Biology subjects

Ali, G.

Publications and source records attributed to Ali, G..

9 recordsLinked to original sources

bioRxiv2026

Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions

Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. {beta}-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8 transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC="FIGDIR/small/708749v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1a9c04forg.highwire.dtl.DTLVardef@190bee2org.highwire.dtl.DTLVardef@1e41664org.highwire.dtl.DTLVardef@17a3ec7_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefWe identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic {beta}-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and--in adult AT2s--inducing a KRT8 transitional state associated with fibrosis. HighlightsO_LICell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition. C_LIO_LIReduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification. C_LIO_LIReduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation. C_LIO_LIIntrinsic {beta}-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8 transitional state associated with fibrosis. C_LI

cell biology↗

bioRxiv2025

A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Alveolar AT1 and AT2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe that AT2s retain fate plasticity until the bZIP transcription factor C/EBP suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBP downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.

developmental biology↗

bioRxiv2025

Seizure-like behavior and hyperactivity in napb knockout zebrafish as a model for autism and epilepsy

We identified N-ethylmaleimide-sensitive factor attachment protein beta (NAPB) as a potential risk gene for autism and epilepsy. Notably, Qatari monozygotic triplets with loss of function mutations in NAPB exhibit early onset epileptic encephalopathy and varying degrees of autism. In this study, we generated NAPB zebrafish model using CRISPR-Cas9-sgRNAs technology for gene editing of the two orthologs napba and napbb. We observed that napb crispants (CR) show shorter motor neuron axons length together with altered locomotion behavior, including significant increases in larvae total distance traveled, swimming velocity, and rotation frequency, indicating that these behavioral changes effectively mimic the human epileptic phenotype. We applied microelectrode array (MEA) technology to monitor neural activity and hyperexcitability in the zebrafish model. The napb CR shows hyperexcitability in the brain region. By combining behavioral tests with electrophysiological MEA assays, the established NAPB zebrafish model can be employed to study the pathophysiological mechanisms of ASD and epilepsy to screen potential therapeutic drugs.

neuroscience↗

bioRxiv2022

Deletion of TRPC6, an autism risk gene, induces hyperexcitability in cortical neurons derived from human pluripotent stem cells

Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder linked to numerous rare, inherited and arising de novo genetic variants. ASD often co-occurs with attention-deficit hyperactivity disorder and epilepsy, which are associated with hyperexcitability of neurons. However, the physiological and molecular mechanisms underlying hyperexcitability in ASD remain poorly understood. Transient receptor potential canonical-6 (TRPC6) is a Ca2+-permeable cation channel that regulates store-operated calcium entry (SOCE) and is a candidate risk gene for ASD. Using human pluripotent stem cell (hPSC)-derived cortical neurons, single cell calcium imaging, and electrophysiological recording, we show that TRPC6 knockout (KO) reduces SOCE signaling and leads to hyperexcitability of neurons by increasing action potential frequency and network burst frequency. Our data provide evidence that reduction of SOCE by TRPC6 KO results in neuronal hyperexcitability, which we hypothesize is an important contributor to the cellular pathophysiology underlying hyperactivity in some ASD.

neuroscience↗

bioRxiv2020

Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repair

COVID-19, SARS, and MERS are featured by fibrinolytic dysfunction. To test the role of the fibrinolytic niche in the regeneration of alveolar epithelium, we compared the self-renewing capacity of alveolar epithelial type 2 (AT2) cells and its differentiation to AT1 cells between wild type (wt) and fibrinolytic niche deficient mice (Plau-/- and Serpine1Tg). A significant reduction in both proliferation and differentiation of deficient AT2 cells was observed in vivo and in 3D organoid cultures. This decrease was mainly restored by uPA derived A6 peptide, a binding fragment to CD44 receptors. The proliferative and differential rate of CD44+ AT2 cells was greater than that of CD44- controls. There was a reduction in transepithelial ion transport in deficient monolayers compared to wt cells. Moreover, we found a marked suppression in total AT2 cells and CD44+ subpopulation in lungs from brain dead patients with acute respiratory distress syndrome (ARDS) and a mouse model infected by influenza viruses. Thus, we demonstrate that the fibrinolytic niche can regulate AT2-mediated homeostasis and regeneration via a novel uPA-A6-CD44+-ENaC cascade.

cell biology↗

bioRxiv2020

Plasmin improves oedematous blood-gas barrier by cleaving epithelial sodium channels

Background and PurposeLung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. We aimed to test whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid. Experimental ApproachesHuman lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, protein docking, and alveolar fluid clearance were combined for identifying plasmin specific cleavage sites and benefits. Key ResultsPlasmin led to a marked increment in lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin specifically activated {beta}{gamma}ENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts ({Delta}432-444, {gamma}{Delta}131-138, {gamma}{Delta}178-193, and {gamma}{Delta}410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human {gamma}ENaC proteins. In addition to confirming the 7 cleavage sites, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin with mass spectrometry. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both and {gamma} subunits were identified to interrupt the plasmin cleavage-induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal. Conclusion and ImplicationsWe demonstrate that plasmin could cleave ENaC to benefit the blood-gas exchange by resolving oedema fluid as a potent fibrinolytic therapy for oedematous pulmonary diseases. Bullet point summaryO_ST_ABSWhat is already knowC_ST_ABSO_LISerine proteases proteolytically cleave epithelial sodium channels, including plasmin and uPA acutely. C_LIO_LIActivity of epithelial sodium channels is increased post proteolysis. C_LI What this study addsO_LIPlasmin cleaves up to 16 sites composed of two proteolytic centres in both full-length and furin-cleaved human {gamma} subunit of epithelial sodium channels in hours. C_LIO_LINon-proteolytic sites in both and {gamma} subunits interrupt the plasmin cleavage-induced channel gating. C_LIO_LIIntratracheally instilled plasmin facilitates alveolar fluid clearance in normal human and injured mouse lungs. C_LI Clinical significanceO_LIActivation of human lung epithelial sodium channels by plasmin may benefit lung oedema resolution as a novel therapy for ARDS. C_LI

pharmacology and toxicology↗

bioRxiv2019

Overexpression of the Arabidopsis thaumatin-like protein 1 in transgenic potato plants enhances resistance against early and late blights

The Arabidopsis thaumatin-like protein 1 (ATLP1), which belongs to the PR5 family of pathogenesis-related proteins, is induced by pathogen attacks and by systemic acquired resistance (SAR)-inducing compounds. To test whether the overexpression of ATLP1 will enhance fungal resistance in transgenic plants, the cDNA of this gene under the control of a constitutive promoter was transferred into Solanum tuberosum Cv. Desiree. The expression of the introduced gene was confirmed by Northern and Western blot analyses. Western blot analysis performed with intercellular fluid (ICF) showed that ATLP1 is secreted to apoplast. Several independent transgenic lines with high-level expression of the ATLP1 were assayed for resistance against early blight (Alternaria solani) and late blight (Phytophthora infestans). The rate of Alternaria lesions development was significantly reduced in the ATLP1 transgenic lines as compared to a control line. Percent reductions in area under the disease progress curve (AUDPC) values for the ATLP1 transgenic lines as compared to control line ranged between 52 and 82%. In response to P. infestans, infection efficiency (IE), lesion size (LS) and sporulation capacity (SC) were significantly reduced in ATLP1 transgenic lines as compared to a control line. On the average, IE, LS and SC were reduced by 18, 22 and 20%, respectively, for all transgenic lines with a maximum reduction of 25% in IE, 25% in LS and 32% in SC. Resistance assays against P. infestans using whole plants showed 40-70% reduction in symptoms as compared to control. These results suggest that constitutive expression of a heterologous ATLP in potato confers enhanced resistance against early and late blights.

plant biology↗

bioRxiv2019

Transcriptional profiling of Impatiens walleriana genes through different stages of downy mildew infection reveals novel genes involved in disease susceptibility

Impatiens downy mildew is a highly destructive disease of Impatiens walleriana, and economically important bedding ornamental crop. This disease is caused by a recently emerged pathogen Plasmopara obducens. Since both the host and pathogen are relatively less studied, there are only a few genomic resources available for both I. walleriana and P. obducens. In this study, we have analyzed transcriptional changes in I. walleriana in response to P. obducens infection during different stages of disease development. Our main goal was to identify candidate genes that may be involved in I. walleriana susceptibility to P. obducens. Since the genome of I. walleriana is not available publicly, we constructed and optimized a de novo transcriptome assembly consisting of 73,022 transcripts. Differential expression analysis based on this optimized de novo transcriptome assembly revealed 3,000 to 4,500 differentially expressed transcripts (DETs) at 0 hr, 12 hr, 48 hr, 120 hr, and 240 hr time points after infection. Functional annotation of these DETs revealed that numerous plant stress responsive genes are activated and deactivated throughout the infection cycle. Genes in the calcium signaling pathways, receptor-like kinases (RLKs) including 10 disease resistance associated RLK transcripts, powdery mildew resistance genes (MLO), and many other plant stress related genes were predominantly differentially expressed in I. walleriana in response to P. obducens. Analyses reported here provides molecular insights into the disease susceptibility mechanism of the Impatiens downy mildew, and lays out a strong foundation for future studies aimed at improving downy mildew resistance in I. walleriana.

plant biology↗

bioRxiv2019

Bioactivity-driven high throughput screening of microbiomes of medicinal plants for discovering new biological control agents

In a preliminary DNA-based microbiome studies, diverse culturable and unculturable bacterial taxa were identified in the roots and rhizospheres of different medicinal plants. In this report, culturable endophytic bacteria were isolated from four economically important medicinal plants Dodonaea viscosa, Fagonia indica, Caralluma tuberculata and Calendula arvensis. On the basis of initial antimicrobial screening, nine bacterial species in seven different genera, Streptomyces, Pseudomonas, Enterobacter, Bacillus, Pantoea, Pseudarthrobacter and Delftia, were selected for further analyses. These bacteria were identified using 16S rRNA gene sequencing. Antimicrobial assays of these selected bacteria revealed that Pseudomonas taiwanensis has strong anti-Phytophthora activity. Volatiles produced by P. taiwanensis inhibited growth of P. parasitica more than 80%. Ethyl acetate extracts of S. alboniger MOSEL-RD3, P. taiwanensis MOSEL-RD23, E. hormaechei MOSEL-FLS1 and B. tequilensis MOSEL-FLS3 and D. lacustris MB322 also displayed high potency against P. parasitica. All these bacterial extracts showed strong inhibition against P. parasitica at different concentrations (4 {micro}g/mL - 400 {micro}g/mL). Bacterial extracts showing higher bioactivity (>80% inhibition in vitro) were selected for detached-leaf assay against P. parasitica on tobacco. In detached-leaf assay, application of 1% ethyl acetate bacterial extract of MOSE L-RD3, MOSEL-RD23, MOSEL-FLS1, MOSEL-FLS3 and MB322 reduced lesion sizes and lesion frequencies caused by P. parasitica by 68 to 81%. Over all P. taiwenensis MOSEL-RD23 showed positive activities for all the assays. Analysing the potential of bacterial endophytes as biological control agents can potentially lead to the formulation of broad-spectrum biopesticides for sustainable production of crops.

microbiology↗