Biology subjects

Zhang, S.

Publications and source records attributed to Zhang, S..

At least 973 records · Page 54Linked to original sources

bioRxiv2021

Active oxygen transport in tissue by interstitial flow

The model of diffusive O2 transport from capillary to tissue was established by Krogh a century ago. This model is incomplete as it ignores the often inevitable convective O2 transport via fluid movement. Here, we propose a one-dimensional physical-phenomenological model to evaluate the contribution of fluid movement to the O2 transport in tissue. Both the O2 gradient and the total O2 flux are found to be sensitive to the fluid movement. For small flow rates with a Peclet number Pe < 1, a critical flow rate, udc, is introduced to characterize the contribution of fluid movement to the O2 transport, as well as to evaluate the fluid contribution in O2-deficient tissues and the cytoplasm movement inside muscle fibers. During hemostasis, the O2 flux contributed by the interstitial flow even below a rate of 2 m/s, although negligible near the capillary, can be significant for the tissue residing far from the capillary. For an isolated intramyocyte mitochondrion, the cytoplasm movement can play a key role in the O2 transport. These considerations point to the scenario of an external force to drive the fluid movement leading to an accelerated O2 transport to sustain the mitochondrial consumption. Our model offers a comprehensive picture of the O2 transport in tissue by including both the concentration gradient and the hydraulic pressure gradient. It predicts that even with a small external force, damaged tissues with higher permeability can yield larger rates of interstitial flow promoting O2 transport for tissue recovery. HighlightsO_LIThe fluid movement can play a significant role in O2 transport in tissue with high Prandtl number{nu} /D ~ 103; C_LIO_LIA critical flow rate, udc, is introduced to evaluate the convective transport flux by the fluid in tissue for Pe < 1. C_LIO_LIO2 transport in tissue is a result of the balance between hydraulic pressure gradient induced flux and concentration gradient induced flux. C_LIO_LIOur model indicates more O2 pumped by convective transport into the O2 -deficient region where the O2 diffusive flux cannot penetrate. C_LIO_LIThe cytoplasm movement can excite more O2 flux to the mitochondria with higher myoglobin concentration. C_LI

physiology↗

bioRxiv2021

Hydroxide ions amplified by water entanglement underly the mechanism of general anesthesia

It is believed that inhaled anesthetics occupy hydrophobic pockets within target proteins, but how inhaled anesthetics with diverse shapes and sizes fit into highly structurally selective pockets is unknown. For hydroxide ions are hydrophobic, we determined whether hydroxide ions could bridge inhaled anesthetics and protein pockets. We found that small additional load of cerebral hydroxide ions decreases anesthetic potency. Multiple-water entanglement network, derived from Ising model, has a great ability to amplify ultralow changes in the cerebral hydroxide ion concentration, and consequently, amplified hydroxide ions account for neural excitability. Molecular dynamics simulations showed that inhaled anesthetics produce anesthesia by attenuating the formation of multiple-water entanglement network. This work suggests amplified hydroxide ions underlying a unified mechanism for the anesthetic action of inhaled anesthetics.

animal behavior and cognition↗

bioRxiv2021

Cell lineage as a predictor of immune response in neuroblastoma

Immunotherapy for patients with neuroblastoma has met with limited success, partly due to an incomplete understanding of the mechanisms underlying immune responsiveness in this clinically and genetically heterogenic tumor. Here, we undertook an unbiased analysis using dimension reduction and UMAP visualization of transcriptional signatures derived from 498 primary neuroblastoma tumors. Four distinct clusters based on differentially expressed genes emerged, of which one, representing about 30% and comprising mainly of MYCN-nonamplified tumors, was notable for the high expression of genes associated with both immune response activation and suppression. This capacity to elicit a productive immune response resided exclusively in tumors with dominant populations of undifferentiated, neural crest-like or mesenchymal cells; by contrast, tumors comprising primarily of committed, adrenergic neuron-like cells were less immunogenic. Mesenchymal neuroblastoma cells were enriched for innate and adaptive immune gene signatures, demonstrated engagement with cytotoxic T and natural killer cells, and induced immune cell infiltration in an immunocompetent mouse model. Transcriptional or targeted therapy-induced reprogramming of adrenergic cells to the mesenchymal state led to reactivation of tumor cell-intrinsic immune genes. Key immune response genes in adrenergic tumor cells were found to be epigenetically silenced by the PRC2 complex, and such repression could be relieved by either mesenchymal cell state reprogramming or EZH2 inhibition, leading to increased activation of natural killer cells by the tumor cells. These data identify cell lineage as a major determinant of the immunogenic potential in neuroblastoma that could be used to stratify patients who are most likely to benefit from immunotherapy.

cancer biology↗

bioRxiv2021

Impact of Prior Infection on Protection and Transmission of SARS-CoV-2 in Golden Hamsters

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 100 million confirmed human infections, and 2 million more deaths globally since its emergence in the end of 2019. Several studies have shown that prior infection provided protective immunity against SARS-CoV-2 in non-human primate models. However, the effect of prior infection on blocking SARS-CoV-2 transmission is not clear. Here, we evaluated the impact of prior infection on protection and transmission of the SARS-CoV-2 virus in golden hamsters. Our results showed that prior infection provided protective immunity against SARS-CoV-2 re-challenge, but it was not sterizing immunity. The transmission experiment results showed that SARS-CoV-2 was efficiently transmitted from naive hamsters to prior infected hamsters by direct contact and airborne route, but not by indirect contact. Further, the virus was efficiently transmitted from prior infected hamsters to naive hamsters by direct contact, but not by airborne route and indirect contact. Surprisingly, the virus can be transmitted between prior infected hamsters by direct contact during a short period of early infection. Taken together, our study demonstrated that prior infected hamsters with good immunity can still be naturally re-infected, and the virus can be transmitted between prior infected hamsters and the naive through different transmission routes, implying the potential possibility of human re-infection and the risk of virus transmission between prior infected population and the healthy. Our study will help to calculate the herd immunity threshold more accurately, make more reasonable public health decisions, formulate an optimized population vaccination program, as well as aid the implementation of appropriate public health and social measures to control COVID-19.

microbiology↗

bioRxiv2021

A novel Wnt/beta-catenin signaling driven adipocyte population that is required for beiging

Wnt/{beta}-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/{beta}-catenin signaling, as revealed by the Tcf/Lef-Gfp reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that the {beta}-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.

physiology↗

bioRxiv2021

Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities in vitro

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the worldwide coronavirus disease 2019 (COVID-19) outbreak. Investigation has confirmed that polysaccharide heparan sulfate can bind to the spike protein and block SARS-CoV-2 infection. Theoretically, similar structure of nature polysaccharides may also have the impact on the virus. Indeed, some marine polysaccharide has been reported to inhibit SARS-Cov-2 infection in vitro, however the convinced targets and mechanism are still vague. By high throughput screening to target 3CLpro enzyme, a key enzyme that plays a pivotal role in the viral replication and transcription using nature polysaccharides library, we discover the mixture polysaccharide 375 from seaweed Ecklonia kurome Okam completely block 3Clpro enzymatic activity (IC50, 0.48 {micro}M). Further, the homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro molecule well (kD value : 4.23 x 10-6). Very interestingly, 37502 also can potently disturb spike protein binding to ACE2 receptor (EC50, 2.01 {micro}M). Importantly, polysaccharide 375 shows good anti-SARS-CoV-2 infection activity in cell culture with EC50 values of 27 nM (99.9% inhibiting rate at the concentration of 20 {micro}g/mL), low toxicity (LD50: 136 mg/Kg on mice). By DEAE ion-exchange chromatography, 37501, 37502 and 37503 polysaccharides are purified from native 375. Bioactivity test show that 37501 and 37503 may impede SARS-Cov-2 infection and virus replication, however their individual impact on the virus is significantly less that of 375. Surprisingly, polysaccharide 37502 has no inhibition effect on SARS-Cov-2. The structure study based on monosaccharide composition, methylation, NMR spectrum analysis suggest that 375 contains guluronic acid, mannuronic acid, mannose, rhamnose, glucouronic acid, galacturonic acid, glucose, galactose, xylose and fucose with ratio of 1.86 : 9.56 : 6.81 : 1.69 : 1.00 : 1.75 : 1.19 : 11.06 : 4.31 : 23.06. However, polysaccharide 37502 is an aginate which composed of mannuronic acid (89.3 %) and guluronic acid (10.7 %), with the molecular weight (Mw) of 27.9 kDa. These results imply that mixture polysaccharides 375 works better than the individual polysaccharide on SARS-Cov-2 may be the cocktail-like polysaccharide synergistic function through targeting multiple key molecules implicated in the virus infection and replication. The results also suggest that 375 may be a potential drug candidate against SARS-CoV-2.

biochemistry↗

bioRxiv2021

Multiomics Integration Elucidates Metabolic Modulators of Drug Resistance in Lymphoma

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Brutons tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug tolerant form. The drug tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug resistant tumor is poorly understood. MethodsIn this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a multi-omics analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation and pharmaceutical inhibition, were further used to identify the key players that contribute to the metabolic reprograming of the drug resistant clone. ResultsGene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that drug resistant clones undergo metabolic reprogramming from glycolysis towards oxidative phosphorylation & is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically. ConclusionsOur report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained Oxidative phosphorylation, additionally we outline the compensatory, pathway that regulates this metabolic reprogramming in the drug resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells.

cancer biology↗

bioRxiv2020

Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patients immunological status, and found dramatic changes in the IGH within the patients immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones during 2-3 weeks of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34 and IGHV4-39 in COVID-19 patients were more abundant than that of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.

immunology↗

bioRxiv2020

Hsp70 chaperons TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation

TAR DNA binding protein 43 kDa (TDP-43) undergoes liquid-liquid phase separation (LLPS) and forms reversible, cytoprotective nuclear bodies (NBs) in response to stress in cells. Abnormal liquid-to-solid phase transition condenses TDP-43 into irreversible pathological fibrils, which is associated with neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, the mechanisms how cells maintain the dynamics of TDP-43 NBs in stressed conditions are not well understood. Here, we show that the molecular chaperon heat shock protein 70 (Hsp70) is recruited into TDP-43 NBs in stressed cells. It co-phase separates with TDP-43 and delays the maturation of TDP-43 droplets in vitro. In cells, downregulation of Hsp70 not only diminishes the formation but also reduces the dynamics of TDP-43 NBs especially during prolonged stress, which potentiates the cytotoxicity of TDP-43. Using NMR, we reveal that Hsp70 binds to the highly aggregation-prone, transient -helix of TDP-43 via its nucleotide-binding domain, which keeps TDP-43 in the highly dynamic, liquid-like phase and prevents pathological aggregation of TDP-43 both in vitro and in cells. Collectively, our findings demonstrate a crucial role of Hsp70 in chaperoning TDP-43 in the liquid-like phase, which provides a novel layer of the molecular mechanism how chaperons help proteins to remain functional and protect cells from stressed and/or diseased conditions.

cell biology↗

bioRxiv2020

Deep manifold learning reveals hidden dynamics of proteasome autoregulation

The 26S proteasome regulates proteostasis and myriad cellular processes. Here we reconstitute the hidden dynamics of human 26S proteasome during protein degradation using cryo-EM data-driven deep learning, which identified 64 proteasomal conformers. These conformers revealed substrate-dependent conformational entanglement of two 19S regulatory particles in the doubly capped holocomplexes. The rate-limiting step in single-nucleotide exchange dynamics of the AAA-ATPase motor is ATPase re-engagement with the substrate, while the rate-limiting step in proteasomal degradation is the initiation of substrate unfolding by the AAA-ATPase motor following deubiquitylation. Nine rare conformers delineated novel ubiquitin-binding sites on the RPN2 and 5 subunits, along with a ubiquitylation site on RPN10, which were verified using site-directed mutagenesis and liquid chromatography-tandem mass spectrometry. Opening of the 20S core particle gate was found to upregulate proteolytic activity by allosterically promoting nucleophilic attack on the scissile peptide bond. Our systematic analyses illuminate a grand hierarchical allostery underlying ubiquitin-mediated proteasome autoregulation.

biochemistry↗

bioRxiv2020

Compressed sensing-based super-resolution ultrasound imaging for faster acquisition and high quality images

Super-resolution ultrasound (SRUS) imaging technique has overcome the diffraction limit of conventional ultrasound imaging, resulting in an improved spatial resolution while preserving imaging depth. Typical SRUS images are reconstructed by localizing ultrasound microbubbles (MBs) injected in a vessel using normalized 2-dimensional cross-correlation (2DCC) between MBs signals and the point spread function of the system. However, current techniques require isolated MBs in a confined area due to inaccurate localization of densely populated MBs. To overcome this limitation, we developed the {ell}1-homotopy based compressed sensing (L1H-CS) based SRUS imaging technique which localizes densely populated MBs to visualize microvasculature in vivo. To evaluate the performance of L1H-CS, we compared the performance of 2DCC, interior-point method based compressed sensing (CVX-CS), and L1H-CS algorithms. Localization efficiency was compared using axially and laterally aligned point targets (PTs) with known distances and randomly distributed PTs generated by simulation. We developed post-processing techniques including clutter reduction, noise equalization, motion compensation, and spatiotemporal noise filtering for in vivo imaging. We then validated the capabilities of L1H-CS based SRUS imaging technique with high-density MBs in a mouse tumor model, kidney, and zebrafish dorsal trunk, and brain. Compared to 2DCC, and CVX-CS algorithm, L1H-CS algorithm, considerable improvement in SRUS image quality and data acquisition time was achieved. These results demonstrate that the L1H-CS based SRUS imaging technique has the potential to examine the microvasculature with reduced acquisition and reconstruction time of SRUS image with enhanced image quality, which may be necessary to translate it into the clinics.

bioengineering↗

bioRxiv2020

Genome-wide DNA mutations in Arabidopsis plants after multigenerational exposure to high temperature

BackgroundElevated temperatures can cause physiological, biochemical, and molecular responses in plants that can greatly affect their growth and development. Mutations are the most fundamental force driving biological evolution. However, how long-term elevations in temperature influence the accumulation of mutations in plants remains unknown. ResultsHere we report that multigenerational exposure of Arabidopsis to extreme heat and moderate warming resulted in significantly increased mutation rates in single-nucleotide variants (SNVs) and small indels. We observed distinctive mutational spectra under extreme and moderately elevated temperatures, with significant increases in transition (C:G[->]T:A) and transversion (A:T[->]T:A) frequencies. Mutation occurred more frequently in intergenic regions, coding regions (especially nonsynonymous mutations), and transposable elements (TEs). At elevated temperatures, more mutations accumulated in genes associated with defense responses, DNA repair, and signaling, including the transcriptional response-related genes HSP70 and HSFA1A. Methylation was observed more frequently at mutation sites, indicating that it contributed significantly to the mutation process at elevated temperatures. Moreover, the mutations in lines and populations grown under elevated temperatures were significantly biased toward low gene density regions, special trinucleotides (GC context), tandem repeats, and adjacent simple repeats. Additionally, 24% (n = 64) of SNVs and 43% (n = 40) of indels found in all mutation accumulation lines overlapped significantly with genetic variations reported in 1001 Genomes, suggesting a non-uniform distribution of de novo mutations through the genome. ConclusionCollectively, our results suggest that elevated temperatures can accelerate the accumulation, and alter the molecular profiles, of DNA mutations in plants, thus providing significant insight into how environmental temperatures fuel plant evolution.

genetics↗

bioRxiv2020

Evolution and insights into the structure and function of the DedA superfamily containing TMEM41B and VMP1

TMEM41B and VMP1 are endoplasmic reticulum (ER)-localizing multi-spanning membrane proteins required for ER-related cellular processes such as autophagosome formation, lipid droplet homeostasis, and lipoprotein secretion in eukaryotes. Both proteins have a VTT domain, which is similar to the DedA domain found in bacterial DedA family proteins. However, the molecular function and structure of the DedA and VTT domains (collectively referred to as DedA domains) and the evolutionary relationships among the DedA domain-containing proteins are largely unknown. Here, we conduct remote homology search and identify a new clade consisting mainly of bacterial PF06695 proteins of unknown function. Phylogenetic analysis reveals that the TMEM41, VMP1, DedA, and PF06695 families form a superfamily with a common origin, which we term the DedA superfamily. Coevolution-based structural prediction suggests that the DedA domain contains two reentrant loops that face each other in the membrane. This topology is biochemically verified by the substituted cysteine accessibility method. The predicted structure is topologically similar to that of the substrate-binding region of Na+-coupled glutamate transporter solute carrier 1. A potential ion-coupled transport function of the DedA superfamily proteins is discussed.

cell biology↗

bioRxiv2020

Sugarcane Nitrogen and Irrigation Level Prediction Based on UAV-Captured Multispectral Image at Elongating Stage

IntroductionSugarcane is the main industrial crop for sugar production; its growth status is closely related to fertilizer, water, and light input. Unmanned aerial vehicle (UAV)-based multispectral imagery is widely used for high-throughput phenotyping because it can rapidly predict crop vigor. This paper mainly studied the potential of multispectral images obtained by low-altitude UAV systems in predicting canopy nitrogen (N) content and irrigation level for sugarcane. MethodsAn experiment was carried out on sugarcane fields with three irrigation levels and five nitrogen levels. A multispectral image at a height of 40 m was acquired during the elongation stage, and the canopy nitrogen content was determined as the ground truth. N prediction models, including partial least square (PLS), backpropagation neural network (BPNN), and extreme learning machine (ELM) models, were established based on different variables. A support vector machine (SVM) model was used to recognize the irrigation level. ResultsThe PLS model based on band reflectance and five vegetation indices had better accuracy (R=0.7693, root mean square error (RMSE)=0.1109) than the BPNN and ELM models. Some spectral information from the multispectral image had obviously different features among the different irrigation levels, and the SVM algorithm was used for irrigation level classification. The classification accuracy reached 77.8%. ConclusionLow-altitude multispectral images could provide effective information for N prediction and water irrigation level recognition.

plant biology↗

bioRxiv2020

Cholecystokinin-like Peptide Mediates Satiety by Inhibiting Sugar Attraction

Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. This Gr64f regulation is by direct action of SK neurons on Gr64f-expressing neurons of the proboscis and proleg tarsi that co-express the SK receptor CCKLR-17D3. Our findings thus demonstrate how nutritional state induces peptide signaling to modulate sweet perception and thereby feeding behavior.

neuroscience↗

bioRxiv2020

Longest Order Conserved Exemplar Subsequences

We propose a new problem whose input data are two linear genomes together with two indexed gene subsequences of them, which asks to find a longest common exemplar subsequence of the two given genomes with a subsequence identical to the given indexed gene subsequences. We present an algorithm for this problem such that the algorithm is allowed to take diminishing time and space to solve the problem by setting the indexed genes with an incremental number. Although an incremental number of indexed genes were selected, the algorithm was verified definite to reach a solution whose length insistently comes very close to a real longest common exemplar subsequence of the two given genomes. Aiming at 23 human/gorilla chromosome pairs, the algorithm was examined for use in questing for longest common exemplar subsequences whose basic units are annotated genes as well as pseudo genes, namely consecutive DNA subsequences. By contrasting the pseudo gene common exemplar subsequences the algorithm had reached for the human chromosomes 7 and 16 and their gorilla homologues with those annotated genes in the human and gorilla chromosomes, we found more than 1 000 and 500 pseudo genes in the human chromosomes 7 and 16 that occur in the same order as they are in the gorilla chromosomes 7 and 16 and, do not overlap with any annotated gene. Author summaryThere is a benefit of the algorithm: It can reach a long enough common exemplar subsequence of two linear genomes in as fast a speed as one requires even if the given genomes would be equipped with too many duplicated genes, which can be done by setting incremental number of indexed genes. We developed a Java software based on the algorithm, that has been available for download on https://github.com/ShuZhang-sdu/LCES. Only in need to set the indexed gene sequences as null, was it verified successful for our algorithm to obtain the longest common exemplar subsequences of the annotated gene summary pairs extracted from 23 human/gorilla chromosome pairs. In convenience for researchers to find new motifs or conserved genes, we devoted for the algorithm to quest pseudo gene (i.e. consecutive DNA subsequences) summary pairs of the 23 human/gorilla chromosome pairs for solutions. There are 20 pseudo gene summary pairs whose longest common exemplar subsequences have been found by the algorithm with null indexed gene sequences. The other 3 pseudo gene summary pairs were verified solvable for the algorithm to reach their longest common exemplar subsequences that have to admit subsequences identical to given indexed gene subsequences. There were informed to exist 2 353 and 1 148 pseudo genes in the gorilla chromosome 7 and 16 that occur in the same order as they are in the human chromosome 7 and 16 and, do not overlap with any annotated gene. These pseudo genes should be significant for annotating the human or gorilla genome.

bioinformatics↗

bioRxiv2020

Catechol-Containing Compounds are a Broad Class of Amyloid Inhibitors: II. Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in HIP Rats

Protein aggregation is associated with a large number of human protein misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/ anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of rosmarinic acid showed the additive effects of two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin, but lead to non-toxic, remodeled protein aggregates. Rosmarinic acid has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of rosmarinic acid treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein misfolding diseases.

pharmacology and toxicology↗

bioRxiv2020

Improved Photocleavable Proteins with Faster and More Efficient Dissociation

The photocleavable protein (PhoCl) is a green-to-red photoconvertible fluorescent protein that, when illuminated with violet light, undergoes main chain cleavage followed by spontaneous dissociation of the resulting fragments. The first generation PhoCl (PhoCl1) exhibited a relative slow rate of dissociation, potentially limiting its utilities for optogenetic control of cell physiology. In this work, we report the X-ray crystal structures of the PhoCl1 green state, red state, and cleaved empty barrel. Using structure-guided engineering and directed evolution, we have developed PhoCl2c with higher contrast ratio and PhoCl2f with faster dissociation. We characterized the performance of these new variants as purified proteins and expressed in cultured cells. Our results demonstrate that PhoCl2 variants exhibit faster and more efficient dissociation, which should enable improved optogenetic manipulations of protein localization and protein-protein interactions in living cells.

synthetic biology↗