Biology subjects

Lei, Y.

Publications and source records attributed to Lei, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Silicon regulation of pectin methyl-esterification and cellulose microfibril organization modulates FERONIA-mediated cell wall integrity signaling for rice adaption to salt stress

The beneficial element silicon (Si) plays a crucial role in mitigating salt stress in plants and can activate intracellular signal transduction pathways that reprogram the transcriptome of salt-stressed plants. However, the mechanisms by which plants perceive Si nutrition, induce the expression of Si-responsive genes, and regulate the activity of Si-responsive proteins remain inadequately understood. In this study, we found that Si enhances cell wall integrity by increasing the degree of pectin methyl-esterification and changing the cellulose microfibril arrangement and functions as a regulatory switch for the activities of cell wall integrity sensors (FER homologs OsFLR1 and OsFLR2) during rice plant adaptation to high salinity. Furthermore, the inhibition of OsFLR1 and OsFLR2 through FER-specific inhibitors could negate the beneficial effects of Si and affect the uptake and accumulation of Si in rice seedlings. In conclusion, these findings suggest that Si signaling initiation involves FER-mediated cell wall integrity signaling pathways during salt stress adaptation in rice.

plant biology↗

bioRxiv2025

Changes in Motor Unit Activity of Co-activated Muscles During Dynamic Force Field Adaptation

Muscle co-contraction plays a critical role in motor adaptation by minimizing movement errors and enhancing joint stability in novel dynamic environments. However, the underlying changes in motor unit (MU) activity within co-activated muscles during adaptation remain largely unexplored. To investigate this, we employed advanced electromyography sensor arrays and signal processing to examine MU activation in the triceps brachii (agonist) and biceps brachii (antagonist) during a reaching task under force-field perturbation. Our results revealed a gradual reduction in movement errors and an increase in velocity with adaptation, accompanied by a decrease in muscle co-contraction from early to late adaptation phases. This reduction was primarily driven by increased triceps activity, while biceps activity remained unchanged throughout the adaptation process. At the MU level, recruitment, amplitude, and firing rate increased in both muscles during adaptation compared to baseline (without force-field perturbation). However, from early to late adaptation phases, triceps MU amplitude continued to increase, while its firing rate stabilized, suggesting a shift in force generation strategy. In contrast, biceps MU activity remained stable throughout the adaptation. These findings indicate that the reduction in co-contraction during motor adaptation is likely mediated by a shift in motor unit control strategy within the agonist muscle. The increased reliance on MU amplitude modulation rather than firing rate in later adaptation may represent a mechanism for optimizing force production while maintaining movement accuracy and joint stability in dynamic environments. NEW & NOTEWORTHYThis study examines how motor unit (MU) activity changes during motor adaptation in dynamic environments. We show that reduced co-contraction during adaptation is primarily driven by increased agonist MU amplitude rather than firing rate changes. In contrast, antagonist MU activity remains stable. These findings highlight a shift in MU control strategy that optimizes force production while maintaining movement accuracy, providing new insights into the underlying neuromuscular mechanisms of motor adaptation.

neuroscience↗

bioRxiv2025

Obesity Increases Atherosclerosis Susceptibility via Inter-tissue miR-30e-SLC7A11 Axis

BackgroundWith obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health later on. Previous studies showed that microRNA-30e (miR-30e) level is elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. MethodsMiRNA data mining and RT-PCR validations were used to demonstrate the positive association among serum level of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (RNA-seq and single-nucleus RNA-seq), metabolomics, and in silico analysis were used to establish a miR-30e-5p-SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC-Slc7a11-/-) and gain or loss of function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. ResultsThe level of adipocyte-derived miR-30e-5p was significantly upregulated in obese humans with coronary artery disease and obese and atherosclerotic mice. Via serum exosomes, the adipocyte-generated miR-30e-5p targeted SLC7A11 mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Exogenously delivered miR-30e-5p phenocopied the increased atherosclerosis in EC-Slc7a11-/- mice. In contrast, miR-30e-5p antagomir treatment reduced atherosclerosis in Apoe-/- and ob/ob mice. ConclusionOur multi-omics approaches demonstrates that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.

molecular biology↗

bioRxiv2025

Spinal Cord Ultrasound Stimulation Modulates Corticospinal Excitability

BackgroundLow-intensity focused ultrasound (LIFU) offers superior tissue penetration and enables precise neuromodulation of cortical and subcortical circuits. However, its effects on neural activity in the human spinal cord remain largely unexplored. ObjectiveTo investigate the effects of LIFU on spinal cord neuromodulation under varying conditions of intensity (spatial-peak pulse-average intensity, ISPPA), duty cycle (DC), and pulse repetition frequency (PRF). MethodsThirty-six healthy human volunteers participated in the study. A 500 kHz ultrasound transducer with a focal depth exceeding 100 mm was used to target the C8 spinal cord. Transcranial magnetic stimulation (TMS) was applied to the primary motor cortex (M1) hotspot corresponding to the first dorsal interosseous (FDI) muscle, innervated by the C8 nerve. A 500 ms-duration LIFU was delivered to the C8 spinal cord 400 ms prior to single-pulse TMS over the FDI hotspot. Spinal cord ultrasound stimulation (SCUS) was administered with varying acoustic parameters: intensities (ISPPA: 2.5 and 10 W/cm{superscript 2}), DCs (10% and 30%), and PRFs (500 and 1000 Hz). Changes in corticospinal excitability were assessed by comparing TMS-elicited motor-evoked potentials (MEPs) between active and sham SCUS conditions. ResultsSCUS with an ISPPA of 10 W/cm{superscript 2}, a DC of 30%, and a PRF of 1000 Hz significantly reduced MEP amplitudes compared to sham stimulation. However, at the high intensity (ISPPA of 10 W/cm{superscript 2}), varying the DC between 10% and 30% did not affect MEP amplitudes. Additionally, while a PRF of 1000 Hz decreased MEP amplitudes at 10 W/cm{superscript 2}, a PRF of 500 Hz did not produce significant changes. ConclusionsThe results indicate that ultrasound stimulation of the spinal cord can suppress corticospinal drive to muscles, especially when utilizing high intensity and high PRF parameters. This suggests that ultrasound stimulation may provide a novel method for modulating human spinal neural activity.

neuroscience↗

bioRxiv2025

Collagen Hydrogel Tube Microbioreactors for Cell and Tissue Manufacturing

The production of mammalian cells in large quantities is essential for various applications. However, scaling up cell culture using existing bioreactors poses significant technical challenges and high costs. To address this, we previously developed an innovative 3D culture system, known as the AlgTube cell culture system, for high-density cell cultivation. This system involves processing cells into microscale alginate hydrogel tubes, which are suspended in the culture medium within a vessel. These hydrogel tubes shield cells from hydrodynamic stress and maintain the cell mass below 400 {micro}m in diameter, facilitating efficient mass transport and creating a favorable microenvironment for cell growth. Under optimized conditions, AlgTubes supported long-term culture with high cell viability, rapid expansion (1000-fold increase over 9 days per passage), and high yield (5x10 cells/mL), offering significant advantages over conventional methods. Despite these benefits, AlgTubes have critical drawbacks. They are mechanically fragile, with frequent breakage during culture leading to cell leakage and production failures. Additionally, many cell types exhibit poor growth due to the inability to adhere to the alginate surface, making alginate hydrogel microtubes unsuitable for industrial-scale cell production. To overcome these challenges, we developed a novel collagen hydrogel tube-based microbioreactor system in this work. This system provides enhanced robustness and adhesion, enabling scalable, cost-effective, and efficient cell production for a wide range of applications.

bioengineering↗

bioRxiv2025

MiRNA Locker: A Modularized DNA Assembly As miRNA Inhibitors

MicroRNAs (miRNAs) are vital post-transcriptional regulators that govern key cellular processes such as proliferation, migration, and apoptosis. Current loss-of-function approaches, including chemically modified antisense oligonucleotides (ASOs), face significant challenges, including high costs, limited scalability, and off-target effects. To overcome these limitations, we developed "miRNA Locker", a novel miRNA inhibition platform created using the Overlapped Oligo Assembly (OOA) method. This innovative platform constructs highly stable dumbbell-shaped single-stranded DNA structures, offering improved target specificity, scalability, and cost-effectiveness. Using miR-214 as a proof-of-concept target, we demonstrated that miRNA Lockers effectively bind Argonaute-miRNA complexes, reduce miRNA levels, and induce downstream changes in gene expression and cellular phenotypes, surpassing the performance of commercial antagomirs. Furthermore, applying miRNA Lockers to miR-654 validated the regulatory role of miR-654 in modulating RNF8 expression and promoting epithelial-mesenchymal transition (EMT) in lung cancer cells. Our results highlight the potential of miRNA Lockers as a versatile tool for studying miRNA function and advancing miRNA-based therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/632138v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@c6ac1eorg.highwire.dtl.DTLVardef@14e2698org.highwire.dtl.DTLVardef@1c7d84aorg.highwire.dtl.DTLVardef@148f9c1_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

Fluid replacement and acute systemic inflammatory response syndrome during eight-hour extreme heat exposure in young men

Prolonged exposure to extreme heat poses significant risks, including systemic inflammatory response syndrome (SIRS), organ damage and hormonal imbalance. While fluid replacement is commonly recommended to mitigate these effects, its efficacy under uncompensable heat stress remains unclear. This study investigated the impacts of fluid replacement on thermoregulation, systemic inflammation, organ stress, cortisol levels and plasma electrolyte balance during eight-hour of extreme heat exposure in healthy young men. Twelve participants (age: 24.7{+/-}1.6 years; body surface area: 1.9{+/-}0.1 m{superscript 2}) underwent two randomized trials (dehydration: 125 mL/hour; euhydration: 375 mL/hour) in a heat chamber (40 {degrees}C, 55% RH). Biomarkers of inflammation (e.g., IL-6, IL-1{beta}), oxidative stress (e.g., MDA, SOD), organ function (ALT, BUN), cortisol, and electrolytes (sodium, potassium, chloride) were measured before and after exposure. Core temperature (Tcore) was continuously monitored. Results showed that fluid replacement significantly reduced Tcore at the end of the exposure (38.0{+/-}0.12 {degrees}C vs. 38.2{+/-}0.10 {degrees}C, p=0.046). However, it exacerbated systemic inflammation (IL-6: euhydration 19.8{+/-}4.3 pg/mL vs. dehydration 12.5{+/-}2.8 pg/mL, p<0.01) and liver stress (ALT: euhydration 45.3{+/-}6.7 U/L vs. dehydration 34.1{+/-}5.5 U/L, p=0.03). Cortisol levels decreased significantly in the euhydration group (p=0.041), potentially indicating attenuated stress resilience. Electrolyte imbalances (reduced sodium and potassium concentrations) were observed in the euhydration condition. Taken together, while fluid replacement reduced Tcore, it did not mitigate SIRS and instead exacerbated systemic inflammation, liver stress, and electrolyte imbalances, potentially through hypotonic osmotic stress. These findings underscore the need for personalized hydration strategies that balance fluid and electrolyte intake during extreme heat exposure to minimize health risks. Key pointsO_LIThis study investigated the effects of fluid replacement on acute inflammatory responses, thermoregulation, and organ stress markers in healthy young males exposed to eight hours of uncompensable heat stress. C_LIO_LIFluid replacement did not mitigate acute systemic inflammatory response syndrome (SIRS) but exacerbated inflammatory and organ stress markers despite reducing core temperature. C_LIO_LICore temperatures remained significantly lower in the euhydration group, but systemic and hepatic inflammatory markers worsened, highlighting the complexity of hydration strategies under extreme heat. C_LIO_LIWe emphasize the need for individualized hydration strategies incorporating electrolyte balance and sweat rate monitoring to minimize SIRS risk. C_LIO_LIWe provide actionable insights into heat stress physiology, with implications for occupational health guidelines, public health policies, and climate change adaptation. C_LI

physiology↗

bioRxiv2024

Modulating Motor Cortex Plasticity via Cortical and Peripheral Somatosensory Stimulation

The interaction between the motor and somatosensory systems is essential for effective motor control, with evidence indicating that somatosensory stimulation influences the excitability of the primary motor cortex (M1). However, the mechanisms by which repetitive stimulation of both cortical and peripheral somatosensory systems affects M1 plasticity are not well understood. To investigate this, we examined the effects of continuous theta-burst stimulation (cTBS) applied to the primary somatosensory cortex (S1) and transcutaneous electrical nerve stimulation (TENS) of the median nerve on various measures of corticospinal excitability and M1 intracortical circuits. Specifically, we assessed motor-evoked potentials (MEPs), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI) before and after administering cTBS and TENS. Our results demonstrated that cTBS increased MEPs for at least 50 minutes, whereas TENS increased MEPs for 10 minutes. Neither cTBS nor TENS had an impact on SICI and ICF. However, cTBS decreased SAI, while TENS did not affect SAI. The sham procedures for both cTBS and TENS did not produce significant changes in MEPs, SICI, ICF, or SAI. These findings suggest that both cortical and peripheral somatosensory stimulation modulate corticospinal excitability, with the effects of cortical stimulation being more prolonged. Neither type of stimulation influences inhibitory and excitatory intracortical neural circuitry within M1. Notably, cortical somatosensory stimulation modulates the interaction between M1 and S1, whereas peripheral somatosensory stimulation does not. This study elucidates distinct mechanisms through which cortical and peripheral somatosensory stimulation influence M1 plasticity. NEW & NOTEWORTHYThis study identifies distinct mechanisms through which cortical and peripheral somatosensory stimulation influence motor cortex (M1) plasticity. Both continuous theta-burst stimulation (cTBS) of the primary somatosensory cortex (S1) and transcutaneous electrical nerve stimulation (TENS) of the median nerve enhance corticospinal excitability, with cTBS exhibiting longer-lasting effects. Importantly, cTBS, but not TENS, modulates the interaction between M1 and S1. These findings form the basis for developing targeted somatosensory interventions aimed at modulating motor function.

neuroscience↗

bioRxiv2024

Mapping the druggable targets displayed by human colonic enteroendocrine cells

Enteroendocrine cells (EECs) are specialized intestinal hormone-secreting cells that play critical roles in metabolic homeostasis, digestion, and gut-brain communication. They detect diverse stimuli including endocrine, immune, neuronal, microbial, and dietary signals, through a complex array of receptors, ion channels, and transporters, to modulate the release of over 20 hormones. These molecular sensors serve as potential drug targets to modulate hormone secretion, but until recently, catalogues of such targets in human colonic EECs have not been produced. To address this gap, we performed bulk and single-cell RNA sequencing on fluorescently labelled EECs isolated from human colonic organoids, identifying and cataloguing potential druggable targets. This catalogue includes receptors, orphan GPCRs, transporters, and hormones not previously reported in human colonic EECs. Comparison with murine EECs highlighted interspecies similarities and differences, key data to facilitate the design and optimise the predictive accuracy of pre-clinical models. We also functionally validated two receptors not previously identified in human EECs: IL-13R1, was expressed in both peptide-producing EECs and serotonin producing Enterochromaffin cells (ECs), and its ligand IL-13 stimulated the secretion of glucagon-like peptide-1 (GLP-1) and serotonin measured in real-time, and GPR173, which was selectively expressed in ECs and, when activated by its agonist Phoenixin-20, also promoted serotonin release. These analyses provide a valuable resource for therapeutic interventions aimed at modulating gut hormone secretion, with potential applications in treating gastrointestinal, metabolic, and other related disorders.

cell biology↗

bioRxiv2024

Loss of 18q alters TGFβ signalling affecting anteroposterior neuroectodermal fate in human embryonic stem cells

Chromosomal abnormalities acquired during cell culture can compromise the differentiation potential of human pluripotent stem cells (hPSCs). In this work, we identified a diminished differentiation capacity to retinal progenitor cells in human embryonic stem cells (hESCs) with loss of chromosome 18q. Time-course gene-expression analysis during spontaneous differentiation and single-cell RNA sequencing found that these variant cell lines poorly specified into anterior neuroectoderm, and, when progressing through differentiation, they yielded poorly pigmented cells, with proliferating and pluripotent cell populations. The variant cell lines showed dysregulation of TGF{beta} signaling during differentiation, and chemical modulation of the TGF{beta} pathways showed that the basis of the improper specification was due to imbalances in the anteroposterior neuroectodermal fate commitment.

cell biology↗

bioRxiv2024

Impact of Acetate and Optimized Nitrate Levels on Mixotrophic Growth and Protein Dynamics in Chlorella Sorokiniana

Microalgae are well-known for their role as sustainable bio-factories, offering a promising solution to the global food and nutrition crisis. To clarify the potential of Chlorella sorokiniana UTEX 1230 for food applications, particularly as an alternative protein source, the study employed a mixotrophic cultivation mode with sodium acetate (NaAc) as a cost-effective organic carbon (NaAc-C) source. Varying levels of NaAc-C and nitrate-sourced nitrogen were investigated, optimizing the effect of metabolic characteristics of the microalgal growth. The designed heterotrophic cultivation confirmed the ability of C. sorokiniana UTEX 1230 to grow on NaAc-C, and then the mixotrophic cultures, when supported by both NaAc-C and CO2, exhibited superior growth performance, achieving double the biomass concentration compared to the autotrophic control. The addition of nitrogen (750 mg/L NaNO) facilitated the thorough metabolism of NaAc-C and enhanced photosynthetic activity indicated by a 196% increase in pigment levels, which resulted in a maximum biomass concentration of 2.82 g/L in the 150 mM NaAc-C group. A detailed analysis of nitrogen and protein concentrations over time revealed that higher nitrogen availability led to greater protein accumulation which was then degraded to support essential life activities under nitrogen starvation. Therefore, it is suggested that supplementing nitrate on the 3rd day and harvesting on the 4th day could be strategically implemented to increase protein yield from 0.17 g/L/d to 0.34 g/L/d. These findings offer theoretical guidance for further refining this microalgal strain for use as an alternative protein.

bioengineering↗

bioRxiv2024

Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study

In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/610643v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12fb447org.highwire.dtl.DTLVardef@e4bfacorg.highwire.dtl.DTLVardef@1e3d262org.highwire.dtl.DTLVardef@93984_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe conditioned stimulus induced larger MEPs compared to the unconditioned stimulus C_LIO_LIThe connectivity between SMC and M1 diminished when the SMC coil was moved forward C_LIO_LIFindings highlight the importance of spatial specificity for modulation of SMC-M1 circuitry C_LI

neuroscience↗

bioRxiv2024

Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.

Dietary interventions such as caloric restriction (CR)1 and methionine restriction2 that prolong lifespan induce the browning of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health3,4. However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans5 reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine {gamma}-lyase (CTH)6, the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via {beta}3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

physiology↗

bioRxiv2024

De novo cancer mutations frequently associate with recurrent chromosomal abnormalities during long-term human pluripotent stem cell culture

Human pluripotent stem cells (hPSC) are pivotal in regenerative medicine, yet their in vitro expansion often leads to genetic abnormalities, raising concerns about their safety in clinical applications. This study analyzed ten human embryonic stem cell lines across multiple passages to elucidate the dynamics of chromosomal abnormalities and single nucleotide variants (SNVs) in 380 cancer-related genes. Prolonged in vitro culture resulted in 80% of the lines acquiring gains of chromosomes 20q or 1q, both known for conferring in vitro growth advantage. 70% of lines also acquired other copy number variants (CNVs) outside the recurrent set. Additionally, we detected 122 SNVs in 88 genes, with all lines acquiring at least one de novo SNV during culture. Our findings show higher loads of both CNVs and SNVs at later passages which are due to the cumulative acquisition of mutations over a longer time in culture and not to an increased rate of mutagenesis over time. Importantly, we observed that SNVs and rare CNVs follow the acquisition of chromosomal gains in 1q and 20q, while most of the low-passage and genetically balanced samples were devoid cancer-associated mutations. This suggests that the recurrent chromosomal abnormalities are the potential drivers for the acquisition of other mutations.

cell 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

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this vulnerable population. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBPs) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work sheds new light on innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

immunology↗

bioRxiv2024

Generalization in motor learning: learning bimanual coordination with one hand

The ability to coordinate movements between the hands is crucial for many daily tasks. However, the precise mechanisms governing the storage and utilization of bimanual movement and the distinct contributions of each limb in this process are currently not fully understood. Two key questions persist: 1) How is the neural representation of bimanual coordination stored in the brain, and 2) How is the information governing bimanual coordination shared between hemispheres? In this investigation, we used a virtual partner (VP) to systematically address these issues by allowing the same coordination pattern (CP) to be acquired with unimanual and bimanual movements. More specifically, we used four experimental groups: unimanual (left, right) VP, bimanual, and control conditions. For each condition, retention and transfer tests were administered immediately and 6 hours after the initial practice. The control condition employed the same protocol as unimanual conditions without practice. As anticipated, performance after practice and during retention sessions indicated that all groups learned to perform the target CP. Furthermore, generalization from unimanual to bimanual occurred when the same type of visual feedback (VF) was provided. Interestingly, the absence of VF impaired motor generalization from unimanual to bimanual condition unless the participants initially practiced the task bimanually. Taken together, our results demonstrated that both limbs could access the memory representation of the CP. However, this globally shared representation appeared to be encoded in the visual-spatial domain. The conditions without VF underscored the importance of proprioception in forming a motor representation in intrinsic coordinates. NEW & NOTEWORTHYConventional views on acquiring bimanual skills stress the need for simultaneous engagement of both hands. However, our study challenges this notion by demonstrating that the coordination pattern learned in unimanual conditions significantly boosts subsequent bimanual coordination--a novel approach to skill acquisition. Yet, this advantage diminishes without visual feedback, resulting in a breakdown of the intended bimanual coordination, highlighting the limitations of relying solely on unimanual practice.

neuroscience↗

bioRxiv2024

Rhizobial effector NopM ubiquitinates Nod factor receptor NFR5 and promotes rhizobial infection in Lotus japonicus

Bacterial pathogens and nitrogen-fixing rhizobia employ type III protein secretion system (T3SS) effectors as potent tools to manipulate plant signaling pathways, thereby facilitating infection and host colonization. However, the molecular mechanisms by which rhizobial effectors affect legume infection remain largely elusive. In this study, we investigated the symbiotic role of T3SS effectors in the interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. Mutants deficient in the T3SS genes Tts1 or NopA showed enhanced rhizobial infection of L. japonicus roots. Further mutant analysis showed that the NopT effector negatively affects infection, while the NopM effector in the absence of NopT promotes infection. Notably, NopM interacts with the Nod factor receptors LjNFR1 and LjNFR5. NopM ubiquitinates LjNFR5 on ten lysine residues as identified using mass spectrometry. Expression of NopM in L. japonicus resulted in an approximately twofold increase in LjNFR5 protein levels and enhanced rhizobial infection. Our findings indicate that NopM directly interferes with the symbiotic signaling pathway through interaction and ubiquitination of Nod factor receptors, which likely benefits rhizobial infection of L. japonicus. Our research contributes to the intricate interplay between the Nod factor signaling pathway and rhizobial T3SS effectors delivered into host cells. Significance StatementThis study unravels intricate mechanisms underlying the symbiotic interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. By focusing on the role of the rhizobial effector NopM, this research sheds light on how bacteria manipulate host symbiotic signaling to promote infection and colonization. NopM interacts with NFRs and ubiquitinates LjNFR5, suggesting a novel strategy employed by rhizobia to enhance symbiotic signaling.

microbiology↗