Miracle-dz/UniFAR-FTUs huggingface dataset:
Aberrant association of chromatin with nuclear periphery induced by Rif1 leads to mitotic defect

Overexpression of Rif1 induces relocation of chromatin to nuclear periphery and mitotic defect, suggesting a role of regulated chromatin–nuclear membrane association in the proper progression of M phase. The architecture and nuclear location of chromosomes affect chromatin events. Rif1, a crucial regulator of replication timing, recognizes G-quadruplex and inhibits origin firing over the 50–100-kb segment in fission yeast, Schizosaccharomyces pombe, leading us to postulate that Rif1 may generate chromatin higher order structures inhibitory for initiation. However, the effects of Rif1 on chromatin localization in nuclei have not been known. We show here that Rif1 overexpression causes growth inhibition and eventually, cell death in fission yeast. Chromatin-binding activity of Rif1, but not recruitment of phosphatase PP1, is required for growth inhibition. Overexpression of a PP1-binding site mutant of Rif1 does not delay the S-phase, but still causes cell death, indicating that cell death is caused not by S-phase problems but by issues in other phases of the cell cycle, most likely the M-phase. Indeed, Rif1 overexpression generates cells with unequally segregated chromosomes. Rif1 overexpression relocates chromatin near nuclear periphery in a manner dependent on its chromatin-binding ability, and this correlates with growth inhibition. Thus, coordinated progression of S- and M-phases may require regulated Rif1-mediated chromatin association with the nuclear periphery.
Proteogenomic characterization of age and sex interactions in cardiac gene expression

The risks of heart diseases are significantly modulated by biological age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here we characterized young adult and early aging mouse hearts using proteogenomics to identify age and sex dependent gene expression signatures in the mouse heart. RNA sequencing from 4 months old and 20 months old female and male C57BL/6J hearts identified thousands of genes with differential transcript abundances both between sexes (male vs. female) and across age groups (20 mo. vs. 4 mo.). Sex-associated cardiac genes are broadly distributed, functioning in the TCA cycle, mitochondrial translation, autophagy, and other processes. In addition, we found over 800 genes with differential aging response between male and female, which are enriched in calmodulin signaling and cell cycle regulations. Comparison with mass spectrometry data shows a cluster of metabolism genes with up-regulated transcripts but down-regulated protein levels in aging hearts, consistent with an uncoupling of transcriptional regulations in the genetic program with protein compositions. An analysis of sex-adjusted aging cardiac transcriptomes further revealed widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the potential impact of the splicing events on proteoform composition in the heart, we applied an RNA-guided-proteomics computational pipeline to analyze the mass spectrometry data, and putatively identified hundreds of splice events with the potential to rewire the cardiac proteome through producing detectable splice isoform specific peptides. Taken together, this study contributes to emerging evidences for considerable sexual dimorphism in the cardiac aging process involving sex-biased aging genes and regulatory networks. Aging hearts are associated with a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes represent an under-investigated aspect of cardiac aging that should be considered in the search for disease mechanisms.
Gateway Identity and Spatial Remapping in a Combined Grid and Place Cell Attractor

The spatial specificities of hippocampal place cells, i.e., their firing fields, are subject to change if the rat enters a new compartment in the experimental maze. This effect is known as remapping. It cannot be explained from path integration (grid cell activity) and local sensory cues alone but requires additional knowledge of the different compartments in the form of context recognition at the gateways between them. Here we present a model for the hippocampalentorhinal interplay in which the activity of place and grid cells follows a joint attractor dynamic. Place cells depend on the current grid cell activity but can also reset the grid cell activity in the remapping process. Remapping is triggered by the passage through a gateway. When this happens, a previously stored pattern of place cell activity associated with the gateway is reactivated from a “gateway database”. The joint attractor will then reinstate the grid cell pattern that was active when the gateway had first been learned and path integration can proceed from there. The model is tested with various mazes used in the experimental literature and reproduces the published results, and we make predictions for remapping in a new maze type. We propose the involvement of memory in the form of “gate cells” that drive the place cells and with them the joint hippocampal-entorhinal loop into the corresponding attractor whenever a compartment is entered.
Delineation and birth of a layered intestinal stem cell niche

Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here we identify the adult mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle cell populations. Diverse sub-cryptal cells provide redundant supportive factors, with certain BMPi and the most potent Wnt co-factor, RSPO2, restricted to single cell types. Niche functions refine during a critical period of postnatal crypt morphogenesis, in part to oppose dense aggregation of BMP-expressing sub-epithelial myofibroblasts that promote epithelial differentiation. A specialized muscle layer, the muscularis mucosae, first appears during this period and supplements neighboring RSPO and BMPi sources. In vivo ablation of smooth muscle raises BMP activity and potently limits a pre-weaning burst of crypt fission. Thus, distinct and progressively specialized mesenchymal components together create the milieu required to propagate crypts during rapid organ growth and to sustain adult ISCs.
Transretinal migration of astrocytes and brain/spinal cord-like cells arising from transplanted human retinal organoids

Human retinal organoid transplantation can potentially restore vision in patients with degenerative retinal diseases. How the recipient retina regulates the maturation, fate specification, and migration of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice, conducted histology and single-cell RNA sequencing analyses, and observed two main classes of graft-derived cells. The first class consisted of retinal astrocytes and brain/spinal cord-like neural precursors, absent or rare in cultured organoids, that migrated into all recipient retinal layers and traveled long distances. The second class consisted of retinal progenitor-derived cells, including rods and cones, that remained in the subretinal space and matured more rapidly than photoreceptors in culture. These data suggest that the recipient subretinal space promotes the maturation of transplanted photoreceptors while inducing or expanding migratory cell populations that are not normally derived from retinal progenitors. These findings have important implications for cell-based treatment of retinal diseases.
High throughput peptidomics elucidates immunoregulatory functions of plant thimet oligopeptidase-directed proteostasis

Targeted proteolysis activities activated during the plant immune response catalyze the synthesis of stable endogenous peptides. Little is known about their biogenesis and biological roles. Herein, we characterize an Arabidopsis thaliana mutant top1top2 in which targeted proteolysis of immune-active peptides is drastically impaired during effector-triggered immunity (ETI). For effective ETI, the redox-sensitive thimet oligopeptidases TOP1 and TOP2 are required. Quantitative mass spectrometry-based peptidomics allowed differential peptidome profiling of wild type (WT) and top1top2 mutant at the early ETI stages. Biological processes of energy-producing and redox homeostasis were enriched, and TOPs were necessary to maintain the dynamics of ATP and NADP(H) accumulation in the plant during ETI. Subsequently, a set of novel TOPs substrates validated in vitro enabled the definition of the TOP-specific cleavage motif and informed an in-silico model of TOP proteolysis to generate bioactive peptide candidates. Several candidates, including those derived from proteins associated with redox metabolism, were confirmed in planta. The top1top2 background rescued WT’s ETI deficiency caused by treatment with peptides derived from targeted proteolysis of the negative immune regulator FBR12, the reductive enzyme APX1, the isoprenoid pathway enzyme DXR, and ATP-subunit β. These results demonstrate TOPs role in orchestrating the production and degradation of phytocytokines.
Structure and mechanism of LARGE1 matriglycan polymerase

Matriglycan is a linear polysaccharide of alternating xylose and glucuronate that binds extracellular matrix proteins and acts as a receptor for Lassa fever virus. LARGE1 synthesizes matriglycan on dystroglycan and mutations in LARGE1 cause muscular dystrophy with abnormal brain development. However, the mechanism of matriglycan polymerization by LARGE1 is unknown. Here, we report the cryo-EM structure of LARGE1. We show that LARGE1 functions as a dimer to polymerize matriglycan by alternating activities between the xylose transferase domain on one protomer and the glucuronate transferase domain on the other protomer. Biochemical analyses using a recombinant Golgi form of dystroglycan reveal that LARGE1 polymerizes matriglycan processively. Our results provide mechanistic insights into LARGE1 function and may facilitate novel therapeutic strategies for treating neuromuscular disorders or arenaviral infections. One-Sentence Summary Dimeric LARGE1 processively polymerizes matriglycan on dystroglycan using orthogonal active sites on alternate protomers.
Comparative Transcriptome Analysis of Hypocotyls During the Developmental Transition of C 3 cotyledons to C 4 Leaves in Halimocnemis mollissima : Exploring Root-Shoot Signalings Involved in the Establishing of C 4 traits

Identification of various aspects of C 4 photosynthesis regulation is essential for introducing the C 4 pathway into C 3 crops. Species with dual photosynthesis in their life cycle are interesting models to study such regulatory mechanisms through comparative analysis due to the lack of phylogenetic noises. Accordingly, the present research used Halimocnemis mollissima, which belonged to the Caroxyleae tribe, with C 3 (in cotyledons) and NAD-ME subtype of C 4 photosynthesis (in first leaves onwards) in its annual life cycle. We focused on exploring long-distance signaling pathways that are probably implicated in the shoot-root coordination associated with the manifestation of the C 4 traits, including efficient resource usage by comparing the mRNA content of hypocotyls before and after C 4 first leaves formation. As most likely part of the gene expression changes in hypocotyls observed in our study reflect those involved in the development of hypocotyls, we tried to exclude them by comparing our data with differentially expressed genes (DEGs) that had previously been identified in developing hypocotyls of flax and hemp. Our analyses revealed that several mobile regulators were differentially expressed in two developmentally different hypocotyls of H. mollissima , which belong to various transcription factors (TFs), phytohormones metabolism, and signaling peptides. Moreover, several up-regulated TFs in hypocotyls after establishing the C 4 first leaves were stress-responsive. Our results provide insights into the necessity of above- and under-ground tissue communication during the developmental transition of photosynthesis strategy in this species to manifest functional C 4 traits, especially nitrogen and water use efficiency and drought resistance.
A label-free method to track individuals and lineages of budding cells

Much of biochemical regulation ultimately controls growth rate, particularly in microbes. Although time-lapse microscopy visualises cells, determining their growth rates is challenging because cells often overlap in images, particularly for those that divide asymmetrically, like Saccharomyces cerevisiae. Here we present the Birth Annotator for Budding Yeast (BABY), an algorithm to determine single-cell growth rates from label-free images. Using a convolutional neural network, BABY resolves overlaps through separating cells by size and assigns buds to mothers by identifying bud necks. BABY uses machine learning to track cells and determine lineages, estimates growth rates as the rate of change of volumes, and identifies cytokinesis by how growth varies. Using BABY and a microfluidic device, we show that bud growth is first sizer- then timer-controlled, that the nuclear concentration of Sfp1, a regulator of ribosome biogenesis, varies before the growth rate does, and that growth rate can be used for real-time control. Growth rate and fitness are strongly correlated, and BABY should therefore generate much biological insight.
B cell receptor stimulation induces IgE plasma cell apoptosis

The proper regulation of IgE production safeguards against allergic disease, yet the mechanisms that restrict IgE plasma cell (PC) longevity are unclear. Here, we demonstrated that high surface B cell receptor (BCR) expression on IgE PCs corresponded with the phosphorylation of BCR signalosome proteins following cognate antigen exposure. Within hours of BCR stimulation in cell culture, IgE PCs lost surface CD138 expression and underwent cell death. This depletion of IgE PCs correlated with the affinity, avidity, amount, and duration of antigen exposure and required Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, after IgE BCR ligation with a monoclonal antibody, IgE PCs were depleted in vitro and in vivo . These findings establish that IgE PC longevity is constrained by BCR stimulation, which may contribute to the mechanisms of allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments. Fc-WT Fc-X antibody-dependent cytotoxicity other mechanisms IgE PC involving Fcγ receptors. These findings demonstrate that ligation of the BCR on IgE PCs in vivo results in IgE PC elimination.
High-resolution kinetic gene expression analysis of T helper cell differentiation reveals a STAT-dependent, unique transcriptional program in Th1/2 hybrid cells

Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo, and their generation could be reproduced in vitro. While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th cell differentiation into Th1, Th2 and Th1/2 hybrid cells. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ∼20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1 or Th2 cell gene expression, another fraction of ∼20% of genes followed a Th1 and Th2 cell-independent transcriptional program under control of the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes.
Modeling ecological communities when composition is manipulated experimentally

In an experimental setting, the composition of ecological communities can be manipulated directly. Starting from a pool of n species, one can co-culture species in different combinations, spanning mono-cultures, pairs of species, and all the way up to the full pool. Here we advance methods aimed at inferring species interactions from data sets reporting the density attained by species in a variety of sub-communities formed from the same pool. First, we introduce a fast and robust algorithm to estimate parameters for simple statistical models describing these data, which can be combined with likelihood maximization approaches. Second, we derive from consumer-resource dynamics statistical models with few parameters, which can be applied to study systems where only a small fraction of the potential sub-communities have been observed. Third, we show how a Weighted Least Squares (WLS) framework can be used to account for the fact that species abundances often display a strong relationship between means and variances. To illustrate our approach, we analyze data sets spanning plants, bacteria, phytoplankton, as well as simulations, recovering a good fit to the data and demonstrating the ability to predict experiments out-of-sample. We greatly extend the applicability of recently proposed methods, opening the door for the analysis of larger pools of species.
The extended second law of thermodynamics suggests a thermodynamic imperative driving the evolution of life systems towards increased complexity

From a thermodynamic point of view life structures can be viewed as dissipative systems capable of self replication. Energy flowing from the external environment into the system allows growth of its self replicative components increasing the system complexity concomitantly with an increase in the entropy of the universe, thus observing the second law of thermodynamics. However, general thermodynamic models of life systems have been hampered by the lack of precise equations modelling far from equilibrium driven systems operating in non-linear response regimes. Recent theoretical advances, applying time reversal symmetry and coarse grained state transitions, have provided theoretical insights into the thermodynamic constraints that bind the behaviour of such far from equilibrium life systems. Setting additional constraints based on empirical observations allows us to apply this theoretical framework to gain a further semiquantitative insight on the thermodynamic boundaries and evolution of complex self replicative life systems. This interpretation suggests a thermodynamic hierarchical organisation based on increasing accessible levels of usable energy, which in turn drives an exponential punctuated growth of the system’s complexity. For the earth life system this growth has historically not been limited by the total energy available from the external driving field, but by the system’s internal adaptability needed to access higher levels of usable energy. Therefore, in the absence of external perturbations, the emergence of an initial self replicative dissipative structure capable of variation that enables access to higher energy levels is sufficient to drive the system’s growth irreversibly towards increased complexity across time and space in a hierarchical manner. This interpretation is consistent with current empirical observation of life systems across both time and space and explains from a thermodynamic point of view the evolutionary patterns of complex life systems on earth.
Intracranial Aneurysms Induced by RUNX1 Through Regulation of NFKB1 in Patients With Hypertension-An Integrated Analysis Based on Multiple Datasets and Algorithms

Objective The purpose of this study was to identify potential therapeutic targets by examining the hub genes contributing to progression of intracranial aneurysm (IA) in patients with hypertension. Methods The bulk RNA sequencing (RNA-seq) datasets of hypertension and IA were obtained from the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo) database. These data were then used to calculate disease-related differentially expressed genes (DEGs) at the individual level. An scRNA-seq dataset of patients with abdominal aortic aneurysms (AAA) was used to analyze monocyte/macrophage-related DEGs. On the basis of the DEG data related to monocytes and macrophages, a TF-genes network has been developed. Hub genes and core sub-networks have also been identified. Furthermore, the key genes have been validated in an external cohort. Results From combined monocyte and macrophage-derived DEGs from abdominal aortic aneurysms, five hub DEGs were detected, including IFI30, SERPINE1, HMOX1, IL24, and RUNX1. A total of 57 genes were found in the IA bulk RNA-seq dataset. A support vector machine-recursive feature elimination algorithm (SVM-RFE) was applied to further screen the seven genes (RPS4Y1, DDX3Y, RUNX1, CLEC10A, PLAC8, SLA, and LILRB3). RUNX1 was the hub gene that regulated NFKB1 in the monocyte/macrophage-related network. And RUNX1 is implicated in IA progression by regulating hematopoietic stem cell differentiation and abnormal platelet production, according to gene set enrichment analysis. Conclusion Among patients with hypertension, RUNX1 in monocytes and macrophages was associated with a higher risk of IA through its regulation of NFKB1.
Commentary: Raw and Cooked Vegetable Consumption and Risk of Cardiovascular Disease: A Study of 400,000 Adults in UK Biobank

The purpose of this commentary is to offer a constructive critique on one of the principal findings of this important and interesting study. As described, the objective of the study is to learn more about the independent effects of raw and cooked vegetable consumption on cardiovascular disease (CVD) (1). Associations between vegetable intake and two primary outcomes, namely CVD incidence and CVDmortality, are modeled, and the key quantities of interest are adjusted hazard ratios (HR). The claim is made that cooked vegetable intake and raw vegetable intake showed different associations with both cardiovascular outcomes. In the Discussion section (1), Feng et al. write “When assessing the independent effect of raw and cooked vegetable intake, only raw vegetable intake showed inverse associations with CVD outcomes, whereas cooked vegetables showed no association. ” The problem with this claim is that, in the case of one of the two primary outcomes, CVDmortality, the evidence does not seem to support such a conclusion.