Biology subjects

Huang, F.

Publications and source records attributed to Huang, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Simultaneous particle tracking, phase retrieval and point spread function reconstruction

3D tracking and localization of particles, typically fluorescently labeled biomolecules, provides a direct means of monitoring cellular transport and communication. However, sample-induced wavefront distortions of emitted fluorescent light as it passes through the sample and onto the detector often yield point spread function (PSF) aberrations, presenting an important challenge to 3D particle tracking using pre-calibrated PSFs. PSF calibration is typically performed outside cellular samples, ignoring sample-induced aberrations, which can result in localization errors on the order of tens to hundreds of nanometers, ultimately compromising sub-diffraction limited tracking. In practice, correcting sample-induced aberrations currently requires sample-specific hardware adjustments, such as adaptive optics. Yet, information on sample-induced aberrations and PSF shape can be directly decoded from data collected using a 3D imaging setup (e.g., bi-focal). To this end, we propose a framework for simultaneous particle tracking, phase retrieval, and PSF reconstruction (SPT-PR) directly from the input data themselves. We apply it to sub-diffraction tracking of lytic granules released at the immunological synapse of T cells revealing slower motions in proximity of the plasma cell membrane, consistent with assembly of the fusion machinery and, ultimately, degranulation and release of toxic payloads. To accomplish this, we operate within a Bayesian paradigm, placing continuous priors on all possible pupil phase and amplitudes warranted by the data without limiting ourselves to a finite Zernike set-thereby allowing capture of intricate pupil phase details. We benchmark our framework using a wide range of synthetic and experimental data from static to diffusing particles, and generalize to multiple diffusing particles with overlapping PSFs. Further, as a result of simultaneous particle tracking, phase retrieval, and PSF reconstruction, we retrieve the pupil phase with errors smaller than 10% under a range of realistic scenarios while demonstrating that for tracking lytic granules under an idealized Gaussian PSF assumption, we recover discrepancies as large as hundreds of nanometers.

biophysics↗

bioRxiv2025

CES1 DEFICIENCY IS ASSOCIATED WITH METABOLIC REPROGRAMING AND ENDOTHELIAL DYSFUNCTION IN PULMONARY ARTERIAL HYPERTENSION

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling, driven by metabolic reprogramming, oxidative stress, and endothelial dysfunction. While BMPR2 mutations contribute to metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), their low penetrance suggests additional genetic modifiers play a role. A genetic screen of PAH PMVECs identified carboxylesterase 1 (CES1)--an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification--as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress. MethodsPAH and healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 expression was modulated in PMVECs using siRNA knockdown and plasmid overexpression. Mitochondrial and ER function were assessed via confocal microscopy and proteomics. CES1 heterozygous knockout (HET KO) and endothelial-specific knockout (ECKO) mice were exposed to normoxia or hypoxia, with lung tissues analyzed by single-cell RNA sequencing (scRNA-seq) and histopathology. ResultsCES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. Confocal imaging and metabolic studies revealed lipid droplet accumulation, reduced fatty acid oxidation, and a glycolytic shift-- phenotypes reversed by CES1 restoration. Mechanistically, CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. In vivo, CES1-deficient mice developed severe pulmonary hypertension (PH) under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways, as confirmed by lung scRNA-seq. ConclusionsCES1 is essential for pulmonary endothelial homeostasis and serves as a critical modifier of BMPR2 signaling. Given the limited efficacy of current PAH therapies in reversing endothelial dysfunction and small-vessel loss, restoring CES1 expression represents a promising therapeutic strategy.

biochemistry↗

bioRxiv2025

Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukemia

Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia, is a highly aggressive malignancy characterized by a poor prognosis, primarily due to the ability of leukemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signaling pathway in monocytic AML. Utilizing RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8+ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8+ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/643466v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@e72e5dorg.highwire.dtl.DTLVardef@19519aeorg.highwire.dtl.DTLVardef@1c8f786org.highwire.dtl.DTLVardef@f2a963_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Reduced processing and toxin binding associated with resistance to Vip3Aa in a resistant strain of fall armyworm (Spodoptera frugiperda) from Louisiana

BackgroundTransgenic crops expressing Cry and Vip3Aa insecticidal proteins from the bacterium Bacillus thuringiensis are a primary tool for controlling fall armyworm (Spodoptera frugiperda) populations. The evolution of resistance to Cry proteins in the native range of the fall armyworm has increased reliance and intensified the selection of resistance to Vip3Aa. In this study, we identified mechanisms of resistance to Vip3Aa in the LA-RR strain of S. frugiperda originating from Louisiana (USA). ResultsMidgut epithelial damage in susceptible larvae was evidenced by a significant drop in midgut pH after feeding on either Vip3Aa protoxin or activated toxin. In contrast, this midgut pH drop was only detected for activated Vip3Aa toxin in LA-RR larvae. Midgut fluids from LA-RR larvae displayed delayed processing of Vip3Aa protoxin when compared to fluids from susceptible larvae, and this slower processing was associated with reduced activity and expression of trypsin and chymotrypsin enzyme genes in the LA-RR strain. In bioassays, LA-RR larvae were significantly more susceptible to Vip3Aa protoxin pre-processed by midgut fluids from susceptible than from LA-RR larvae. In addition, midgut brush border membrane vesicles from LA-RR larvae exhibited lower specific Vip3Aa toxin binding than vesicles from the susceptible strain. ConclusionThe results of this study support that both slower proteolytic processing and reduced specific binding are associated with resistance to Vip3Aa in an S. frugiperda strain from the Western hemisphere, the native range of this pest. This information increases our understanding of resistance to Vip3Aa and advances monitoring and fall armyworm management.

plant biology↗

bioRxiv2025

SPTnet: a deep learning framework for end-to-end single-particle tracking and motion dynamics analysis

Single-particle tracking (SPT) provides high-resolution spatial-temporal information on biomolecule dynamics. However, localization inaccuracies, limited track lengths, heterogeneous fluorescence backgrounds, and potential molecular motion blur pose significant challenges that hinder the accurate extraction of movement trajectories and their underlying motion behavior. The conventional SPT pipeline struggles to comprehensively address detection, localization, linkage, and motion parameter inference simultaneously, resulting in information loss during sequential processing. To overcome these challenges, we propose SPTnet, an end-to-end deep learning framework that leverages a Transformer-based architecture to optimize trajectory and motion parameter estimations in parallel through a global loss. SPTnet bypasses traditional SPT processes, directly inferring molecular trajectories and motion parameters from fluorescence microscopy videos with a precision approaching the statistical information limit. Our results demonstrate that SPTnet outperforms conventional methods under commonly encountered but challenging conditions such as short trajectories, low signal-to-noise ratio (SNR), heterogeneous backgrounds, motion blur, and especially when molecules exhibit non-Brownian behaviors.

biophysics↗

bioRxiv2025

Interferometric Ultra-High Resolution 3D Imaging through Brain Sections

Single-molecule super-resolution microscopy allows pin-pointing individual molecular positions in cells with nanometer precision. However, achieving molecular resolution through tissues is often difficult because of optical scattering and aberrations. We introduced 4Pi single-molecule nanoscopy for brain with in-situ point spread function retrieval through opaque tissue (4Pi-BRAINSPOT), integrating 4Pi single-molecule switching nanoscopy with dynamic in-situ coherent PSF modeling, single-molecule compatible tissue clearing, light-sheet illumination, and a novel quantitative analysis pipeline utilizing the highly accurate 3D molecular coordinates. This approach enables the quantification of protein distribution with sub-15-nm resolution in all three dimensions in complex tissue specimens. We demonstrated 4Pi-BRAINSPOTs capacities in revealing the molecular arrangements in various sub-cellular organelles and resolved the membrane morphology of individual dendritic spines through 50-{micro}m transgenic mouse brain slices. This ultra-high-resolution approach allows us to decipher nanoscale organelle architecture and molecular distribution in both isolated cells and native tissue environments with precision down to a few nanometers.

neuroscience↗

bioRxiv2025

ViFIT-assisted Histopathology: From H&E Style Standardization to Virtual Fiber Image Transformation

Deep learning-based virtual fiber staining provides a promising complement to routine H&E pathology. However, the reliance on predefined staining style inputs and manual intervention limits the clinical applicability of existing methods. To address these challenges, we introduce ViFIT-assisted histopathology, a two-stage diagnostic approach that integrates our proposed unsupervised deep learning-based virtual fiber transformation model (ViFIT). This approach enables the conversion of H&E-stained images with diverse styles into pathologist-preferred H&E images, while simultaneously generating content-consistent virtual fiber images containing label-free collagen fibers and stained reticular and elastic fibers. ViFIT-assisted histopathology reveals tumor-associated fibers and provides quantitative metrics across multiple intraoperative and postoperative cases. Experimental results demonstrate that ViFIT significantly outperforms state-of-the-art unsupervised methods in both style standardization and virtual staining, across various downstream tasks and cancer types. By eliminating the need for staining variation and manual annotation, ViFIT-assisted histopathology streamlines histopathology workflows, making it well-suited for multi-center consultations and differential diagnosis.

pathology↗

bioRxiv2024

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult for the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA sequencing approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2 and NFKBIA that associated with mTOR pathway, inflammatory response and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, {gamma}-H2AX, {beta}-Gal and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of drug-resistant epilepsy patients with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent markers expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

neuroscience↗

bioRxiv2024

Hypusinated and unhypusinated isoforms of eIF5A exert distinct effects in models of pancreas development and function

Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5AHyp) in cellular proliferation is well-characterized, the role of its unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent effects on cellular replication and metabolism distinct from the loss of eIF5AHyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and {beta}-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by the dysregulation of mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely due to the lack of eIF5AHyp. In mice, {beta} cell-specific deletion of DHPS impaired {beta} cell mass expansion and glucose tolerance, while eIF5A deletion had no statistically significant effects. These findings reveal an independent role for eIF5ALys in regulating developmental and functional responses and that a balance in levels of the hypusinated and unhypusinated isoforms of eIF5A may be pivotal in cellular phenotypes in health and disease.

cell biology↗

bioRxiv2024

Cholecystokinin-expressing GABA neurons elicit long-term potentiation in the cortical inhibitory synapses and attenuate sound-shock associative memory

Neuronal interactions between inhibitory and excitatory neurons play a pivotal role in regulating the balance of excitation and inhibition in the central nervous system (CNS). Consequently, the efficacy of inhibitory/excitatory synapses profoundly affects neural network processing and overall neuronal functions. Here, we describe a novel form of long-term potentiation (LTP) induced at cortical inhibitory synapses and its behavioral consequences. We show that high-frequency laser stimulation (HFLS) of GABAergic neurons elicit inhibitory LTP (i-LTP) in pyramidal neurons of the auditory cortex (AC). The selective activation of cholecystokinin-expressing GABA (GABACCK) neurons is essential for the formation of HFLS-induced i-LTP, rather than the classical parvalbumin (PV) neurons and somatostatin (SST) neurons. Intriguingly, i-LTP can be evoked in the AC by adding the exogenous neuropeptide CCK when PV neurons and SST neurons are selectively activated in PV-Cre and SST-Cre mice, respectively. Additionally, we discovered that low-frequency laser stimulation (LFLS) of PV neurons paired with HFLS of GABACCK neurons potentiates the inhibitory effect of PV interneurons on pyramidal neurons, thereby generating heterosynaptic i-LTP in the AC. Notably, light activation of GABACCK neurons in CCK-Cre mice significantly attenuates sound-shock associative memory, while stimulation of PV neurons does not affect this memory in PV-Cre mice. In conclusion, these results demonstrate a critical mechanism regulating the excitation-inhibition balance and modulating learning and memory in cortical circuits. This mechanism might serve as a potential target for the treatment of neurological disorders, including epilepsy and Alzheimers disease.

neuroscience↗

bioRxiv2024

Impaired experience-dependent inter-areal network connectivity across the visual cortex in Fmr1 KO mice

Fragile X syndrome (FX) is the most prevalent inheritable form of autism spectrum disorder (ASD), characterized by hypersensitivity, difficulty in habituating to new sensory stimuli, and intellectual disability. Individuals with FX often experience visual perception and learning deficits. Visual experience leads to the emergence of the familiarity-evoked theta band oscillations in the primary visual cortex (V1) and the lateromedial area (LM) of mice. These theta oscillations in V1 and LM are synchronized with each other, providing a mechanism of sensory multi-areal binding. However, how this multi-areal binding and the corresponding theta oscillations are altered in FX is not known. Using iDISCO whole brain clearing with light-sheet microscopy, we quantified immediate early gene Fos expression in V1 and LM, identifying deficits in experience-dependent neural activity in FX mice. We performed simultaneous in vivo recordings with silicon probes in V1 and LM of awake mice and channelrhodopsin-2-assisted circuit mapping (CRACM) in acute brain slices to examine the neural activity and strength of long-range synaptic connections between V1 and LM in both wildtype (WT) and Fmr1 knockout (KO) mice, the model of FX, before and after visual experience. Our findings reveal synchronized familiarity-evoked theta oscillations in V1 and LM, the increased strength of V1[->]LM functional and synaptic connections, which correlated with the corresponding changes of presynaptic short-term plasticity in WT mice. The LM oscillations were attenuated in FX mice and correlated with impaired functional and synaptic connectivity and short-term plasticity in the feedforward (FF) V1[->]LM and feedback (FB) LM[->]V1 pathways. Finally, using 4Pi single-molecule localization microscopy (SMLM) in thick brain tissue, we identified experience-dependent changes in the density and shape of dendritic spines in layer 5 pyramidal cells of WT mice, which correlated with the functional synaptic measurements. Interestingly, there was an increased dendritic spine density and length in naive FX mice that failed to respond to experience. Our study provides the first comprehensive characterization of the role of visual experience in triggering inter-areal neural synchrony and shaping synaptic connectivity in WT and FX mice.

neuroscience↗

bioRxiv2024

Nanoscale organization is changed in native, surface AMPARs by mouse brain region and tauopathy

The distribution of synaptic and extra-synaptic AMPA receptors (AMPARs) on neuronal plasma membranes is correlated with learning and memory. Although AMPAR organization has been extensively studied in neuronal cultures, its native cell-surface distribution in intact adult brain tissue across distinct brain regions and in neurodegenerative pathology remains poorly understood. Here, we combine a selective small-molecule labeling strategy with two-color 3D super-resolution dSTORM imaging to map native surface AMPAR organization at the nanoscale in 30 micron thick mouse brain slices. We find that wild-type mice exhibit marked regional differences in AMPAR organization, with the CA1 hippocampus containing a substantially larger extrasynaptic AMPAR pool than the nearby motor and somatosensory cortex. In the PS19 tauopathy mouse model, at an age preceding overt neurodegeneration, AMPAR organization is selectively disrupted in the hippocampus but largely preserved in the cortex. Specifically, we observe depletion of the extrasynaptic receptor pool together with reduced synaptic nanodomain organization, revealing early molecular-scale synaptic remodeling associated with tau pathology. These findings provide direct structural insight into region- and disease-dependent AMPAR organization in intact adult brain tissue and establish a broadly applicable framework for nanoscale investigation of synaptic receptor architecture in health and neurological disease.

neuroscience↗

bioRxiv2024

Smooth Muscle Cells-Expressed Bmal1 Regulates Vascular Calcification Independent of the Canonical Circadian Pathway

Vascular calcification is a major cardiovascular issue that increases morbidity and mortality in diabetes patients. While dysregulation of the circadian master regulator Basic Helix-Loop-Helix ARNT-Like Protein 1 (Bmal1) in vascular smooth muscle cells (VSMC) under diabetic conditions has been suggested, its role in vascular calcification is unclear. In VSMC, Bmal1 was upregulated under high glucose treatment and in aortic tissues from a diabetic mouse model. RNA sequencing from isolated VSMC between Bmal1 deletion and wildtype mice indicated Bmal1s pro-calcification role. Indeed, reduced levels of the osteogenic master regulator, Runt-Related Transcription Factor 2 (Runx2), were found in Bmal1 deletion VSMC under diabetic conditions. Alizarin red staining showed reduced calcification in Bmal1 deletion VSMC in vitro and vascular rings ex vivo. Furthermore, in a diabetic mouse model, SMC-Bmal1 deletion showed reduced calcium deposition in aortas. Collectively, diabetes-upregulated circadian regulator Bmal1 in VSMC contributes to vascular calcification. Maintaining normal circadian regulation may improve vascular health in diabetes.

molecular biology↗

bioRxiv2024

Genomic evolution reshapes cell type diversification in the amniote brain

Over 320 million years of evolution, amniotes have developed complex brains and cognition through largely unexplored genetic and gene expression mechanisms. We created a comprehensive single-cell atlas of over 1.3 million cells from the telencephalon and cerebellum of turtles, zebra finches, pigeons, mice, and macaques, employing single-cell resolution spatial transcriptomics to validate gene expression patterns across species. Our study revealed significant species-specific variations in cell types, highlighting their conservation and diversification in evolution. We found pronounced differences in telencephalon excitatory neurons (EX) and cerebellar cell types between birds and mammals. Birds predominantly express SLC17A6 in EX, whereas mammals expressed SLC17A7 in neocortex and SLC17A6 elsewhere, possibly due to loss of SLC17A7 function loss in birds. Additionally, we identified a novel bird-specific Purkinje cell subtype (SVIL+), implicating the LSD11/KDM1A pathway in learning and circadian rhythms, and related numerous positively selected genes in birds, suggesting an evolutionary optimization of cerebellar functions for ecological and behavioral adaptation. Our findings elucidate the complex interplay between genetic evolution and environmental adaptation, underscoring the role of genetic diversification in the development of specialized cell types across amniotes.

evolutionary biology↗

bioRxiv2024

H2A.Z deposition at meiotic prophase I underlies homologous recombination and pachytene genome activation during male meiosis

Accurate meiotic progression is important for gamete formation and the generation of genetic diversity. However, little is known about the identity of chromatin regulators that underlie mammalian meiosis in vivo. Here, we identify the multifaceted functions of the chromatin remodeler ZNHIT1 in governing meiosis. The expression of Znhit1 gradually increases during the meiotic prophase, and Znhit1 knockout in spermatocytes results in arrested pachytene development, impaired DNA double-strand break repair, and defective homologous recombination. Single-cell RNA sequencing and transcriptome analysis reveal that Znhit1 loss dysregulates meiotic transcriptional programs at the pachytene stage. Chromatin immunoprecipitation data show that ZNHIT1 is needed for the incorporation of the histone variant H2A.Z into pachytene chromatin. Moreover, we found that H2A.Z cooperates with the transcription factor A-MYB to co-bind DNA elements and control gene activity. Our findings provide insights into the regulatory mechanisms governing meiotic progression and highlight ZNHIT1 as a critical regulator of meiotic progression.

developmental biology↗

bioRxiv2024

Targeting protein tyrosine phosphatase non-receptor type 2 with a novel inhibitor for AML therapy

Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.

cancer biology↗

bioRxiv2024

Flexibility in the face of climate change? A rapid and dramatic shift toward later spring migration in Hudsonian Godwits (Limosa haemastica)

With rapid environmental change, shifts in migration timing are vitally important for maintaining population stability and have been widely documented. However, little remains known about how migrants are driving these shifts and what factors may influence the effective utilization of these strategies, limiting our ability to accurately assess species- and population-level vulnerability to climate change. The Hudsonian godwit (Limosa haemastica) is an extreme long-distance migratory shorebird that has (1) previously shifted its population-level migration timing and (2) exhibits sex-specific morphological differences. Therefore, we combined over a decade of light-level geolocator tracking data from a single breeding population with a historical predictive model to assess on-going shifts in migration timing while determining the time-shifting strategies utilized by each sex. Surprisingly, we found that godwit departure and arrival timing rapidly shifted 6 days later from 2010-2023 with no differences in timing between the sexes. Despite this change in migration timing, the population has maintained an average migratory duration of 24 days, suggesting that godwits are driving shifts in arrival timing entirely by shifting their nonbreeding ground departure, something rarely documented in long-distance migrants. Yet, we also found that godwits are not shifting their migration timing in the direction predicted by our model, providing evidence that this response may not be adaptive. These results emphasize the urgent need for a more holistic approach to assessing the relative vulnerability of migratory species and the adaptiveness of changes in migration timing.

ecology↗

bioRxiv2024

Glial state changes and neuroinflammatory RIPK1 signaling are a key feature of ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron loss in the brain and spinal cord. Neuroinflammation driven by activated microglia and astrocytes is prominent in ALS, but an understanding of cell state dynamics and which pathways contribute to the disease remains unclear. Single nucleus RNA sequencing of ALS spinal cords demonstrated striking changes in glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. Activation of the necroptosis pathway in ALS spinal cords was confirmed in a large bulk RNA sequencing dataset and at the protein level. Blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses in SOD1G93A mice. We used a human iPSC-derived motor neuron, astrocyte, and microglia tri-culture system to identify potential biomarkers secreted upon RIPK1 activation, inhibited pharmacologically in vitro, and modulated in the CSF of people with ALS treated with a RIPK1 inhibitor. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

neuroscience↗