Biology subjects

Guha, A.

Publications and source records attributed to Guha, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Miniscope Zero: a fully wireless, single-cell-resolution miniature microscope for imaging neural dynamics in freely behaving animals

Imaging neural fluorescence dynamics during unconstrained behavior remains a major challenge in neuroscience. Head-mounted miniature one-photon microscopes enable in vivo recordings from freely behaving animals. Still, their power and data requirements typically necessitate tethers or heavy batteries, which constrain experiments and may introduce behavioral artifacts. We present Miniscope Zero, a fully wireless miniature microscope platform combining quasistatic cavity resonance (QSCR) wireless power transfer with a high-bandwidth optical data link. The system delivers >500 mW of receiver power across a 2,500 cm2 behavioral arena and streams imaging data at 8 Mbps, supporting real-time data acquisition. Miniscope Zero provides a typical field of view of 600 m x 600 m and a 2.6-fold higher light-collection efficiency than the UCLA Miniscope v4. We demonstrate wireless CA1 GCaMP6f recordings during open-field navigation, enclosed-maze exploration, simultaneous multi-animal imaging, and extended three-dimensional behavior, enabling long-duration cellular-resolution imaging without tether-induced constraints.

neuroscience↗

bioRxiv2026

Beyond air-seeding: Dynamic, multiphase interactionsreveal a two-step mechanism of embolism propagation inangiosperm xylem

BackgroundThe mechanism underlying drought-induced embolism in angiosperm xylem has been attributed to air-seeding. This concept describes the bulk flow of gas from embolised to neighbouring conduits through the penetration of gas-liquid menisci across pores in interconduit pit membranes. While there is compelling evidence for the spatial propagation of embolism, air-seeding rests on various simplifying assumptions. Among others, air-seeding presumes that xylem sap has physical properties comparable to pure water, that pit membranes can be approximated as structures with simple pores, and that embolism occurs whenever a gas-liquid interface crosses a pit membrane. ScopeRecent experimental and theoretical work demonstrates that the biophysical conditions and processes governing gas-liquid interactions at interconduit pit membranes are fundamentally more dynamic and complex than assumed by air-seeding. These phenomena include: (1) gas movement through constriction pore networks, (2) insoluble, polar lipids at conduit surfaces and interfaces, (3) dynamic surface tension of xylem sap that depends on the local packing density of interfacial lipids, (4) bubble snap-off dynamics within pit membranes, (5) surfactant-stabilized nanobubbles in sap that is oversaturated with dissolved gas, and (6) electrostatic interactions between charged interfaces. Importantly, embolism propagation involves bubble generation and embolism formation as distinct, temporarily and spatially separated processes. Embolism formation occurs when nanobubbles become unstable, whereas nanobubbles below critical stability thresholds can remain stable in sap-filled conduits. ConclusionsTogether, these findings reconfirm that pit membranes function as safety valves enabling water transport according to the cohesion-tension theory, and provide mechanistic insights into embolism propagation. They address the question why plants do not suffer constant embolism formation despite negative xylem pressures. We conclude that a revised framework explicitly accounting for the 3D structure of pit membranes, and multiphase, dynamic processes operating within them are required to explain the biophysics underlying water transport and embolism resistance in angiosperm xylem.

plant biology↗

bioRxiv2026

Integrative structure determination of a human mitochondrial contact site and cristae organizing system (MICOS) sub-assembly

The Mitochondrial contact site and Cristae Organizing System (MICOS) complex is an inner mitochondrial membrane (IMM) assembly present at the cristae junction. It is responsible for regulating cristae formation and remodeling. However, its structure is not known. We applied Bayesian integrative structure determination to characterize the structure of the Mic60, Mic19, Mic10, and Mic13-containing MICOS complex combining AlphaFold predictions with data from crosslinking mass spectrometry, biochemical assays, electron tomography, homology modeling, and sequence alignments. The integrative structure revealed novel mutual interfaces among Mic10N,C, Mic60LBS1,LBS2,mitofilin, and Mic13central,C, which were experimentally validated. Several likely-pathogenic missense mutations also localize to these novel interfaces, highlighting their importance. Our results indicate that Mic13 likely facilitates MICOS assembly by binding Mic10 in the IMM-proximal region and Mic60 in the intermembrane space. Taken together, our integrative approach sheds light on the structure and assembly of the MICOS complex.

bioinformatics↗

bioRxiv2026

Breast cancer stem cells mediated CD8+ T cell exhaustion among different molecular subtypes of breast cancer regulated via NOTCH1/RBPJ/PD-L1 axis

BackgroundBreast cancer stem cells (BCSCs) contribute significantly to breast cancer (BC) mortality among women globally. It underpins tumor heterogeneity in BC by driving variations in stemness potential and altering immune microenvironment. However, how BCSCs, subpopulations of breast cancer cells from distinct molecular subtypes differentially modulate CD8 T-cell exhaustion and immune dysfunction remain unclear. MethodsWe conducted our study from patients with BC of four subtypes. MACS sorted (Lin-CD44+CD24-) BCSCs were prepared for mammosphere formation assay from mastectomies samples. Flow-cytometry was used to analyze breast cancer stem cells (BCSCs). Immunofluorescence, immunohistochemistry, Real Time and Reverse Transcriptase PCR array, Chromatin-immunoprecipitation assay, Transwell, ELISA, Western blotting, Cloning, Transfection, Knockdown, chromatin immunoprecipitation approaches were used to investigate the underlying mechanisms. ResultsHere, we report that BCSCs actively participate in tumor progression by modulating effector CD8 T-cells. Triple-negative breast cancer (TNBC), being the subtype with the most adverse outcomes, sustains the enrichment of stem cell regulating transcription factors like NANOG, OCT4 and SOX2 compared to HER2, Luminal B, and Luminal A subtypes. Tumor from TNBC patients exhibited an exhausted phenotype within CD8 T-cell infiltrates with PD1high TIM3high LAG3 high IFN{gamma}low signature. BCSCs induced increased proportion of exhausted CD8 T-cells, predominantly in the TNBC subtype. Cell-surface Notch1 expression was upregulated in BCSCs across all molecular BC subtypes, with the highest elevation observed in TNBC. Knockdown or inhibition of Notch1 downregulated stemness-associated genes and diminished CSC-mediated induction of CD8 T-cell exhaustion. Cumulatively, these findings suggest that assessment of high Notch1 and Nanog frequency within BCSCs can guide Notch1-targeted therapies and may formulate for new combinatorial treatment strategies to improve patient outcomes. Additionally, therapeutic targeting of BCSC-intrinsic NOTCH1-NANOG/NOTCH1-PD-L1 axis could represent an effective strategy to reduce stemness programs and alter BCSC-driven CD8 T-cell exhaustion, majorly in aggressive subtypes such as TNBC. ConclusionsBCSCs aggressiveness is perpetuated through Notch1-mediated axis. Targeting Notch1 would reduce stemness (majorly NANOG), survival, as well as prevent CD8 T-cell exhaustion (upregulating PD-1, TIM3, LAG3), thereby weakening tumor progression.

cancer biology↗

bioRxiv2026

A regulatory role of novel long non-coding RNA, BAZ1A-AS1, in vascular smooth muscle cell functions during neointima formation in human saphenous veins

BackgroundNeointimal proliferation (NP) is a major cause of stenosis and occlusion in arteries and veins. Human saphenous veins (HSV), often used for coronary artery bypass grafting, frequently fail in part due to NP. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of vascular smooth muscle cell (VSMC) phenotype, yet lncRNAs governing NP in human veins remain largely uncharacterized. Methods and ResultsUsing an ex vivo model of NP in human SV, we performed bulk RNA sequencing on SV tissues with and without NP. Among differentially expressed lncRNAs, we identified a previously uncharacterized transcript, Bromodomain Adjacent to Zinc Finger A1 antisense 1 (BAZ1A-AS1), and its predicted cis-regulatory partner gene BAZ1A, as markedly upregulated during NP and predominantly enriched in VSMCs. Both transcripts were induced by genotoxic stimuli, with BAZ1A-AS1 showing transient induction preceding sustained BAZ1A upregulation, consistent with a priming role in the DNA damage response. Silencing of either BAZ1A-AS1 or BAZ1A attenuated VSMC proliferation and migration, accompanied by upregulation of contractile markers and suppression of proliferative and inflammatory transcriptional programs. ChIRP-qPCR demonstrated that BAZ1A-AS1 physically interacts with 3' distal exons of BAZ1A at the DNA level while selectively engaging CNN1, CCND1, and IL6 mRNAs, indicating mechanistically distinct chromatin- and RNA-level regulatory functions. Baz1a haploinsufficiency attenuated neointima formation and preserved VSMC contractile identity in a mouse carotid artery ligation model. ConclusionsWe identify BAZ1A-AS1 and BAZ1A as stress-responsive regulators of VSMC phenotype, operating through dual mechanisms of cis-regulatory chromatin interaction and selective mRNA engagement, and demonstrate a novel role for the BAZ1A-AS1/BAZ1A axis in promoting NP.

physiology↗

bioRxiv2025

Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity

Of the [~]1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B12 chaperone MMADHC and cytosolic B12-dependent methionine synthase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC. Significance StatementHumans have only two vitamin B12-dependent enzymes - mitochondrial MMUT and cytosolic MTR - and both require a common B12 chaperone MMADHC. We discover that MMADHC is a low abundant, short-lived protein that is continuously imported and degraded by energized mitochondria. Upon collapse of the mitochondrial proton motive force, MMADHC accumulates in the cytosol and increases the levels and activity of MTR, critical for one-carbon metabolism. This PMF-dependent regulation of MMADHC stability and localization is important for understanding cofactor rationing and spatiotemporal compartmentalization of B12 metabolism.

biochemistry↗

bioRxiv2025

Notch and Wnt signalling interact for proper prosensory and non-sensory domain formation

The prosensory domain (PSD) of the developing inner ear develops into the sensory hair cells, supporting cells, and neurons necessary for hearing and balance. Although Notch-Jag1 signalling is known to maintain Sox2 expression in this domain, the mechanisms by which Notch sustains prosensory identity have remained unclear. Here, we show that this function does not require canonical RBPJ{kappa}-dependent transcription. Using chick in ovo electroporation, Notch reporter assays, and conditional mouse mutants, we find that canonical Notch signalling is active during neurogenesis but not within the Sox2-positive PSD. Jag1 loss leads to a gradual loss of Sox2, yet RBPJ{kappa} mutants retain Sox2, indicating a non- canonical Notch pathway. We further reveal that the non-sensory determinant Lmx1a is regulated by Wnt/{beta}-catenin signalling and that manipulating Wnt activity shifts the balance between Lmx1a and Sox2 expression. Finally, we show that NICD can directly interact with {beta}-catenin in the cytoplasm, suggesting that NICD sequesters {beta}-catenin to suppress Wnt activity and stabilise Sox2 in the PSD. Collectively, these findings support a model where prosensory maintenance occurs through non-canonical Notch signalling acting together with Wnt, forming a combined WNTCH regulatory module that coordinates sensory and non-sensory fate specification.

developmental biology↗

bioRxiv2025

Tumor-Educated-Platelets interact with Breast Cancer-Stem-Cells via P-selectin- PSGL1 and ensure stemness and metastasis through WNT-β-Catenin-VEGF-VEGFR2 intra-cellular signaling: Therapeutic modulation by aspirin

BackgroundProtagonistic role of platelets promote capillary infiltration of tumors for distant metastasis along with immunosurveillance. Despite existing reports highlighting role of platelets in tumorigenesis, its impact on breast cancer stem cells (BCSCs) remain underexplored. Our first ever report on murine and human system, accentuate that, tumor educated platelets (TEPs) of luminal A and TNBC subtypes are distinct from healthy counterparts, collaborating with BCSCs to generate sub-variants that elevate tumor aggressiveness. MethodsImpact of TEPs on BCSCs was evaluated from primary breast tumor and blood samples of luminal A/TNBC patients along with EC/4T1 murine breast tumor models and MCF-7/MDA-MB-231 cell lines. For downstream assays, TEPs were co-cultured with breast tumor samples or cell lines, followed by magnetic sorting of lin-CD44+CD24- BCSCs. TEP induced alterations of BCSCs were evaluated from 3D tumorsphere, colony formation, transwell migration, scratch-wound healing, matrigel invasion, in-vitro tube formation assays. Fluorescence-confocal microscopy, RT-PCR, flow-cytometry, western-blotting was utilized to decipher the role of genes and protein involved in stemness, metastasis along with the transcription factors in the downstream signaling cascade, followed by verifications by RNAi. ResultsTEPs have elevated expression of P-selectin and interacts with BCSCs via P-selectin and PSGL1 on BCSCs surface. Treatment with aspirin had restorative impact on P-selectin level, converting TEPs from active to resting platelet (RP) state. Under TEPs influence, BCSCs were tumorigenic, clonogenic, multidrug resistant, invasive with numerous invadopodia and remained skewed towards mesenchymal phenotype. Administration of RP reduced TEP associated BCSC virulence both in-vivo and in-vitro. P-selectin-PSGL1 interaction results in binding of WNT to FRIZZLED followed by stabilization and nuclear translocation of {beta}-Catenin. Nuclear {beta}-Catenin promotes stemness-EMT (Epithelial to mesenchymal transition)- metastasis, along with stimulation of autocrine VEGF-VEGFR2 cascade. Inhibition of WNT and VEGFR2 by RNAi confirmed the critical role of this axis in regulating TEPs influence on BCSCs. ConclusionThese insights into TEPs-BCSC interplay, acknowledges TEPs, as-well-as unveils novel receptor-ligand signaling cascade between TEPs and BCSCs, that could be a beneficial therapeutic strategy to target cancer metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/657784v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@11db5d0org.highwire.dtl.DTLVardef@18b7270org.highwire.dtl.DTLVardef@64c2borg.highwire.dtl.DTLVardef@172d68f_HPS_FORMAT_FIGEXP M_FIG C_FIG Cellular interaction between TEPs P-selectin and BCSCs PSGL1 to regulate stemness, EMT, metastasis and angiogenesis via WNT-{beta}-Catenin-VEGF-VEGFR2 cascade: Modulation by pharmacological inhibitor and RNAi.

cancer biology↗

bioRxiv2024

Notch signaling stabilizes lengths of motile cilia in multiciliated cells in the lung

Airway multiciliated cells (MCs) maintain respiratory health by clearing mucus and trapped particles through the beating of motile cilia. While it is known that ciliary lengths decrease along the proximal-distal (P-D) axis of the tracheobronchial tree, how this is regulated is unclear. Here, we demonstrate that canonical Notch signaling in MCs plays a critical role in stabilizing ciliary length. Inhibition of Notch signaling in MCs results in ciliary shortening in the trachea, lengthening in the distal airway, and to region-specific alterations in gene expression. We probe how environmental challenges impact MC homeostasis using germ-free and Mycobacterium tuberculosis (M. tb) infection models. While germ-free conditions do not perturb ciliary lengths, M. tb infection leads to lengthening of distal airway cilia, correlating with a downregulation of Notch signaling. These findings reveal that ciliary length and the P-D gradient in the airways are actively regulated, with Notch signaling serving as a stabilizing mechanism.

cell biology↗

bioRxiv2024

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, {beta}-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

neuroscience↗

bioRxiv2023

Integrative multiomics analysis of neointima proliferation in human saphenous vein: implications for bypass graft disease

IntroductionHuman saphenous veins (SV) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima proliferation (NP). NP involves complex interplay between vascular smooth muscle cells (VSMC) and fibroblasts. Little is known, however, regarding the transcriptomic and proteomic dynamics of NP. Here, we performed multi-omics analysis in an ex vivo tissue culture model of NP in human SV procured for CABG surgery. Methods and resultsHistological examination demonstrated significant elastin degradation and NP (indicated by increased neointima area and neointima/media ratio) in SV subjected to tissue culture. Analysis of data from 73 patients suggest that the process of SV adaptation and NP may differ according to sex and body mass index. RNA sequencing confirmed upregulation of pro-inflammatory and proliferation-related genes during NP and identified novel processes, including increased cellular stress and DNA damage responses, which may reflect tissue trauma associated with SV harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics detected transdifferentiating VSMC in the intima on the day of harvesting and highlighted dynamic alterations in fibroblast and VSMC phenotype and behavior during NP. Specifically, we identified new cell subpopulations contributing to NP, including SPP1+, LGALS3+ VSMC and MMP2+, MMP14+ fibroblasts. ConclusionDynamic alterations of gene and protein expression occur during NP in human SV. Identification of the human-specific molecular and cellular mechanisms may provide novel insight into SV bypass graft disease.

genomics↗

bioRxiv2023

NEUROEPITHELIAL BODIES AND TERMINAL BRONCHIOLES ARE NICHES FOR DISTINCTIVE CLUB CELLS THAT CAN REPAIR AIRWAYS FOLLOWING ACUTE NOTCH INHIBITION

Airway club cells (CCs) have the dual role of a secretory cell and a progenitor cell. Using pharmacological, genetic, and cell-ablation approaches we probe the role of canonical Notch signalling in the regulation of the regenerative capacity of CCs. We report that in response to its perturbation, different subpopulations of CCs adopt distinct fates. Upon acute inhibition of Notch, the majority transdifferentiate into multiciliated cells. However, a "variant" subpopulation (v-CCs), juxtaposed with Neuroepithelial Bodies (5-10%) and neighbouring bronchioalveolar duct junctions (>80%), does not. Instead, v-CCs transition into partially differentiated/lineage ambiguous states but can revert to a CC fate upon restoration of Notch signalling and repopulate the airways with CCs and multiciliated cells. Analysis of a v-CC lineage marker (Uroplakin3a), coupled with sequential Notch inhibition, reveals that differential responses of v-CCs to Notch inhibition are regulated by their cellular microenvironment. We propose that perturbations to Notch signalling may be a common consequence of airway injury and that microenvironmental signals diversify CCs to create a robust pool that can repair airways upon acute Notch inhibition.

cell biology↗

bioRxiv2023

H2S preconditioning induces long-lived perturbations in O2 metabolism

Hydrogen sulfide exposure in moderate doses can induce profound but reversible hypometabolism in mammals. At a cellular level, H2S inhibits the electron transport chain (ETC), augments aerobic glycolysis, and glutamine-dependent carbon utilization via reductive carboxylation; however, the durability of these changes is unknown. We report that despite its volatility, H2S preconditioning increases P50(O2), the O2 pressure for half maximal cellular respiration, and has pleiotropic effects on oxidative metabolism that persist up to 24-48 h later. Notably, cyanide, another complex IV inhibitor, does not induce this type of metabolic memory. Sulfide-mediated prolonged fractional inhibition of complex IV by H2S is modulated by sulfide quinone oxidoreductase, which commits sulfide to oxidative catabolism. Since induced hypometabolism can be beneficial in disease settings that involve insufficient or interrupted blood flow, our study has important implications for attenuating reperfusion-induced ischemic injury, and/or prolonging shelf life of biologics like platelets.

biochemistry↗

bioRxiv2023

Cobalt-sulfur coordination chemistry drives B12 loading onto methionine synthase

Cobalt-sulfur (Co-S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in Nature. Cobalamin (or vitamin B12) is an essential cobalt-containing organometallic cofactor in mammals, and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination, for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the {beta}-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.

biochemistry↗

bioRxiv2023

Hepatocyte-specific disruption of soluble epoxide hydrolase attenuates abdominal aortic aneurysm formation: novel role of the liver in aneurysm pathogenesis

IntroductionInflammation is a key pathogenic feature of abdominal aortic aneurysm (AAA). Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme that converts cytochrome P450-derived epoxides of fatty acids to the corresponding diols, and pharmacological inhibition of sEH prevented AAA formation. Both cytochrome P450 enzymes and sEH are highly expressed in the liver. Here, we investigated the role of hepatic sEH in AAA using a selective pharmacological inhibitor of sEH and hepatocyte-specific Ephx2 (which encodes sEH gene) knockout (KO) mice in two models of AAA [angiotensin II (AngII) infusion and calcium chloride (CaCl2) application]. Methods and resultssEH expression and activity were strikingly higher in mouse liver compared with aorta and further increased the context of AAA, in conjunction with elevated expression of the transcription factor Sp1 and the epigenetic regulator Jarid1b, which have been reported to positively regulate sEH expression. Pharmacological sEH inhibition, or liver-specific sEH disruption, achieved by crossing sEH floxed mice with albumin-cre mice, prevented AAA formation in both models, concomitant with reduced expression of hepatic sEH as well as complement factor 3 (C3) and serum amyloid A (SAA), liver-derived factors linked to AAA formation. Moreover, sEH antagonism markedly reduced C3 and SAA protein accumulation in the aortic wall. Co-incubation of liver ex vivo with aneurysm-prone aorta resulted in induction of sEH in the liver, concomitant with upregulation of Sp1, Jarid1b, C3 and SAA gene expression, suggesting that the aneurysm-prone aorta secretes factors that activate sEH and downstream inflammatory signaling in the liver. Using an unbiased proteomic approach, we identified a number of dysregulated proteins [e.g., plastin-2, galectin-3 (gal-3), cathepsin S] released by aneurysm-prone aorta as potential candidate mediators of hepatic sEH induction. ConclusionWe provide the first direct evidence of the livers role in orchestrating AAA via the enzyme sEH. These findings not only provide novel insight into AAA pathogenesis, but they have potentially important implications with regard to developing effective medical therapies for AAA.

pharmacology and toxicology↗

bioRxiv2022

Connectome-based predictive modeling of empathy in adolescents with and without the low-prosocial emotion specifier

Empathy impairments are an important part of a broader affective impairments defining the youth antisocial phenotype callous-unemotional (CU) traits and the DSM-5 low prosocial emotion (LPE) specifier. While functional connectivity underlying empathy and CU traits have been well studied, less is known about what functional connections underly differences in empathy amongst adolescents qualifying for the LPE specifier. Such information can provide mechanistic distinctions for this clinically relevant specifier. The present study uses connectome-based predictive modeling that uses whole-brain resting-state functional connectivity data to predict cognitive and affective empathy for those meeting the LPE specifier (n= 29) and those that do not (n= 57). Additionally, we tested if models of empathy generalized between groups as well as density differences for each model of empathy between groups. Results indicate the LPE group had lower cognitive and affective empathy as well as higher CU traits and conduct problems. Negative and positive models were identified for affective empathy for both groups, but only the negative model for the LPE and positive model for the normative group reliably predicted cognitive empathy. Models predicting empathy did not generalize between groups. Density differences within the default mode, salience, executive control, limbic, and cerebellar networks were found as well as between the executive control, salience, and default mode networks. And, importantly, connections between the executive control and default mode networks characterized empathy differences the LPE group such that more positive connections characterized cognitive differences and less negative connections characterized affective differences. These findings indicate neural differences in empathy for those meeting LPE criteria that may explain decrements in empathy amongst these youth. These findings support theoretical accounts of empathy decrements in the LPE clinical specifier and extend them to identify specific circuits accounting for variation in empathy impairments. The identified negative models help understand what connections inhibit empathy whereas the positive models reveal what brain patterns are being used to support empathy in those with the LPE specifier. LPE differences from the normative group and could be an appropriate biomarker for predicting CU trait severity. Replication and validation using other large datasets are important next steps.

neuroscience↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part I: 2D Space Perception by 2D Linear Translation

Visual perception plays a critical role in navigating space and extracting useful semantic information crucial to survival. To identify distant landmarks, we constantly shift gaze vectors through saccades, while still maintaining the visual perception of stable allocentric space. How can we sustain stable allocentric space so effortlessly? To solve this question, we have developed a new concept of NHT (Neural Holography Tomography). This model states that retinotopy is invisible (not available to consciousness) and must be converted to a time code by traveling alpha brainwaves to perceive objects consciously. According to this framework, if identical alpha phases are continually assigned to a landmark, we perceive its exact and consistent allocentric location. To test this hypothesis, we designed reaction time (RT) experiments to observe evidence of the predicted space-to-time conversion. Various visual stimuli were generated at a wide range of eccentricities either on a large TV (up to 40{degrees}) or by LED strips on a hemispherical dome (up to 60{degrees}). Participants were instructed to report the observed patterns promptly under either covert (no eye movement) or overt (with eye movement) conditions. As predicted, stimuli presented at the center of fixation always produced the fastest RTs. The additional RT delay was precisely proportional to the eccentricity of the peripheral stimulus presentation. Furthermore, both covert and overt attention protocols created the same RT delays, and trajectories of saccadic eye motions were in parallel to the overt RT vs. eccentricity. These findings strongly support our NHT model, in which the observed RT-eccentricity dependence is indicative of the spatiotemporal conversion required for maintaining a stable allocentric frame of reference. That is, we perceive space by time.

neuroscience↗

bioRxiv2021

A redox cycle with complex II promotes sulfide quinone oxidoreductase dependent H2S oxidation

The dueling roles of H2S as an endogenously synthesized respiratory substrate and as a toxin, raise questions as to how it is cleared when the electron transport chain is inhibited. Sulfide quinone oxidoreductase (SQOR) is a mitochondrial inner membrane flavoprotein that catalyzes the first step in the H2S oxidation pathway and uses coenzyme Q (CoQ) as an electron acceptor. However, complex IV poisoning by H2S inhibits complex III-dependent recycling of CoQH2, which is needed to sustain H2S oxidation. We have discovered that under these conditions, reversal of complex II activity using fumarate as an electron acceptor, establishes a new redox cycle with SQOR. The purine nucleotide cycle and the malate aspartate shuttle are sources of fumarate in H2S treated cells, which accumulate succinate. Complex II knockdown decreases the efficiency of H2S clearance and increases recovery time to the basal respiration rate in H2S treated cells. In contrast, attenuation of complex I, which is a major competitor for the mitochondrial CoQ pool, has the opposite effects. Targeted knockout of complex II in murine intestinal epithelial cells that are routinely exposed to microbiota derived H2S, decreases serum, urine, and fecal thiosulfate, a product of H2S oxidation. Our study identifies a metabolic reprogramming response to H2S that furnishes fumarate as an alternate electron acceptor and supports H2S oxidation independent of complex IV activity. Complex II-linked redox cycling of SQOR has important implications for gut H2S metabolism as colonocytes are routinely exposed to high concentrations of this gas derived from the microbiota. One Sentence SummaryReversal of complex II sustains and prioritizes H2S oxidation when respiration is poisoned.

biochemistry↗