Biology subjects

Sen, S.

Publications and source records attributed to Sen, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Robustness of a Bistable Biomolecular PositiveFeedback Circuit to Global Parametric Perturbations

Achieving robustness to multi-parametric perturbations where all parameters can change at the same time is challenging because the controller would also face the same disturbance as the plant. For nonlinear positive feedback, an important mechanism for cell fate determination in biomolecular contexts, quantitative aspects of robustness to such perturbations are generally unclear. Here we used mathematical methods of control and dynamical systems, interval analysis, and a benchmark model of a bistable biomolecular positive feedback circuit to address this. We confirmed that such perturbations can change the qualitative behaviour of the system extinguishing bistability. We obtained a quantitative relation between the relative variation in the stable steady state and the unstable steady state in terms of the relative changes in the parameters. We showed how the deviation in the trajectories near the unstable steady state due to multi-parametric perturbations could diverge almost exponentially after an initial transient, which could have a significant impact on the bistable switching dynamics. We found that the size of the eigenvalue for the unstable steady state was greater than that for the stable steady state, and proved this for certain parameters using a rigorous numerical construction. We noted a tradeoff between enhancing the parameter space of bistability and the increased sensitivity in the bistable dynamics due to parametric perturbations. We obtained rigorous bounds on the entire transient response for multi-parametric perturbations. These results provide a quantitative insight into the robustness of a bistable biomolecular positive feedback circuit to multi-parametric perturbations.

systems biology↗

bioRxiv2025

Tool-use brain representations are independent of the acting body part and motor experience

The sensorimotor system is broadly organized somatotopically. However, an action-type organization has also been found: a division based on action-type independent of acting body parts has been shown for reaching and grasping actions. Does this generalization extend to non-ethological actions? Here, we examined fMRI responses for tool-use actions that participants performed with their hands or feet. We additionally tested individuals born without hands to control for hand motor imagery when performing foot actions. We show that the primary sensorimotor cortices have hand and foot selectivity, consistent with a somatotopic organization. In contrast, higher-level motor areas within the tool-use network, such as the premotor cortex, supplementary motor area, and superior parietal cortices, showed a shared preference for tool-use independent of the executing body part and sensorimotor experience. Multivariate decoding of action-type in these areas generalized between controls hand and foot and was successful in individuals born without hands. Finally, the temporal dynamics pattern in primary and association areas carried effector-specific and action-type information, respectively. Altogether, we show that the tool-use network in motor association areas represents higher-order action information beyond concrete motor parameters associated with specific effectors, and regardless of hand motor experience. This suggests that an action-type, effector-independent organization extends beyond ethological actions, supporting a hierarchical organization in the action domain. Further, it shows that functional organization in congenital handlessness is based on the hierarchical organization of the intact cortex.

neuroscience↗

bioRxiv2024

Coral anthozoan-specific opsins employ a novel chloride counterion for spectral tuning

Animal opsins are G protein coupled receptors that have evolved to sense light by covalently binding a retinal chromophore via a protonated (positively charged) Schiff base. A negatively charged amino acid in the opsin, acting as a counterion, stabilizes the proton on the Schiff base, which is essential for sensitivity to visible light. In this study, we investigate the spectroscopic properties of a unique class of opsins from a reef-building coral belonging to the anthozoan-specific opsin II group (ASO-II opsins), which intriguingly lack a counterion residue at any of established sites. Our findings reveal that, unlike other known animal opsins, the protonated state of the Schiff base in visible light-sensitive ASO-II opsins is highly dependent on exogenously supplied chloride ions (Cl-). By using structural modelling and QM/MM calculations to interpret spectroscopy data, we conclude that, in the dark state, ASO-II opsins employ environmental Cl- as their native counterion, while a nearby polar residue, Glu292 in its protonated neutral form, facilitates Cl- binding. In contrast, Glu292 plays a crucial role in maintaining the protonation state of the Schiff base in the light-activated protein, serving as the counterion in the photoproduct. Furthermore, Glu292 is involved in G protein activation of the ASO-II opsin, suggesting that this novel counterion system coordinates multiple functional properties.

biophysics↗

bioRxiv2024

mTOR signaling governs the formation of epithelial apical projection via S6K1-RhoA and aPKC-Lgl2 axes

In metazoans, epithelia perform functions of absorption, diffusion, and secretion. The actin-based apical projections on the epithelial cells, contribute to these functions and are formed via cell-autonomous mechanisms that control cell polarity, intracellular transport, and the cytoskeleton. However, the cues that function upstream of these cell-autonomous regulators remain poorly known. Using microridges on zebrafish epithelial cells as a paradigm, we show that mTOR, a metabolic sensor, regulates the formation of apical projections. Mechanistically, mTORC1 controls the RhoA-ROCK activity via S6K1 to prevent the overactivation of Non-muscle Myosin II (NMII) to restrict microridge elongation. Furthermore, genetic, biochemical, and molecular dynamics simulation analyses reveal that mTORC2 regulates microridge pattern by modulating the activity of aPKC via its differential phosphorylation at two conserved sites. We propose that mTOR integrates the developmental and/or metabolic status of epithelial cells with cell autonomously acting RhoA and aPKC to regulate tissue wide formation of apical projections.

cell biology↗

bioRxiv2024

Centromere-proximal crossovers disrupt proper homologous chromosome disjunction during meiosis

Centromere-proximal crossovers (C-COs) are repressed during meiosis across all species. Moreover, aberrant C-COs are strongly correlated with meiotic aneuploidy such as in Down syndrome. Despite decades of work in understanding C-CO repression, the molecular basis of how they cause chromosomal mis-segregation is unclear. Here, we show that increased C-COs result in mis-segregation of homologs during meiosis I in Schizosaccharomyces pombe. C-COs cause either nondisjunction events where the entire bivalent moves into the same nucleus at meiosis I or result in biorientation of sister chromatids leading to their premature separation. Since meiosis I segregation appears normal in pericentric cohesion deficient mutants, we rule out centromeric cohesion disruption as the primary driver of segregation defects due to C-COs, as suggested in some other species. In contrast, reduced pericentric cohesion alleviates the meiosis I nondisjunction events, thereby supporting the previously suggested "entanglement model" that proposes physical entwining of the bivalent due to retention of sister-chromatid cohesion at centromeres, a hallmark of anaphase I. This alteration also uncovers biorientation of sister-chromatids in meiosis I suggesting mono-orientation disruption as a parallel way to promote mis-segregation in the presence of C-COs. These molecular insights will improve our understanding of infertility and aneuploidy-associated developmental disorders in humans.

genetics↗

bioRxiv2024

Design of Parameter Intervals to Meet Steady-State Specifications in Biomolecular Circuits using Interval Analysis

It is often desired, in the analysis or the design of biomolecular circuits, to search for parameters that satisfy certain specifications, such as on the number of the steady states or on their magnitudes. These problems are challenging because of the presence of multiple parameters, the nonlinear mapping between the parameters and the steady states, as well as the specifications themselves, such as when multiple steady states are desired. Typically, exact analytical solutions are limited and numerical approaches, if they converge, may not capture all solutions. We used Interval Analysis versions of Bisection and Constraint Propagation to obtain rigorous and guaranteed estimates of circuit parameters for the design problem. We established criteria that rule out the existence of design solutions in a given parameter space. We presented algorithms to rigorously bound all solutions and developed variants that enclosed the solutions as accurately as required. These theoretical results were illustrated on benchmark feedback and feedforward circuits. These results should aid in the analysis and design of biomolecular circuits as well as in other contexts with similar modelling frameworks. The rigorous nature of the results may be particularly useful for resource optimization and safety criticality in synthetic biology applications, such as in therapeutic applications and drug delivery.

synthetic biology↗

bioRxiv2024

Creating a biomedical knowledge base by addressing GPT inaccurate responses and benchmarking context

We created GNQA, a generative pre-trained transformer (GPT) knowledge base driven by a performant retrieval augmented generation (RAG) with a focus on aging, dementia, Alzheimers and diabetes. We uploaded a corpus of three thousand peer reviewed publications on these topics into the RAG. To address concerns about inaccurate responses and GPT hallucinations, we implemented a context provenance tracking mechanism that enables researchers to validate responses against the original material and to get references to the original papers. To assess the effectiveness of contextual information we collected evaluations and feedback from both domain expert users and citizen scientists on the relevance of GPT responses. A key innovation of our study is automated evaluation by way of a RAG assessment system (RAGAS). RAGAS combines human expert assessment with AI-driven evaluation to measure the effectiveness of RAG systems. When evaluating the responses to their questions, human respondents give a "thumbs-up" 76% of the time. Meanwhile, RAGAS scores 90% on answer relevance on questions posed by experts. And when GPT-generates questions, RAGAS scores 74% on answer relevance. With RAGAS we created a benchmark that can be used to continuously assess the performance of our knowledge base. Full GNQA functionality is embedded in the free GeneNetwork.org web service, an open-source system containing over 25 years of experimental data on model organisms and human. The code developed for this study is published under a free and open-source software license at https://git.genenetwork.org/gn-ai/tree/README.md.

scientific communication and education↗

bioRxiv2024

A thiol--ene click-based strategy to customize injectable polymer--nanoparticle hydrogel properties for therapeutic delivery

Polymer-nanoparticle (PNP) hydrogels are a promising injectable biomaterial platform that has been used for a wide range of biomedical applications including adhesion prevention, adoptive cell delivery, and controlled drug release. By tuning the chemical, mechanical, and erosion properties of injected hydrogel depots, additional control over cell compatibility and pharmaceutical release kinetics may be realized. Here, we employ thiol-ene click chemistry to prepare a library of modified hydroxypropylmethylcellulose (HPMC) derivatives for subsequent use in PNP hydrogel applications. When combined with poly(ethylene glycol)-b-poly(lactic acid) nanoparticles, we demonstrate that systematically altering the hydrophobic, steric, or pi stacking character of HPMC modifications can readily tailor the mechanical properties of PNP hydrogels. Additionally, we highlight the compatibility of the synthetic platform for the incorporation of cysteine-bearing peptides to access PNP hydrogels with improved bioactivity. Finally, through leveraging the tunable physical properties afforded by this method, we show hydrogel retention time in vivo can be dramatically altered without sacrificing mesh size or cargo diffusion rates. This work offers a route to optimize PNP hydrogels for a variety of translational applications and holds promise in the highly tunable delivery of pharmaceuticals and adoptive cells.

bioengineering↗

bioRxiv2024

Observation of the protein-inorganic interface of ferritin by cryo-electron microscopy

Visualizing the structure of the protein-inorganic interface is critically important for our more complete understanding of biomineralization. Unfortunately, there are limited approaches for the direct and detailed study of biomolecules that interact with inorganic materials. Here we use single particle cryo-EM to study the protein-nanoparticle interactions of human light chain ferritin and visualize the high-resolution details of the protein-inorganic interface. In this work, we determined the 2.85 [A] structure of human light chain ferritin bound to its native iron oxide nanoparticle substrate. The resulting cryo-EM maps confirmed and enhanced previously proposed interactions of the protein with the material along the B-helix, and revealed new interaction at the C-terminus of light chain ferritin. This work sheds new light on the mechanisms of ferritin biomineralization and further demonstrates the application of cryo-EM for the study of protein-inorganic systems.

biochemistry↗

bioRxiv2024

Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function

Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to {beta}-cell toxicity through nutrient deprivation, membrane rupture and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col I)--whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic & cation-{pi} interactions regulate amylin binding to Col I, with fibrillar collagen driving faster amylin aggregation. Amylin-entangled Col I matrices containing high amounts of amylin induce death and loss of function of INS1E {beta}-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting {beta}-cell viability and insulin secretion.

biophysics↗

bioRxiv2024

Highly extensible physically crosslinked hydrogels for high-speed 3D bioprinting

Hydrogels have emerged as promising materials for bioprinting and many other biomedical applications due to their high degree of biocompatibility and ability to support and/or modulate cell viability and function. Yet, many hydrogel bioinks have suffered from low efficiency due to limitations on accessible printing speeds, often limiting cell viability and/or the constructs which can be generated. In this study, we report a highly extensible bioink system created by modulating the rheology of physically crosslinked hydrogels comprising hydrophobically-modified cellulosics and either surfactants or cyclodextrins. We demonstrate that these hydrogels are highly shear-thinning with broadly tunable viscoelasticity and stress-relaxation through simple modulation of the composition. Rheological experiments demonstrate that increasing concentration of rheology-modifying additives yields hydrogel materials exhibiting extensional strain-to-break values up to 2000%, which is amongst the most extensible examples of physically crosslinked hydrogels of this type. We demonstrate the potential of these hydrogels for use as bioinks by evaluating the relationship between extensibility and printability, demonstrating that greater hydrogel extensibility enables faster print speeds and smaller print features. Our findings suggest that optimizing hydrogel extensibility can enhance high-speed 3D bioprinting capabilities, reporting over 5000-fold enhancement in speed index compared to existing works reported for hydrogel-based bioinks in extrusion-based printing.

bioengineering↗

bioRxiv2024

Exploring the impacts of human breast milk functional lipidome on infant health and growth outcomes in early life using lipid bioinformatics

Human breast milk lipidome is complex, and how changes in the functional lipid metabolism converge systematically to alter infants health outcomes is poorly understood. We used human breast milk and infant-mother dyads as a test system to demonstrate how the application of improved lipid bioinformatics can be effective in discerning systematic changes in functional lipid metabolism providing novel discoveries of how lactational programming in early life can influence infant health and growth outcomes. The study consisted of 40 mother-infant dyads where breast milk, maternal diet, infant anthropometrics [fat mass index (FMI), length z score, BMI z score, fat-free mass index (FFMI)], and infant atopic disease outcome (ear infection, cold, wheezing, diarrhea, and eczema) were collected at one and four months postpartum. Integrated Lipid Bioinformatics analyses were conducted using XLSTAT, Metaboanalyst 5.0. R software, Lipid Search, Xcalibur, and Cytoscape software. The results showed breast milk lipidome ordinated into distinct clusters based on maternal BMI status, and differences in developmental and atopic disease outcomes following redundancy analysis. Specifically, lipids from obese mothers clustered with FMI and eczema, while lipids from non-obese mothers clustered with FFM and wheezing. Receiver operating analysis was effective in identifying potential lipid biomarkers that were significantly associated with infant FMI, FFMI, and eczema during early life. Sphingolipid and glycerophospholipid pathways were significantly associated with the altered breast milk lipidome impacting infant development and atopic disease outcome during the first year of life. The findings following the advanced lipid bioinformatics suggest that the breastmilk functional lipid metabolism appears to play a key role in lipid-mediated lactational programming influencing development and atopic disease outcome, and present opportunities for potential dietary intervention in early life.

bioinformatics↗

bioRxiv2024

Distinct structural and functional heterochromatin partitioning of lamin B1 and B2 revealed using genome-wide Nicking Enzyme Epitope targeted DNA sequencing.

A genome-wide chromatin profiling technology, named as Nicking Enzyme Epitope targeted DNA sequencing (NEED-seq) in which antibody-targeted controlled nicking by Nt.CviPII-pGL is used to study specific protein-DNA complexes. NEED-seq is performed in situ in formaldehyde fixed cells, allowing for both visual and genomic resolution of epitope bound chromatin. When applied to nuclei, NEED-seq yielded genome-wide chromatin associated proteins and histone post-translational modifications (PTMs). NEED-seq of lamin B1/B2 demonstrated their association with heterochromatin. Lamin B1 and B2 associated domains (LAD) segregated to three different states, and states with stronger LAD correlated with heterochromatic marks. Hi-C analysis displayed A and B compartment with equal lamin B1/B2 distribution, although methylated DNA remained high in B compartment. LAD clustering with Hi-C resulted in subcompartments, with lamin B1-B2 partitioning to facultative and constitutive heterochromatin respectively and were associated with neuronal development. Thus, lamin B1 and B2 have structural and functional partitioning in mammalian nucleus. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/603107v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@44c36forg.highwire.dtl.DTLVardef@7ab1adorg.highwire.dtl.DTLVardef@126e99eorg.highwire.dtl.DTLVardef@1b38bd7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Graphical abstract: Model depicting association of lamin B1 and B2 in A (facultative heterochromatin) and B (constitutive heterochromatin) compartmentalization. C_FIG

genomics↗

bioRxiv2024

Eugenol loaded lipid nanoparticles derived hydrogels ameliorate psoriasis-like skin lesions by lowering oxidative stress and modulating inflammation

Psoriasis is a chronic T-cell-mediated autoimmune skin disorder characterized by excessive epidermal thickening, keratinocyte over-proliferation, disruption of epidermal cell differentiation, and increased blood vessel growth in the dermal layer. Despite the common use of corticosteroids in psoriasis treatment, their limited efficacy and numerous side effects pose significant challenges. This research introduces a promising alternative approach by presenting hydrogels loaded with Eugenol (EU) in combination with Carbopol 974P (EUNPGel) for potential psoriasis management. EUN-loaded lipid nanoparticles (EUNPs) exhibit superior drug loading, enhanced release kinetics, long-term stability, and the ability to scavenge reactive oxygen species (ROS). Furthermore, EUNPs have been shown to inhibit keratinocyte proliferation, induce apoptosis, and augment the uptake of IL-6-mediated inflammation in human keratinocyte cells. Application of EUNPs-loaded gels (EUNPGel) to imiquimod-induced psoriatic lesions has demonstrated effective dermal penetration, suppressing keratinocyte hyperplasia and restoring epidermal growth. This led to a remarkable reduction in the Psoriasis Area and Severity Index (PASI) score from 3. 75 to 0. 5 within five days. These findings highlight the potential of EUNPGel as an innovative nanomedicine for treating inflammation. This novel approach enhances ROS scavenging capacity, improves cellular uptake, facilitates skin penetration and retention, reduces the activity of hyperactive immune cells, and suggests potential applications for treating other immune-related disorders such as acne and atopic dermatitis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/599274v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1f12fe6org.highwire.dtl.DTLVardef@17fa70forg.highwire.dtl.DTLVardef@1b0f28forg.highwire.dtl.DTLVardef@4ae07_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHydrogel loaded with eugenol is an innovative alternative for psoriasis management. C_LIO_LISuperior drug loading, release kinetics, stability, and ROS scavenging capacity. C_LIO_LICurb (human keratinocyte) HaCaT cells proliferation, induce apoptosis, lower IL-6 mediated inflammation. C_LIO_LIEffective dermal penetration and retention both in vivo and ex vivo. C_LI

immunology↗

bioRxiv2024

Transcutaneous delivery of disease specific PI3K/Akt/mTOR inhibitor based hybrid nanoparticles in hydrogel system for the management of psoriasis: Insights from in vivo studies

We have reported robust and scalable lipid polymeric conjugated hybrid nanoparticles comprised of phospholipid shell and polymeric core that combine the benefit of both polymeric and lipid nanoparticles. Rapamycin, a PI3K/Akt/mTORC1 inhibitor, was encapsulated inside the lipid-polymeric conjugated spherical-shaped hybrid nanoparticles (RPMN), having an encapsulation efficiency of {approx} 83% and particle size {approx} 277.6 nm. Further, RPMN was converted into the carpool-based hydrogel system (RPMNGel), which enhanced release kinetics, long-term stability and skin residence time. Specifically, in an in-vivo imiquimod-induced psoriatic model, RPMNGel showed high accumulation and deeper penetration inside the epidermis, slowly diffusing away inside the psoriatic skin without causing any side effect to normal skin. This leads to longer and sustained retention over more than three days without being affected by sweat, humidity or wiping due to adherence between the stratum corneum and epidermis. Similarly, the cumulative PASI score was also reduced from 10.25 to 1.75 on day 7 in the group treated with RPMNGel. Overall, RPMNGel has a potential role in treating and managing psoriasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/599287v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1366d88org.highwire.dtl.DTLVardef@51255forg.highwire.dtl.DTLVardef@16ca71dorg.highwire.dtl.DTLVardef@4f93e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

CD44/Integrin β1 association drives fast motility on HA substrates

In addition to proteins such as collagen (Col) and fibronectin, the extracellular matrix (ECM) is enriched with bulky proteoglycan molecules such as hyaluronic acid (HA). However, how ECM proteins and proteoglycans collectively regulate cellular processes has not been adequately explored. Here, we address this question by studying cytoskeletal and focal adhesion organization and dynamics on cells cultured on polyacrylamide hydrogels functionalized with Col, HA and a combination of Col and HA (Col/HA). We show that fastest migration on HA substrates is attributed to the presence of smaller and weaker focal adhesions. Integrin {beta}1 co-localization and its association with CD44--which is the receptor for HA, and insensitivity of cell spreading to RGD on HA substrates suggests that focal adhesions on HA substrates are formed via integrin association with HA bound CD44. Consistent with this, adhesion formation and cell motility were inhibited when CD44 was knocked out. Collectively, our results suggest that association of integrin {beta}1 with CD44 drives fast motility on HA substrates.

cell biology↗

bioRxiv2024

Condensin II activation by M18BP1

Condensin complexes promote the drastic spatial rearrangement of the genome upon mitotic entry. Condensin II initiates chromosome condensation in early mitosis. To prevent chromosome condensation during interphase, condensin II is inhibited by MCPH1, but the mechanism is unknown. Through genetic and proteomic approaches, we identify M18BP1, a protein previously associated with centromere identity, as a factor required for condensin II localization to chromatin. M18BP1 directly binds condensin IIs CAP-G2 subunit and competes with MCPH1 for binding. Upon mitotic entry, CDK1 mediated phosphorylation may promote a switch from MCPH1 to M18BP1 binding to activate condensin II. Our results identify a fundamental and evolutionarily conserved mechanism of condensin II activation.

cell biology↗

bioRxiv2024

Genomic surveillance reveals that the dengue 2 virus lineage responsible for the 2023-2024 epidemic in the French Caribbean Islands is resistant to Mosnodenvir

Dengue fever is the most important arbovirosis for public health, with more than 5 million cases worldwide in 2023. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. Here, by analyzing dengue virus (DENV) genomes from the ongoing epidemic in the French Caribbean Islands, we show that they all exhibit mutation NS4B:V91A, previously associated with strong resistance to mosnodenvir in vitro. Using antiviral activity tests on clinical and reverse-genetic strains, we confirm a 600-fold decrease in mosnodenvir sensitivity. Finally, combining phylogenetic analysis and experimental testing for resistance, we find that the V91A resistance mutation likely emerged multiple times over the last 30 years in DENV-2 and DENV-3. These results call for increased genomic surveillance, in particular to track lineages with resistance mutations. These efforts should allow to better assess the activity profile of DENV treatments in development against circulating strains.

microbiology↗