Biology subjects

Qiao, Y.

Publications and source records attributed to Qiao, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Specific Pupylation as IDEntity Reporter (SPIDER) for the identification of Protein-Biomolecule interactions

Protein-biomolecule interactions play pivotal roles in almost all biological processes, the identification of the interacting protein is essential. By combining a substrate-based proximity labelling activity from the pupylation pathway of Mycobacterium tuberculosis, and the streptavidin (SA)-biotin system, we developed Specific Pupylation as IDEntity Reporter (SPIDER) for identifying protein-biomolecular interactions. As a proof of principle, SPIDER was successfully applied for global identification of interacting proteins, including substrates for enzyme (CobB), the readers of m6A, the protein interactome of mRNA, and the target proteins of drug (lenalidomide). In addition, by SPIDER, we identified SARS-CoV-2 Omicron variant specific receptors on cell membrane and performed in-depth analysis for one candidate, Protein-g. These potential receptors could explain the differences between the Omicron variant and the Prototype strain, and further serve as target for combating the Omicron variant. Overall, we provide a robust technology which is applicable for a wide-range of protein-biomolecular interaction studies.

systems biology↗

bioRxiv2022

Retinal ganglion cell endowment is correlated with optic tract fiber cross section, not density

There is substantial variation between healthy individuals in the number of retinal ganglion cells (RGC) in the eye, with commensurate variation in the number of axons in the optic tracts. Fixel-based analysis of diffusion MR produces estimates of fiber density (FD) and cross section (FC). Using these fixel measurements along with retinal imaging, we asked if individual differences in RGC tissue volume are correlated with individual differences in FD and FC measurements obtained from the optic tracts, and subsequent structures along the cortical visual pathway. We find that RGC endowment is correlated with optic tract FC, but not with FD. RGC volume had a decreasing relationship with measurements from subsequent regions of the visual system (LGN volume, optic radiation FC/FD, and V1 surface area). However, we also found that the variations in each visual area were correlated with the variations in its immediately adjacent visual structure. We only observed these serial correlations when FC is used as the measure of interest for the optic tract and radiations, but no significant relationship was found when FD represented these white matter structures. From these results, we conclude that the variations in RGC endowment, LGN volume, and V1 surface area are better predicted by the overall cross section of the optic tract and optic radiations as compare to the intra-axonal restricted signal component of these white matter pathways. Additionally, the presence of significant correlations between adjacent, but not distant, anatomical structures suggests that there are multiple, local sources of anatomical variation along the visual pathway.

neuroscience↗

bioRxiv2022

Angiotensin converting enzyme 2 (ACE2): Virus accomplice or host defender

The current coronavirus disease-19 (COVID-19) caused by the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has seriously disrupted the daily life of human, mainly attributed to the fact that we know too little about SARS-CoV-2. Increasing studies show that viral infection alters host cells glucose metabolism, which is crucial for viral nucleic acid replication. Here, we integrated RNA-sequencing results and found that SARS-CoV-2 infection alters the aerobic glycolysis, pentose phosphate pathway (oxiPPP), and DNA replication in lung tissues and cells. However, the direction of metabolic flux and DNA replication were dominated by angiotensin-converting enzyme 2 (ACE2), a host cell-expressed viral receptor protein. More interesting, although hosts with high expression of ACE2 are more likely to be infected with SARS-CoV-2, the invading virus cannot perform nucleic acid replication well due to the restriction of glucose metabolism, and eventually resulting prolonged infection-cycle or infection failure. Our findings, after a typical epidemiological investigation and modeling analysis, preliminarily explain the reasons for the emergence of asymptomatic infections or lower copy virus at early stage in host with higher ACE2 levels, which will provide important help for the development of more accurate and effective detection methods for diagnosing COVID-19. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/483197v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@b51fcforg.highwire.dtl.DTLVardef@13b7f9corg.highwire.dtl.DTLVardef@136fe46org.highwire.dtl.DTLVardef@16fc92a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2021

Eukaryotic translation initiation factor eIF4E-5 is required for spermiogenesis in Drosophila melanogaster

Drosophila sperm development is characterized by extensive post-transcriptional regulation whereby thousands of transcripts are preserved for translation during later stages. A key step in translation initiation is the binding of eukaryotic initiation factor 4E (eIF4E) to the 5 mRNA cap. Drosophila has multiple paralogs of eIF4E, including four (eIF4E-3, -4, -5, and -7) that are highly expressed in the testis. Other than eIF4E-3, none of these has been characterized genetically. Here, using CRISPR/Cas9 mutagenesis, we determined that eIF4E-5 is essential for male fertility. eIF4E-5 mutants exhibit defects during post-meiotic stages, including a fully penetrant defect in individualization, resulting in failure to produce mature sperm. eIF4E-5 protein localizes to the distal ends of elongated spermatid cysts, where it regulates non-apoptotic caspase activity during individualization by promoting local accumulation of the E3 ubiquitin ligase inhibitor Soti. eIF4E-5 mutants also have mild defects in spermatid cyst polarization, similar to mutants affecting the cytoplasmic polyadenylation-element binding protein Orb2 and atypical protein kinase C (aPKC). Our results further extend the diversity of non-canonical eIF4Es that carry out distinct spatiotemporal roles during spermatogenesis. Summary StatementThe testis-enriched translation initiation factor eIF4E-5 is needed for spermatid cyst polarization, individualization of mature sperm and male fertility in Drosophila.

developmental biology↗

bioRxiv2021

Memory mapped parallel BAM file access API for high throughput sequence analysis informatics

MotivationIn time-critical clinical settings, such as precision medicine, genomic data needs to be processed as fast as possible to arrive at data-informed treatment decisions in a timely fashion. While sequencing throughput has dramatically increased over the past decade, bioinformatics analysis throughput has not, and consequently has now turned into the primary bottleneck. Modern computational hardware are capable of much higher performance than current genomic informatics algorithms can typically utilize, therefore presenting opportunities for significant improvement of performance. Accessing the raw sequencing data from BAM files, for example, is a necessary and time-consuming step in nearly all sequence analysis tools, however existing programming libraries for BAM access do not take full advantage of the parallel input/output capabilities of storage devices. ResultsIn an effort to stimulate the development of a new generation of faster sequence analysis tools, We developed quickBAM, a software library to accelerate sequencing data access by exploiting the parallelism in commodity storage hardware currently widely available. We demonstrate that analysis software ported to quickBAM consistently outperforms their current versions, in some cases finishing an analysis in under 4 minutes while the original version took 1.5 hours, using the same storage solution. Availability and ImplementationOpen source and freely available at https://gitlab.com/yiq/quickbam/, we envision that quickBAM will enable a new generation of high performance informatics tools, either directly boosting their performance if they are currently dataaccess bottlenecked, or allow data-access to keep up with further optimizations in algorithms and compute techniques. Contactyi.qiao@genetics.utah.edu.

bioinformatics↗

bioRxiv2021

Evaluating the utility of identity-by-descent segment numbers for relatedness inference via information theory and classification

Despite decades of methods development for classifying relatives in genetic studies, pairwise relatedness methods recalls are above 90% only for first through third degree relatives. The top-performing approaches, which leverage identity-by-descent (IBD) segments, often use only kinship coefficients, while others, including ERSA, use the number of segments relatives share. To quantify the potential for using segment numbers in relatedness inference, we leveraged information theory measures to analyze exact (i.e., produced by a simulator) IBD segments from simulated relatives. Over a range of settings, we found that the mutual information between the relatives degree of relatedness and a tuple of their kinship coefficient and segment number is on average 4.6% larger than between the degree and the kinship coefficient alone. We further evaluated IBD segment number utility by building a Bayes classifier to predict first through sixth degree relationships using different feature sets. When trained and tested with exact segments, the inclusion of segment numbers improves the recall by between 0.0028 and 0.030 for second through sixth degree relatives. However, the recalls improve by less than 0.018 per degree when using inferred segments, suggesting limitations due to IBD detection accuracy. Lastly, we compared our Bayes classifier that includes segment numbers with ERSA and IBIS and found comparable results, with the Bayes classifier and ERSA slightly outperforming each other across different degrees. Overall, this study shows that IBD segment numbers can improve relatedness inference but that errors from current SNP array-based detection methods yield dampened signals in practice.

genetics↗

bioRxiv2021

TOR signalling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila

When infected by enteric pathogenic bacteria, animals need to initiate local and whole-body defence strategies. While most attention has focused on the role of innate immune anti-bacterial responses, less is known about how changes in host metabolism contribute to host defence. Using Drosophila as a model system, we identify induction of intestinal target-of-rapamycin (TOR) kinase signalling as a key adaptive metabolic response to enteric infection. We find TOR is induced independently of the IMD innate immune pathway, and functions together with IMD signalling to promote infection survival. These protective effects of TOR signalling are associated with re-modelling of host lipid metabolism. Thus, we see that TOR switches intestinal metabolism to lipolysis and fatty acid oxidation. In addition, TOR is required to limit excessive infection mediated wasting of adipose lipid stores by promoting an increase in the levels of fat body-expressed de novo lipid synthesis genes. Our data support a model in which induction of TOR represents a host tolerance response to counteract infection-mediated lipid wasting in order to promote survival.

physiology↗

bioRxiv2021

MPI8 is Potent Against SARS-CoV-2 by Inhibiting Dually and Selectively the SARS-CoV-2 Main Protease and the Host Cathepsin L

A number of inhibitors have been developed for the SARS-CoV-2 main protease (MPro) as potential COVID-19 medications but little is known about their selectivity. Using enzymatic assays, we characterized inhibition of TMPRSS2, furin, and cathepsins B/K/L by more than a dozen of previously developed MPro inhibitors including MPI1-9, GC376, 11a, 10-1, 10-2, and 10- 3. MPI1-9, GC376 and 11a all contain an aldehyde for the formation of a reversible covalent hemiacetal adduct with the MPro active site cysteine and 10-1, 10-2 and 10-3 contain a labile ester to exchange with the MPro active site cysteine for the formation of a thioester. Our data revealed that all these inhibitors are inert toward TMPRSS2 and furin. Diaryl esters also showed low inhibition of cathepsins. However, all aldehyde inhibitors displayed high potency in inhibiting three cathepsins. Their determined IC50 values vary from 4.1 to 380 nM for cathepsin B, 0.079 to 2.3 nM for cathepsin L, and 0.35 to 180 nM for cathepsin K. All aldehyde inhibitors showed similar inhibition levels toward cathepsin L. A cellular analysis indicated high potency of MPI5 and MPI8 in inhibiting lysosomal activity, which is probably attributed to their inhibition of cathepsins. Among all aldehyde inhibitors, MPI8 shows the best selectivity toward cathepsin L. With respect to cathepsins B and K, the selective indices are 192 and 150, respectively. MPI8 is the most potent compound among all aldehyde inhibitors in cellular MPro inhibition potency and anti-SARS-CoV-2 activity in Vero E6 cells. Cathepsin L has been demonstrated to play a critical role in the SARS-CoV-2 cell entry. By selectively inhibiting both SARS-CoV-2 MPro and the host cathepsin L, MPI8 potentiates dual inhibition effects to synergize its overall antiviral potency and efficacy. Due to its high selectivity toward cathepsin L that reduces potential toxicity toward host cells and high cellular and antiviral potency, we urge serious consideration of MPI8 for preclinical and clinical investigations for treating COVID-19.

pharmacology and toxicology↗

bioRxiv2021

Cellular Activities of SARS-CoV-2 Main Protease Inhibitors Reveal Their Unique Characteristics

As an essential enzyme of SARS-CoV-2, the pathogen of COVID-19, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor with cellular potency. By coupling this toxicity alleviation with the expression of an MPro-eGFP fusion protein in a human cell host for straightforward characterization with fluorescent flow cytometry, we developed an effective method that allows bulk analysis of cellular potency of MPro inhibitors. In comparison to an antiviral assay in which MPro inhibitors may target host proteases or other processes in the SARS-CoV-2 life cycle to convene strong antiviral effects, this novel assay is more advantageous in providing precise cellular MPro inhibition information for assessment and optimization of MPro inhibitors. We used this assay to analyze 30 literature reported MPro inhibitors including MPI1-9 that were newly developed aldehyde-based reversible covalent inhibitors of MPro, GC376 and 11a that are two investigational drugs undergoing clinical trials for the treatment of COVID-19 patients in United States, boceprevir, calpain inhibitor II, calpain inhibitor XII, ebselen, bepridil that is an antianginal drug with potent anti-SARS-CoV-2 activity, and chloroquine and hydroxychloroquine that were previously shown to inhibit MPro. Our results showed that most inhibitors displayed cellular potency much weaker than their potency in direct inhibition of the enzyme. Many inhibitors exhibited weak or undetectable cellular potency up to 10 M. On contrary to their strong antiviral effects, 11a, calpain inhibitor II, calpain XII, ebselen, and bepridil showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle to convene potent antiviral effects. characterization of these molecules on their antiviral mechanisms will likely reveal novel drug targets for COVID-19. Chloroquine and hydroxychloroquine showed close to undetectable cellular potency to inhibit MPro. Kinetic recharacterization of these two compounds rules out their possibility as MPro inhibitors. Our results also revealed that MPI5, 6, 7, and 8 have high cellular and antiviral potency with both IC50 and EC50 values respectively below 1 M. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Given its strong cellular and antiviral potency, we cautiously suggest that MPI8 is ready for preclinical and clinical investigations for the treatment of COVID-19.

biochemistry↗

bioRxiv2021

Dice-XMBD: Deep learning-based cell segmentation for imaging mass cytometry

Highly multiplexed imaging technology is a powerful tool to facilitate understanding cells composition and interaction in tumor microenvironment at subcellular resolution, which is crucial for both basic research and clinical applications. Imaging mass cytometry (IMC), a multiplex imaging method recently introduced, can measure up to 40 markers simultaneously in one tissue section by using a high-resolution laser with a mass cytometer. However, due to its high resolution and large number of channels, how to process and interpret the image data from IMC remains a key challenge for its further applications. Accurate and reliable single cell segmentation is the first and a critical step to process IMC image data. Unfortunately, existing segmentation pipelines either produce inaccurate cell segmentation results, or require manual annotation which is very time-consuming. Here, we developed Dice-XMBD, a Deep learnIng-based Cell sEgmentation algorithm for tissue multiplexed imaging data. In comparison with other state-of-the-art cell segmentation methods currently used in IMC, Dice-XMBD generates more accurate single cell masks efficiently on IMC images produced with different nuclear, membrane and cytoplasm markers. All codes and datasets are available at https://github.com/xmuyulab/Dice-XMBD.

bioinformatics↗

bioRxiv2021

Drug Repurposing for the SARS-CoV-2 Papain-Like Protease

As the pathogen of COVID-19, SARS-CoV-2 encodes two essential cysteine proteases that process the pathogens two large polypeptide translates ORF1a and ORF1ab in human host cells to form 15 functionally important, mature nonstructural proteins. One of the two enzymes, papain-like protease or PLpro, also possesses deubiquitination and deISGylation activities that suppresses host innate immune responses toward SARS-CoV-2 infection. Therefore, PLpro is a potential COVID-19 drug target. To repurpose drugs for PLpro, we experimentally screened 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PLpro. Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit potent inhibition of PLpro at 200 M. More comprehensive characterizations revealed 7 inhibitors GRL0617, SJB2-043, TCID, DUB-IN-1, DUB-IN-3, PR-619, and S130 with an IC50 value below 60 M and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC50 value below 10 M. Among four inhibitors with an IC50 value below 10 M, SJB2-043 is the most unique in that it doesnt fully inhibit PLpro but has an outstanding IC50 value of 0.56 M. SJB2-043 likely binds to an allosteric site of PLpro to convene its inhibition effect, which needs to be further investigated. As a pilot study, the current work indicates that COVID-19 drug repurposing by targeting PLpro holds promises but in-depth analysis of repurposed drugs is necessary to avoid omitting allosteric inhibitors.

biochemistry↗

bioRxiv2021

Novel temporal and spatial patterns of metastatic colonization from rapid-autopsy tumor biopsies

BackgroundMetastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult, and thus poorly understood. ResultsVia rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumors evolution at subclonal resolution. The most unique, previously not reported aspect of the tumors evolution we observed in this patient was the presence of "subclone incubators", i.e. already metastatic sites where substantial tumor evolution occurred before colonization of additional sites and organs by subclones that evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g. abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion; subclones at this site were the source of all four subsequent metastatic waves; and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known driver or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patients metastases for effective clinical intervention. ConclusionsOur analysis revealed the presence of substantial tumor evolution at metastatic incubator sites, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

cancer biology↗

bioRxiv2021

Microfluidic Streptomyces Cultivation for Whole Lifecycle Characterization and Phenotypic Assays Enabled by Nanogap-stabilized Air-Water Interface

Streptomyces is a model filamentous prokaryote to study multicellular differentiation and a rich reservoir for antibiotics discovery. In their natural conditions, Streptomyces grows at the interface of porous soil, air, and water. The morphological development of Streptomyces is traditionally performed on agar plates and mostly studied at the population levels. However, the detailed lifecycle of Streptomyces has not been well studied due to its complexity and lack of research tools which can mimic their natural conditions in the soil. Here, we developed a simple assembled microfluidic device for cultivation and the entire lifecycle observation of Streptomyces development from single-cell level. The microfluidic device composed of a microchannel for loading samples and supplying nutrients, microwell arrays for seeding and growth of single spores, and air-filled chambers aside of the microwells that facilitate growth of aerial hyphae and spores. A unique feature of this device is that each microwell is surrounded by a 1.5 {micro}m gap connected to an air-filled chamber which provide stabilized water-air interface. We used this device to observe the development of single Streptomyces spores and found that unlike those in bulk liquid culture, Streptomyces can differentiate at water-air interfaces in microscale liquid culture. Finally, we demonstrated that phenotypic A-Factor assay can be performed at defined time point of its lifecycle. This microfluidic device could become a robust tool for studying Streptomyces multi-cellular differentiation and interaction at single cell level. IMPORTANCEWe describe a microfluidic device that mimics the natural porous environment for the growth and development of Streptomyces, the model system for bacterial multicellularity. The microfluidic device is used for cultivation and the entire lifecycle observation of Streptomyces development from single-cell level, including growth of aerial filaments. The aerial hyphae development of Streptomyces at the water-air interface was observed at real time in the microfluidic device. The early growth, opportunistic transformation (in the gap), and merging of aerial hyphae of Streptomyces in the microfluidic device were observed for the first time. It will play an important role in finding single-cell heterogeneity to study secondary metabolites related to the complex lifecycle of Streptomyces.

developmental biology↗

bioRxiv2021

Fluorescence-Activated Droplet Sorting of Polyethylene terephthalate Degrading Enzymes

Enzymes that can decompose synthetic plastics such as polyethylene terephthalate (PET) are urgently needed. However, a bottleneck remains due to a lack of techniques for detecting and sorting environmental microorganisms with vast diversity and abundance. Here, we developed a fluorescence-activated droplet sorting (FADS) pipeline for high-throughput screening of PET-degrading microorganisms or enzymes (PETases). The pipeline comprises three steps: generation and incubation of droplets encapsulating single cells, picoinjection of fluorescein dibenzoate (FDBz) as the fluorogenic probe, and screening of droplets to obtain PET-degrading cells. We characterized critical factors associated with this method, including specificity and sensitivity for discriminating PETase from other enzymes. We then optimized its performance and compatibility with environmental samples. The system was used to screen a wastewater sample from a PET textile mill. We successfully obtained PET-degrading species from nine different genera. Moreover, two putative PETases from isolates Kineococcus endophyticus Un-5 and Staphylococcus epidermidis Un-C2-8 were genetically derived, heterologously expressed, and preliminarily validated for PET-degrading activities. We speculate that the FADS pipeline can be widely adopted to discover new PET-degrading microorganisms and enzymes in various environments and may be utilized in the directed evolution of PETases using synthetic biology.

microbiology↗

bioRxiv2021

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

Model systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/433268v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@134d5cdorg.highwire.dtl.DTLVardef@1c0a419org.highwire.dtl.DTLVardef@556a4forg.highwire.dtl.DTLVardef@1b68c9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Hippocampal Asymmetry of Regional Development and Structural Covariance in Preterm Neonates

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, the putative role of hippocampus dysfunction remains poorly understood in preterm neonates. Particularly, hemispherical asymmetry of the hippocampus has been well-noted, either structurally or functionally. How the preterm birth impairs the hippocampal development, and to what extent the hippocampus was impaired by preterm birth asymmetrical has not been well studied. In this study, we compared regional and local hippocampal development in term born neonates (n=361) and prematurely born infants at term-born equivalent age on MRI studies (n = 53) using T2 MRI images collected from the Developing Human Connectome Project (dHCP); We compared 1) volumetric growth; 2) shape development in the hippocampal hemispheres using Laplace-Beltrami eigen-projection and boundary deformation between the two groups; and 3) structural covariance between hippocampal vertices and the cortical thickness in cerebral cortex regions. We demonstrated that premature infants have smaller volume for the right hippocampi, while no difference was observed for the left hippocampi. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared to full-term peers, while an accelerated hippocampal thickness growth rate was found in left hippocampus only. Structural covariance analysis demonstrated that in premature infants, the structural covariance between hippocampi and limbic lobe were severely impaired compared to healthy term neonates only in left hemisphere. These data suggest that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure, with high degree of asymmetry. These findings suggested that the hippocampus shows high degree of vulnerability, particularly asymmetrical vulnerability or plasticity, in preterm neonates at the term-born equivalent age compared to full-term healthy controls.

neuroscience↗

bioRxiv2020

A Novel Water-Soluble Photosensitizer for Photodynamic Inactivation of Gram-Positive Bacteria

Antimicrobial photodynamic therapy (APDT) is a promising alternative to traditional antibiotics for bacterial infections, which inactivates a broad spectrum of bacteria. However, it has some disadvantages including poor water solubility and easy aggregation of hydrophobic photosensitizers (PS), and poor tissue penetration and cytotoxicity when using UV as the light source, leading to undesired photodynamic therapy efficacy. Herein, we develop a novel water-soluble natural PS (sorbicillinoids) obtained by microbial fermentation using recombinant filamentous fungus Trichoderma reesei (T. reesei). Sorbicillinoids could effectively generate singlet oxygen (1O2) under ultraviolet (UV) light irradiation, and ultimately display photoinactivation activity on Gram-positive bacteria, but not Gram-negative ones. Staphylococcus aureus (S. aureus) treated with sorbicillinoids and UV light displayed high levels of intracellular reactive oxygen species (ROS), notable DNA photocleavage, and compromised cell semi-permeability without overt cell membrane disruption. Moreover, the dark toxicity, phototoxicity or hemolysis activity of sorbicillinoids is negligible, showing its excellent biocompatibility. Therefore, sorbicillinoids, a type of secondary metabolite from fungus, has a promising future as a new PS for APDT using nontoxic dose of UV light irradiation. ImportanceIt is of great value to develop novel PSs for APDT to enhance its efficacy for the reason that many traditional PSs have disadvantages like low water solubility and poor biocompatibility. In this study, we develop a novel water-soluble natural PS - sorbicillinoids obtained by microbial fermentation using T. reesei. Sorbicillinoids could effectively generate singlet oxygen under UV light irradiation, and ultimately display photoinactivation activity on Gram-positive bacteria, but not Gram-negative ones. More importantly, UV light can generally only be used to inactivate bacteria on the surface due to its weak penetration. However, it can penetrate deep into the solution and inactivate bacteria in the presence of sorbicillinoids. Therefore, sorbicillinoids, a type of secondary metabolite from fungus, has a promising future as a new PS for APDT using nontoxic dose of UV light irradiation.

microbiology↗

bioRxiv2020

OncoGEMINI: Software for Investigating Tumor Variants From Multiple Biopsies With Integrated Cancer Annotations

DNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem. Here we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling timepoints and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution.

cancer biology↗