotransduction.

"Emerging Trends in Agricultural Economics and Extension" is a groundbreaking book that delves into the dynamic and evolving field of agricultural economics and extension. This comprehensive volume explores the latest developments, challenges, and opportunities in agriculture, shedding light on the critical role of economics and extension services in shaping the future of farming and food security. It provides a comprehensive and up-to-date exploration of the multifaceted field of agricultural economics and extension. This book is essential reading for students, researchers, policymakers, and anyone interested in the future of agriculture and the critical role that economics and extension services play in ensuring food security and sustainable farming practices. It offers valuable insights into the evolving challenges and opportunities in agriculture, paving the way for a more resilient and prosperous agricultural sector. Economics, often referred to as the "dismal science," is the study of how societies allocate their scarce resources to meet their diverse needs and desires. It forms the intellectual foundation for understanding how individuals, businesses, governments, and societies make choices in the face of limited resources. Economics is not just about numbers and graphs; it's about the fundamental decisions that shape our world. Extension, on the other hand, is the conduit through which knowledge and innovation flow from experts, researchers, and institutions to the grassroots level. It is the bridge that connects the latest advancements in various fields, including agriculture, community development, health, and education, to those who can benefit most from these innovations. Extension professionals are the unsung heroes who empower individuals and communities to make informed choices, adapt to change, and improve their quality of life. We extend our gratitude to the experts, practitioners, and scholars who have contributed their knowledge and insights to ma

Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone-associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro-topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro-topographies after long-term culture conditions. Also, this influence of micro-topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re-cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype.

Background: Several pioneering studies investigated deep brain stimulation (DBS) in treatment-refractory anorexia nervosa (AN) patients, but overall effects remain yet unclear. Aim of this study was to obtain estimates of efficacy of DBS in AN-patients using meta-analysis. Methods: We searched three electronic databases until 1st of November 2021, using terms related to DBS and AN. We included trials that investigated the clinical effects of DBS in AN-patients. We obtained data including psychiatric comorbidities, medication use, DBS target, and study duration. Primary outcome was Body Mass Index (BMI), secondary outcome was quality of life, and the severity of psychiatric symptoms, including eating disorder, obsessive-compulsive, depressive, and anxiety symptoms. We assessed the risk of bias using the ROBINS-I tool. Results: Four studies were included for meta-analysis, with a total of 56 patients with treatment-refractory AN. Follow-up ranged from 6–24 months. Random effects meta-analysis showed a significant increase in BMI following DBS, with a large effect size (Hedges’s g = 1 ∙ 13; 95% CI = 0 ∙ 80 to 1 ∙ 46; Z-value = 6 ∙ 75; P < 0 ∙ 001), without heterogeneity (I2= 0 ∙ 00, P = 0 ∙ 901). Random effects meta-analysis also showed a significant increase in quality of life (Hedges’s g = 0 ∙ 86; 95% CI = 0 ∙ 44 to 1 ∙ 28; Z-value = 4 ∙ 01, P < 0 ∙ 001). Furthermore, DBS decreased the severity of psychiatric symptoms (Hedges’s g = 0 ∙ 89; 95% CI = 0 ∙ 57 to 1 ∙ 21; Z-value = 5 ∙ 47; P < 0 ∙ 001, I2= 4 ∙ 29, P = 0 ∙ 371). Discussion: In this first meta-analysis, DBS showed statistically large beneficial effects on weight restoration, quality of life, and reduction of psychiatric symptoms in patients with treatment-refractory AN. These outcomes call for more extensive naturalistic studies to determine the clinical relevance for functional recovery. This study is preregistered in PROSPERO,CRD42022295

Neuronal migration is a fundamental process of mammalian brain development. In migrating neurons, the nuclear membrane protein Nesprin-2 has been shown to serve as an adaptor to pull the nucleus along microtubule tracks. Current evidence has shown that Nesprin-2 binds to both the minus-end-directed motor dynein as well as the plus-end-directed motor kinesin. However, translocation of neuronal nucleus has long been thought to be primarily driven by dynein motors. Intriguing questions could be raised about the role of kinesin in nuclear transport and how the activities of opposing motors are coordinated through interactions with Nesprin. Combining evidence from recent studies, we propose that Nesprin-2 serves as a switchboard in mediating bidirectional neuronal nuclear movements.

Cellular migration is essential for an assortment of developmental processes ranging from embryogenesis to neurodevelopment. Oftentimes, cellular migration through narrow spaces is limited by nuclear migration,such as is the case for cancer metastasis and in immune response (i.e. white blood cells rushing to the site of injury). Nuclear migration through small constrictions has been studied in vitro but not in vivo. Here, we look at nuclear migration in the context of the developing vulval and neural precursors of Caenorhabditis elegans. During the mid-L1 larval stage, six pairs of P-cell nuclei migrate from the lateral half of the worm to the ventral cord, where they will divide and progress into the vulval and neural precursor cells. These nuclei must migrate through a constriction between the cuticle and the muscle of the developing animal that is about 5% of the diameter of nucleus in the early L1 stage. We explore the mechanisms which allow them to stably migrate in this normal developmental process. Typically, this process has been facilitated by the microtubule-based SUN-KASH pathway, which serve as the tracks for the migrating nuclei. Previous studies have shown that in the absence of the SUN-KASH pathway, these nuclei still migrate at 15°C. We found that there is an actin-based pathway which aids the migration process at 15°C in parallel and in absence of the SUN-KASH pathway. We hypothesized that FLN-2, a filamin, crosslinks branched actin networks and organized actin bundles to support stable nuclear migration through narrow spaces. We found that in the absence of unc-84 (a SUN protein) and/or fln-2, that nuclear rupture events were more prevalent in the migrating P cells, while the absence of unc-84 resulted in the formation of micronuclei in the early and mid-migration stages. We propose future work to determine how FLN-2 may be facilitating P-cell nuclear migration, along with its relationship to UNC-84, LMN-1 (lamin), and CGEF-1 (Cdc42 guanine exchang

Cellular migration is essential for an assortment of developmental processes ranging from embryogenesis to neurodevelopment. Oftentimes, cellular migration through narrow spaces is limited by nuclear migration,such as is the case for cancer metastasis and in immune response (i.e. white blood cells rushing to the site of injury). Nuclear migration through small constrictions has been studied in vitro but not in vivo. Here, we look at nuclear migration in the context of the developing vulval and neural precursors of Caenorhabditis elegans. During the mid-L1 larval stage, six pairs of P-cell nuclei migrate from the lateral half of the worm to the ventral cord, where they will divide and progress into the vulval and neural precursor cells. These nuclei must migrate through a constriction between the cuticle and the muscle of the developing animal that is about 5% of the diameter of nucleus in the early L1 stage. We explore the mechanisms which allow them to stably migrate in this normal developmental process. Typically, this process has been facilitated by the microtubule-based SUN-KASH pathway, which serve as the tracks for the migrating nuclei. Previous studies have shown that in the absence of the SUN-KASH pathway, these nuclei still migrate at 15°C. We found that there is an actin-based pathway which aids the migration process at 15°C in parallel and in absence of the SUN-KASH pathway. We hypothesized that FLN-2, a filamin, crosslinks branched actin networks and organized actin bundles to support stable nuclear migration through narrow spaces. We found that in the absence of unc-84 (a SUN protein) and/or fln-2, that nuclear rupture events were more prevalent in the migrating P cells, while the absence of unc-84 resulted in the formation of micronuclei in the early and mid-migration stages. We propose future work to determine how FLN-2 may be facilitating P-cell nuclear migration, along with its relationship to UNC-84, LMN-1 (lamin), and CGEF-1 (Cdc42 guanine exchang

This article is devoted to programmed cell death - apoptosis. Death occurs after the cell has performed all its vital functions in an apoptotic manner. This is a natural process. In doing so, the molecules that make up the cell structure are gradually broken down into parts, allowing other cells in the same organism to use them. Apoptosis cannot be equated with necrosis at all. In apoptosis, cell-killing software — genes — work. Apoptosis is the programmed death of a cell that is controlled by self-killing genes. The process of apoptosis is not rapid and is different from necrosis. First the mitochondria then the nucleus and finally the cytoplasm breaks down into fragments, i.e. the cell divides into fragments and apoptotic bodies are formed, which are phagocytosed or dissolved by macrophages. Apoptosis as an immunomodulatory form of cell death plays a stabilizing role in maintaining the number of cells in the body. Although much information and evidence has been provided about apoptosis, there is insufficient information on the role of mitochondria in their origin. Therefore, this article provides information on the impact of impaired mitochondrial dysfunction on the development of cell-programmed death - apoptosis.

A nucleus on a meet-semilattice A is a closure operation that preserves binary meets. The nuclei form a semilattice N A that is isomorphic to the system NA of all nuclear ranges, ordered by dual inclusion. The nuclear ranges are those closure ranges which are total subalgebras (l-ideals). Nuclei have been studied intensively in the case of complete Heyting algebras. We extend, as far as possible, results on nuclei and their ranges to the non-complete setting of implicative semilattices (whose unary meet translations have adjoints). A central tool are so-called r-morphisms, that is, residuated semilattice homomorphisms, and their adjoints, the l-morphisms. Such morphisms transport nuclear ranges and preserve implicativity. Certain completeness properties are necessary and sufficient for the existence of a least nucleus above a prenucleus or of a greatest nucleus below a weak nucleus. As in pointfree topology, of great importance for structural investigations are three specific kinds of l-ideals, called basic open, boolean and basic closed. © 2022, The Author(s).

The reconstruction of the signal from hadrons and jets emerging from the proton-proton collisions at the Large Hadron Collider (LHC) and entering the ATLAS calorimeters is based on a three-dimensional topological clustering of individual calorimeter cell signals. The cluster formation follows cell signal-significance patterns generated by electromagnetic and hadronic showers. In this, the clustering algorithm implicitly performs a topological noise suppression by removing cells with insignificant signals which are not in close proximity to cells with significant signals. The resulting topological cell clusters have shape and location information, which is exploited to apply a local energy calibration and corrections depending on the nature of the cluster. Topological cell clustering is established as a well-performing calorimeter signal definition for jet and missing transverse momentum reconstruction in ATLAS.

A measurement of the calorimeter response to isolated charged hadrons in the ATLAS detector at the LHC is presented. This measurement is performed with 3.2 nb(-1) of proton-proton collision data at root s = 7 TeV from 2010 and 0.1 nb(-1) of data at root s = 8 TeV from 2012. A number of aspects of the calorimeter response to isolated hadrons are explored. After accounting for energy deposited by neutral particles, there is a 5% discrepancy in the modelling, using various sets of GEANT4 hadronic physics models, of the calorimeter response to isolated charged hadrons in the central calorimeter region. The description of the response to anti-protons at low momenta is found to be improved with respect to previous analyses. The electromagnetic and hadronic calorimeters are also examined separately, and the detector simulation is found to describe the response in the hadronic calorimeter well. The jet energy scale uncertainty and correlations in scale between jets of different momenta and pseudorapidity are derived based on these studies. The uncertainty is 2-5% for jets with transverse momenta above 2 TeV, where this method provides the jet energy scale uncertainty for ATLAS.

This paper describes the trigger and offline reconstruction, identification and energy calibration algorithms for hadronic decays of tau leptons employed for the data collected from pp collisions in 2012 with the ATLAS detector at the LHC center-of-mass energy root s = 8 TeV. The performance of these algorithms is measured in most cases with Z decays to tau leptons using the full 2012 dataset, corresponding to an integrated luminosity of 20.3 fb(-1). An uncertainty on the offline reconstructed tau energy scale of 2-4%, depending on transverse energy and pseudorapidity, is achieved using two independent methods. The offline tau identification efficiency is measured with a precision of 2.5% for hadronically decaying tau leptons with one associated track, and of 4% for the case of three associated tracks, inclusive in pseudorapidity and for a visible transverse energy greater than 20 GeV. For hadronic tau lepton decays selected by offline algorithms, the tau trigger identification efficiency is measured with a precision of 2-8%, depending on the transverse energy. The performance of the tau algorithms, both offline and at the trigger level, is found to be stable with respect to the number of concurrent proton-proton interactions and has supported a variety of physics results using hadronically decaying tau leptons at ATLAS.

The reconstruction of the signal from hadrons and jets emerging from the proton-proton collisions at the Large Hadron Collider (LHC) and entering the ATLAS calorimeters is based on a three-dimensional topological clustering of individual calorimeter cell signals. The cluster formation follows cell signal-significance patterns generated by electromagnetic and hadronic showers. In this, the clustering algorithm implicitly performs a topological noise suppression by removing cells with insignificant signals which are not in close proximity to cells with significant signals. The resulting topological cell clusters have shape and location information, which is exploited to apply a local energy calibration and corrections depending on the nature of the cluster. Topological cell clustering is established as a well-performing calorimeter signal definition for jet and missing transverse momentum reconstruction in ATLAS.

This paper describes the trigger and offline reconstruction, identification and energy calibration algorithms for hadronic decays of tau leptons employed for the data collected from pp collisions in 2012 with the ATLAS detector at the LHC center-of-mass energy root s = 8 TeV. The performance of these algorithms is measured in most cases with Z decays to tau leptons using the full 2012 dataset, corresponding to an integrated luminosity of 20.3 fb(-1). An uncertainty on the offline reconstructed tau energy scale of 2-4%, depending on transverse energy and pseudorapidity, is achieved using two independent methods. The offline tau identification efficiency is measured with a precision of 2.5% for hadronically decaying tau leptons with one associated track, and of 4% for the case of three associated tracks, inclusive in pseudorapidity and for a visible transverse energy greater than 20 GeV. For hadronic tau lepton decays selected by offline algorithms, the tau trigger identification efficiency is measured with a precision of 2-8%, depending on the transverse energy. The performance of the tau algorithms, both offline and at the trigger level, is found to be stable with respect to the number of concurrent proton-proton interactions and has supported a variety of physics results using hadronically decaying tau leptons at ATLAS.

A measurement of the calorimeter response to isolated charged hadrons in the ATLAS detector at the LHC is presented. This measurement is performed with 3.2 nb(-1) of proton-proton collision data at root s = 7 TeV from 2010 and 0.1 nb(-1) of data at root s = 8 TeV from 2012. A number of aspects of the calorimeter response to isolated hadrons are explored. After accounting for energy deposited by neutral particles, there is a 5% discrepancy in the modelling, using various sets of GEANT4 hadronic physics models, of the calorimeter response to isolated charged hadrons in the central calorimeter region. The description of the response to anti-protons at low momenta is found to be improved with respect to previous analyses. The electromagnetic and hadronic calorimeters are also examined separately, and the detector simulation is found to describe the response in the hadronic calorimeter well. The jet energy scale uncertainty and correlations in scale between jets of different momenta and pseudorapidity are derived based on these studies. The uncertainty is 2-5% for jets with transverse momenta above 2 TeV, where this method provides the jet energy scale uncertainty for ATLAS.

Gray-level co-occurrence matrix (GLCM) analysis is a contemporary and innovative computational method for the assessment of textural patterns, applicable in almost any area of microscopy. The aim of our research was to perform the GLCM analysis of cell nuclei in Saccharomyces cerevisiae yeast cells after the induction of sublethal cell damage with ethyl alcohol, and to evaluate the performance of various machine learning (ML) models regarding their ability to separate damaged from intact cells. For each cell nucleus, five GLCM parameters were calculated: angular second moment, inverse difference moment, GLCM contrast, GLCM correlation, and textural variance. Based on the obtained GLCM data, we applied three ML approaches: neural network, random trees, and binomial logistic regression. Statistically significant differences in GLCM features were observed between treated and untreated cells. The multilayer perceptron neural network had the highest classification accuracy. The model also showed a relatively high level of sensitivity and specificity, as well as an excellent discriminatory power in the separation of treated from untreated cells. To the best of our knowledge, this is the first study to demonstrate that it is possible to create a relatively sensitive GLCM-based ML model for the detection of alcohol-induced damage in Saccharomyces cerevisiae cell nuclei.

Actin cytoskeletal dynamics drive cellular shape changes, linking numerous cell functions to physiological and pathological cues. Mutations in actin regulators that are differentially expressed or enriched in immune cells cause severe human diseases known as primary immunodeficiencies underscoring the importance of efficienct actin remodeling in immune cell homeostasis. Here we discuss recent findings on how immune cells sense the mechanical properties of their environement. Moreover, while the organization and biochemical regulation of cytoplasmic actin have been extensively studied, nuclear actin reorganization is a rapidly emerging field that has only begun to be explored in immune cells. Based on the critical and multifaceted contributions of cytoplasmic actin in immune cell functionality, nuclear actin regulation is anticipated to have a large impact on our understanding of immune cell development and functionality., QC 20240829

The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. While recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription, and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome, and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons.

[ES] El cáncer de mama (CM) es uno de los tres tipos de cáncer más comunes en el mundo, con 1,7 millones de pacientes diagnosticados en el año 2017. A pesar de que el diagnóstico y las terapias contra el CM han mejorado mucho en las últimas décadas, todavía existen casos de CM muy agresivo, dífiles de diagnosticar y metastáticos, por lo que es de vital importancia la búsqueda de nuevos biomarcadores para monitorizar estos casos. Las células tumorales atraviesan una profunda reprogramación de su metabolismo como consecuencia de las mutaciones oncogénicas, lo que les permite mantener una elevada tasa de proliferación. Debido a estas modificaciones, las células tumorales presentan un perfil metabolómico diferente a las células de tejido sano. El estudio del metaboloma de estas células, mediante técnicas como la resonancia magnética nuclear (RMN), es clave para llegar a comprender los cambios que se producen a nivel molecular y encontrar nuevos biomarcadores para el CM. El objetivo de este estudio fue analizar el efecto que tiene el CM agresivo metastático en modelo de ratón en el metaboloma de las mitocondrias y los núcelos de diferentes órganos (pulmón, hígado y riñón). El análisis de los perfiles metabolómicos de estas fracciones celulares en concreto, lo que no se había hecho nunca antes, podría revelar información valiosa sobre el mecanismo de esta enfermedad y la forma en la que afecta a los distintos tejidos del organismo, que previamete no se había encontrado en el metaboloma celular completo. Para ello, se realizó un aislamiento mitocondrial y nuclear a partir de los tres tipos de tejidos, además de tejido tumoral, seguido de un aislamiento de los metabolitos. Posteriormente, se analizó su composición mediante RMN. Los datos obtenidos a partir de los espectros fueron analizados estadísticmanete con la finalidad de comparar los perfiles metabólicos de los distintos grupos de muestras. Como resultado del estudio, se encontró una mayor diferenciación entre las mue, [EN] Breast cancer (BC) is one of the three most common types of cancer in the world, with 1.7 million patients diagnosed in 2017. Although the diagnosis and therapies against BC have improved a lot in the last decades, there are still cases of aggressive BC, characterized by a difficult diagnosis and metastatic. Therefore, the research of new biomarkers to monitor these cases is key for the improvement of the management of this disease. Tumor cells undergo a profound reprogramming of their metabolism as a result of oncogenic mutations, allowing them to maintain a high proliferation rate. Because of these modifications, tumor cells have a different metabolomic profile from healthy tissue cells. The study of the metabolome of these cells, using techniques such as nuclear magnetic resonance (NMR), is key to understand at a molecular level the changes that occur and to find new biomarkers for BC. The goal of this study was to analyze the effect of metastatic aggressive BC in a mouse model on the metabolome of mitochondria and the nuclei of different organs (lung, liver and kidney). The analysis of the metabolomic profiles of these particular cell fractions, which had never been done before, could reveal valuable information about the mechanism of BC and could provide information about how it affects other organs of the organism. To do this, mitochondrial and nuclear isolation was performed from the three tissue types, in addition to tumor tissue, followed by an isolation of the metabolites. Then, its composition was analyzed using NMR. The data obtained from the spectra were analyzed statistically in order to compare the metabolic profiles of the different groups of samples. As a result of the study, a greater differentiation was found between samples obtained from healthy mice and with breast tumor in the case of lung followed by liver, reflecting the spontaneous metastasis that occurs in these organs. These differences were more clearly observed in mitochondria, indi

[ES] El cáncer de mama (CM) es uno de los tres tipos de cáncer más comunes en el mundo, con 1,7 millones de pacientes diagnosticados en el año 2017. A pesar de que el diagnóstico y las terapias contra el CM han mejorado mucho en las últimas décadas, todavía existen casos de CM muy agresivo, dífiles de diagnosticar y metastáticos, por lo que es de vital importancia la búsqueda de nuevos biomarcadores para monitorizar estos casos. Las células tumorales atraviesan una profunda reprogramación de su metabolismo como consecuencia de las mutaciones oncogénicas, lo que les permite mantener una elevada tasa de proliferación. Debido a estas modificaciones, las células tumorales presentan un perfil metabolómico diferente a las células de tejido sano. El estudio del metaboloma de estas células, mediante técnicas como la resonancia magnética nuclear (RMN), es clave para llegar a comprender los cambios que se producen a nivel molecular y encontrar nuevos biomarcadores para el CM. El objetivo de este estudio fue analizar el efecto que tiene el CM agresivo metastático en modelo de ratón en el metaboloma de las mitocondrias y los núcelos de diferentes órganos (pulmón, hígado y riñón). El análisis de los perfiles metabolómicos de estas fracciones celulares en concreto, lo que no se había hecho nunca antes, podría revelar información valiosa sobre el mecanismo de esta enfermedad y la forma en la que afecta a los distintos tejidos del organismo, que previamete no se había encontrado en el metaboloma celular completo. Para ello, se realizó un aislamiento mitocondrial y nuclear a partir de los tres tipos de tejidos, además de tejido tumoral, seguido de un aislamiento de los metabolitos. Posteriormente, se analizó su composición mediante RMN. Los datos obtenidos a partir de los espectros fueron analizados estadísticmanete con la finalidad de comparar los perfiles metabólicos de los distintos grupos de muestras. Como resultado del estudio, se encontró una mayor diferenciación entre las mue, [EN] Breast cancer (BC) is one of the three most common types of cancer in the world, with 1.7 million patients diagnosed in 2017. Although the diagnosis and therapies against BC have improved a lot in the last decades, there are still cases of aggressive BC, characterized by a difficult diagnosis and metastatic. Therefore, the research of new biomarkers to monitor these cases is key for the improvement of the management of this disease. Tumor cells undergo a profound reprogramming of their metabolism as a result of oncogenic mutations, allowing them to maintain a high proliferation rate. Because of these modifications, tumor cells have a different metabolomic profile from healthy tissue cells. The study of the metabolome of these cells, using techniques such as nuclear magnetic resonance (NMR), is key to understand at a molecular level the changes that occur and to find new biomarkers for BC. The goal of this study was to analyze the effect of metastatic aggressive BC in a mouse model on the metabolome of mitochondria and the nuclei of different organs (lung, liver and kidney). The analysis of the metabolomic profiles of these particular cell fractions, which had never been done before, could reveal valuable information about the mechanism of BC and could provide information about how it affects other organs of the organism. To do this, mitochondrial and nuclear isolation was performed from the three tissue types, in addition to tumor tissue, followed by an isolation of the metabolites. Then, its composition was analyzed using NMR. The data obtained from the spectra were analyzed statistically in order to compare the metabolic profiles of the different groups of samples. As a result of the study, a greater differentiation was found between samples obtained from healthy mice and with breast tumor in the case of lung followed by liver, reflecting the spontaneous metastasis that occurs in these organs. These differences were more clearly observed in mitochondria, indi

The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. While recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription, and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome, and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons.

[ES] El cáncer de mama (CM) es uno de los tres tipos de cáncer más comunes en el mundo, con 1,7 millones de pacientes diagnosticados en el año 2017. A pesar de que el diagnóstico y las terapias contra el CM han mejorado mucho en las últimas décadas, todavía existen casos de CM muy agresivo, dífiles de diagnosticar y metastáticos, por lo que es de vital importancia la búsqueda de nuevos biomarcadores para monitorizar estos casos. Las células tumorales atraviesan una profunda reprogramación de su metabolismo como consecuencia de las mutaciones oncogénicas, lo que les permite mantener una elevada tasa de proliferación. Debido a estas modificaciones, las células tumorales presentan un perfil metabolómico diferente a las células de tejido sano. El estudio del metaboloma de estas células, mediante técnicas como la resonancia magnética nuclear (RMN), es clave para llegar a comprender los cambios que se producen a nivel molecular y encontrar nuevos biomarcadores para el CM. El objetivo de este estudio fue analizar el efecto que tiene el CM agresivo metastático en modelo de ratón en el metaboloma de las mitocondrias y los núcelos de diferentes órganos (pulmón, hígado y riñón). El análisis de los perfiles metabolómicos de estas fracciones celulares en concreto, lo que no se había hecho nunca antes, podría revelar información valiosa sobre el mecanismo de esta enfermedad y la forma en la que afecta a los distintos tejidos del organismo, que previamete no se había encontrado en el metaboloma celular completo. Para ello, se realizó un aislamiento mitocondrial y nuclear a partir de los tres tipos de tejidos, además de tejido tumoral, seguido de un aislamiento de los metabolitos. Posteriormente, se analizó su composición mediante RMN. Los datos obtenidos a partir de los espectros fueron analizados estadísticmanete con la finalidad de comparar los perfiles metabólicos de los distintos grupos de muestras. Como resultado del estudio, se encontró una mayor diferenciación entre las mue, [EN] Breast cancer (BC) is one of the three most common types of cancer in the world, with 1.7 million patients diagnosed in 2017. Although the diagnosis and therapies against BC have improved a lot in the last decades, there are still cases of aggressive BC, characterized by a difficult diagnosis and metastatic. Therefore, the research of new biomarkers to monitor these cases is key for the improvement of the management of this disease. Tumor cells undergo a profound reprogramming of their metabolism as a result of oncogenic mutations, allowing them to maintain a high proliferation rate. Because of these modifications, tumor cells have a different metabolomic profile from healthy tissue cells. The study of the metabolome of these cells, using techniques such as nuclear magnetic resonance (NMR), is key to understand at a molecular level the changes that occur and to find new biomarkers for BC. The goal of this study was to analyze the effect of metastatic aggressive BC in a mouse model on the metabolome of mitochondria and the nuclei of different organs (lung, liver and kidney). The analysis of the metabolomic profiles of these particular cell fractions, which had never been done before, could reveal valuable information about the mechanism of BC and could provide information about how it affects other organs of the organism. To do this, mitochondrial and nuclear isolation was performed from the three tissue types, in addition to tumor tissue, followed by an isolation of the metabolites. Then, its composition was analyzed using NMR. The data obtained from the spectra were analyzed statistically in order to compare the metabolic profiles of the different groups of samples. As a result of the study, a greater differentiation was found between samples obtained from healthy mice and with breast tumor in the case of lung followed by liver, reflecting the spontaneous metastasis that occurs in these organs. These differences were more clearly observed in mitochondria, indi

How nuclei are shaped within cells is one of the fundamental questions of cellular spatial patterning. This question has been mainly investigated in metazoan cells, as misshapen nuclei are prominent features of cancer and aging in humans. The giant ciliate Stentor coeruleus provides an opportunity to learn more about the mechanisms behind nuclear shape, because Stentor undergoes a dramatic and developmentally regulated nuclear shape change. During cell division and regeneration, the macronucleus dramatically changes shape before dividing amitotically into two daughter cells. The moniliform macronucleus condenses into single sphere, extends, and renodulates in 2-3 hours near the end of cell division and regeneration. It is unclear how this extreme macronuclear shape change is regulated. While microsurgical and electron microscopy studies addressed this question in the past, we have had virtu- ally no molecular insight into this feat of subcellular morphogenesis. Here we identify the first molecular driver of macronuclear condensation: the nuclear transport factor CSE1. In other model systems, CSE1 is needed to export importin-alpha, thus CSE1 is necessary for the overall import of proteins into the nucleus. In Stentor, we found that knocking down CSE1 using RNAi reduced the ability of Stentor to increase its macronuclear volume during condensation, and it also prevented the nodes from fusing together into a single mass. Immunofluorescence data showed that CSE1 is mainly cytoplasmic during interphase, and then becomes mainly intranuclear while the macronucleus is condensed. We also found that as the macronucleus elongates, its volume decreases, and there are no longer any detectable levels of CSE1 in the cell. This data comes together in our model of how CSE1 drives macronuclear condensation in Stentor. Increased nuclear import driven by CSE1 increases the volume of the macronucleus, and the macronucleus changes shape into a sphere to accommodate this volume increase.

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions. Opening of unopposed hemichannels, located at the lateral surface of cardiomyocytes, may compromise cell homeostasis and may be involved in ischemia/reperfusion injury. In addition, connexins located at non-canonical cell structures, including mitochondria and the nucleus, have been demonstrated to be involved in cardioprotection and in regulation of cell growth and differentiation. In this review, we will provide, first, an overview on connexin biology, including their synthesis and degradation, their regulation and their interactions. Then, we will conduct an in-depth examination of the role of connexins in cardiac pathophysiology, including new findings regarding their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription or signaling regulation

Actin cytoskeletal dynamics drive cellular shape changes, linking numerous cell functions to physiological and pathological cues. Mutations in actin regulators that are differentially expressed or enriched in immune cells cause severe human diseases known as primary immunodeficiencies underscoring the importance of efficienct actin remodeling in immune cell homeostasis. Here we discuss recent findings on how immune cells sense the mechanical properties of their environement. Moreover, while the organization and biochemical regulation of cytoplasmic actin have been extensively studied, nuclear actin reorganization is a rapidly emerging field that has only begun to be explored in immune cells. Based on the critical and multifaceted contributions of cytoplasmic actin in immune cell functionality, nuclear actin regulation is anticipated to have a large impact on our understanding of immune cell development and functionality.

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mueller, R. L., Combs, B., Alhadidy, M. M., Brady, S. T., Morfini, G. A., & Kanaan, N. M. Tau: a signaling hub protein. Frontiers in Molecular Neuroscience, 14, (2021): 647054, https://doi.org/10.3389/fnmol.2021.647054., Over four decades ago, in vitro experiments showed that tau protein interacts with and stabilizes microtubules in a phosphorylation-dependent manner. This observation fueled the widespread hypotheses that these properties extend to living neurons and that reduced stability of microtubules represents a major disease-driving event induced by pathological forms of tau in Alzheimer’s disease and other tauopathies. Accordingly, most research efforts to date have addressed this protein as a substrate, focusing on evaluating how specific mutations, phosphorylation, and other post-translational modifications impact its microtubule-binding and stabilizing properties. In contrast, fewer efforts were made to illuminate potential mechanisms linking physiological and disease-related forms of tau to the normal and pathological regulation of kinases and phosphatases. Here, we discuss published work indicating that, through interactions with various kinases and phosphatases, tau may normally act as a scaffolding protein to regulate phosphorylation-based signaling pathways. Expanding on this concept, we also review experimental evidence linking disease-related tau species to the misregulation of these pathways. Collectively, the available evidence supports the participation of tau in multiple cellular processes sustaining neuronal and glial function through various mechanisms involving the scaffolding and regulation of selected kinases and phosphatases at discrete subcellular compartments. The notion that the repertoire of tau functions includes a role as a signaling hub should widen our interpretation of experimental results and increase our understanding of tau biology in normal and disease conditions., This work was supported by NIH grants (R01AG067762 and R01AG044372 to NK, R01NS082730 to NK and SB, R01NS118177 and R21NS120126 to GM, R01NS023868 and R01NS041170 to SB), a gift from Neurodegenerative Research Inc. (GM), a Zenith Award from the Alzheimer’s Association (SB), a grant from the Secchia Family Foundation (NK), NIH/National Institute on Aging (NIA) funded Michigan Alzheimer’s Disease Research Center 5P30AG053760 (BC), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Alzheimer’s Research Program (Award No. W81XWH-20-1-0174 to BC), and an Alzheimer’s Association Research Grant 20-682085 (BC).

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mueller, R. L., Combs, B., Alhadidy, M. M., Brady, S. T., Morfini, G. A., & Kanaan, N. M. Tau: a signaling hub protein. Frontiers in Molecular Neuroscience, 14, (2021): 647054, https://doi.org/10.3389/fnmol.2021.647054., Over four decades ago, in vitro experiments showed that tau protein interacts with and stabilizes microtubules in a phosphorylation-dependent manner. This observation fueled the widespread hypotheses that these properties extend to living neurons and that reduced stability of microtubules represents a major disease-driving event induced by pathological forms of tau in Alzheimer’s disease and other tauopathies. Accordingly, most research efforts to date have addressed this protein as a substrate, focusing on evaluating how specific mutations, phosphorylation, and other post-translational modifications impact its microtubule-binding and stabilizing properties. In contrast, fewer efforts were made to illuminate potential mechanisms linking physiological and disease-related forms of tau to the normal and pathological regulation of kinases and phosphatases. Here, we discuss published work indicating that, through interactions with various kinases and phosphatases, tau may normally act as a scaffolding protein to regulate phosphorylation-based signaling pathways. Expanding on this concept, we also review experimental evidence linking disease-related tau species to the misregulation of these pathways. Collectively, the available evidence supports the participation of tau in multiple cellular processes sustaining neuronal and glial function through various mechanisms involving the scaffolding and regulation of selected kinases and phosphatases at discrete subcellular compartments. The notion that the repertoire of tau functions includes a role as a signaling hub should widen our interpretation of experimental results and increase our understanding of tau biology in normal and disease conditions., This work was supported by NIH grants (R01AG067762 and R01AG044372 to NK, R01NS082730 to NK and SB, R01NS118177 and R21NS120126 to GM, R01NS023868 and R01NS041170 to SB), a gift from Neurodegenerative Research Inc. (GM), a Zenith Award from the Alzheimer’s Association (SB), a grant from the Secchia Family Foundation (NK), NIH/National Institute on Aging (NIA) funded Michigan Alzheimer’s Disease Research Center 5P30AG053760 (BC), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Alzheimer’s Research Program (Award No. W81XWH-20-1-0174 to BC), and an Alzheimer’s Association Research Grant 20-682085 (BC).

How nuclei are shaped within cells is one of the fundamental questions of cellular spatial patterning. This question has been mainly investigated in metazoan cells, as misshapen nuclei are prominent features of cancer and aging in humans. The giant ciliate Stentor coeruleus provides an opportunity to learn more about the mechanisms behind nuclear shape, because Stentor undergoes a dramatic and developmentally regulated nuclear shape change. During cell division and regeneration, the macronucleus dramatically changes shape before dividing amitotically into two daughter cells. The moniliform macronucleus condenses into single sphere, extends, and renodulates in 2-3 hours near the end of cell division and regeneration. It is unclear how this extreme macronuclear shape change is regulated. While microsurgical and electron microscopy studies addressed this question in the past, we have had virtu- ally no molecular insight into this feat of subcellular morphogenesis. Here we identify the first molecular driver of macronuclear condensation: the nuclear transport factor CSE1. In other model systems, CSE1 is needed to export importin-alpha, thus CSE1 is necessary for the overall import of proteins into the nucleus. In Stentor, we found that knocking down CSE1 using RNAi reduced the ability of Stentor to increase its macronuclear volume during condensation, and it also prevented the nodes from fusing together into a single mass. Immunofluorescence data showed that CSE1 is mainly cytoplasmic during interphase, and then becomes mainly intranuclear while the macronucleus is condensed. We also found that as the macronucleus elongates, its volume decreases, and there are no longer any detectable levels of CSE1 in the cell. This data comes together in our model of how CSE1 drives macronuclear condensation in Stentor. Increased nuclear import driven by CSE1 increases the volume of the macronucleus, and the macronucleus changes shape into a sphere to accommodate this volume increase.

The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. While recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription, and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome, and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons.

Ezrin-Radixin-Moesin (ERM) proteins play an essential role in the cytoplasm by cross-linking actin filaments with plasma membrane proteins. Research has identified the nuclear localization of ERMs, as well as the involvement of a single Drosophila ERM protein, Moesin, in nuclear mRNA exports. However, the question of how important the nuclear activity of ERM proteins are for the life of an organism has so far not been explored. Here, we present the first attempt to reveal the in vivo relevance of nuclear localization of Moesin in Drosophila. With the help of a nuclear export signal, we decreased the amount of Moesin in the nuclei of the animals. Furthermore, we observed various developmental defects, demonstrating the importance of ERM function in the nucleus for the first time. Transcriptome analysis of the mutant flies revealed that the lack of nuclear Moesin function leads to expression changes in nearly 700 genes, among them heat-shock genes. This result together with additional findings revealed that in Drosophila the expression of protein chaperones requires the nuclear functions of Moesin.

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

Cells and tissues are continuously exposed to both chemical and physical stimuli and dy-namically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue‐specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post‐translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM‐driven modulation of Rho GTPases provides a versatile mechanism for their com-partmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities.

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of di

Unlike in most eukaryotic cells, the genetic information of budding yeast in the exponential growth phase is only present in the form of decondensed chromatin, a configuration that does not allow its visualization in cell nuclei conventionally prepared for transmission electron microscopy. In this work, we studied the distribution of chromatin and its relationships to the nucleolus using different cytochemical and immunocytological approaches applied to yeast cells subjected to hyperosmotic shock. Our results show that osmotic shock induces the formation of heterochromatin patches in the nucleoplasm and intranucleolar regions of the yeast nucleus. In the nucleolus, we further revealed the presence of osmotic shock-resistant DNA in the fibrillar cords which, in places, take on a pinnate appearance reminiscent of ribosomal genes in active transcription as observed after molecular spreading (“Christmas trees”). We also identified chromatin-associated granules whose size, composition and behaviour after osmotic shock are reminiscent of that of mammalian perichromatin granules. Altogether, these data reveal that it is possible to visualize heterochromatin in yeast and suggest that the yeast nucleus displays a less-effective compartmentalized organization than that of mammals., SCOPUS: ar.j, info:eu-repo/semantics/published

RESEARCH ID S-2443-2016 (Miguel Gisbert Garzarán) ORCID 0000-0001-9815-0354 (Miguel Gisbert Garzarán) RESEARCH ID B-5081-2017 (Daniel Lozano Borregón) ORCID 0000-0001-5902-9201 (Daniel Lozano Borregón) RESEARCHER ID M-3378-2014 (María Vallet Regí) ORCID 0000-0002-6104-4889 (María Vallet Regí), Current chemotherapy treatments lack of great selectivity towards tumoral cells, which 13 leads to nonspecific drug distribution and subsequent side effects. In this regard, the use of 14 nanoparticles able to encapsulate and release therapeutic agents has attracted growing attention. In 15 this sense, mesoporous silica nanoparticles (MSNs) have been widely employed as drug carriers 16 owing to their exquisite physico-chemical properties. Because MSNs present a surface full of silanol 17 groups, they can be easily functionalized to endow the nanoparticles with many different 18 functionalities, including the introduction of moieties with affinity for the cell membrane or relevant 19 compartments within the cell, thus increasing the efficacy of the treatments. This review manuscript 20 will provide the state-of-the-art on MSNs functionalized for targeting subcellular compartments, 21 focusing on the cytoplasm, the mitochondria and the nucleus., Unión Europea. Horizonte 2020, Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub