Biology subjects

Xu, W.

Publications and source records attributed to Xu, W..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

An intracellular calcium sensory complex CPKs/ECA1 controls cytosolic calcium homeostasis for plant osmosensitivity

Intracellular Ca2+ controls various cellular functions and local Ca2+ dynamics is tightly regulated upon environmental cues. Maintaining cellular Ca2+ balance is essential for plant survival. Here we report a calcium-dependent protein kinases (CPKs)-mediated signaling pathway, in conjunction with the ER membrane-resident Ca2+-ATPase ECA1, acts influentially for cytosolic Ca2+ homeostasis and osmotic stress tolerance. We show that targeting cytosolic Ca2+ efflux via specific inhibitors or eca1 mutation results in augmented [Ca2+]cyt spikes, elevated cytoplasmic ABA ([ABA]cyt) level and ultimately hypersensitive to osmotic stress. Screening of Arabidopsis CPKs revealed direct binding of CPK2/6/11 to ECA1. Moreover, CPK2/6/11 phosphorylate the N-terminal of ECA1 at Ser5, thereby enhancing its activity for cytosolic Ca2+ efflux into ER and subsequently lower [ABA]cyt. The cumulative effect of ECA1 and CPKs mutation on Arabidopsis plant sensitivity to osmotic stress further illustrates that CPKs/ECA1 acts an intracellular sensory module for plant stress tolerance via regulating [Ca2+]cyt and [ABA]cyt homeostasis. One-sentence summary: CPKs/ECA1 acts an intracellular sensory module for plant osmotic stress tolerance via regulating cytosolic Ca2+ and ABA homeostasis.

plant biology↗

bioRxiv2024

Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening

The hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminal stretch of the envelope (Env) gp41 subunit1-3. The receptor-binding gp120 subunit of Env forms a heterodimer with gp41 and assembles into a trimer, in which FP is accessible for antibody binding3. Env conformational changes or "opening" that follow receptor binding result in FP relocating to a newly formed interprotomer pocket at the gp41-gp120 interface where it is sterically inaccessible to antibody4. The mechanistic steps connecting the entry-related transition of antibody accessible-to-inaccessible FP configurations remain unresolved. Here, using SOSIP-stabilized Env ectodomains5, we visualized atomic-level details of a functional entry intermediate, where partially open Env was bound to receptor CD4, co-receptor mimetic antibody 17b, and FP-targeting antibody VRC34.01, demonstrating that FP remains antibody accessible despite substantial receptor-induced Env opening. We determined a series of structures delineating stepwise opening of Env from its closed state to a newly resolved intermediate and defining downstream re-organizations of the gp120-gp41 interface that ultimately resulted in FP burial in an antibody-inaccessible configuration. Our studies improve our understanding of HIV-1 entry and provide information on entry-related conformation reorganization of a key site of HIV vulnerability to neutralizing antibody.

microbiology↗

bioRxiv2024

ElixirSeeker: A Machine Learning Framework Utilizing Attention-Driven Fusion of Molecular Fingerprints for the Discovery of Anti-Aging Compounds

Despite the growing interest in anti-aging drug development, high cost and low success rate pose a significant challenge. We present ElixirSeeker, a new machine-learning framework designed to help speed up the discovery of potential anti-aging compounds by utilizing the attention-driven fusion of molecular fingerprints. Our approach integrates molecular fingerprints generated by different algorithms and utilizes XGBoost to select optimal fingerprint lengths. Subsequently, we assign weights to the molecular fingerprints and employ Kernel Principal Component Analysis (KPCA) to reduce dimensionality, integrating different attention-driven methods. We trained the algorithm using DrugAge database. Our comprehensive analyses demonstrate that 64-bit Attention-ElixirFP maintains high predictive accuracy and F1 score while minimizing computational cost. Using ElixirSeeker to screen external compound databases, we identified a number of promising candidate anti-aging drugs. We tested top 6 hits and found that 4 of these compounds extend the lifespan of Caenorhabditis elegans, including Polyphyllin , Medrysone, Thymoquinone and Medrysone. This study illustrates that attention-driven fusion of fingerprints maximizes the learning of molecular activity features, providing a novel approach for high-throughput machine learning discovery of anti-aging molecules.

systems biology↗

bioRxiv2024

Enzymatic Degrading Chlorophenol Wastewater by Mixed Strains of Immobilized White Rot Fungi

To address chlorophenol wastewater pollution, immobilized mixed white rot fungi (WRF) strain microsphere was designed as a solid degradation agent, using lignin peroxidase (LiP), manganese peroxidase (MnP), and laccase (Lac) to degradating the wastewater. Considering the diverse physical and chemical properties of the fungal sphere, the immobilization agent formula is optimized and comprehensive environmental factor design response surface analysis are implemented to determine the delivery conditions. Consequently, the 2,4-DCP treatment rate and extracellular enzyme activity for a 1:1 encapsulation of T. versicolor and P. sajor-caju significantly outperform those of individual strains. Using polyvinyl alcohol (PVA), sodium alginate (SA), and biochar as carriers, with sodium dihydrogen phosphate solution as crosslinker and SiO2/zeolite as additives, immobilizing mixed bacteria yielded a high-quality solid agent. This achieved a 99.33% 2,4-DCP degradation rate over 96 hours, with optimal dosage, pH, and initial 2,4-DCP concentration at 11.5 g/L, 5.5, and 40 mg/L. The degradation of 2,4-DCP by WRF selectively removes adjacent chlorine atoms to produce 4-CP, enhancing the dechlorination efficiency. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/611973v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1653067org.highwire.dtl.DTLVardef@4cc31dorg.highwire.dtl.DTLVardef@19daa33org.highwire.dtl.DTLVardef@1115c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Estimating soil mineral nitrogen from data-sparse field experiments using crop model-guided machine learning approach

Sandy soils are susceptible to excessive nitrogen (N) leaching under intensive crop production which is linked with the soils low nutrient holding capacity and high-water infiltration rate. Estimating soil mineral nitrogen (SMN) at the daily time-step is crucial in providing fertilizer recommendations balancing plant nitrogen use efficiency (NUE) and N losses to the environment. Crop models [e.g., Decision Support System for Agrotechnology Transfer (DSSAT)] can simulate the trend of SMN in varied fertilizer rates and timing of application but are unable to replicate its magnitude due to the inability to capture high-water table conditions in a sub-irrigated soil. As an alternative to such physics-based model, time-series deep learning (DL) models based on a long short-term memory (LSTM) are promising in understanding nonlinearity among complex variables. Yet, purely data-driven DL models for crops are difficult to obtain due to the insufficient amount of data available and the excessive costs with producing more data. To address this challenge, a hybrid model (hybrid-LSTM) was developed by leveraging both the DSSAT and LSTM models to estimate daily SMN primarily using daily weather, applied fertilizer rates-timings, and the SMN sparse observations. This study used the observations from field trials conducted between 2010-2014 in Hastings, FL. The first step was to calibrate the DSSAT-SUBSTOR-Potato model to produce reliable SMN of the topsoil for treatments with varied N applied fertilizer rates split among the pre-planting, emergence, and tuber-initiation stages of the potato crop. Thereafter, the hybrid-LSTM model was trained on the calibrated DSSAT simulated SMN time-series and fine-tuned its predictions using the observed SMN to improve DSSAT simulated SMN. The hybrid-LSTM model was then tested on both calibrated and uncalibrated DSSAT SMN simulations where it outperformed the DSSAT model (range of improvement ranged [~]18-30% on comparing the normalized root mean squared error) in providing reliable estimates of SMN across most of the farms and years. This novel hybrid modeling approach could guide stakeholders and farmers to build sustainable N management with improved crop NUE and yield and help in minimizing environmental losses.

physiology↗

bioRxiv2024

A Novel Partitivirus Confers Dual Contradictory Effect to Its Host Fungus: Growth Attenuation and Virulence Enhancement

Mycoviruses represent potential role in the biocontrol approach due to their ability to reduce both virulence and vegetative growth in some phytopathogenic fungi. However, the mycoviruses enhancing the damage caused by these fungi remains poorly identified and characterized. In this study, a novel double-stranded RNA (dsRNA) fungal virus, tentatively named Sinodiscula camellicola partitivirus 1 (ScPV1), was identified in the phytopathogenic fungus Sinodiscula camellicola, isolated from tea leaves. ScPV1 possesses two genomic components of 1835 and 1697 bp, each containing an open reading frame (ORF) that encodes the putative RNA-dependent RNA polymerase (RdRp) and coat protein (CP), respectively, as confirmed by mass spectrometry. Phylogenetic analysis of the amino acid sequences of the RdRps from ScPV1 and related mycoviruses placed ScPV1 within a newly proposed genus, Epsilonpartitivirus, of the family Partitiviridae. Viral purification via ultracentrifugation and transmission electron microscopy observations revealed that ScPV1 dsRNA genomes are encapsidated within virus particles approximately 31 nm in size, ranging from 24.9 to 36.8 nm, along with the RdRp protein in an unexpected size. Transfection experiments with purified virions exhibited transfectants with significant reduced growth rates while increased virulence, indicating that ScPV1 has two-sided effect on its host fungus. This finding represents a significant advancement in understanding the complex interactions between mycoviruses and their host fungi. Author summaryTo characterize new molecular and biological traits of partitiviruses will provide substantial contributions for a better understanding of mycoviruses, as partitiviruses are prevalent across a wide range of hosts, including plants, protists, and fungi. Here, we identified a novel partitivirus, tentatively named Sinodiscula camellicola partitivirus 1 (ScPV1), from a fungus infecting tea plant, marking the first report of a partitivirus from a phytopathogenic fungus infecting tea plant. ScPV1 is characterized by two dsRNA genomic components encapsidated in particles of varying sizes, along with an RNA-dependent RNA polymerase protein of an expected size and containing some unique amino acids, indicating its distinct molecular and morphological traits. Our biological tests on transfectants generated via protoplast transfection with purified virions have rigorously demonstrated that ScPV1 impairs vegetative growth while enhancing virulence in its fungal host. This finding represents the first instance of a mycovirus responsible for hypervirulence and exhibiting dual effects on a phytopathogenic fungus through virion-transfection, as well as the first case of a partitivirus conferring hypervirulence while promoting vegetative growth in a phytopathogenic fungus. We anticipate that these findings will significantly advance our understanding of the complex interactions between mycoviruses and their host fungi.

microbiology↗

bioRxiv2024

SpinalTRAQ: A novel volumetric cervical spinal cord atlas identifies the corticospinal tract synaptic projectome in healthy and post-stroke mice

Abstract/SummaryDescending corticospinal tract (CST) connections to the neurons of the cervical spinal cord are vital for performance of forelimb-specific fine motor skills. In rodents, CST axons are almost entirely crossed at the level of the medullary decussation. While specific contralateral axon projections have been well-characterized using anatomic and molecular approaches, the field currently lacks a cohesive imaging modality allowing rapid quantitative assessment of the entire, bilateral cervical cord projectome at the level of individual laminae and cervical levels. This is potentially important as the CST is known to undergo marked structural remodeling in development, injury, and disease. We developed SpinalTRAQ (Spinal cord Tomographic Registration and Automated Quantification), a novel volumetric cervical spinal cord atlas and machine learning-driven microscopy acquisition and analysis pipeline that uses serial two-photon tomography-images to generate unbiased, region-specific quantification of the fluorescent pixels of anterograde AAV-labeled CST pre-synaptic terminals. In adult mice, the CST synaptic projectome densely innervates the contralateral hemicord, particularly in laminae 5 and 7, with sparse, monosynaptic input to motoneurons in lamina 9. Motor pools supplying axial musculature in the upper cervical cord are bilaterally innervated. The remainder of the ipsilateral cord has sparse labeling in a distinct distribution compared to the contralateral side. Following a focal stroke of the motor cortex, there is a complete loss of descending corticospinal axons from the injured side. Consistent with prior reports of axon collateralization, the CST spinal projectome increases at four weeks post-stroke and continues to elevate by six weeks post stroke. At six weeks post-stroke, we observed striking synapse formation in the denervated hemicord from the uninjured CST in a homotopic distribution. Additionally, CST synaptic reinnervation increases in the denervated lamina 9 in nearly all motoneuron pools, exhibiting novel patterns of connectivity. Detailed level- and lamina-specific quantification of the bilateral cervical spinal cord synaptic projectome reveals previously undescribed patterns of CST connectivity in health and injury-related plasticity.

neuroscience↗

bioRxiv2024

Characterisation of coastal reef fish assemblages across an estuarine-urbanisation gradient using underwater visual survey and environmental DNA metabarcoding

The ongoing urbanisation of coastlines around the globe jeopardises biodiversity, including coastal marine fishes. In many places, baseline data on fish communities are inadequate for understanding the ecological and conservation impacts of this urbanisation. Here, we document spatiotemporal patterns in fish diversity (at genus level) across an estuarine gradient around Hong Kong, a highly urbanised coastal megacity bordering the estuary of the Pearl River, the second largest river in the Peoples Republic of China. We combined underwater visual census (UVC) with eDNA metabarcoding (eDNA) to overcome challenges associated with the high turbidity of Hong Kongs aquatic environment that limits the capacity for visual observations. Similar to previous studies, UVC and eDNA captured different components of the fish community, sharing only 36.5 % fish genera in common. Nevertheless, we recorded 17 % of the known fish diversity and provided a comprehensive picture of patterns in fish diversity across the gradient, despite limited sampling effort. Fish richness was reduced by 1.6-to 3-fold under the highly turbid estuarine conditions found around Lantau compared to other regions. However, overall, there were only moderate changes in the fish community regionally. Seasonal variations in fish richness and assemblage structure were observed using both approaches, taken to reflect changes in fish behaviour, physiology, and naturally occurring events (i.e., spawning and recruitment) between seasons. A notable, consistent reduction in eDNA richness in the semi-enclosed Port Shelter might reflect limited exchange of water and genetic materials. A total of eleven species that had not been previously reported from Hong Kong were detected. These potentially novel species, as well as other ecologically and economically important species in Hong Kong, might be insufficiently protected from unregulated fishing activities due to the limited spatial coverage of marine protected areas.

ecology↗

bioRxiv2024

Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis

Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage of OA patients. Thus far no systematic attempt has been made to characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of OA patients. Here we used single-cell whole genome sequencing to quantitatively analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 single chondrocytes isolated from the cartilage of hip femoral heads of 17 subjects aged from 26 to 90 years, including 9 OA patients and 8 non-OA donors. Both SNVs and InDels were found to accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate of these mutations was found to be lower in OA chondrocytes compared with chondrocytes from non-OA control subjects.

genomics↗

bioRxiv2024

Seq2Topt: a sequence-based deep learning predictor of enzyme optimal temperature

An accurate deep learning predictor is needed for enzyme optimal temperature (Topt), which quantitatively describes how temperature affects the enzyme catalytic activity. Seq2Topt, developed in this study, reached a superior accuracy on Topt prediction just using protein sequences (RMSE = 13.3 and R2=0.48) in comparison with existing models, and could capture key protein regions for enzyme Topt with multi-head attention on residues. Through case studies on thermophilic enzyme selection and predicting enzyme Topt shifts caused by point mutations, Seq2Topt was demonstrated as a promising computational tool for enzyme mining and in-silico enzyme design. Additionally, accurate deep learning predictors of enzyme optimal pH (Seq2pHopt, RMSE=0.92 and R2=0.37) and melting temperature (Seq2Tm, RMSE=7.57 and R2=0.64) were developed based on the model architecture of Seq2Topt, suggesting that the development of Seq2Topt could potentially give rise to a useful prediction platform of enzymes.

bioinformatics↗

bioRxiv2024

Genesis and regulation of C-terminal cyclic imides from protein damage

C-Terminal cyclic imides are post-translational modifications (PTMs) that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase (GSS) that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight to the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.

biochemistry↗

bioRxiv2024

Origin and stepwise improvement of vertebrate lungs

Lungs, essential for terrestrial vertebrates and present in bony fishes but absent in cartilaginous fishes, provide an ideal model for studying organ origination. Our study analyzed single-cell RNA sequencing data from mature and developing vertebrate lungs, revealing substantial similarities in cell composition, developmental trajectories and gene expression pattern across species. Notably, most lung-related genes are also present in cartilaginous fishes, indicating that gene presence alone does not guarantee lung development. We identified thousands of lung regulatory elements specific to bony fishes, with higher concentrations around genes such as tbx4 and the hoxb gene cluster. These regulatory changes might contribute to lung emergence as well as the unique co-expression patterns in lung epithelial cells, such as those related to pulmonary surfactants and cell morphology. Our research also revealed that AT1 cells are specific to mammals, and we identified a mammal-specific gene, sfta2. Knockout experiments demonstrated that sfta2 deletion causes severe respiratory defects in mice, underscoring its critical role in specialized mammalian lungs. In conclusion, our results demonstrate that the origin and evolution of lungs are driven by a complex interplay of regulatory network modifications and the emergence of new genes, underscoring the multifaceted nature of organ evolution.

evolutionary 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

Nuclear receptor E75/NR1D2 drives tumor malignant transformation by integrating Hippo and Notch pathways

Hormone therapy resistance and the ensuing aggressive progression of tumors present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy by hormone inhibition remain poorly understood. Here we show that Drosophila malignant epithelial tumors exhibit a comparable decrease in ecdysone signaling, the primary steroid hormone pathway in Drosophila. Furthermore, we find that ectopic expression of the nuclear receptor E75 partially mimics ecdysone signaling inhibition, specifically promoting the malignant transformation of benign tumors by integrating the Hippo and Notch signaling pathways. Genome-wide DNA binding profiles and biochemistry data reveal that E75 not only physically interacts with the transcription factors of both Hippo and Notch pathways, but also exhibits widespread co-binding to their target genes, thus contributing to tumor malignancy. Moreover, we validate these findings by demonstrating that depletion of NR1D2, the mammalian equivalent of E75, inhibits the activation of Hippo and Notch target genes, impeding glioblastoma progression in vivo. In summary, our study unveils a previously unrecognized mechanism by which hormone inhibition promotes tumor malignant transformation, while providing a conserved mechanistic understanding of how Hippo and Notch pathways are integrated by the oncogene E75/NR1D2 during tumor progression.

cancer biology↗

bioRxiv2024

Electrostatic interactions in nucleosome and higher-order structures are regulated by protonation state of histone ionizable residue

The nucleosome serves as the fundamental unit of chromatin organization, with electrostatic interactions acting as the driving forces in the folding of nucleosomes into chromatin. Perturbations in cellular pH conditions can lead to changes in the protonation states of titratable histone residues, impacting nucleosome surface electrostatic potentials and interactions. However, the effects of proton uptake or release of histone ionizable groups on nucleosome-partner protein interactions and higher-order chromatin structures remain largely unexplored. Here, we conducted comprehensive analyses of histone titratable residue pKa values in various nucleosome contexts, utilizing 96 experimentally determined structures. We revealed that pH-induced changes in histone residue protonation states modulated nucleosome surface electrostatic potentials and significantly influenced nucleosome-partner protein interactions. Furthermore, we observed that proton uptake or release often accompanied nucleosome-partner protein interactions, facilitating their binding processes. Additionally, using a dataset of 1266 recurrent histone cancer mutations, we systematically characterized their impact on nucleosome surface electrostatics, demonstrating their profound effects on electrostatic interactions between nucleosomes and partner proteins. Finally, our findings suggest that alterations in histone protonation or cancer mutations can also regulate nucleosome self-association, thereby modulating the organization and dynamics of higher-order chromatin structure.

biophysics↗

bioRxiv2024

Horizontally acquired CSP genes contribute to wheat adaptation and improvement

Although horizontal gene transfer (HGT) often facilitates environmental adaptation of recipient organisms, whether and how they might affect crop evolution and domestication is unclear. Here we show that three genes encoding cold shock proteins (CSPs) were transferred from bacteria to the last common ancestor of Triticeae, a tribe of the grass family that includes several major staple crops such as wheat, barley, and rye. The acquired CSP genes in wheat (TaCSPs) are functionally conserved with their bacterial homologs by encoding a nucleic acid binding protein. Experimental evidence indicates that TaCSP genes positively regulate drought response and improve photosynthetic efficiency under water deficit conditions, by directly targeting a type 1 metallothionein gene to increase ROS scavenging, which in turn contributed to the geographic expansion of wheat. We identified an elite CSP haplotype in Aegilops-tauschii, introduction of which to wheat significantly increased drought tolerance, photosynthetic efficiency and grain yields. These findings not only provide major insights into the role of HGT in crop adaptation and domestication, but also demonstrate that novel microbial genes introduced through HGT offer a stable and naturally optimized resource for transgenic crop breeding and improvement.

plant biology↗

bioRxiv2024

Pandemic Vibrio parahaemolyticus wave succession by gene loss

While spontaneous mutation and gene acquisition are well-established drivers of pathogen adaptation, the role of gene loss remains underexplored. Here, we investigated the emergence and diversification of the pandemic clone (PC) of Vibrio parahaemolyticus through large-scale phylogenomic analysis of 8,684 global isolates. The PC rapidly acquired multiple marker genes and genomic islands, subsequently diverging into successive sublineages mediating independent waves of cross-country transmission, as also observed in V. cholerae. Wave succession in the last two decades was driven by loss of putrescine utilization (Puu) genes, conferring phenotypic advantages for environmental adaptation (enhanced biofilm formation) and human transmission (increased cell adhesion/intestinal colonization, reduced virulence), consistent with the virulence trade-off hypothesis. We identified Puu-gene loss in multiple bacterial genera, with effects on biofilm and adhesion replicated in V. cholerae and Escherichia coli, suggesting convergent evolution and universal phenotypic effects. Our results highlight the indispensable role of gene loss in bacterial pathogen adaptation.

microbiology↗

bioRxiv2024

Medial amygdalar tau is associated with anxiety symptoms in preclinical Alzheimer's disease

BACKGROUNDWhile the amygdala receives early tau deposition in Alzheimers disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODSWe examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTSAmyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4, 442)=14.61, p=0.00045; F(4, 442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (rs=-0.103, p=0.015). CONCLUSIONSOur findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.

neuroscience↗