Biology subjects

O'Brien, J.

Publications and source records attributed to O'Brien, J..

At least 19 recordsLinked to original sources

bioRxiv2026

The Ocean Microbiomics Database reveals thermal niches and projected pressure on marine microbes in a warming ocean

Temperature is a key driver of ocean microbial community structure, yet its role in shaping global distributions and their response to warming remains unclear due to fragmented studies, inconsistent methods, and limited environmental context. We present the Ocean Microbiomics Database (OMDB) containing 274,282 genomes forming 31,058 species-level clusters, searchable at https://omdb.microbiomics.io. We show surface temperature is predicted from community composition, driven by thermal niche partitioning among congeneric taxa. Using these thermal niches to model present-day distributions globally, we find that projected warming results in microbial richness declining faster than relative abundance, with losses concentrated at high latitudes and among poorly characterized lineages. Resolving 5,891 species into four thermal clusters reveals ecological structure correlated with genome streamlining, protein thermostability, and marker-gene physicochemistry, enabling prediction of a microorganism's abundance-maximizing temperature directly from its coding sequence. This positions OMDB as a platform spanning molecular traits to global ecology, offering a genome-resolved foundation for understanding how temperature, shown to be a primary driver of ocean microbial life, will continue to shape it as the ocean warms.

microbiology↗

bioRxiv2026

Its just a phase: moonlight and rainfall influence the activity of a threatened cave-roosting bat in the Pilbara

Wildlife monitoring in arid environments is complicated by substantial temporal and spatial variation in animal activity driven by unpredictable environmental conditions. For highly mobile species, movements across the landscape may further influence activity recorded at fixed monitoring locations, raising questions about whether short-term surveys adequately represent patterns of site use. We examined temporal variation in acoustic activity of the threatened Pilbara Leaf-nosed Bat (Rhinonicteris aurantia Pilbara form), a highly mobile, cave-roosting insectivorous bat inhabiting the arid Pilbara region of north-western Australia. Acoustic activity was monitored continuously at two permanent diurnal roosts for up to two years, comprising 1601 detector-nights across three detector locations. We tested relationships between nightly activity and environmental conditions, detector location and anthropogenic disturbance. Activity varied substantially through time and among detector locations. Moon illumination and cumulative rainfall were strongly associated with activity, but their interaction differed between roosts: activity was highest under low moon illumination and low cumulative rainfall at Chateau Cave, whereas activity at Daltons was highest under low moon illumination and higher cumulative rainfall. Activity also differed markedly between detector positions within Chateau Cave, and humidity, temperature and artificial light at night had additional location-specific effects. Other measures of anthropogenic disturbance, including cave entry, blasting and mining activity, had comparatively weak support. The contrasting environmental relationships among locations demonstrate that acoustic activity at permanent roosts is strongly context dependent. For a species capable of extensive movements among roosts, temporal variation in activity may reflect behavioural responses and redistribution of individuals across the landscape rather than rapid demographic change. We suggest that facultative nomadism may provide a useful hypothesis for understanding temporal variation in roost use by Pilbara Leaf-nosed Bat. More broadly, our results demonstrate that short-duration acoustic surveys of highly mobile species in arid environments may provide an incomplete representation of longer-term site use and should incorporate temporal replication and environmental context when used for conservation and impact assessment.

ecology↗

bioRxiv2026

Retinal electrical synapse plasticity is required for optimal visual performance

Most electrical synapses in the mammalian central nervous system are composed of Connexin 36 (Cx36). Electrical synapses are functionally plastic, changing their degree of coupling based on the activity of the cell or connected cells, or based on activation of neurotransmitter or neurohormone receptors. Plasticity can reach an extreme in which electrical synapses become functionally silent, which is a normal operational condition for some circuits. Cx36 coupling is regulated by phosphorylation, which opens the channels. In retinal circuits, Cx36 is often maintained in a poorly phosphorylated, poorly coupled state. We reasoned that phosphomimetic mutants of Cx36 could remain constitutively open and maintain circuits in a well-coupled state that will interrogate the need for plasticity. We developed a constitutively open Cx36 mutant by systematically replacing phosphorylatable residues that regulate coupling with acidic residues. Single mutants of serine 315 significantly modified functional regulation of coupling in HeLa cells, but mutation of four residues was required to produce a mutant that was constitutively open. This mutant, Cx36-S110D, T111E, S293D, S315D, called Cx36-DEDD, displayed high coupling in control conditions and only modest changes under phosphorylating and dephosphorylating conditions. We developed a conditional knockin mouse that expresses Cx36-DEDD and cytoplasmic tdTomato in cells that expressed Cre recombinase. When crossed with Six3-Cre mice, Cx36-DEDD expressed widely in the retina including in photoreceptors, bipolar, amacrine and ganglion cells. Rod-cone electrical coupling displayed the maximum of its physiological dynamic range, and photopic visual acuity and contrast sensitivity were significantly reduced in Cx36-DEDD homozygous animals. We conclude that reduction of coupling in some retinal circuits is required for optimal daylight vision. Significance StatementTwo types of synapses, chemical and electrical, work together throughout the central nervous system to perform neurological functions. While it is widely understood for chemical synapses that plasticity, changing the strength of synaptic connections, plays critical roles in many processes, this is far less understood for electrical synapses. By developing an electrical synapse protein mutant that locks channels in an open state, we have investigated retinal circuits that retain functional electrical synapses but lack their latitude for plasticity. This perturbation significantly compromises visual acuity and contrast sensitivity in the daylight, revealing that electrical synapse plasticity is necessary to tune retinal functions for optimal performance. Thus, electrical synapse plasticity along with chemical synapse plasticity is required for neural function.

neuroscience↗

bioRxiv2026

Electrical and chemical synapses share similar organizational principle

Electrical transmission is mediated by intercellular channels that cluster into structures known as gap junctions (GJ). In vertebrates, GJ channels are encoded by the gene family of connexin (Cx) proteins that assemble as hexamers, termed hemichannels, in the pre- and postsynaptic membranes, and that subsequently dock to form GJ channels. Auditory contacts on the fish Mauthner cells serve as model to study the properties and organization of vertebrate electrical synapses. Electrical transmission at these synapses is mediated by multiple co-existing GJs at which the presence of intercellular channels is regulated by a molecular scaffold. Zebrafish contain four homologs of the neuronal Cx36: Cx35.5 and Cx35.1 (gjd2a and b, respectively), and Cx34.1 and Cx34.7 (gjd1a and b). Cx mutations suggested that GJs are formed by heterotypic channels made of presynaptic Cx35.5 and postsynaptic Cx34.1. Using transgenic fish in which Cxs were tagged, we found that a second Cx, Cx34.7, is present together with Cx34.1 on the postsynaptic side at some but not all GJs at these terminals. When exogenously expressed, both Cx34.1 and Cx34.7 formed heterotypic functional channels with Cx35.5, each with substantially different voltage-dependent properties, indicating they can serve differential functions. However, we previously demonstrated that electrical transmission is lost in Cx34.1 but not Cx34.7 null mutants, suggesting that Cx34.7 cannot compensate for the loss of Cx34, despite the intrinsic ability of Cx34.1 and Cx34.7 to create functional channels. The findings reveal an unanticipated functional organization in the electrical synapse, where Cx34.1 is obligatory and Cx34.7 accessory, roles that appear to be defined by the postsynaptic molecular scaffold, with two postsynaptic Cxs possibly assembling under specific functional contexts. Thus, our results indicate that electrical synapses share an organizational motif with chemical synapses, akin to how they combine postsynaptic receptor types to modify synaptic function.

neuroscience↗

bioRxiv2026

A multiomic lifespan signature in genetically diverse, diet-restricted mice

Dietary restriction extends lifespan across model organisms, but the plasma molecular changes mediating this effect remain incompletely characterized. We present a longitudinal multiomic analysis of 2,234 plasma samples from 960 Diversity Outbred mice subjected to intermittent fasting or caloric restriction and followed to natural death. Using mass spectrometry, we quantified 1,512 metabolites, lipids, and proteins and mapped their associations with diet, age and longevity. DR-induced molecular changes scale with caloric intake and modulate inflammatory, lipid catabolism, and oxidative stress pathways. Aging showed a biphasic signature with sharp acceleration beyond 85% of lifespan, demarcating terminal decline. Mediation and survival modeling both identified superoxide dismutase (SODE) and vascular cell adhesion molecule (VCAM1) as top lifespan predictors. Genetic analysis revealed 9,599 QTL, nine of which coincided with previously identified lifespan QTLs, and were largely related to immune regulation. These findings provide a rich multiomic and genetic resource for the aging research community.

systems biology↗

bioRxiv2026

ML-guided robotic microinjection of single neurons in human brain organoids

Human brain organoids have emerged as powerful models for studying the physiology, pathology, and evolution of the human brain. When combined with single-cell approaches, they offer the potential to directly probe the dynamics and mechanisms underlying cell fate decisions. A major technical bottleneck, however, remains the ability to reliably visualize and manipulate individual cells within their dense and heterogeneous tissue environment. Microinjection has proven effective for this purpose, allowing direct delivery of membrane-impermeable probes into single cells within intact tissue. Despite its versatility, widespread adoption of microinjection has been limited by its technically demanding and low-throughput nature. Automated microinjection systems developed for murine tissue have demonstrated that robotics can overcome these limitations, enabling systematic single-cell lineage tracing at scale. Here, we present a vision-guided robotic system capable of imaging organoid slices, identifying tissue boundaries, and targeting specific single cells for microinjection. This approach is generalizable across murine and human tissues and enables high-throughput single-cell manipulation, opening new avenues for studying human brain development at scale.

bioengineering↗

bioRxiv2025

Molecular determinants of low affinity complexes formed by the electrical synapse proteins Connexin36 (Cx36) and ZO-1

Although chemical and electrical synapses function fundamentally differently, they evidently share common design principles. Like neurotransmitter receptors, Connexin 36 (Cx36) containing gap junction channels, key constituents of electrical synapses, are anchored to scaffolding proteins that stabilize the connexin at the synapse. One of the most prominent proteins that has been described in this context is the Zonula occludens protein 1 (ZO-1). ZO-1 interacts with Cx36 via one of its three PDZ domains. This interaction is inherently weak and was suggested to facilitate the dynamic regulation of electrical synapses. In the present study, we have combined Gaussian accelerated molecular dynamics simulations and binding assays to identify the exact residues in the PDZ binding motif of Cx36 that are necessary to sustain these low affinity interactions. Among the different Cx36 mutations we have generated, we discovered a single substitution at position 319 within the PDZ binding motif that massively increases binding in different experimental settings. In addition to this site, we found that acidic residues adjacent to the PDZ binding motif (PBM) in Cx36 and its fish orthologues are evolutionarily tuned to weaken PDZ interactions as well. We were able to enhance PDZ1 binding drastically by substituting these residues with hydrophobic or positively charged amino acids. Finally, we demonstrate that the weak PDZ1/Cx36 interaction is sensitive to CaMKII mediated phosphorylation of Cx36, suggesting that ZO-1 unbinding may be a necessary event to potentiate electrical synapses. In summary, our study provides a detailed analysis of different mechanisms that can be exploited to modify the interaction between two key components of an electrical synapse: Cx36 and ZO-1.

biochemistry↗

bioRxiv2025

Gene model for the ortholog of Ilp3 in Drosophila eugracilis

Gene model for the ortholog of Insulin-like peptide 3 (Ilp3) in the D. eugracilis Apr. 2013 (BCM-HGSC/Deug_2.0) (DeugGB2) Genome Assembly of D. eugracilis (GenBank Accession: GCA_000236325.2) of Drosophila eugracilis. This ortholog was characterized as part of a dataset to study the evolution of the Insulin/ insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

genomics↗

bioRxiv2025

Maternal opioid use with and without hepatitis C infection disrupts the structure and immune landscape of the maternal-fetal interface

Maternal opioid use disorder (OUD) poses significant risks to maternal and fetal health. Adverse outcomes associated with maternal OUD are believed to be mediated, in part, by changes in placenta structure and function; however, few studies have addressed this question. Here, we utilized a combination of flow cytometry, histology, spatial and single-cell transcriptomics to uncover the impact of OUD on placental tissues. Given that nearly half of subjects with chronic OUD contract hepatitis C (HCV), we further stratified our findings by maternal HCV status. Our results indicate that maternal OUD leads to a higher incidence of vascular malperfusion accompanied by increased levels of inflammatory markers and dysregulated secretion of placental development factors. Furthermore, spatial transcriptomics revealed that maternal OUD disrupts the communication between trophoblasts and immune cells important for placental vascular development. Additionally, CellChat analysis revealed aberrant VEGF and FN1 signaling across trophoblast, endothelial, and myeloid cells. Processes associated with tissue homeostasis and repair were also downregulated across trophoblast and leukocytes. Frequencies and responses to ex-vivo stimulation of decidual macrophages and cytolytic NK cells, critical for tissue remodeling and fetal tolerance, were decreased. Finally, transcriptional analyses of placental leukocytes also indicate shifts towards more regulatory/tissue surveillant phenotypes. Altogether, these results highlight the significant disruptions to placental health by maternal OUD. One Sentence SummaryMaternal opioid use disorder {+/-} hepatitis C coinfection disrupts placental structure, immune function, and cell-cell communication.

immunology↗

bioRxiv2025

Mapping functional hemodynamic and metabolic responses to dementia: a broadband spectroscopy pilot study

SignificanceBroadband near-infrared spectroscopy (bNIRS) can simultaneously monitor several chromophores including the oxidative state of cytochrome c-oxidase (oxCCO), an oxygen metabolism biomarker whose activity is altered in Alzheimers disease. Being a portable and non-invasive neuromonitoring technique, bNIRS could thus provide accessibility to brain-specific biomarkers and aid in the dementia diagnostic pathway. AimWe use bNIRS recorded functional haemodynamic and oxCCO changes to assess their relevance in Alzheimers disease dementia as potential biomarkers. ApproachUsing a visual-stimulus paradigm, we recorded functional changes in oxy-, deoxy-haemoglobin and oxCCO in three similarly aged cohorts: healthy controls (n=5), individuals with mild cognitive impairment (n=7) and individuals with Alzheimers dementia (n=7). We then selected features from these functional responses to find the best correlation with clinical cognitive markers (cognitive and behavioural test scores and clinical diagnosis) using canonical correlation analysis. ResultsWe found individual variations in peak amplitude and time-to-peak for all the stimulus-evoked bNIRS signals across the three cohorts. Canonical correlation analysis showed a strong correlation between bNIRS features and the clinical cognitive markers (r=0.902). However, repeating the same analysis by excluding the bNIRS oxCCO features leads to a significantly lower correlation (r=0.687) with the clinical markers. ConclusionsoxCCO could be a crucial biomarker, partly explaining cognitive differences with dementia. bNIRS uniquely provides a portable and non-invasive technique to monitor several chromophores simultaneously including oxCCO with potential future applications in tracking dementia progression.

bioengineering↗

bioRxiv2025

Master control genes in the regeneration of rod photoreceptors from endogenous progenitor cells in zebrafish retina

Retinitis Pigmentosa is a chronic retinal degenerative disease characterized by the gradual loss of rod, and later, cone photoreceptors until the individual is completely blind. Regeneration of photoreceptors from endogenous progenitor cells is a possible therapeutic approach, but mammals do not do this naturally. Mammalian models can be induced to generate retinal progenitors from Muller glial cells, but there has been limited success in rod photoreceptor specific regeneration. Unlike mammals, zebrafish have the natural ability to regenerate neurons after injury or disease and can provide insight into the molecular mechanisms of regeneration. In this study, we used a zebrafish model of Retinitis Pigmentosa to investigate the class of progenitors responsible for rod photoreceptor regeneration in the context of chronic disease. Using bioinformatic analyses of single-cell RNA sequencing datasets, we identified master regulator genes responsible for proliferation of retinal progenitors, differentiation of progenitors into rod photoreceptors, and maturation of the new rod photoreceptors. Using transient knockdown of gene expression in adult regenerating retina we determined that e2f1, e2f2, e2f3 and aurkb are critical for proliferation of progenitors, and prdm1a is critical for differentiation of progenitors into rod photoreceptors. This study provides a list of master regulators responsible for the specific regeneration of rod photoreceptors during chronic retinal degeneration. Impact StatementIdentification of master regulating genes that drive the proliferation of progenitor cells and their differentiation specifically into rod photoreceptors provides insight that can be used to develop regenerative therapies for retinal degenerative diseases.

neuroscience↗

bioRxiv2024

Uncovering the electrical synapse proteome in retinal neurons via in vivo proximity labeling

AbstractElectrical synapses containing Connexin 36 (Cx36) represent the main means for direct electrical communication among neurons in the mammalian nervous system. However, little is known about the protein complexes that constitute these synapses. In the present study, we applied different BioID strategies to screen the interactomes of Connexin 36 and its zebrafish orthologue Cx35b in retinal neurons. For in vivo proximity labeling in mice, we took advantage of the Cx36-EGFP strain and expressed a GFP-nanobody-TurboID fusion construct selectively in AII amacrine cells. For in vivo BioID in zebrafish, we generated a transgenic line expressing a Cx35b-TurboID fusion under control of the Cx35b promoter. Both strategies allowed us to capture a plethora of molecules that were associated with electrical synapses and showed a high degree of evolutionary conservation in the proteomes of both species. Besides known interactors of Cx36 such as ZO-1 and ZO-2 we have identified more than 50 new proteins, such as scaffold proteins, adhesion molecules and regulators of the cytoskeleton. Moreover, we determined the subcellular localization of these proteins in mouse retina and tested potential binding interactions with Cx36. Amongst these new interactors, we identified signal induced proliferation associated 1 like 3 (Sipa1l3), a protein that has been implicated in cell junction formation and cell polarity, as a new scaffold of electrical synapses. Interestingly, Sipa1l3 was able to interact with ZO-1, ZO-2 and Cx36, suggesting a pivotal role in electrical synapse function. In summary, our study provides the first detailed view of the electrical synapse proteome in retinal neurons, which is likely to apply to electrical synapses elsewhere.

neuroscience↗

bioRxiv2024

Testing for heavy metals in drinking water collected from Dog Aging Project participants

Heavy metals are commonly found in groundwater and can affect the quality of drinking water. In this pilot study, we analyzed the quality of drinking water for dogs participating in the Dog Aging Project (DAP) who lived in homes not served by a municipal water supply. In order to capture both diverse and localized environmental factors that may affect drinking water, 200 owners of DAP dogs located in one of 10 selected states were invited to participate. We tested for the presence of 28 metals in dogs drinking water, including eight (8) heavy metals that have maximum contaminant levels (MCLs) designated by the Environmental Protection Agency (EPA) and five (5) heavy metals that have EPA health guidance levels. The eight metals with MCLs are known to cause chronic health issues in humans after long-term ingestion. Our aim in this pilot was to determine whether such elements could be detected by at-home sampling of dogs drinking water. We found detectable levels of all metals tested. There were 126 instances when an analyte (arsenic, lead, copper, sodium, strontium, nickel, or vanadium) was above the EPA MCL or health guidance level. We further identified potential association between the presence of titanium and chromium, and occurrence of a known health condition in dogs. This prompts further investigation with a larger, stratified sample analyzing dogs drinking water composition and long-term health and wellness outcomes in dogs living in diverse geographies. These results may impact veterinary care decisions and husbandry, and underscore the validity and importance of utilizing dogs as sentinels of human health outcomes in the context of drinking water contamination.

ecology↗

bioRxiv2024

Computer vision guided rapid and precise automated cranial microsurgeries in rodents

Neuroscientists employ various experimental procedures to interface with the brain to study and perturb the neural activity during behavior. A common procedure that allows such physical interfacing is cranial microsurgery, wherein small to large craniotomies are performed in the overlying skull for insertion of neural interfaces or implantation of optically clear windows for long-term cranial observation. Performing craniotomies is, however, a skilled task that requires significant time and practice and further needs to be carried out precisely to ensure that the procedure does not cause damage to the underlying brain and dura. Here, we present a computer vision-guided craniotomy robot (CV-Craniobot) that utilizes machine learning to accurately estimate the dorsal skull anatomy from optical coherence tomography (OCT) images. Instantaneous information of the skull morphology is used by a robotic mill to rapidly and precisely remove the skull from a desired craniotomy location. We show that the CV-Craniobot can perform small (2 - 4 mm diameter) craniotomies with near 100% success rates within 2 minutes and large craniotomies encompassing most of the dorsal cortex in less than 5 minutes. Thus, the CV-Craniobot enables rapid and precise craniotomies, significantly reducing surgery time as compared to human practitioners and eliminating the need for long training.

neuroscience↗

bioRxiv2024

ninjaCap: A fully customizable and 3D printable headgear for fNIRS and EEG brain imaging

SignificanceAccurate sensor placement is vital for non-invasive brain imaging, particularly for functional near infrared spectroscopy (fNIRS) and diffuse optical tomography (DOT), which lack standardized layouts like EEG. Custom, manually prepared probe layouts on textile caps are often imprecise and labor-intensive. AimWe introduce a method for creating personalized, 3D-printed headgear, enabling accurate translation of 3D brain coordinates to 2D printable panels for custom fNIRS and EEG sensor layouts, reducing costs and manual labor. ApproachOur approach uses atlas-based or subject-specific head models and a spring-relaxation algorithm for flattening 3D coordinates onto 2D panels, using 10-5 EEG coordinates for reference. This process ensures geometrical fidelity, crucial for accurate probe placement. Probe geometries and holder types are customizable and printed directly on the cap, making the approach agnostic to instrument manufacturers and probe types. ResultsOur ninjaCap method offers 2.2{+/-}1.5 mm probe placement accuracy. Over the last five years, we have developed and validated this approach with over 50 cap models and 500 participants. A cloud-based ninjaCap generation pipeline along with detailed instructions is now available at openfnirs.org. ConclusionsThe ninjaCap marks a significant advancement in creating individualized neuroimaging caps, reducing costs and labor while improving probe placement accuracy, thereby reducing variability in research.

neuroscience↗

bioRxiv2024

Trafficking of Connexin36 (Cx36) in the early secretory pathway

Gap junctions formed by the major neuronal connexin Cx36 function as electrical synapses in the nervous system and provide unique functions such as synchronizing activities or network oscillations. Although the physiological significance of electrical synapses for neuronal networks is well established, little is known about the pathways that regulate the transport of its main component: Cx36. Here we have used HEK293T cells as an expression system in combination with siRNA and BioID screens to study the transition of Cx36 from the ER to the cis Golgi. Our data indicate that the C-terminal tip of Cx36 is a key factor in this process, mediating binding interactions with two distinct components in the early secretory pathway: the COPII complex and the Golgi stacking protein Grasp55. The C-terminal amino acid valine serves as an ER export signal to recruit COPII cargo receptors Sec24A/B/C at ER exit sites, whereas the PDZ binding motif "SAYV" mediates an interaction with Grasp55. These two interactions have opposing effects in their respective compartments. While Sec24 subunits carry Cx36 out of the ER, Grasp55 stabilizes Cx36 in the Golgi as shown in over expression experiments. These early regulatory steps of Cx36 are expected to be essential for the formation, function, regulation and plasticity of electrical synapses in the developing and mature nervous system.

biochemistry↗

bioRxiv2023

Path integration selectively predicts midlife risk of Alzheimer's disease

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimers disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

neuroscience↗

bioRxiv2023

Epidermal SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical pain. The role of skin mechanoreceptors in the development of mechanical pain (allodynia) is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating A{beta} axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

neuroscience↗