Biology subjects

Hamidi, H.

Publications and source records attributed to Hamidi, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Toward Textile-Integrated Electrochemical Systems: A Flexible PCB Potentiostat for Wearable Glucose Monitoring

Flexible and textile-integrated electrochemical systems offer a convenient, user-friendly and non-invasive platform for continuous biochemical monitoring. In this study, a fully flexible and low-profile electrochemical system was developed by fabricating both the glucose biosensor and a compact potentiostat implemented on a polyimide (PI) filament circuit. The glucose biosensor was realized via direct laser writing (DLW), enabling precise electrode patterning and seamless integration with the potentiostat filament circuit. The integrated system exhibited a linear chronoamperometric response to glucose concentrations ranging from 0 to 0.25 mM in artificial sweat (AS). Further evaluation on cotton textiles soaked in AS and under mechanical bending confirmed stable performance, flexibility, and robustness. These findings highlight the potential of the PI-based potentiostat-sensor system for wearable, textile-integrated glucose monitoring and broader healthcare applications.

biochemistry↗

bioRxiv2026

Leupaxin inhibits the durotaxis and mechanosensitivity of metastatic breast cancer cells

Efficient cancer cell migration is essential for invasion and metastasis and is driven by cancer cell interaction with their extracellular matrix (ECM). Thus, ECM properties determine the migration phenotype. For example, ECM stiffness can guide cancer cell migration through durotaxis; however, the mechanisms regulating cancer cell durotaxis remain poorly understood. Using in-house stiffness gradient hydrogels, we discovered that MDA-MB-231 breast cancer cell metastatic variants selected for either bone or brain organotropism display impaired durotaxis. Moreover, akin to cells conditioned on soft substrates, these cells have altered mechanoresponses to increasing stiffness, including reduced cell spreading and focal adhesion assembly and signaling. We observed upregulation of the LIM-domain protein leupaxin, a focal adhesion component, in these variants and in soft-conditioned MDA-MB-231 cells compared to parental cells. Leupaxin silencing in brain-tropic metastatic cells restored durotaxis, whereas its overexpression in parental cells impaired durotaxis and mechanosensing, phenocopying the metastatic variants. Mechanistically, leupaxin disrupted paxillin-focal adhesion kinase (FAK) signaling, thereby inhibiting durotaxis. Together, these findings identify leupaxin as a negative regulator of durotaxis in metastatic cells and suggest a mechanism by which tumor cells adapt to mechanical heterogeneity to facilitate metastatic progression.

cell biology↗

bioRxiv2025

Highly Efficient Coreactant-Free Electrochemiluminescence Sensing Platform Using Novel Microfabricated Multiplexed Entwined Spiral Microelectrodes for Point-of-Care Applications

Luminol-based Electrochemiluminescence (ECL) generates weak signals in neutral media and typically requires H2O2 as a coreactant. However, H2O2 instability and the need for on-site addition hinder real-time diagnostic applications. Compact integrated sensing platforms are ideal for point-of-care (POC) testing due to portability, low sample requirements, and multiplexing. However, as sensor dimensions decrease, the low light emission issue in ECL becomes severe. We introduce a novel fully integrated miniaturized silicon device consisting of three sensors comprised of unique entwined micro-spiral electrodes in a generator-collector configuration. This enables highly sensitive, coreactant-free multiplexed sensing at physiological pH by accelerating in-situ reactive oxygen species production and boosting ECL intensity. Systematic optimization of electrode geometry (gaps and widths) yields an 11-fold improvement in ECL signal compared to a single-electrode setup, as well as excellent reproducibility and stability. In addition to Trolox and H2O2 detection, the platform demonstrates multiplex immunosensing through selective functionalization of the collector electrodes with chitosan nanocomposites, followed by Protein A/G-assisted immobilization of anti-IgG antibodies with peptide-based antifouling. The immunosensors exhibit high analytical performance (linear range: 0.001-100 pg{middle dot}mL-1, detection limit: 0.8 fg{middle dot}mL-1) with excellent reproducibility and reliability in 25% fetal bovine serum, highlighting the platforms potential for sensitive, coreactant-free multi-analyte POC diagnostics.

bioengineering↗

bioRxiv2025

A Novel Approach to Fabricating Sustainable Enzymatic Lactate Biofuel Cells Using Direct Laser Writing Technology for Wearable Real-Time Monitoring Applications

Lactate is a key biomarker of metabolic activity, with elevated levels serving as indicators of various physiological and pathological states. Continuous monitoring of lactate is therefore essential for both healthcare and performance optimization, while enzymatic biofuel cells (EBFCs) provide a sustainable approach to powering wearable biosensing systems. Despite lactates abundance in biofluids, lactate-based EBFCs remain underexplored, particularly on scalable electrode platforms. Here, we report the first lactate/oxygen EBFC fabricated on laser-induced graphene (LIG) electrodes prepared by direct laser writing. The bioanode and biocathode were functionalized exclusively with essential components including lactate oxidase with tetrathiafulvalene and bilirubin oxidase with ABTS, respectively. The device exhibited an open-circuit potential (OCP) of about 600 mV and a maximum power density of 48.1 {micro}W{middle dot}cm-2 at 20 mM lactate. Importantly, the power density increased linearly with lactate concentration across the physiologically relevant sweat range (5-20 mM, slope 2.9 {micro}W{middle dot}cm-2{middle dot}mM{square}1, R2 = 0.997), underscoring its suitability for sweat-based biosensing. These findings demonstrate the viability of LIG as a sustainable and scalable electrode material and highlight the potential of simplified EBFC architectures for future integration into wearable and self-powered biosensing technologies.

bioengineering↗

bioRxiv2025

RAS pathway activation drives clonal selection and monocytic differentiation in FLT3 and BCL2 inhibitor resistance

Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition. COIC.C.S. has provided educational talks for Astellas Pharma, served on advisory boards for Genentech/Abbvie and received research funding from Abbvie. B.C., Y.S. and J.H. are employees of Abbvie. M.S. and H.H. are or were previously employees of Genentech. FundingThis work was supported in part by Abbvie. C.C.S. is a Leukemia & Lymphoma Society Scholar in Clinical Research and a Damon Runyon-Richard Lumsden Foundation Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-99-18). Statement of SignificanceMutational and non-mutational RAS signaling activation drives clonal selection, monocytic differentiation and treatment resistance to FLT3 and BCL2 inhibition in AML. MEK inhibition can resensitize resistant AML cells, suggesting therapeutic potential for combined FLT3, BCL2 and RAS pathway inhibition in AML.

cancer biology↗

bioRxiv2025

Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups

Immunotherapy is now standard of care for multiple myeloma, where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D but strategies to identify additional targets are needed. We have utilized two large datasets of genomic data and integrated them with existing databases to identify expressed cell surface targets in myeloma patients. Importantly, we also identify targets specific to genomic defined subgroups of patients including primary translocations and high-risk subgroups. Examples of subgroup targets include ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), GPRC5D in 1q+, and ADAM28 in biallelic TP53 samples. Expression was validated by flow cytometry and CRISPR-Cas9 knock out models. Sub-clonal differences in expression were noted, as was alternative splicing of existing immunotherapy targets such as FCRL5. These results highlight the use of genomic stratification to identify novel therapeutic targets. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/635544v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@6965e6org.highwire.dtl.DTLVardef@1a0e567org.highwire.dtl.DTLVardef@34fc30org.highwire.dtl.DTLVardef@98c3d4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Signaling downstream of tumor-stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity

Mucinous colorectal carcinoma (MUC CRC) dissemination into the tumor stroma and metastasis to multiple organs, including the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either a conventional apical-in or an inverted apical-out polarity phenotype that influence patient outcome. Identifying the mechanisms controlling MUC CRC polarity is critical to understand disease progression. Here, we analyze patient-derived MUC CRC xenografts, with apical-in or apical-out polarity, ex vivo or within collagen gels to mimic the peritumoral stroma. Single-cell analyses reveal 2{beta}1-integrin as a key collagen-binding receptor in these models. Collagen-2{beta}1-integrin interaction activates Src and ERK/MAPK signaling and upregulates the expression of SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity and carcinoma-stroma interactions by promoting integrin recycling to the plasma membrane and HER2/HER3 expression through a positive feedback mechanism. Accordingly, we observe positive correlation between HER2, HER3 and SorLA in patient samples with the highest HER2 expression in apical-in-presenting tissues. Treatment of tumor spheres with clinically relevant HER2/HER3-targeting antibodies reverts sphere polarity and impedes collagen remodeling and adhesion to mouse peritoneum. This SorLA--integrin--HER2/HER3 signaling axis may represent a basis for MUC CRC-patient stratification and shed light on other carcinomas with similar apical-out phenotypes.

cancer biology↗

bioRxiv2024

Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancer

Increased extracellular matrix (ECM) and matrix stiffness promote solid tumor progression. However, mechanotransduction in cancers arising in mechanically active tissues remains underexplored. Here, we report upregulation of multiple ECM components accompanied by tissue stiffening in vocal fold cancer (VFC). We compare non-cancerous (NC) and patient- derived VFC cells - from early (mobile, T1) to advanced-stage (immobile, T3) cancers - revealing an association between VFC progression and cell-surface receptor heterogeneity, reduced laminin-binding integrin cell-cell junction localization and a flocking mode of collective cell motility. Mimicking physiological movement of healthy vocal fold tissue (stretching/vibration), decreases oncogenic nuclear {beta}-catenin and YAP levels in VFC. Multiplex immunohistochemistry of VFC tumors uncovered a correlation between ECM content, nuclear YAP and patient survival, concordant with VFC sensitivity to YAP-TEAD inhibitors in vitro. Our findings present evidence that VFC is a mechanically sensitive malignancy and restoration of tumor mechanophenotype or YAP/TAZ targeting, represents a tractable anti-oncogenic therapeutic avenue for VFC.

cell biology↗

bioRxiv2024

EPLINα controls integrin recycling from Rab21 endosomes to drive breast cancer cell migration

EPLIN, an actin-binding protein, has been described as both a tumour promoter and tumour suppressor in different cancers. EPLIN isoform( or {beta})-specific functions, which remain largely unknown, could explain these opposing roles. We observed distinct EPLIN-isoform localization; EPLIN is recruited to actin in plasma membrane ruffles and endosomes, while EPLIN{beta} resides on actin stress fibers. We identified two EPLIN actin-binding regions and demonstrated EPLIN interaction with Rab21, an established regulator of {beta}1-integrin endosomal traffic. EPLIN co-localizes with Rab21 and F-actin on recycling endosomes in an actin binding-dependent manner and supports {beta}1-integrin recycling and cell migration. Using BioID, we identified coronin 1C as an EPLIN proximal protein, which localizes at Rab21-containing endosomes in an EPLIN-dependent manner. EPLIN expression was linked to increased breast cancer cell motility, and high EPLIN-to-EPLIN{beta} ratio correlated with a mesenchymal phenotype in patient samples. Our work unveils unprecedented EPLIN isoform-specific functions relevant to breast cancer and beyond.

cell biology↗

bioRxiv2023

Gradient-based implementation of linear model outperforms deep learning models

Deep learning has been widely considered more effective than traditional statistical models in modeling biological complex data such as single-cell omics. Here we show the devil is hidden in details: by adapting a modern gradient solver to a traditional linear mixed model, we showed that conventional models can outperform deep models in terms of both speed and accuracy. This work reveals the potential of re-implementing traditional models with modern solvers.

bioinformatics↗

bioRxiv2023

Constitutive protein degradation induces acute cell death via proteolysis products

Modulation of proteolysis is an emerging therapeutic mainstay. The clinical success of thalidomide and analogs has inspired development of rationally-designed therapeutics that repurpose endogenous degradation machinery to target pathogenic proteins. However, it is unknown whether target removal is the critical effect that drives degrader-induced efficacy. Here we report that proteasome-generated peptides actively initiate degrader-induced cell death. Utilizing BET family degraders as exemplars, we find that induced proteasomal degradation of the BRD4-long isoform (BRD4-L) generates neo-amino-terminal peptides that neutralize Inhibitor of Apoptosis (IAP) proteins to precipitate cell death. Depletion of BRD4-L paradoxically suppresses caspase activation induced by numerous BET degraders. An unbiased screen revealed that other degrader compounds, including clinical CELMoDs, rely on the same mechanism to potentiate caspase activation and apoptosis. Finally, in the context of constitutive immunoglobulin proteostasis within multiple myeloma cells, we report that therapeutic proteasomal protease inhibition alters the peptide repertoire to neutralize IAPs, thus contributing to the clinical efficacy of bortezomib. Together, these findings clarify the counterintuitive clinical benefit achieved by combining thalidomide analogs with proteasome inhibitors. Our study reveals a previously unrealized pro-apoptotic function of the peptides generated by a variety of proteolysis-modulating compounds, that provide design considerations to maximize therapeutic benefit.

cell biology↗

bioRxiv2022

Targeting a broad spectrum of KRAS-mutant cancers by hyperactivation-induced cell death

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where numerous different activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds overactive mutant forms to limit oncogenic KRAS signalling and maintain RAS- activity at an optimal level. Depletion of SHANK3 results in hyperactivation of KRAS/mitogen-activated protein kinase (MAPK) signalling, which in turn selectively induces MAPK/ERK-dependent cell death in KRAS-mutant cancers. Furthermore, targeting of this therapeutic vulnerability through nanobody- or RNA interference- mediated disruption of the SHANK3-KRAS interaction reduces tumour growth in vivo. Thus, inhibition of the SHANK3-KRAS interaction represents a new pan-KRAS-mutant compatible strategy for selective killing of KRAS- mutant cancer cells through excessive signalling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/508660v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@87e71forg.highwire.dtl.DTLVardef@56cf94org.highwire.dtl.DTLVardef@1561136org.highwire.dtl.DTLVardef@183f711_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic model of SHANK3-controlled cell fate in KRAS-mutant cancers. SHANK3 directly interacts with KRAS and competes with RAF for KRAS binding to sustain oncogenic RAS-MAPK/ERK signalling at an optimal level (i.e. below toxic oncogenic signalling) in KRAS-mutant cancers. SHANK3 silencing (1) and inhibition of SHANK3-KRAS interaction (2) drive KRAS-mutant cells into cell death.

cancer biology↗

bioRxiv2022

Regulation of cell dynamics by rapid transport of integrins through the biosynthetic pathway

Cells sense and respond to the extracellular matrix (ECM) milieu through integrin proteins. Integrin availability on the plasma membrane, regulated by endosomal receptor uptake and recycling, has been extensively studied and regulates cell dynamics in various normal and pathological contexts1-5. In contrast, the role of integrin transport through the biosynthetic pathway has been considered primarily as a mechanism to replenish the receptor pool and too slow to influence cell dynamics6. Here, we adopted the RUSH (Retention Using Selective Hooks) assay to synchronize integrin anterograde transport from the endoplasmic reticulum (ER), allowing spatial and temporal analysis of newly synthesized receptor traffic. We observe that the delivery of new integrins to the plasma membrane is polarized in response to specific ECM ligands, facilitates integrin recruitment specifically to the membrane-proximal tip of focal adhesions (FA) and contributes to cell protrusion and FA growth. We explain the augmented adhesion growth using a computational molecular clutch model7, where increased integrin availability drives recruitment of additional integrins. Notably, a subset of newly synthesized integrins undergo rapid traffic from the ER to the cell surface to facilitate localized cell spreading, seemingly bypassing the Golgi. This unconventional secretion is dependent on cell adhesion and mediated by Golgi reassembling stacking proteins (GRASPs) association with the PDZ-binding motif in the integrin 5 cytoplasmic tail. This spatially targeted delivery of integrins through the biosynthetic pathway may propel cell dynamics by rapidly altering adhesion receptor availability, providing cells with an additional degree of plasticity to respond to their environment.

cell biology↗

bioRxiv2021

Signatures of Mutational Processes in Human DNA Evolution

The human genome contains over 100 million SNPs, most of which are C/T (G/A) variations. The type and sequence context of these SNPs are not random, suggesting that they are caused by distinct mutational processes. Deciphering the mutational signatures is a crucial step to discovering the molecular processes responsible for DNA variations across human populations, and potentially for causing genetic diseases. Our analyses of the 1000 Genomes Project SNPs and germline de novo mutations suggest that at least four mutational processes are responsible for human genetic variations. One process is European-specific and no longer active. The remaining three processes are currently active in all human populations. Two of the active processes co-occur and leave a single joint mutational signature in human nuclear DNA. The third active process is specific to mitochondrial DNA, and inflicts C-to-T mutations at mostly non-CG sites. We found neither evidence of APOBEC-induced cytosine deamination in the human germline, nor de novo mutation enrichment within certain regions of the human genome.

evolutionary biology↗

bioRxiv2019

A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

scientific communication and education↗

bioRxiv2019

Mechano-responsiveness of fibrillar adhesions on stiffness-gradient gels

Fibrillar adhesions are important structural and adhesive components in fibroblasts that are critical for fibronectin fibrillogenesis. While nascent and focal adhesions are known to respond to mechanical cues, the mechanoresponsive nature of fibrillar adhesions remains unclear. Here, we used ratiometric analysis of paired adhesion components to determine an appropriate fibrillar adhesion marker. We found that active 5{beta}1-integrin exhibits the most definitive fibrillar adhesion localisation compared to other proteins, such as tensin-1, reported to be in fibrillar adhesions. To elucidate the mechanoresponsiveness of fibrillar adhesions, we designed and fabricated thin polyacrylamide (PA) hydrogels, embedded with fluorescently labelled beads, with physiologically relevant stiffness gradients using a cost-effective and reproducible technique. We generated a correlation curve between bead density and hydrogel stiffness, thus allowing the use of bead density as a readout of stiffness, eliminating the need for specialised knowhow including atomic force microscopy (AFM). We find that stiffness promotes the growth of fibrillar adhesions in a tensin-dependent manner. Thus, the formation of these extracellular matrix-depositing structures is coupled to the mechanical parameters of the cell environment and may enable cells to fine-tune their matrix environment in response to alternating physical conditions.

cell biology↗

bioRxiv2018

Filopodome mapping identifies p130Cas as a mechanosensitive regulator of filopodia stability

Filopodia are adhesive cellular protrusions specialised in the detection of extracellular matrix (ECM)-derived cues. While ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (\"adhesome\") to fine-tune cellular behaviour, the components of the filopodia adhesions remain undefined. Here, we performed a structured illumination microscopy-based screen to map the localisation of 80 target proteins, linked to cell adhesion and migration, within filopodia. We demonstrate preferential enrichment of several adhesion proteins to either filopodia tips, filopodia shafts, or shaft subdomains suggesting divergent, spatially restricted functions for these proteins. Moreover, proteins with phospho-inositide (PI) binding sites are particularly enriched in filopodia. This, together with the strong localisation of PI(3,4)P2 in filopodia tips, predicts critical roles for PIs in regulating filopodia ultra-structure and function. Our mapping further reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions and fibrillar adhesions. Using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. Finally, we demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its CCHD domain and acts as a mechanosensitive regulator of filopodia stability.

cell biology↗

bioRxiv2017

ProLIF: a quantitative assay for investigating integrin cytoplasmic protein interactions and synergistic membrane effects on proteoliposomes

Integrin transmembrane heterodimeric receptors control a wide range of biological interactions by triggering the assembly of large multiprotein complexes at their cytoplasmic interface. A diverse set of methods have been used to investigate cytoplasmic interactions between integrins and intracellular proteins. These predominantly consist of peptide-based pull-downs and biochemical immuno-isolations from detergent-solubilized cell lysates. However, quantitative methods to probe integrin-protein interactions in a more biologically relevant context where the integrin is embedded within a lipid bilayer have been lacking. Here we describe a technique called ProLIF (Protein-Liposome Iinenteractions by Flow cytometry) to reconstitute recombinant integrin transmembrane domain (TMD) and cytoplasmic tail (CT) fragments on liposomes as individual or {beta} subunits or as {beta} heterodimers and, using flow cytometry, to rapidly and quantitatively measure protein interactions with these membrane-embedded integrins. Importantly, the assay can analyse binding of fluorescent proteins directly from cell lysates without further purification steps. By combining integrins with membrane lipids to generate proteoliposomes, the effects of membrane composition such as PI(4,5)P2 presence on protein recruitment to the integrin CTs can be analyzed. ProLIF requires no specific instrumentation, apart from a standard flow cytometer and can be applied to measure a broad range of membrane-dependent protein-protein interactions with the potential for high-throughput/multiplex analyses.

molecular biology↗