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Results for “cell biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 163 records · Page 9Linked to original sources

bioRxiv2025

Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties in vitro and in vivo

The atrioventricular node (AVN) ensures synchronized heart contractions by establishing the electrical connection between the atria and ventricles. Dysfunction of the pacemaker cells of the AVN leads to atrioventricular block (AV block), a life-threatening condition managed with electronic pacemakers (EPMs). EPMs have drawbacks that could be overcome by a human pluripotent stem cell (hPSC)-derived biological conduction bridge (BioCB). Recent studies demonstrated the differentiation of AVN-like cells from hPSCs, but their conduction properties upon engraftment in vivo remain unexplored. Here we report the generation of AVN-like pacemaker cells (AVNLPCs) from hPSCs using WNT and BMP signaling modulation. These AVNLPCs transcriptionally resemble fetal AVN pacemaker cells, exhibit pacemaker action potentials, and display unique AVN-like conduction properties. Notably, when transplanted into the guinea pig heart, AVNLPCs replicate the functional properties of the AVN. Our study highlights the potential of an AVNLPC-based BioCB as novel cell therapy to improve treatment for AV block patients.

developmental biology↗

bioRxiv2024

Prevalence and environmental abundance of the elusive membrane trafficking complex TSET in five cosmopolitan eukaryotic groups

Eukaryotic cell biology is largely understood from paradigms established on few model organisms, largely from the animal and fungi (opisthokonts) and to a lesser extent plants. These organisms, however, constitute only a small proportion of eukaryotic diversity, and the principles of their cell biology may not be universal to other, understudied but globally impactful, organisms. Intriguingly, there are cellular components that are present in diverse eukaryotes, but are not in the animals and fungi on which the best developed models of cell biology are derived. Consequently, these components are not included in the generally adopted frameworks of cellular function that are meant to explain eukaryotic biology. The membrane complex TSET is the best studied such example, well established to play a role in cell division and endocytosis in plants. It is found across eukaryotes, but is highly reduced in opisthokonts. Its general prevalence, abundance, and relevance in eukaryotic cellular activity is unclear. Here we show that TSET is encoded in genomes of five cosmopolitan and critical groups of primarily photosynthetic eukaryotes (green algae, red algae, stramenopiles, haptophytes and cryptophytes), with particular prevalence in the green algae and some stramenopile groups. A meta-analysis of published gene expression data from the model diatom Phaeodactylum tricornutum shows that this complex is coregulated with components of the endomembrane trafficking machinery. Moreover, meta-transcriptomic data from Tara Oceans reveals that TSET genes are both present and expressed by diatoms in the wild. These data suggest that TSET may be playing an important and underrecognized role in cellular activities within marine ecosystems. More broadly, the results support the idea that use of systems-level data for non-model organisms can illuminate our understanding of core principles of eukaryotic cell function, and may reveal important and under-appreciated players that deserve to be integrated into the pervasive models of cellular capacity.

microbiology↗

bioRxiv2026

Sterilization and material compatibility of 3D-printed devices for cell culture

Three-dimensional (3D) printing is increasingly used in cell biology to prototype custom cell culture devices, microscopy chambers, and other experimental hardware, but practical guidance on sterilization and material compatibility remains limited. Here, we develop and validate a low-temperature paraformaldehyde vapor sterilization method for fused filament fabrication (FFF) components that avoids heat-induced deformation. Using bacterial challenge assays with Escherichia coli and Geobacillus stearothermophilus, we confirm effective sterilization of 3D printed components. We also assess the effects of common filaments and adhesives on HL-60 human cell growth to identify materials suitable for cell culture workflows. Most untreated plastics were well tolerated over 48 hours, whereas some formaldehyde-treated materials required post-treatment with ammonia vapor to restore compatibility. Together, these results provide a practical framework for sterilizing and deploying 3D-printed materials in cell culture and biological research. Multidisciplinary Abstract3D printers allow laboratories to quickly make custom experimental equipment, but many printed materials cannot be sterilized using standard methods. We developed a low-temperature sterilization procedure using paraformaldehyde vapor and tested whether common printing materials and adhesives are compatible with cultured human cells. We identified several plastics, silicone-based adhesives and acrylic tapes that can be safely used after sterilization, while others require additional ammonia treatment. These results provide guidance for researchers using 3D printing to build custom laboratory and cell culture devices. Methods SummaryA low-temperature paraformaldehyde vapor sterilization method for 3D-printed FFF components was developed and validated using bacterial challenge assays. Compatibility of common printing filaments, adhesives, and tapes with cell culture workflows was assessed by exposing HL-60 cells to untreated, sterilized, and ammonia- neutralized materials and quantifying cell growth by flow cytometry.

cell biology↗

bioRxiv2025

A temperature sensitive mutant screen reveals translational stress-induced cell cycle regulation in a thermophilic archaeon

The homology of the archaeal and eukaryotic ribosome provides one of the key pieces of evidence that underpins the idea that eukaryotes acquired their core information processing machinery from archaea. Since this discovery, reverse genetics has been used to study the functions of many archaeal proteins with eukaryotic homologues. Yet, our general understanding of archaeal growth and division remains unclear, in part because of difficulties of carrying out unbiased genetic screens in archaea. Here, by overcoming several technical hurdles we have used a screen of temperature sensitive mutants in Sulfolobus acidocaldarius to identify core regulators of cell growth and division. First, flow cytometry was used to define DNA content, identifying a set of mutants defective in cell cycle progression at elevated growth temperatures. Using genome sequencing and plasmid rescue, we then identified a point mutation in the large ribosomal subunit that inhibits translation and prevents entry into division following a shift to the restrictive temperature. This study reveals a link between translation and cell cycle control, and opens up the future possibility of using forward genetic screens in archaea to further our understanding of the similarities and differences in the cell biology of archaea, bacteria and eukaryotes. Significance statementO_LICurrent knowledge of archaeal cell biology is limited by the lack of forward genetics. C_LIO_LIWhole genome sequencing and plasmid rescue identifies causative mutation in a temperature sensitive mutant strain. C_LIO_LIA mutation in a ribosomal subunit blocks translation to prevent entry into division. C_LI

cell biology↗

bioRxiv2021

Label-free three-dimensional analyses of live cells with deep-learning-based segmentation exploiting refractive index distributions

Visualisations and analyses of cellular and subcellular organelles in biological cells is crucial for the study of cell biology. However, existing imaging methods require the use of exogenous labelling agents, which prevents the long-time assessments of live cells in their native states. Here we propose and experimentally demonstrate three-dimensional segmentation of subcellular organelles in unlabelled live cells, exploiting a 3D U-Net-based architecture. We present the high-precision three-dimensional segmentation of cell membrane, nucleus membrane, nucleoli, and lipid droplets of various cell types. Time-lapse analyses of dynamics of activated immune cells are also analysed using label-free segmentation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/445351v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@b92093org.highwire.dtl.DTLVardef@9caa8org.highwire.dtl.DTLVardef@d81408org.highwire.dtl.DTLVardef@b3c87_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

A green fluorescent protein for live imaging in hyperthermophiles

Hyperthermophiles, organisms that thrive at temperatures above 60 {degrees}C, have played important roles in biotechnology and promise to reveal new biology. However, how these cells live remains poorly understood in part due to the lack of bright, thermostable fluorescent proteins that can be used to study protein localisation and dynamics at high temperatures. To overcome this challenge, here we describe the development of "Matcha", a green fluorescent protein that we have engineered from Thermal Green Protein by directed evolution in the thermophilic archaeon Sulfolobus acidocaldarius. The screen identified 7 mutations that when combined led to an [~]50-fold increase in the brightness of Matcha in vivo at physiological temperatures. Since this is sufficient for live cell imaging, we were then able to use Matcha-fusion proteins to study the division ring dynamics in Sulfolobus. Remarkably, this analysis reveals that, while ESCRT-III rings are disassembled as cells complete division, CdvA forms a stable polymeric ring that persists, and is asymmetrically inherited by one of the two daughter cells following cytokinesis. This study highlights the power of Matcha as a tool to shed light on our understanding of the cell biology of hyperthermophiles.

cell biology↗

bioRxiv2024

Expressive modeling and fast simulation for dynamic compartments

Compartmentalization is vital for cell biological processes. The field of rule-based stochastic simulation has acknowledged this, and many tools and methods have capabilities for compartmentalization. However, mostly, this is limited to a static compartmental hierarchy and does not integrate compartmental changes. Integrating compartmental dynamics is challenging for the design of the modeling language and the simulation engine. The language should support a concise yet flexible modeling of compartmental dynamics. Our work is based on ML-Rules, a rule-based language for multi-level cell biological modeling that supports a wide variety of compartmental dynamics, whose syntax we slightly adapt. To develop an efficient simulation engine for compartmental dynamics, we combine specific data structures and new and existing algorithms and implement them in the Rust programming language. We evaluate the concept and implementation using two case studies from existing cell-biological models. The execution of these models outperforms previous simulations of ML-Rules by two orders of magnitude. Finally, we present a prototype of a WebAssembly-based implementation to allow for a low barrier of entry when exploring the language and associated models without the need for local installation. Author summaryBiochemical dynamics are constrained by and influence the dynamics of cellular compartments. Basic constraints are considered by many modeling and simulation tools, e.g., certain reactions may only occur in specific cellular compartments and at a speed influenced by the compartmental volume. However, to capture the functioning of complex compartmental dynamics such as cell proliferation or the fission or fusion of mitochondria, additional efforts are required from tool designers. These refer to how the modeler can specify these dynamics succinctly and unambiguously and how the resulting model can be executed efficiently. For modeling, we rely on ML-Rules, an expressive, formal rule-based language for modeling biochemical systems, which ships with the required features and which we only slightly adapt in our re-implementation. We design a new simulation engine that combines efficient data structures and various algorithms for efficient simulation. The achieved efficiency will enable thorough analysis, calibration, and validation of compartmental dynamics and, thus, allow the "in-silico" pursuit of research questions for which compartmental dynamics are essential. To further facilitate exploring the interplay of compartmental and non-compartmental dynamics, we exploit recent advances in web technology so that ML-Rules models can be run efficiently in the web browser.

systems biology↗

bioRxiv2025

A heat method to interpolate z-stacked cell images that preserves interfaces without explicit identification of object boundaries

A multitude of methods have been developed to morph one image into another. In scientific and medical imaging, it is common to have lower resolution in one imaging direction. To improve the quality of surface meshes generated from these images, morphing is used to produce intermediate images to achieve equal resolution in all directions. The most common method is based on interpolating signed distance functions that describe the shapes of objects in the images. Most methods rely on identification and recording of object boundaries. The situation becomes more complex in the case of interpolating images containing multiple objects of interest wherein the morphing method must not introduce gaps or overlaps of objects in the intermediate images. The goal of the present work was to develop an interpolation method for biological cells in transmission electron microscopy images meeting the constraints listed above. A heat diffusion method was developed that produces steady state isotherms in a 3D model of the intervening space between two images. The isotherms are then used to produce paths from pixels that are unique to a biological cell in one frame towards the overlap region. Instead of identifying boundaries, only membership in the overlap region is tested. For each pixel that terminates paths, the path lengths of all members are normalized to the maximum path length. The path lengths are then used to produce intermediate frames. The method succeeds in avoiding the introduction of gaps or overlap between neighboring biological cells without the need for boundary identification.

bioengineering↗

bioRxiv2023

Mechanical Dissociation of Tissues for Single Cell Analysis Using a Simple Motorized Device

ABSTRACT/SUMMARYThe use of single cell analysis methods has grown rapidly in the last two decades and has led to rapid discoveries in cell biology and beyond. Single cell analysis requires complex systems like tissues to be dissociated, separating individual cells from extracellular tissue materials. This requires manual processing of tissues and materials through chopping, pipetting, and suspension with enzymes for degradation of the structural elements of the tissue. Manual processing can be time consuming and lead to variability between scientists. Automating this process through motorized dissociation could thus improve reproducibility of research and reduce time of cell manipulation prior to analysis. Here, we have designed a low-cost, customizable automatic tissue dissociator device that can be easily assembled by research groups for individual use. Our device allows for customizable programmed dissociation protocols for ease of use and reproducibility between researchers and can be placed into heat or cold environments based on the protocol need. We have found this device comparable in cell viability and reproducibility to manual dissociation, while significantly reducing time spent and even enhancing cells extracted from more fibrous tissues. Broad dissemination and use of this device could enhance single cell analysis reproducibility and provide a time-saving alternative to the currently used manual dissociation protocols.

cell biology↗

bioRxiv2023

Microtubule reorganization during mitotic cell division in the dinoflagellate Ostreospis cf. ovata

Dinoflagellates are marine organisms that undergo seasonal explosive proliferation events known as algal blooms. Vegetative cell proliferation is a main contributing factor in these events. However, mechanistical understanding of mitosis and cytokinesis in dinoflagellate remains rudimentary. Using an optimized immunofluorescence protocol, we analysed changes in microtubule organization occurring during the mitotic cycle of the toxic dinoflagellate Ostreopsis cf. ovata. This study revealed important features of dinoflagellate cell division. We find that the two flagella and the cortical microtubule array persist throughout the mitotic cycle. Two microtubule bundles are present in the cytoplasm originating from the ventral area, where the basal bodies are located: a cortical bundle and a cytoplasmic ventral bundle. The latter associates with the nucleus in the cell centre in preparation for mitosis and with the acentrosomal extranuclear spindle during mitosis. Analysis of tubulin post-translational modifications identifies two populations of spindle microtubules: polar acetylated microtubules whose length is stable throughout mitosis and central tyrosinated microtubules which elongate during chromosome segregation. During cell division a microtubule rich structure forms along the dorsal-ventral axis, associated with the site of cytokinesis, consistent with a cytokinetic mechanism independent of the actomyosin ring typical of animal and yeast cells. Summary statementOur study describes special features of mitosis and cytokinesis in dinoflagellates and uncovers a new alternative mechanism for cell division, highlighting the plasticity of cell biological process in eukaryotic cells.

cell biology↗

bioRxiv2024

Differential interference with actin-binding protein function by acute Cytochalasin B

Dynamic actin filament remodeling is crucial for a plethora of fundamental cell biological processes, ranging from cell division and migration to cell communication, intracellular trafficking or tissue development. Cytochalasin B and -D are fungal secondary metabolites frequently used for interference with such processes. Although generally assumed to block actin filament polymerization at their rapidly growing barbed ends and compete with regulators at these sites, our molecular understanding of their precise effects in dynamic actin structures is scarce. Here we combine live cell imaging and analysis of fluorescent actin-binding protein dynamics with acute treatment of lamellipodia in migrating cells with cytochalasin B. Our results show that in spite of an abrupt halt of lamellipodium protrusion, cytochalasin B affects various actin filament barbed end-binding proteins in a differential fashion. Cytochalasin B enhances instead of diminishes the accumulation of prominent barbed end-binding factors such as Ena/VASP family proteins and heterodimeric capping protein (CP) in the lamellipodium. Similar results were obtained with cytochalasin D. All these effects are highly specific, as cytochalasin-induced VASP accumulation requires the presence of CP, but not vice versa, and coincides with abrogation of both actin and VASP turnover. Cytochalasin B can also increase apparent barbed end interactions with the actin-binding {beta}-tentacle of CP and partially mimic its Arp2/3 complex-promoting activity in the lamellipodium. In conclusion, our results reveal a new spectrum of cytochalasin activities on barbed end-binding factors, with important implications for the interpretation of their effects on dynamic actin structures.

cell biology↗

bioRxiv2024

Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms

Proteins that transmit molecules and signals across the plasma membrane are crucial in cell biology because they enable cells to sense and respond to their surroundings. A major challenge for studying cell-surface proteins is that often they do not fold or traffic properly to the plasma membrane when produced in heterologous cells. We developed a strategy for quantifying surface localization from fluorescence microscopy images of surface-stained cells. Using clustered protocadherins, a protein family important for cell-cell recognition during neuronal development, we found that surface delivery levels vary among clustered protocadherin isoforms and between wildtype and engineered variants. Quantifying these differences provides evidence that cis dimerization is not tightly coupled to surface delivery for clustered protocadherins. This work establishes a generalizable framework for screening proteins and variants of interest for proper cell surface localization. SignificanceSurface proteins allow cells to interact with their environments, and their activities are often regulated by their delivery to and removal from the plasma membrane. We developed a strategy to quantitatively compare the surface delivery of proteins based on established epitope tag-based surface staining methods. Using natural and engineered variants of clustered protocadherins, cell-surface proteins essential for neuron development, we show that quantitative comparisons of surface trafficking levels facilitate the interpretation of mutational effects and can shed light on key regulatory mechanisms. We find that surface trafficking levels differ between variants and that, contrary to what was previously thought, a domain that inhibits surface delivery in some clustered protocadherins does so without directly relying on its protein-protein interface.

cell biology↗

bioRxiv2026

Single-Cell Proteo-Transcriptomic Profiling Uncovers Post-Translational Regulatory Layers in Human Hematopoiesis

Background: Hematopoietic stem cells (HSCs) have the unique ability to produce all mature cell types in the blood and understanding the mechanisms governing their differentiation and renewal is a driving question in stem cell biology. While single-cell RNA sequencing has transformed our view of human hematopoiesis, mRNA abundance represents an incomplete proxy for functional cell states. Here, we apply single-cell multimodal profiling to simultaneously measure 280 surface and intracellular protein targets alongside whole transcriptomes within individual adult human hematopoietic stem and progenitor cells. Results: By directly coupling modalities within single cells, we show that protein-RNA correlations peak dynamically in transitioning intermediate progenitors across lineages, consistent with pervasive post-transcriptional mechanics underlying lineage choice. Furthermore, key transcription factor proteins maintain multilineage co-expression longer into commitment than their transcripts, demarcating a possible window of fate decision reversibility. Moreover, low and flat CTNNB1 mRNA levels mask late-erythroid {beta}-catenin protein enrichment, apparently pairing with E-cadherin expression and suggesting post-translational stabilization at the cell membrane. Conclusions: This dataset enables the observation of translational dynamics and RNA-protein relationships throughout the differentiation landscape at an unprecedented level of granularity. Together, our findings demonstrate that transcriptomics alone misses fundamental regulatory programs, establishing single-cell proteo-transcriptomics as a powerful tool for decoding human stem cell fate.

cell biology↗

bioRxiv2024

The essential host genome for Cryptosporidium intracellular survival exposes metabolic dependencies that can be leveraged for treatment

Mapping how pathogens interact with their host cells can reveal unexpected pathogen and host cell biology, paving the way for new treatments. Cryptosporidium is an intracellular parasite of intestinal epithelial cells, and a leading cause of diarrheal death and disease in infants worldwide. Despite this, very little is known about the cell biology of infection of this eukaryotic pathogen. Here, we designed and implemented a unique microscopy-based arrayed CRISPR-Cas9 screen to interrogate the effects of the loss of every protein-coding human gene on a Cryptosporidium infection. As the experimental readout is image-based, we extracted multiple phenotypic features of infection, including parasite growth, progression of the parasite to its sexual life stage, and recruitment of host actin to pedestals beneath the parasite vacuole. Using this dataset, we discovered a tipping point in the host cholesterol biosynthesis pathway that controls Cryptosporidium infection. Parasite growth can either be inhibited or promoted by the intermediary metabolite squalene. A build-up of squalene in epithelial cells creates a reducing environment, with more reduced host glutathione available for uptake by the parasite. Because Cryptosporidium has lost the ability to synthesise glutathione, this uptake from the host cell is required for growth and progression through its life cycle. We demonstrate that this dependency can be leveraged for treatment with the abandoned drug lapaquistat, an inhibitor of host squalene synthase that has efficacy against Cryptosporidium in vitro and in vivo.

cell biology↗

bioRxiv2019

Dual-matrix 3D culture system as a biomimetic model of epithelial tissues

Recent years have seen an unprecedented rise in the use of 3D culture systems, both in fundamental research and in more translational settings such as drug testing and disease modeling. However, 3D cultures often remain underused by cell biology labs, both due to technical difficulties in system setup and inherent drawbacks of many of the common systems. Here we describe an easy to use, inexpensive and rapidly assembled 3D culture system, suitable for generation of both normal polarized epithelial cysts and in-situ tumor spheroids. This system allows for exploration of many questions of normal and cancer cell biology, including morphogenesis, epithelial polarization, cell motility, intra- and intercellular communication, invasion, metastasis, and tumor-stoma interaction. The 3D cultures are made up of a stiffness tunable, dual-matrix model that can incorporate co-culture of multiple cell types. The model allows for increased physiological relevance by mimicking the organization, ligand composition and stiffness present in-vivo. The setup allows for a wide spectrum of manipulation, including removing cells from the system for DNA/protein expression, transfection and high-resolution imaging of live or fixed cells.

cell biology↗

bioRxiv2026

Multiscale three-dimensional ultrastructural mapping of intestinal tissues and organoids

Understanding cell biology in native environments requires imaging of subcellular organization in three dimensions. In the intestinal epithelium, multiple cell types organize along the crypt-villus axis, where cell-cell interfaces and subcellular architecture control cell differentiation, tissue organization and epithelial function. Resolving these features volumetrically remains challenging: light microscopy offers molecular specificity but has limited resolution, whereas electron microscopy provides ultrastructural detail but is poorly suited to volumetric acquisition combined with specific protein labeling. Here, we show that expansion microscopy enables the multiscale volumetric study of epithelial ultrastructure in tissue sections and organoid models. Using an optimized workflow, we resolve epithelial tissue architecture, cell types and subcellular features within volumes across scales. Application to a microvillus inclusion disease (MVID) organoid model revealed disease-associated ultrastructural phenotypes that were only observed using electron microscopy. Our results establish expansion microscopy as key technology for studying three-dimensional cell biology within intestinal tissue and tissue mimics.

cell biology↗

bioRxiv2020

Macromolecular and biochemical changes of G0 fission yeast nuclei

When starved of nitrogen, fission yeast Schizosaccharomyces pombe cells enter a quiescent "G0" state with smaller nuclei and transcriptional repression. The genomics of S. pombe G0 cells has been well studied, but much of its nuclear cell biology remains unknown. Here we use confocal microscopy, immunoblots, and electron cryotomography to investigate the cytological, biochemical, and ultrastructural differences between S. pombe proliferating, G1-arrested, and G0 cell nuclei, with an emphasis on the histone acetylation, RNA polymerase II fates, and macromolecular complex packing. Compared to proliferating cells, G0 cells have lower levels of histone acetylation, nuclear RNA polymerase II, and active transcription. The G0 nucleus has similar macromolecular crowding yet fewer chromatin-associated multi-megadalton globular complexes. Induced histone hyperacetylation in G0 results in cells that have larger nuclei and therefore less compact chromatin. However, these histone-hyperacetylated G0 cells remain transcriptionally repressed with similar nuclear crowding. Canonical nucleosomes - those that resemble the crystal structure - are rare in proliferating, G1-arrested, and G0 cells. Our study therefore shows that extreme changes in nucleus physiology are possible without extreme reorganisation at the macromolecular level. SummaryWe use multiple cell-biological techniques to compare proliferating and quiescent G0 fission yeast cell nucleus transcription, histone acetylation, macromolecular packing.

cell biology↗

bioRxiv2019

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in multiple neurodegenerative diseases. Although the loss of normal TDP-43 functions likely contributes to disease pathogenesis, the cell biological consequences of human TDP-43 depletion are not well understood. We therefore generated human TDP-43 knockout cells and subjected them to parallel cell biological and transcriptomic analyses. These efforts yielded three important discoveries. First, complete loss of TDP-43 resulted in widespread morphological defects related to multiple organelles including: Golgi, endosomes, lysosomes, mitochondria and the nuclear envelope. Second, we identified a new role for TDP-43 in controlling mRNA splicing of Nup188 (nuclear pore protein). Third, analysis of multiple amyotrophic lateral sclerosis (ALS) causing TDP-43 mutations revealed a broad ability to support splicing of TDP-43 target genes. However, as some TDP-43 disease causing mutants failed to support the regulation of specific target transcripts, our results raise the possibility of mutation-specific loss-of-function contributions to disease pathology.

cell biology↗