Biology subjects

Schneider, P.

Publications and source records attributed to Schneider, P..

At least 19 recordsLinked to original sources

bioRxiv2026

A conserved enhancer cluster regulates efnb2 expression in the vertebrate dorsal retina

The vertebrate retina is patterned along its dorsal-ventral (DV) axis by conserved signaling centers, yet the cis-regulatory architecture maintaining these territories remains unclear. Using the four-eyed fish Anableps anableps, which enables physical separation of dorsal and ventral retina, we integrated RNA-seq, ATAC-seq and Hi-C to map DV regulatory landscapes. We identify a 29-kb dorsal-enriched enhancer cluster within a gene poor region between efnb2a and gtpbp8, embedded in a conserved topologically associating domain spanning efnb2a-gtpbp8-slc10a2. Dorsal-biased chromatin contacts link this cluster to the efnb2a promoter. The orthologous human region contains a genome-wide significant association with retinal thickness (rs2575134; P = 2e-14). Leveraging the compact genome of Tetraodon nigroviridis, we cloned the orthologous interval and show that it drives dorsal retina-specific reporter expression in zebrafish and mouse. Together, these results identify an evolutionarily conserved regulatory domain controlling retinal axial identity and linking enhancer architecture to human ocular variation. Funding, National Science Foundation.

evolutionary biology↗

bioRxiv2025

Malaria parasites adjust liver stage development to synchronise the blood stage of infection with host daily rhythms.

Synchronised multiplication of Plasmodium parasites within red blood cells causes periodic malaria fevers. Aligning blood-stage development with the vertebrate hosts feeding-fasting rhythm facilitates within-host survival and between-host transmission. We use the rodent model Plasmodium chabaudi to test when, following development in the liver, the blood stage of infection begins. We find egress from the liver into the blood is aligned with the time of day of rhythmic host feeding, but only in wild type hosts, with egress occurring after a fixed period of pre-erythrocytic development in hosts without a functional canonical clock. However, perturbing the duration over which parasites enter the bloodstream does not affect their multiplication rate in the first few IDCs, suggesting fitness benefits from timing egress anticipates rhythmic challenges or opportunities later in the infection.

microbiology↗

bioRxiv2025

Evolutionary remodeling of the ventral retina enables aerial vision in the four-eyed fish Anableps anableps

The emergence of evolutionary novelties remains a central challenge in biology, particularly for complex organs such as the vertebrate eye. While visual systems have repeatedly undergone degeneration or loss, examples of innovation are rare and poorly understood. Mechanistic insight into such gains requires tractable systems in which novel visual functions have evolved. Here we leverage the four-eyed fish Anableps anableps to uncover the cellular and molecular basis of adaptation to simultaneous aerial and aquatic light. Combining single-nucleus and spatial transcriptomics, we show that the Anableps ventral retina has been developmentally and functionally reconfigured for aerial vision. In fully aquatic teleosts such as zebrafish, ventral photoreceptors are tuned to red-shifted, downwelling light. In contrast, we show that Anableps exhibits an expanded and diversified ventral cone population encompassing ultraviolet-, blue-, green-, and red-sensitive types, enabling broad-spectrum, high-intensity vision from above water. To estimate Anableps opsin spectral properties, we employed OPTICS, a machine-learning model of opsin spectral tuning, which predicts that the ventrally expressed opn1mw2 opsin is red-shifted relative to typical green-sensitive pigments. Analysis of dorsal-ventral patterning markers reveals an overrepresentation of ventral retinal cell types. Consistent with this, comparative spatial transcriptomic profiling of developing and adult Anableps and the killifish (Fundulus heteroclitus) indicates a dorsal displacement of the dorsal-ventral boundary in Anableps, resulting in a proportionally larger ventral retinal domain. Collectively, our results reveal that Anableps achieved its unique dual visual capacity by developmentally expanding and functionally reprogramming the ventral retina for aerial light detection, an evolutionary innovation that redefines how retinal domains can adapt to radically different visual environments.

evolutionary biology↗

bioRxiv2025

BCMA signaling from the Golgi apparatus in B cells

B-cell maturation antigen (BCMA) targeting gained a rapid approval for multiple myeloma, and is currently investigated in B-cell lymphomas. Here, we report that the trans Golgi network (TGN) retained BCMA due to a motif in its transmembrane/cytoplasmic domain in diffuse large B-cell lymphomas (DLBCL). To achieve signaling, one of its ligands, a proliferation inducing ligand (APRIL), bound to surface heparan sulfate proteoglycans (HSPGs), got endocytosed by the calveolin pathway and trafficked to the TGN via the retrograde route. In the TGN, APRIL/BCMA interactions activated the NF-{kappa}B pathway. BCMA ubiquitination followed by proteosomal degradation mediated signal termination. Growth impairment of DLBCL xenografts in APRIL-deficient animals confirmed the in vivo activity of TGN BCMA. Our study constitutes the first description for a signal activity from the Golgi apparatus among the TNF receptor family.

cell biology↗

bioRxiv2024

Human adipose-derived mesenchymal stromal cells improved wound healing in enterocutaneous fistulizing disease mouse model

A significant complication of Crohns disease is the formation of perianal fistulas. While local application of human adipose tissue-derived mesenchymal stromal cells (AT-MSC INN Darvadstrocel, Takeda) is an approved therapy for this condition, challenges in studying human clinical tissue and the absence of a robust experimental model have hindered deeper understanding of the preclinical efficacy and mechanisms behind the therapy. We have developed a model that closely mimics the clinical scenario, using human gut tissue transplanted subcutaneously into SCID mice. In this model, enterocutaneous fistulas are reliably induced by combining imiquimod-induced psoriatic dermatitis above the transplant with systemic lipopolysaccharide (LPS), a major component of the bacterial cell wall. Similar to clinical observations, local application of AT-MSC significantly improved fistula wound healing and re-epithelialization. This model system enabled comprehensive tissue harvesting for histopathological analysis, spatial transcriptomics, and protein profiling. Our findings demonstrate that AT-MSC applied around the fistula wound survive for up to three weeks, migrating into the fistula tract and further into the inflamed human gut tissue. Within the fistula tract, AT-MSCs acquired immune-active properties, with increased expression of SOD2 and CCL2, and were associated with a substantial population of M2 macrophages. In contrast, AT-MSC located in healthy tissue near the fistula remained stationary, adopting a fibroblast-like phenotype within a collagen-rich extracellular matrix. These preclinical results support the safety and efficacy of AT-MSC for treating fistulizing gut disease. Furthermore, our data suggest that the inflamed fistula tract acts as a scaffold promoting AT-MSC activity and migration. Enhancing SOD2 and CCL2 expression through pre-activation or genetic modification may further improve the therapeutic potential of these cells.

pathology↗

bioRxiv2024

A bioactive soluble recombinant mouse LIGHT promotes effective tumor immune cell infiltration delaying tumor growth

The TNF family member LIGHT (TNFSF14) binds to two receptors, HVEM (TNFSFR14) and LT{beta}R (TNFSFR3). HVEM functions as a costimulatory molecule, whereas LT{beta}R is involved in the development of lymph nodes and ectopic tertiary lymphoid structures at chronic inflammation sites. The classical approach of fusing soluble recombinant proteins to the Fc fragment of IgG resulted in a functionally inactive Ig.mouse (m) LIGHT protein. However, in line with the fact that TNF family members cluster receptors as trimers, addition of a small homotrimeric domain (foldon) N-terminal of mLIGHT produced an active Ig.Foldon-mLIGHT protein able to bind and engage HVEM and LT{beta}R in a reporter cell-based bioassay. In the tumor model of B16.F10 melanoma cells implanted into syngeneic recipients, cells transduced with membrane-bound mLIGHT grew as aggressively as mock-transduced cells, but growth of tumors of B16.F10 cells expressing Ig.Foldon-mLIGHT was delayed and characterized by significant immune cell infiltration. This work unveils the potential of active soluble LIGHT, as a single agent, to recruit cytotoxic cells and dendritic cells at the tumor site to inhibit tumor growth. This effect may be further enhanced with immune checkpoint blockade therapies.

immunology↗

bioRxiv2024

Ancestral versus Modern Substrate Scope in Family-1 Glycosidases

Experimental studies support that protein engineering based on ancestral sequence reconstruction often leads to variants with biotechnologically useful biomolecular properties. These may include high stability, enhanced conformational flexibility and a modified catalysis range. Carbohydrate-active enzymes have numerous applications related with the degradation and synthesis of carbohydrates and glycoconjugates. Here, we explore how ancestral reconstruction may impact substrate scope in glycosidases, highly diverse enzymes that catalyze the hydrolysis of glycosidic bonds in all living cells and find applications as catalysts of the reverse reaction. To this end, we screen a library of [~]500 potential glycosidase substrates for degradation by both, a modern family-1 glycosidase from Halothermothrix orenii and a putative ancestral family-1 glycosidase derived from sequence reconstruction at a bacterial-eukaryotic common ancestor. The modern enzyme is the better catalyst for most substrates. But the ancestral glycosidase is more efficient with flavonoid glycosides bearing large aglycon moieties. Analysis of the catalytic parameters for a selected set of substrates, alongside analysis of the library data using a supervised learning algorithm, support the hypothesis that the modern enzyme tends to become less catalytically efficient with increasing substrate size, while this trend is not observed for the ancestral glycosidase. Molecular simulations support that the ancestral catalysis pattern is linked to the existence of a highly flexible region of the ancestral structure and a cavity capable of accommodating large aglycons. Our results provide guidelines for the engineering of enzymes for the synthesis and hydrolysis of large glycoconjugates.

biochemistry↗

bioRxiv2023

Testing a non-destructive assay to track Plasmodium sporozoites in mosquitoes over time

BackgroundThe extrinsic incubation period (EIP), defined as the time it takes for malaria parasites in a mosquito to become infectious to a vertebrate host, is one of the most influential parameters for malaria transmission but remains poorly understood. The EIP is usually estimated by quantifying salivary gland sporozoites in subsets of mosquitoes, which requires terminal sampling. However, assays that allow repeated sampling of individual mosquitoes over time could provide better resolution of the EIP. MethodsWe tested a non-destructive assay to quantify sporozoites of two rodent malaria species, Plasmodium chabaudi and Plasmodium berghei, expelled throughout 24hr windows, from sugar-feeding substrates using quantitative PCR. ResultsThe assay can quantify sporozoites from sugar-feeding substrates, but the prevalence of parasite positive substrates is low. Multiple methods to increase the detection of expelled parasites (running additional technical replicates; using groups rather than individual mosquitoes) did not increase the detection rate, suggesting that expulsion of sporozoites is variable and infrequent. ConclusionsWe reveal successful detection of expelled sporozoites from sugar-feeding substrates. However, investigations of the biological causes underlying the low detection rate of sporozoites (e.g. mosquito feeding behaviour, frequency of sporozoite expulsion, or sporozoite clumping) are needed to maximise the utility of using non-destructive assays to quantify sporozoite dynamics. Increasing detection rates will facilitate the detailed investigation on infection dynamics within mosquitoes, which is necessary to explain Plasmodiums highly variable EIP and improve understanding of malaria transmission dynamics.

microbiology↗

bioRxiv2023

Virulence is associated with daily rhythms in the within-host replication of the malaria parasite Plasmodium chabaudi

Asexually replicating stages of most malaria (Plasmodium spp.) parasite species replicate synchronously within the red blood cells of their vertebrate host. Rhythmicity in this intraerythrocytic developmental cycle (IDC) enables parasites to maximise exploitation of the host and align transmission activities with the time of day that mosquito vectors blood feed. The IDC is also responsible for the major pathologies associated with malaria, and plasticity in the parasites rhythm can confer tolerance to antimalarial drugs. Both the severity of infection (virulence) and synchrony of the IDC vary across species and between genotypes of Plasmodium, yet this variation is poorly understood. Theory predicts that virulence and IDC synchrony are negatively correlated and we tested this hypothesis using two closely related genotypes of the rodent malaria model Plasmodium chabaudi that differ markedly in virulence. We also test the predictions that in response to perturbations to the timing (phase) of the IDC schedule relative to the phase of host rhythms (misalignment), the virulent parasite genotype recovers the correct phase relationship faster, incurs less fitness loss, and so, hosts benefit less from misalignment of the virulent genotype. Our predictions are partially supported; the virulent parasite genotype was less synchronous in some circumstances and recovered faster from misalignment. While hosts were less anaemic when infected by misaligned parasites, the extent of this benefit did not depend on parasite virulence. Overall, our results suggest that interventions to perturb the alignment between the IDC schedule and host rhythms, and increase synchrony between parasites within each IDC, could alleviate disease symptoms. However, virulent parasites, which are better at withstanding conventional antimalarial treatment, would also be intrinsically better able to tolerate such interventions.

evolutionary biology↗

bioRxiv2023

Regional assessment of male murine bone exposes spatial heterogeneity in osteocyte lacunar volume associated with intracortical canals and regulation by VEGF

The porous bone cortex comprises an interconnected network of intracortical vascular canals and osteocyte lacunae, embedded within the bone mineral. Increases in cortical porosity reduce bone strength and increase fracture risk. To date, our understanding of mechanisms coupling the arrangements of the vascular: lacunar network in the bone cortex is poorly understood yet it could be key in establishing regulation of cortical porosity evident with age. Using synchrotron radiation-based computed tomography we develop automated tools to characterise the 3D spatial organisation and morphology of osteocyte lacunae, and the bone vasculature at the tibiofibular junction (TFJ), defining posterior, medial, lateral, and anterior regions in male C57BL/6 mice (n = 3). We also investigate the role of osteoblast-derived VEGF in regulating the 3D spatial arrangement by conditional disruption of VEGF in osteocalcin-expressing cells (OcnVEGFKO versus WT, n = 3). Regional lacunar phenotypes were assessed by 3D distance mapping of lacunar organisation surrounding the vascular compartments, including endosteal and periosteal surfaces, or intracortical canals. Surface-associated lacunae were indistinct in size across posterior, medial, lateral and anterior regions. However, lacunae associated with intracortical canals were significantly larger exclusively within the posterior region. In the absence of VEGF, the increased lacunar volume associated with posterior intracortical canals was lost. Our results suggest that the influence of intracortical canals on lacunar volumes is spatially regulated and sensitive to locally produced growth factors such as osteoblast-derived VEGF.

bioengineering↗

bioRxiv2021

A Discriminative Characterization of Heschl's Gyrus Morphology using Spectral Graph Features

Heschls Gyrus (HG), which hosts the primary auditory cortex, exhibits large variability not only in size but also in its gyrification patterns, within (i.e., between hemispheres) and between individuals. Conventional structural measures such as volume, surface area and thickness do not capture the full morphological complexity of HG, in particular, with regards to its shape. We present a method for characterizing the morphology of HG in terms of Laplacian eigenmodes of surface-based and volume-based graph representations of its structure, and derive a set of spectral graph features that can be used to discriminate HG subtypes. We applied this method to a dataset of 177 adults previously shown to display considerable variability in the shape of their HG, including data from amateur and professional musicians, as well as non-musicians. Results show the superiority of the proposed spectral graph features over conventional ones in differentiating HG subtypes, in particular, single HG versus Common Stem Duplications (CSDs). We anticipate the proposed shape features to be found beneficial in the domains of language, music and associated pathologies, in which variability of HG morphology has previously been established.

neuroscience↗

bioRxiv2021

Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome

BackgroundComplex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. MethodsTo identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed: i) whole-exome sequencing of 87 HLHS parent-offspring trios, ii) nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, iii) single cell RNA sequencing and iv) 3D modeling in iPSCs from 3 patients with HLHS and 3 controls. ResultsGene set enrichment and protein network analyses of damaging de-novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell-cycle and cardiomyocyte maturation. Single-cell and 3D modeling with iPSCs demonstrated intrinsic defects in the cell-cycle/UPR/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte-subtype differentiation/maturation in HLHS. Additionally, premature cell-cycle exit of ventricular cardiomyocytes from HLHS patients prevented normal tissue responses to developmental signals for growth leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. ConclusionsOur results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

developmental biology↗

bioRxiv2021

A robust, semi-automated approach for counting cementum increments imaged with X-ray computed tomography

Cementum, the tissue attaching mammal tooth roots to the periodontal ligament, grows appositionally throughout life, displaying a series of circum-annual incremental features. These have been studied for decades as a direct record of chronological lifespan. The majority of previous studies on cementum have used traditional thin-section histological methods to image and analyse increments. However, several caveats have been raised in terms of studying cementum increments in thin-sections. Firstly, the limited number of thin-sections and the two-dimensional perspective they impart provide an incomplete interpretation of cementum structure, and studies often struggle or fail to overcome complications in increment patterns that complicate or inhibit increment counting. Increments have been repeatedly shown to both split and coalesce, creating accessory increments that can bias increment counts. Secondly, identification and counting of cementum increments using human vision is subjective, and it has led to inaccurate readings in several experiments studying individuals of known age. Here, we have attempted to optimise a recently introduced imaging modality for cementum imaging; X-ray propagation-based phase-contrast imaging (PPCI). X-ray PPCI was performed for a sample of rhesus macaque (Macaca mulatta) lower first molars (n=10) from a laboratory population of known age. A new method for semi-automatic incrementcounting was then integrated into a purpose-built software package for studying cementum increments. Comparison with data from conventional cementochronology, based on histological examination of tissue sections, confirmed that X-ray PPCI reliably records cementum increments. Validation of the increment counting algorithm suggests that it is robust and provides accurate estimates of increment counts. In summary, we show that our new increment counting method has the potential to overcome caveats of conventional cementochronology approaches, when used to analyse 3D images provided by X-ray PPCI.

ecology↗

bioRxiv2019

The hair cycle underlies regulation of Langerhans cell renewal.

In the epidermis, Langerhans cells (LCs) provide an essential link between the innate and adaptive immune systems. They self-renew in situ and continuously transport antigen from skin to lymph node (LN) T cells in the steady state. The cyclic renewal of hair follicles (HF) causes profound alterations in the cutaneous microenvironment, however little is known about its impact on LC homeostasis. Here we show that mouse LCs developed normally in the absence of hair but perceived critical transition periods in the hair cycle. LCs underwent a proliferation burst during the HF growth phase (anagen). Reinitiation or abolishment of anagen as well as loss of the HF had direct consequences on LC self-renewal. Because dividing LCs were found close to the anagen HF, we searched for the proliferative signal within this structure and identified increased Il34 expression by HF stem cells and their progeny. Inhibition of the IL-34 receptor CSF-1R at the onset of anagen completely and specifically blocked LC proliferation. Altogether, our findings demonstrate that the hair cycle directly oversees LC self-renewal and migration.

immunology↗

bioRxiv2019

Reptile-like physiology in Early Jurassic stem-mammals

There is uncertainty regarding the timing and fossil species in which mammalian endothermy arose, with few studies of stem-mammals on key aspects of endothermy such as basal or maximum metabolic rates, or placing them in the context of living vertebrate metabolic ranges. Synchrotron X-ray imaging of incremental tooth cementum shows two Early Jurassic stem-mammals, Morganucodon and Kuehneotherium, had lifespans (a basal metabolic rate proxy) considerably longer than comparably sized living mammals, but similar to reptiles, and that Morganucodon had femoral blood flow rates (a maximum metabolic rate proxy) intermediate between living mammals and reptiles. This shows maximum metabolic rates increased evolutionarily before basal rates, and that contrary to previous suggestions of a Triassic origin, Early Jurassic stem-mammals lacked the endothermic metabolism of living mammals.One Sentence Summary Surprisingly long lifespans and low femoral blood flow suggest reptile-like physiology in key Early Jurassic stem-mammals.View Full Text

paleontology↗

bioRxiv2018

Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning

The generation of patterns during development is generally viewed as a direct process. In the mouse jaw, however, the sequential patterning of molars initiates with abortive tooth signaling centers called MS and R2, thought to be vestiges of the lost rodent premolars. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that Edar expression reveals the hidden dynamics of signalling centers patterning. First, Edar expression evidenced a hidden two-step patterning process that we modelled with a single activator-inhibitor pair: the epithelium is initially broadly activated, then activation becomes restricted in space to give rise to the signalling centers. Second, Edar expression unveils successive phases of pattern making and pattern erasing events, a phenomenon that we called a developmental palimpsest. MS is erased by a broad activation for the benefit of R2, which itself is erased before it recovers when the first molar signaling center forms. In the lower but not the upper jaw, the two neighboring signaling centers then fuse into a single elongated center. Our model recapitulated the erasure of the R2 signaling center by the wave of activation that precedes the formation of M1 signaling center, and predicted the surprising rescue of R2 in the context of an Edar mutant with reduced activation. It suggested that R2 was not intrinsically defective, but actively outcompeted by M1 formation. We confirmed this by cultivating R2 separately from the posterior tissue and showing it could then generate a tooth. Finally, by introducing chemotaxis as a secondary process of tooth germ maturation, we recapitulated the fusion of R2 and M1 in the lower jaw only, and the loss of fusion when Edar function is impaired in organ cultures. In conclusion, we have uncovered a highly indirect and dynamic nature of pattern formation in the molar field that could nevertheless be simulated with simple mathematical models. Our study argues for viewing embryonic patterns as dynamical objects rather than as fixed endpoints, where dynamics is essential to the outcome of the patterning process.

developmental biology↗

bioRxiv2018

Using digital epidemiology methods to monitor influenza-like illness in the Netherlands in real-time: the 2017-2018 season

IntroductionDespite the early development of Google Flu Trends in 2009, digital epidemiology methods have not been adopted widely, with most research focusing on the USA. In this article we demonstrate the prediction of real-time trends in influenza-like illness (ILI) in the Netherlands using search engine query data.\n\nMethodsWe used flu-related search query data from Google Trends in combination with traditional surveillance data from 40 general sentinel practices to build our predictive models. We introduced an artificial 4-week delay in the use of GP data in the models, in order to test the predictive performance of the search engine data.\n\nSimulating the weekly use of a prediction model across the 2017/2018 flu season we used lasso regression to fit 52 prediction models (one for each week) for weekly ILI incidence. We used rolling forecast cross-validation for lambda optimization in each model, minimizing the maximum absolute error.\n\nResultsThe models accurately predicted the number of ILI cases during the 2017/18 ILI epidemic in real time with a mean absolute error of 1.40 (per 10,000 population) and a maximum absolute error of 6.36. The model would also have identified the onset, peak, and end of the epidemic with reasonable accuracy\n\nThe number of predictors that were retained in the prediction models was small, ranging from 3 to 5, with a single keyword ( Griep = Flu) having by far the most weight in all models.\n\nDiscussionThis study demonstrates the feasibility of accurate real-time ILI incidence predictions in the Netherlands using internet search query data. Digital ILI monitoring strategies may be useful in countries with poor surveillance systems, or for monitoring emergent diseases, including influenza pandemics. We hope that this transparent and accessible case study inspires and supports further developments in field of digital epidemiology in Europe and beyond.

epidemiology↗

bioRxiv2018

Marker-based watershed transform method for fully automatic mandibular segmentation from low-dose CBCT images

Introduction Introduction Methods and materials Results Discussion Conclusions Funding References Three-dimensional mandibular models are useful for planning maxillofacial surgery and orthodontic treatment.1,2 In studies of growth, mandibular models are important for assessing morphological changes over time.3,4 Such models are typically obtained from conventional computed tomography (CT), using high radiation dose to capture fine detail of the bony structure. Cone beam computed tomography (CBCT) shows promise for oral and craniofacial imaging applications due to lower radiation dose, lower cost and shorter acquisition time compared to CT. However, CBCT images have lower contrast and higher levels of ...

bioinformatics↗