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Ray, R.

Publications and source records attributed to Ray, R..

At least 19 recordsLinked to original sources

Four numbers, one axis: deep learning models reveal what leaf spectrum constrains about Farquhar-von Caemmerer-Berry photosynthesis

Leaf reflectance spectra are emerging as a viable substitute for gas-exchange measurements of photosynthetic capacity, with a community benchmark reporting that a spectrum accurately recovers most Farquhar-von Caemmerer-Berry (FvCB) parameters. This study re-scores the recovery under dataset-blocked, species-blocked, and leave-one-dataset-out designs, measuring the split-half reliability of each curated parameter. We constructed a convolutional encoder that maps a spectrum to the four parameters through a fixed, differentiable FvCB decoder trained on measured assimilation. A conspecific of 97.4% of held-out leaves were present in the training set, and accuracy is lost along the dataset axis but not along the species axis. Under blocked evaluation, a spectrum constrains a single capacity axis. Jmax25 retains only 17% of its recovery when Vcmax25 is held constant, and the Jmax25:Vcmax25 ratio is not predicted above a median null. The curated values of TPU25 are not reproducible, whereas those of Rday25 are well determined, but its recovery fails due to the loss. The published study measures interpolation rather than transfer, and spectra constrain less of the FvCB parameter space than assumed, including the carboxylation to electron transport balance. Routing predictions through explicit biochemistry makes identifiability measurable, although it does not improve prediction accuracy.

plant biology↗

A validated set of neural gene reporter mice and chemical tracers tools for mapping knee innervating neurons

Joint pain is an increasing concern for our aging population, as current therapies to slow joint disease progression or reduce pain are largely ineffective and often carry significant health and dependency risks. Age and joint disease induce changes to all tissues that make up the joint, including the dense neural network that innervates the joint. Several studies have correlated joint innervation changes in diseases such as osteoarthritis or rheumatoid arthritis, but little is known about their respective functional consequences. How subtypes of knee-innervating neurons affect pain experience remains relatively uncharacterized. A few studies focused on a single neural subtype due to the limited availability of validated tools to study joint innervation. To better understand the relationship between aging, joint disease, and pain, systematic characterization of nociceptors and other neural subtypes regulating joint homeostasis and pain is urgently needed. This studys objective was to establish a validated molecular and genetic toolbox for accurate mapping of the neuro-architecture in the murine knee. We screened genetic reporter mice, containing different combinations of Cre and Flp recombinase alleles along with recombinase responsive reporter alleles to either highlight peripheral nociceptors or post-ganglionic sympathetic neurons for their specificity and accuracy in labeling specific neural subtypes in the dorsal root ganglia, sympathetic ganglia, and the knee joint. Additionally, we compared the performance of a series of conventional retrograde tracers for effective labelling of sensory and sympathetic neurons innervating the knee joint. The validated molecular and genetic tools identified in this study will facilitate the creation of comprehensive joint innervation maps in physiological and pathological contexts, setting the stage for identifying the cellular and molecular changes responsible for mediating joint pain, a necessary goal for improved therapeutic interventions. Lay summaryJoint diseases, such as Rheumatoid Arthritis and Osteoarthritis significantly affect the neural landscape in joints, impacting pain, balance, and joint health. Understanding these nerve changes can provide insights into the drivers of joint pain and potential treatments. Our study evaluated genetic and conventional neural tracer tools to visualize and track knee innervating nerve fibers. We found two genetic mouse lines that specifically highlight sensory and sympathetic nerves, making them suitable models for knee joint studies. Additionally, the fluorescent tracer True Blue, effectively marks cell bodies of knee-innervating neurons. These tools will help researchers better understand nerve changes in painful joint pathologies.

neuroscience↗

Spectral network analysis illuminates coordinated trait adaptation across plant populations

O_LIUnderstanding how plant populations respond to environmental variation through functional leaf traits remains challenging due to limitations of traditional phenotyping approaches. Hyperspectral reflectance offers a rapid, non-destructive and high-throughput method to capture functional trait variation and detect signatures of local adaptation across populations. C_LIO_LIWe combined hyperspectral data, inverse modeling, and network analysis to investigate population-level variation in Streptanthus tortuosus. Using a common garden experiment with four geographically distinct populations, we applied partial least square discriminant analysis (PLS-DA) and ridge regression for population discrimination, inverse PROSPECT modeling to estimate leaf biochemical traits, and canonical correlation analysis to examine trait-climate relationships across historical (1900-1994) and recent (1995-2024) periods. We developed a spectral network approach treating wavelength correlations as biologically meaningful trait networks. C_LIO_LIPopulations showed distinct, heritable spectral signatures with high classification accuracy. Significant population differences emerged in anthocyanins, carotenoids, chlorophyll, and water content. Trait-climate correlations shifted between time periods, consistent with historical climate adaptation. Network analysis revealed population-specific integration patterns, with more variable environments displaying greater spectral modularity. C_LIO_LIHyperspectral signatures provide a high-throughput tool for detecting population-level adaptation and trait coordination. Our findings provide a framework to investigate how plant populations respond to climate change through evolved shifts in trait networks rather than isolated traits alone. C_LI

plant biology↗

Gene-specific response to MuSK agonist antibody in the treatment of Congenital Myasthenic Syndromes

Congenital myasthenic syndromes (CMS) are a group of rare disorders characterized by fatigable muscle weakness and caused by impaired neuromuscular junction (NMJ) function. CMS symptoms are highly variable, but can be detrimental and lead to death. There are over 40 different genetic subtypes, including Agrn-CMS and ColQ-CMS. Agrn encodes for neural AGRIN, which is released from the nerve terminal and triggers muscle-specific kinase phosphorylation (pMuSK). pMuSK is essential for NMJ development and maintenance, thus AGRIN deficiency causes NMJ impairment. ColQ encodes for collagenous subunit Q (ColQ), which anchors acetylcholinesterase and stabilizes MuSK. As a result, ColQ deficiency results in NMJ degeneration from prolonged transmission signals and decreased pMuSK. Current treatments for Agrn-CMS and ColQ-CMS are limited, highlighting the importance of finding more efficient therapies. Recently, a MuSK agonist antibody with high affinity for the Frizzled-like domain showed remarkable rescue of a Dok7-CMS mouse model. We hypothesized a similar antibody could benefit Agrn- and ColQ-CMS mouse models. Agrn-CMS mice were treated at postnatal day 5 (P5), P15 and P35, and ColQ-CMS mice were treated weekly from P22 to P57. In Agrn-CMS mice, 3B2 treatment rescued survival, bodyweight, fibre type switching and pMuSK levels, and improved grip strength and NMJ morphology. In ColQ-CMS mice, 3B2 treatment was unable to rescue deficits observed. Our findings suggest that MuSK agonists may benefit patients with Agrn-CMS, which should be tested in clinical trials. Our study emphasizes that effective CMS treatment is gene-dependent and relies on an accurate genetic diagnosis.

molecular biology↗

SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells

Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observed a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we found that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein. These findings identify ERAD as a novel regulator of PC2 biology and an essential mechanism for maintaining cell function.

cell biology↗

Tropical island endemic birds' demographic responses to climate are modulated by habitat availability and species traits

Climate change and associated habitat fluctuations can expedite the diversification of insular lineages or lead to isolation and extinction. Tropical island birds are a model system to assess responses to climate change owing to their insular nature and ability to diversify rapidly. While there is some understanding of the diversification of tropical island avian clades, we are yet to understand the vulnerability of these species to climate change. Long-term species genetic diversity and historical demography are critical predictors of this. Therefore, we investigated the sensitivity of tropical island endemic birds to climate change and analysed how species traits determine these responses by comparing species traits with demographic histories and paleohabitat fluctuations during the Last Glacial Period (LGP). From publicly available whole genome and paleoclimatic datasets, we reconstructed tropical island endemics past demographic histories (effective population size (Ne)) using Pairwise Sequential Markovian Coalescent (PSMC) (n = 23) and suitable habitat (n = 29) during the LGP and the Holocene. We observed that most species experienced an increase in suitable habitat between the Last Interglacial and the Last Glacial Maximum. However, a concomitant increase in Ne was only observed in the hyper-diverse passerine clade, attesting to their ability to rapidly diversify. Overall, diet specialists and large-bodied species showed a decrease in Ne during the LGP. Our results indicate that species traits dictate tropical island endemics demographic responses to climate, and a plastic response to habitat availability could be a consequence of clades abilities to rapidly occupy new niches and diversify. Further, our analyses revealed that most species entered the Holocene with low effective population sizes. Given that tropical island endemics have small geographic ranges and are groups vulnerable to climate change, special efforts are necessary to conserve them. We recommend that conservation management policies add components like historical demography and species traits while assessing extinction threats for island populations.

evolutionary biology↗

Physiological modeling and biomechanical insights of cytokine modulation in COVID-19 and pulmonary fibrosis through graph-based approach

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

bioinformatics↗

Deciphering the Biochemical and Physiological Mechanisms of Mycobacterium Tuberculosis β-Carbonic Anhydrase 3 and Its Modulators through Mechanistic QSAR Model and Integrated Systems Biology Approaches

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

bioinformatics↗

Multimolecular feature-based machine learning: system biology enhanced RF-QSAR modeling for the efficient prediction of the inhibitory potential of diverse SARS CoV-2 3CL Protease inhibitors

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

bioinformatics↗

Neural Network and Random Forest Algorithms as Catalysts in QSAR/QSAAR Modeling: Targeting β-Carbonic Anhydrase for Antituberculosis Drug Design

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

bioinformatics↗

Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Synapse formation in the mammalian brain is a complex and dynamic process requiring coordinated function of dozens of molecular families such as cell adhesion molecules (CAMs) and ligand-receptor pairs (Ephs/Ephrins, Neuroligins/Neurexins, Semaphorins/Plexins). Due to the large number of molecular players and possible functional redundancies within gene families, it is challenging to determine the precise synaptogenic roles of individual molecules, which is key to understanding the consequences of mutations in these genes for brain function. Furthermore, few molecules are known to exclusively regulate either GABAergic or glutamatergic synapses, and cell and molecular mechanisms underlying GABAergic synapse formation in particular are not thoroughly understood. However, we previously demonstrated that Semaphorin-4D (Sema4D) regulates GABAergic synapse development in the mammalian hippocampus while having no effect on glutamatergic synapse development, and this effect occurs through binding to its high affinity receptor, Plexin-B1. Furthermore, Plexin-B2 contributes to GABAergic synapse formation as well but is not required for GABAergic synapse formation induced by binding to Sema4D. Here, we perform a structure-function study of the Plexin-B1 and Plexin-B2 receptors to identify the protein domains in each receptor that are required for its synaptogenic function. We also provide evidence that Plexin-B2 expression in presynaptic parvalbumin-positive interneurons is required for formation of GABAergic synapses onto excitatory pyramidal neurons in CA1. Our data reveal that Plexin-B1 and Plexin-B2 function non-redundantly to regulate GABAergic synapse formation and suggest that the transmembrane domain may underlie these functional distinctions. These findings lay the groundwork for future investigations into the precise signaling pathways required for synapse formation downstream of Plexin-B receptor signaling.

neuroscience↗

Association of leaf spectral variation with functional genetic variants

The application of in-field and aerial spectroscopy to assess functional and phylogenetic variation in plants has led to novel ecological insights and supports global assessments of plant biodiversity. Understanding how plant genetic variation influences reflectance spectra will help harness this potential for biodiversity monitoring and improve understanding of why plants differ in functional responses to environmental change. Here, we use a well-resolved genetic mapping population derived from Multi-parent Advanced Generation Inter-cross (MAGIC) lines of Nicotiana attenuata to associate genetic differences with differences in leaf spectra between plants in a field experiment in their natural environment. We analyzed the leaf reflectance spectra using a hand-held spectroradiometer (350-2500 nm) on 616 fully genotyped plants of N. attenuata grown in a randomized block design. We tested three approaches to conducting Genome-Wide Association Studies on spectral variants. We introduce a new Hierarchical Spectral Clustering with Parallel Analysis (HSC-PA) method. This method efficiently captured the variation in our high-dimensional dataset and allowed us to discover a novel association, between a locus on chromosome 1 and the 734-1143 nm spectral range, spanning the red-edge and near-infrared regions that are sensitive to leaf structure and photosynthetic activity. This locus contains a candidate gene annotated as carbonic anhydrase, an enzyme involved in CO2 hydration and regulation of photosynthetic efficiency, suggesting a physiological link between variation in leaf optical properties and carbon assimilation. In contrast, an approach treating single wavelengths as phenotypes identified the same associations as HSC-PA, but without the statistical power to pinpoint significant associations. An index-based approach, which reduces complex spectra to a few dimensionless variables, detected two significant associations for ARDSI_Cw (a water-content-related index) with loci on chromosome 1 near genes annotated as a Zeta toxin domain-containing protein, and an Exocyst subunit Exo70 family protein. While these findings are biologically plausible, they represent a very narrow subset of the spectral variation captured by HSC-PA. The HSC-PA approach supports a comprehensive understanding of the genetic determinants of leaf spectral variation which is data-driven but human-interpretable, and lays a robust foundation for future research in linking plant genetics with biodiversity monitoring, large-scale ecological assessment and remote-sensing applications.

ecology↗

CCR3 inhibition suppresses inflammation-driven recruitment of peripheral immune cells to the eye

C-C chemokine receptor type 3 (CCR3) has been linked with age-related macular degeneration (AMD) pathologies. Specifically, its function as an immune modulator in AMD remains unclear. To address this question, we investigated the impact of CCR3 inhibition on inflammation, a key driver of AMD pathologies, by assessing inflammatory cytokines and infiltrating immune cells in two models of ocular inflammation. Mice were orally dosed twice a day with AKST4290, a CCR3 small molecular inhibitor, in the sodium iodate (NaIO3) and myelin oligodendrocyte glycoprotein (MOG) models. A combination of autoradiography and analytical chemistry techniques were used to assess drug concentration and distribution. Bead-based multiplexing technology was used to determine cytokine concentrations, and flow cytometry and immunohistochemistry was used to ascertain ocular immune-cell composition. CCR3 expression was detected in the retinal pigment epithelium (RPE)/choroid complex where AKST4290 was found to preferentially accumulate at sustained levels. In the NaIO3 model, inhibition of CCR3 with AKST4290 significantly decreased both the concentration of specific chemokines and the number of multiple populations of infiltrating peripheral immune cell. Furthermore, effects of CCR3 inhibition on immune cell infiltration were confirmed in the MOG model. These data demonstrate that CCR3 inhibition strongly modulates local inflammation by impacting both cytokine concentrations and immune cell composition in ocular diseases. Moreover, these findings together with the known role of CCR3 in promoting pathologic angiogenesis implicate a pleiotropic role for CCR3 in AMD.

cell biology↗

Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes

Central noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS) and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. Therefore, we fully characterized the cumulative fate maps and acute adult expression patterns of all three Vesicular Glutamate Transporters (Slc17a7 (Vglut1), Slc17a6 (Vglut2), and Slc17a8 (Vglut3)) in NA neurons, identifying a novel, dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the NA system. In contrast to our initial hypothesis that NA derived glutamate is required to breathing, our functional studies showed that loss of Vglut2 throughout the NA system failed to alter breathing or metabolism under room air, hypercapnia, or hypoxia in unrestrained and unanesthetized mice. These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes. These outcomes challenge the current understanding of central NA neurons in the control of breathing and suggests that glutamate may not be a critical target to understand NA neuron dysfunction in respiratory diseases.

neuroscience↗

Breathe Easy, an automated respiratory data pipeline for waveform characteristic analysis

Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic, and degenerative diseases converging on autonomic control failure. A lack of tools for high-throughput analysis of respiratory datasets remains a major challenge. We present Breathe Easy, a novel open-source pipeline for processing raw recordings and associated metadata into operative outcomes, publication-worthy graphs, and robust statistical analyses including QQ and residual plots for assumption queries and data transformations. This pipeline uses a facile graphical user interface for uploading data files, setting waveform feature thresholds, and defining experimental variables. Breathe Easy was validated against manual selection by experts, which represents the current standard in the field. We demonstrate Breathe Easys utility by examining a 2-year longitudinal study of an Alzheimers Disease mouse model to assess contributions of forebrain pathology in disordered breathing. Whole body plethysmography has become an important experimental outcome measure for a variety of diseases with primary and secondary respiratory indications. Respiratory dysfunction, while not an initial symptom in many of these disorders, often drives disability or death in patient outcomes. Breathe Easy provides an open-source respiratory analysis tool for all respiratory datasets and represents a necessary improvement upon current analytical methods in the field.

physiology↗

Partial EMT and associated changes in cellular plasticity in oncovirus-positive samples

Oncoviruses exploit diverse host mechanisms to survive and proliferate. These adaptive strategies overlap with mechanisms employed by malignant cells during their adaptation to dynamic micro-environments and for evasion of immune attack. While the role of individual oncoviruses in mediating cancer progression has been extensively characterized, little is known about the common gene regulatory features of oncovirus-induced cancers. Here, we focus on defining the interplay between several cancer hallmarks, including Epithelial-Mesenchymal Transition (EMT), metabolic alterations, and immune evasion across major oncoviruses by examining publicly available transcriptomics data sets containing both oncovirus-positive and oncovirus-negative samples. We observe that oncovirus-positive samples display varying degrees of EMT and metabolic reprogramming. While the progression of EMT generally associated with an enriched glycolytic metabolic program and suppressed fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), partial EMT correlated well with glycolysis. Furthermore, oncovirus-positive samples had higher activity and/or expression levels of immune checkpoint molecules, such as PD-L1, which was associated with a partial EMT program. These analyses thus decode common pathways in oncovirus-positive samples that may be used in pinpointing new therapeutic vulnerabilities for oncovirus-associated cancer cell plasticity.

cancer biology↗

Cellular reprogramming with ATOH1, GFI1, and POU4F3 implicate epigenetic changes and cell-cell signaling as obstacles to hair cell regeneration in mature mammals

Reprogramming of the cochlea with hair cell-specific transcription factors such as ATOH1 has been proposed as a potential therapeutic strategy for hearing loss. ATOH1 expression in the developing cochlea can efficiently induce hair cell regeneration but the efficiency of hair cell reprogramming declines rapidly as the cochlea matures. We developed Cre-inducible mice to compare hair cell reprogramming with ATOH1 alone or in combination with two other hair cell transcription factors, GFI1 and POU4F3. In newborn mice, all transcription factor combinations tested produced large numbers of cells with the morphology of hair cells and rudimentary mechanotransduction properties. However, one week later, only a combination of ATOH1, GFI1 and POU4F3 could reprogram non-sensory cells of the cochlea to a hair cell fate, and these new cells were less mature than cells generated by reprogramming one week earlier. We used scRNA-seq and combined scRNA-seq and ATAC-seq to suggest at least two impediments to hair cell reprogramming in older animals. First, hair cell gene loci become less epigenetically accessible in non-sensory cells of the cochlea with increasing age. Second, signaling from hair cells to supporting cells, including Notch signaling, can prevent reprogramming of many supporting cells to hair cells, even with three hair cell transcription factors. Our results shed light on the molecular barriers that must be overcome to promote hair cell regeneration in the adult cochlea.

developmental biology↗