Biology subjects

Xiao, Y.

Publications and source records attributed to Xiao, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2022

Changes of platelet morphology, ultrastructure and function in patients with acute ischemic stroke based on super-resolution microscopy.

Platelets are important in acute ischemic stroke (AIS) thrombosis. The observation and evaluation of platelet ultrastructure and efficacy of antiplatelet drug in AIS patients is difficult due to microscopic limitations and sensitivity of platelet. The new super-resolution microscope (SIM) can accurately, quickly analyze the platelet ultrastructure and antiplatelet drug in AIS patients. We applied SIM to observe the morphology and ultrastructure of platelets with AIS patients in different state. SIM images were analyzed to specify the dense granules and granules change of platelets in AIS patients. Testing platelet factor 4 (PF4) to reflect platelet releasing function. We observed that platelet activation in AIS patients was greater after stimulation, with granule showing a pattern of parenchymatous masses. SIM images analyzing showed diameter of platelets, average size of granules, area% of granules per field and mean area of granules per platelet in AIS patient were lower than healthy people. Platelet releasing function was suppressed at rest stage and more efficacy release after stimulation. 2MeSamp inhibited parenchymatous masses of granules and reduced PF4 release of platelets after stimulation. According to the results, the structure and function of platelets in AIS patients are indeed altered. Additionally, SIM could be used as a new method to indicates the onset of AIS and assess antiplatelet drugs.

cell biology↗

bioRxiv2022

Structure-Kinetic Relationship for Drug Design Revealed by PLS Model with Retrosynthesis-Based Pre-trained Molecular Representation and Molecular Dynamics Simulation

Drug design based on their molecular kinetic properties is growing in application. Pre-trained molecular representation based on retrosynthesis prediction model (PMRRP) was trained from 501 inhibitors of 55 proteins and successfully predicted the koff values of 38 inhibitors for HSP90 protein from an independent dataset. Our PMRRP molecular representation outperforms others such as GEM, MPG, and common molecular descriptors from RDKit. Furthermore, we optimized the accelerated molecular dynamics to calculate relative retention times for 128 inhibitors of HSP90. We observed high correlation between the simulated, predicted, and experimental -log(koff) scores. Combining machine learning (ML) and molecular dynamics (MD) simulation help design a drug with specific selectivity to the target of interest. Protein-ligand interaction fingerprints (IFPs) derived from accelerated MD further expedite the design of new drugs with the desired kinetic properties. To further validate our koff ML model, from the set of potential HSP90 inhibitors obtained by similarity search of commercial databases, we identified two novel molecules with better predicted koff values and longer simulated retention time than the reference molecules. The IFPs of the novel molecules with the newly discovered interacting residues along the dissociation pathways of HSP90 shed light on the nature of the selectivity of HSP90 protein. We believe the ML model described here is transferable to predict koff of other proteins and enhance the kinetics-based drug design endeavor.

biophysics↗

bioRxiv2022

scCDC: a computational method for gene-specific contamination detection and correction in single-cell and single-nucleus RNA-seq data

In droplet-based single-cell RNA-seq (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) assays, systematic contamination of ambient RNA molecules biases the estimation of genuine transcriptional levels. To correct the contamination, several computational methods have been developed. However, these methods do not distinguish the contamination-causing genes and thus either under- or over-corrected the contamination in our in-house snRNA-seq data of virgin and lactating mammary glands. Hence, we developed scCDC as the first method that specifically detects the contamination-causing genes and only corrects the expression counts of these genes. Benchmarked against existing methods on synthetic and real scRNA-seq and snRNA-seq datasets, scCDC achieved the best contamination correction accuracy with minimal data alteration. Moreover, scCDC applies to processed scRNA-seq and snRNA-seq data with empty droplets removed. In conclusion, scCDC is a flexible, accurate decontamination method that detects the contamination-causing genes, corrects the contamination, and avoids the over-correction of other genes.

bioinformatics↗

bioRxiv2022

Epigenomic tomography for probing spatially-defined molecular state in the brain

Spatially-resolved genomic profiling is critical for understanding biology in a spatially ordered organ such as mammalian brain. Single-cell spatial genomic assays were developed recently for this purpose but they remain costly and labor-intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here we demonstrate a new approach, brain epigenomic tomography, that maps spatial epigenomic variations at the scale of centimeters. We profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness using a low-input technology. H3K27me3 or H3K27ac features across these slices were grouped into clusters based on their spatial variation patterns. Our approach reveals striking dynamics in frontal and caudal cortex due to kainic acid-induced seizure, linked with transmembrane ion transporter, exocytosis of synaptic vesicles, and secretion of neurotransmitter. Epigenomic tomography provides a powerful and cost-effective tool for profiling and discerning brain samples based on their spatial epigenomes.

genomics↗

bioRxiv2022

Subtle Structural Translation Remarkably Modulates the Super-Resolution Imaging of Self-blinking Rhodamines

The evolution of super-resolution imaging techniques is benefited from the ongoing competition for optimal rhodamine fluorophores. Yet, it seems blinded to select the best one among different rhodamine derivatives for specific labeling and imaging, without the knowledge on imaging impact of even the minimum structural transform. Herein, we have designed a pair of self-blinking sulforhodamines (STMR, SRhB) with the bare distinction of methyl or ethyl substituents, and engineered them with Halo protein ligands. Although the two present similar spectral properties ({lambda}ab, {lambda}fl, {square}, etc.), they demonstrated unique single-molecule characteristics preferring to individual imaging applications. Experimentally, STMR with high emissive rates was qualified for imaging structures with rapid dynamics (endoplasmic reticulum, mitochondria), and SRhB with prolonged on-times and photostability was suited for relatively "static" nuclei and microtubules. Utilized this new knowledge, the mitochondrial morphology during apoptosis and ferroptosis was first super-resolved by STMR. Our study highlights the significance of even the smallest structural modification to the modulation of super-resolution imaging performance, and would provide insight for future fluorophore design.

biochemistry↗

bioRxiv2022

Stomatal density affects rice mesophyll cell size and shape and modulates a conserved pattern of cells through the leaf

The structure of the mesophyll influences how light, CO2 and water travels inside a leaf, affecting the rates of both photosynthesis and transpiration. Recent studies in wheat and Arabidopsis have shown that the structure of the mesophyll is influenced by the density and activity of stomata, consistent with the hypothesis that gas flow via stomata can modulate internal cell growth and separation to co-ordinate leaf structure and function. To investigate whether this also occurs in rice, a staple food crop for a large fraction of the worlds population, we examined mesophyll structure in rice mutants with altered stomatal density. Our data show that stomatal function modulates mesophyll structure in rice. Variation in the degree of mesophyll lobing made a major contribution to altered mesophyll structure, suggesting that modified leaf gas flux through stomata influences an aspect of cell shape directly linked to gas exchange capacity in rice. In addition, our analysis revealed a previously unreported underlying pattern in cell size, shape and axiality across layers of the rice mesophyll, which further investigation revealed is present in a range of rice species and cultivars. The potential origin and significance of this mesophyll patterning are discussed. HIGHLIGHTWe describe a previously unreported cellular pattern in rice leaves and show that it is modulated by stomata. These results shed new light on leaf structure and function.

plant biology↗

bioRxiv2022

The conformational ensemble of an intrinsically disordered protein explains peak shapes under DNP conditions

Elucidating the conformational preferences of regions of intrinsic disorder in biologically relevant contexts represents a frontier of structural biology. The sensitivity enhancements conferred by DNP enable structural studies of proteins in native contexts by MAS NMR. However, DNP requires low temperatures which results in broad peaks, particularly for for regions of intrinsic disorder. We describe an approach to predict and interpret peak shapes for frozen regions of intrinsic disorder in terms of dihedral angle populations. We demonstrate the method using the protein a-synuclein. This approach can be used to obtain experimental structural restraints for regions of intrinsic disorder in both simplified and biological settings, providing information that eludes characterization by diffraction-based methods as well as solution-state NMR spectroscopy and molecular dynamics due to molecular size limitations.

biophysics↗

bioRxiv2022

Turn-on Rate Determines the Blinking Propensity of Rhodamine Fluorophores for Super-Resolution Imaging

Live-cell single-molecule localization microscopy has advanced with the development of self-blinking rhodamines. A pKcycling of <6 is recognized as the criterion for self-blinking, yet partial rhodamines matching the standard fail for super-resolution reconstruction. To resolve this controversy, we constructed two typical self-blinking rhodamines (pKcycling = 5.67, 5.35) and a tetramethylsulfonamide rhodamine with unfit pKcycling characteristic (7.00). Kinetic study uncovered slow equilibrium rates and limited blink numbers resulted in the reconstruction failure of partial rhodamines. From the kinetic disparity, a turn-on rate was abstracted to reveal the natural blinking frequency. The new parameter independent from applying laser satisfactorily explained the imaging failure, efficacious for determining the propensity of self-blinking from a kinetic perspective. Following the prediction from this parameter, the tetramethylsulfonamide rhodamine enabled live-cell super-resolution imaging of various organelles through Halo-tag technology. It is convinced that the turn-on rate would be a practical indicator of self-blinking and imaging performance.

biochemistry↗

bioRxiv2022

An expandable FLP-ON::TIR1 system for precise spatiotemporal protein degradation in C. elegans

The auxin-inducible degradation system has been widely adopted in the C. elegans research community for its ability to empirically control the spatiotemporal expression of target proteins. This system can efficiently degrade auxin-inducible degron (AID)-tagged proteins via the expression of a ligand-activatable AtTIR1 protein derived from A. thaliana that adapts target proteins to the endogenous C. elegans proteosome. While broad expression of AtTIR1 using strong, ubiquitous promoters can lead to rapid degradation of AID-tagged proteins, cell type-specific expression of AtTIR1 using spatially restricted promoters often results in less efficient target protein degradation. To circumvent this limitation, we have developed a FLP/FRT3-based system that functions to reanimate a dormant, high-powered promoter that can drive sufficient AtTIR1expression in a cell type-specific manner. We benchmark the utility of this system by generating a number of tissue specific FLP-ON::TIR1 drivers to reveal genetically separable cell type-specific phenotypes for several target proteins. We also demonstrate that the FLP-ON::TIR1 system is compatible with enhanced degron epitopes. Finally, we provide an expandable toolkit utilizing the basic FLP-ON::TIR1 system that can be adapted to drive optimized AtTIR1expression in any tissue or cell type of interest.

developmental biology↗

bioRxiv2022

Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function

SWItch/Sucrose Non-Fermenting (SWI/SNF) complexes are a family of chromatin remodellers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here we identify an alanine to valine causing mutation in the SWI/SNF subunit snfc-5 (SMARCB1 in humans) that prevents embryonic lethality in C. elegans nematodes harbouring a loss-of-function mutation in the SWI/SNF subunit swsn-1 (SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 (UBR5 in humans) or hecd-1 (HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating this specific subset of genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 might be viable therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.

developmental biology↗

bioRxiv2022

The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae.

The presence of anticancer clerodane diterpenoids is a chemotaxonomic marker for the traditional Chinese medicinal plant Scutellaria barbata, although the molecular mechanisms behind clerodane biosynthesis are unknown. Here, we report a high-quality assembly of the 414.98 Mb genome of S. barbata into thirteen pseudochromosomes. Using phylogenomic and biochemical data, we mapped the plastidial metabolism of kaurene (gibberellins), abietane and clerodane diterpenes in three species of the family Lamiaceae (Scutellaria barbata, Scutellaria baicalensis and Salvia splendens), facilitating the identification of genes involved in the biosynthesis of the clerodanes, kolavenol and isokolavenol. We show that clerodane biosynthesis evolved through recruitment and neofunctionalization of genes from gibberellin and abietane metabolism. Despite the assumed monophyletic origin of clerodane biosynthesis which is widespread in species of the Lamiaceae, our data show distinct evolutionary lineages and suggest polyphyletic origins of clerodane biosynthesis in the family Lamiaceae. Our study not only provides significant insights into the evolution of clerodane biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the elucidation of anticancer clerodanes biosynthesis and future metabolic engineering efforts to increase the production of these high-value chemicals.

plant biology↗

bioRxiv2022

Quercetin reduces APP expression, oxidative stress and mitochondrial dysfunction in the N2a/APPswe cells via ERK1/2 and AKT pathways

Abnormal amyloid-{beta} (A{beta}) abnormal accumulation and oxidative stress play important roles in Alzheimers disease (AD). Quercetin has been reported to possess antioxidant and anti-inflammatory properties, and thus of therapeutic interests for neurodegenerative disorders. In the present study, we aimed to characterize the mechanisms by which quercetin exerts neuroprotective effects in murine neuroblastoma N2a cells stably expressing human Swedishh mutant amyloid precursor protein (APP). Quercetin treatment exhibited low cytoxicity, attenuated APP expression and APP-induced oxidative neurotoxicity in N2a/APP cells. We found that quercetin effected via the down-regulation of phospho-extracellular signal{square}regulated protein kinase (p-ERK1/2) pathway and up-regulation of phospho-protein kinase B (p-AKT) pathway in N2a/APP cells. In addition, quercetin ameliorated the elevated levels of reactive oxygen species using DCFH-DA flow-cytometry in N2a/APP cells, lipid peroxidation using (4-HNE), and DNA oxidation (8-OHdG assays). Quercetin ameliorated the loss of mitochondrial membrane potential using JC-1 fluorescence assay in N2a/APP cells in a dose-dependent mannor. In conclusion, we domenstrated the neuroprotective effects of quercetin against the APP expression induced oxidative neurotoxicity, impairment of mitochondrial function and oxidative stress through inactivation of the ERK1/2 signaling pathway and activation of AKT signaling pathways.

neuroscience↗

bioRxiv2022

Global genomic analysis reveals the genetic origin and secondary invasion of fall armyworm in the Eastern hemisphere

The major plant pest fall armyworm (FAW), Spodoptera frugiperda, is native to the Americas and has colonized African and Asian countries in the Eastern hemisphere since 2016, causing severe damage to multiple agricultural crop species. However, the genetic origin of these invasive populations require more in-depth exploration. We analyzed genetic variation across FAW genomes of 153 newly sequenced individuals from Eastern hemisphere and 127 individuals mostly originating from the Americas. The global genetic structure of FAW shows that the FAW in American has experienced deep differentiation, largely consistent with the Z-chromosomal Tpi haplotypes commonly used to differentiate "corn-strain" and "rice-strain" populations. Results indicate that the invasive Eastern hemisphere populations are different from the American ones and have relatively homogeneous population structure, consistent with the common origin and recent spreading from Africa to Asia. Our analyses suggest that north-and central American "corn-strain" FAW are the most likely sources of the invasion into the Eastern hemisphere. Furthermore, evidence based on genomic, transcriptomic and mitochondrial haplotype network analysis suggest that there has been an earlier independent introduction of FAW into Africa that introgressed into the recent invasive population.

molecular biology↗

bioRxiv2022

The injury-induced circular RNA circGLIS3 activates dermal fibroblasts to promote wound healing

Delayed skin wound healing and excessive scarring are consequences of an impaired healing process and represent a major health and economic burden worldwide. Current intervention strategies lack efficacy and suffer from high recurrence rates necessitating the investigation into alternative treatment modalities like circular RNAs (circRNAs). By RNA sequencing, we profiled circRNA expression changes during human skin wound healing as well as in keratinocytes and fibroblasts isolated from donor-matched skin and acute wounds. CircGLIS3 was found to be transiently upregulated in the dermal fibroblasts upon skin injury, which was at least partially due to the activated IL-1 signaling. Similarly, overabundant circGLIS3 expression was detected in human keloid lesions compared to the surrounding healthy skin. We found that circGLIS3 resided mainly in the cytoplasm, where it interacted with and stabilized Procollagen C-endopeptidase enhancer 1 (PCPE-1) protein to enhance TGF-{beta} signaling, fibroblast activation, and production of extracellular matrix - important biological processes required for wound repair. Accordingly, knockdown of circGLIS3 in human ex vivo wounds potently reduced wound contraction and delayed re-epithelialization. Collectively, we have identified a previously uncharacterized circRNA regulator of human skin wound healing that may open an avenue for circRNA-based therapeutics for abnormal scarring or nonhealing wounds. One Sentence SummaryTransient increase of the circular RNA circGLIS3 promotes the wound fibroblast activation and extracellular matrix production to facilitate wound closure.

molecular biology↗

bioRxiv2022

Host mixotrophy, habitat stability and recombination may all decrease geographic differentiation between symbiont populations in Western Pacific deep-sea mussels

The intra-host composition of horizontally transmitted microbial symbionts can vary across host populations due to interactive effects of host genetics, environmental and geographic factors. While adaptation to local habitat conditions can drive geographic subdivision of symbiont strains, it is unknown whether these patterns are universal and how differences in ecological characteristics among host-symbiont associations influence the genomic structure of symbiont populations. To address this question, we sequenced metagenomes of different populations of the deep-sea mussel Bathymodiolus septemdierum, which are common at Western Pacific deep-sea hydrothermal vents and show characteristic patterns of niche partitioning with sympatric gastropod symbioses. Bathymodiolus septemdierum lives in close symbiotic relationship with sulfur-oxidizing chemosynthetic bacteria but supplements its symbiotrophic diet through filter-feeding, enabling it to occupy ecological niches with less exposure to geochemical reductants. Our analyses indicate that symbiont populations associated with B. septemdierum show structuring by geographic location, but that the dominant symbiont strain is uncorrelated with vent site. These patterns are in contrast to co-occurring Alviniconcha and Ifremeria symbioses that exhibit greater symbiont nutritional dependence and occupy habitats with higher spatial variability in environmental conditions. Our results suggest that relative habitat homogeneity combined with sufficient symbiont dispersal and genomic mixing might promote persistence of similar symbiont strains across geographic locations, while mixotrophy might decrease selective pressures on the host to affiliate with locally adapted symbiont strains. Overall, these data contribute to our understanding of the potential mechanisms influencing symbiont population structure across a spectrum of marine microbial symbioses that vary in ecological niche and relative host dependency.

evolutionary biology↗

bioRxiv2022

An evolutionally conserved archaeal KEOPS complex functions in DNA repair

KEOPS is a multi-subunit protein complex conserved in eukaryotes and archaea. It is composed of Pcc1, Kae1, Bud32, Cgi121, and Gon7 in eukaryotes and is primarily involved in N6-threonylcarbamoyl adenosine (t6A) modification of tRNAs. Recently, KEOPS is reported to participate in homologous recombination repair in yeast. To characterize the KEOPS in archaea (aKEOPS), we conducted genetic and biochemical analyses of its encoding genes in the hyperthermophilic archaeon Saccharolobus islandicus. We show that aKEOPS also possesses five subunits, Pcc1, Kae1, Bud32, Cgi121, and Pcc1-like (or Gon7-like), just as eukaryotic KEOPS. Pcc1-like has physical interactions with Kae1 and Pcc1 and can mediate the monomerization of the dimeric subcomplex (Kae1-Pcc1-Pcc1-Kae1), suggesting that Pcc1-like is a functional homolog of the eukaryotic Gon7 subunit. Strikingly, none of the genes encoding aKEOPS subunits, including Pcc1 and Pcc1-like, can be deleted in the wild type and in a t6A modification complementary strain named TsaKI, implying that aKEOPS complex is essential for an additional cellular process in this archaeon. Knock-down of the Cgi121 subunit leads to severe growth retardance in the wild type which is partially rescued in TsaKI. These results suggest that aKEOPS plays an essential role independent of cellular t6A modification level. In addition, archaeal Cgi121 possesses dsDNA-binding activity which relies on its tRNA 3 CCA tail binding module. Our study clarifies the subunit organization of archaeal KEOPS and suggests of an origin of eukaryotic Gon7. The study also reveals a possible link between the function in t6A modification and the additional function presumably homologous recombination.

microbiology↗

bioRxiv2022

Targeting Epsins by nanotherapy regulates lipid metabolism and promotes 1 ABCG1-mediated cholesterol efflux to fortify atheroma regression

BACKGROUNDExcess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically-target macrophage Epsins with specially-designed S2P-conjugated lipid nanoparticles (NPs), which encapsulate small interfering RNAs to suppress Epsins. METHODSWe used single cell RNA sequencing (scRNA-seq) with our newly developed algorithm MEBOCOST to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (LysM-DKO-ABCG1fl/+). The NPs targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis. RESULTSWe revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific NP delivery of Epsin siRNAs, we showed that silencing of macrophage Epsins markedly diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1. CONCLUSIONSOur findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux. Novelty and SignificanceO_ST_ABSWHAT IS KNOWN?C_ST_ABSO_LIEpsin endocytic adaptor proteins are upregulated in human and mouse atherosclerotic lesions C_LIO_LILesional macrophages internalize lipids primarily through scavenger receptor-mediated endocytosis such as CD36 and SR-A C_LIO_LIMacrophage-mediated cholesterol efflux and reverse cholesterol transport is crucial to atheroma resolution C_LI WHAT NEW INFORMATION DOES THIS ARTICLE CONTRIBUTE?O_LIScRNA-seq combined with the newly-developed algorithm MEBOCOST reveals that Epsins are involved in macrophage-mediated lipid metabolic regulation C_LIO_LIMacrophage epsins promote lipid uptake by targeting CD36 endocytosis and membrane recycling via the Epsin ENTH domain C_LIO_LIEpsins bind ubiquitinated ABCG1--resulting in the endocytosis and lysosomal degradation of this cholesterol transporter, which reduces cholesterol efflux. C_LIO_LIMacrophage-specific, nanoparticle-mediated RNAi delivery exhibits a therapeutic benefit for the treatment of atherosclerosis C_LIO_LIAtherosclerotic plaque regression using this nanoparticle delivery platform represents a clinically-relevant approach for the treatment of advance atherosclerosis C_LI BRIEF SUMMARYDespite the development of new cholesterol-lowering therapies, including the recently approved PCSK9 small interfering RNA (siRNA) antagonists, patients still face a tremendous risk of developing major acute cardiovascular events resulting from chronic inflammation in the plaque. We employed a novel nanomedicine platform containing a stabilin-2 targeting peptide (S2P) to deliver Epsin-specific siRNAs to lesional macrophages. We discovered that inhibition of these adaptor proteins in lesional macrophages significantly diminished plaque size and necrotic core area, increased fibrous cap thickness, and promoted plaque regression.

cell biology↗

bioRxiv2022

Warm blood meal increases digestion rate and milk protein production to maximize reproductive output for the tsetse fly, Glossina morsitans

The ingestion of blood represents a significant pressure that immediately increases water, oxidative, and thermal stress, but provides a significant nutrient source to generate resources necessary for the development of progeny. Thermal stress has been assumed to solely be a negative byproduct that has to be alleviated to prevent stress. Here, we examined if the short thermal bouts incurred during a warm blood meal are beneficial to reproduction. To do so, we examined the duration of pregnancy and milk gland protein expression in the tsetse fly, Glossina morsitans, that consumed a warm or cool blood meal. We noted that an optimal temperature for blood ingestion yielded a reduction in the duration of pregnancy. This decline in the duration of pregnancy is due to increased rate of blood digestion when consuming warm blood. This increased digestion likely provided more energy that leads to increased expression of transcript for milk-associated proteins. The shorter duration of pregnancy is predicted to yield an increase in population growth compared to those that consume cool or above host temperatures. These studies provide evidence that consumption of a warm blood meal is likely beneficial for specific aspects of vector biology.

physiology↗