Biology subjects

Li, E.

Publications and source records attributed to Li, E..

84 records · Page 5Linked to original sources

bioRxiv2020

Knockdown of LC3 increases mitochondria-to-micronucleus transition

Nuclear-localized mitochondria were discovered over sixty years ago1; however, the function of these organelles in the initiation of nuclear formation and development remains unknown. Here, we showed that mitochondria fragmented into dense particles to initiate and develop a nucleus, and multiple nuclei were separately and simultaneously formed by fragmented mitochondria in a single cell. The combination of nuclei individually constructed by the mitochondrial assembly of dense particles for nuclear transition partitioned the cytoplasm to form an intranuclear inclusion (INC), whose formation was not related to herniation or invagination of the cytoplasm. During nuclear conversion of itself and neighbouring organelles, the mitochondrion was incorporated into the nucleus to become a nuclear mitochondrion. Knockdown of microtubule-associated protein light chain 3 (LC3), a key autophagic protein, increased free micronuclei by delaying nuclear fusion and enhancing the mitochondria-to-micronuclei transition.

cell biology↗

bioRxiv2020

Mitochondria fragment and reassemble to initiate the formation and development of the nucleus

The function of nuclear-localized mitochondria remains unknown. We found that mitochondria assembled dense particles to fragment and disperse into the particles, which reassembled to initiate nuclear formation and development. Individually-formed nuclei in one single cell were joined together by mitochondrial fragmentation concurrently partitioning cytoplasm to form an intranuclear inclusion (INC), whose creation was not related to herniation or invagination of the cytoplasm. Along with the nuclear transition of a mitochondrion and its neighboring counterparts, the organelle included itself in the nucleus to become nuclear mitochondrion through peripherally assembling of dense particles. New medium reversed the nuclear formation of the organelles to recovery and re-establishment via the return of the particles, which consisted of dense microvesicles (MIVs).

cell biology↗

bioRxiv2020

Diversity of carbapenem-resistant Acinetobacter baumannii and bacteriophage-mediated spread of the Oxa23 carbapenemase

Carbapenem-resistant A. baumannii are prevalent in low- and middle-income countries such as Egypt, but little is known about the molecular epidemiology and mechanisms of resistance in these settings. Here we characterise carbapenem-resistant A. baumannii from Alexandria, Egypt, and place it in a regional context. 54 carbapenem-resistant isolates from Alexandria Main University Hospital, Egypt, collected between 2010 and 2015 were genome sequenced using Illumina technology. Genomes were de novo assembled and annotated. Genomes for 36 isolates from the Middle East region were downloaded from GenBank. Core gene compliment was determined using Roary, and analyses of recombination were performed in Gubbins. MLST sequence type and antibiotic resistance genes were identified. The majority of Egyptian isolates belonged to one of 3 major clades, corresponding to Pasteur MLST clonal complex (CCPAS) 1, CCPAS2 and sequence type (STPAS) 158. Strains belonging to STPAS158 have been reported almost exclusively from North Africa, the Middle East and Pakistan, and may represent a region-specific lineage. All isolates carried an oxa23 gene, six carried blaNDM-1, and one carried blaNDM-2. The oxa23 gene was located on a variety of different mobile elements, with Tn2006 predominant in CCPAS2 strains, and Tn2008 predominant in other lineages. Of particular concern, in 8 of the 11 CCPAS1 strains, the carbapenemase gene was located in a temperate bacteriophage phiOXA, previously identified only once before in a CCPAS1 clone from the US military. The carbapenem-resistant A. baumannii population in Alexandria Main University hospital is very diverse, and indicates an endemic circulating population, including a region-specific lineage. The major mechanism for oxa23 dissemination in CCPAS1 isolates appears to be a bacteriophage, presenting new concerns about the ability of these carbapenemases to spread throughout the bacterial population. Data SummaryThe whole genome shotgun sequences of the isolates from this study have been deposited at DDBJ/ENA/GenBank under the BioProject accession number PRJNA659545. The individual genome accession numbers for each isolate are as follows: A1a, JACSUC000000000; A2, JACSUB000000000; A4, JACSVQ000000000; A5, JACSUA000000000; A6, JACSTZ000000000; A7-T, JACSVP000000000; A8-T, JACSVO000000000; A8a, JACSTY000000000; A9, JACSTX000000000; A10, JACSTW000000000; A10a, JACSTV000000000; A11a, JACSTU000000000; A13a, JACSTT000000000; A14a, JACSTS000000000; A15, JACSTR000000000; A16, JACSTQ000000000; A18, JACSTP000000000; A21, JACSVN000000000; A22, JACSTO000000000; A27, JACSTN000000000; A30, JACSTM000000000; A31, JACSTL000000000; A34, JACSTK000000000; A35, JACSTJ000000000; A36, JACSTI000000000; A39, JACSTH000000000; A40, JACSTG000000000; A41, JACSTF000000000; A42, JACSTE000000000; A43, JACSTD000000000; A44, JACSTC000000000; A45, JACSTB000000000; A46, JACSTA000000000; A64, JACSSZ000000000; A68, JACSSY000000000; A69, JACSSX000000000; A70, JACSSW000000000; A71, JACSVM000000000; A72, JACSSV000000000; A73, JACSSU000000000; A74, JACSST000000000; A75, JACSSS000000000; A78, JACSSR000000000; A82, JACSSQ000000000; A83, JACSVL000000000; A84, JACSSP000000000; A85, JACSSO000000000; A86, JACSVK000000000; A87, JACSSN000000000; A88, JACSSM000000000; A89, JACSSL000000000; A92, JACSSK000000000; A5910, JACSSJ000000000; A6135, JACSVJ000000000.

microbiology↗

bioRxiv2020

Bacterial evolution in high osmolarity environments

Bacteria must maintain a cytosolic osmolarity higher than that of their environment in order to take up water. High osmolarity environments therefore present a formidable stress to bacteria. To explore the evolutionary mechanisms by which bacteria adapt to high osmolarity environments, we selected Escherichia coli in media with a variety of osmolytes and concentrations for 250 generations. Adaptation was osmolyte-dependent, with sorbitol stress generally resulting in increased fitness in conditions with higher osmolarity, while selection in high concentrations of proline resulted in increased fitness specifically on proline. Consistent with these phenotypes, sequencing of the evolved populations showed that passaging in proline resulted in specific mutations in an associated metabolic pathway that increases the ability to utilize proline for growth, while evolution in sorbitol resulted in mutations in many different genes that generally improve growth in high osmolarity conditions at the expense of growth at low osmolarity. High osmolarity decreased growth rate but increased mean cell volume compared with growth on proline as the sole carbon source, demonstrating that osmolarity-induced changes in growth rate and cell size follow an orthogonal relationship from the classical Growth Law relating cell size and nutrient quality. Isolates from a sorbitol-evolved population that capture the likely temporal sequence of mutations revealed by metagenomic sequencing demonstrate a tradeoff between growth at high and low osmolarity. Our study highlights the utility of experimental evolution for dissecting complex cellular networks and environmental interactions, particularly in the case of behaviors that can involve both specific and general metabolic stressors. ImportanceFor bacteria, maintaining higher internal solute concentrations than the environment allows cells to take up water. As a result, survival is challenging in high osmolarity environments. To investigate how bacteria adapt to high osmolarity environments, we evolved Escherichia coli in a variety of high osmolarity solutions for hundreds of generations. We found that evolved populations adopted different strategies to improve their growth depending on the osmotic passaging condition, either generally adapting to high osmolarity conditions or better metabolizing the osmolyte as carbon source. Single-cell imaging demonstrated that enhanced fitness was coupled to faster growth, and metagenomic sequencing revealed mutations that reflect growth tradeoffs across osmolarities. Our study demonstrates the utility of long-term evolution experiments for probing adaptation during environmental stress.

microbiology↗

bioRxiv2020

miRNAs and neural alternative polyadenylation specify the virgin behavioral state

How are diverse regulatory strategies integrated to impose appropriately patterned gene expression that underlie in vivo phenotypes? Here, we reveal how coordinated miRNA regulation and neural-specific alternative polyadenylation (APA) of a single locus controls complex behaviors. Our entry was the unexpected observation that deletion of Bithorax-Complex (BX-C) miRNAs converts virgin female flies into a subjective post-mated behavioral state, normally induced by seminal proteins following copulation. Strikingly, this behavioral switch is directly attributable to misregulation of homothorax (hth). We localize specific CNS abdominal neurons where de-repressed Hth compromises virgin behavior in BX-C miRNA mutants. Moreover, we use genome engineering to demonstrate that precise mutation of hth 3UTR sites for BX-C miRNAs, or deletion of its neural 3 UTR extension containing most of these sites, both induce post-mated behaviors in virgins. Thus, facilitation of miRNA-mediated repression by neural APA is required for virgin females to execute behaviors appropriate to their internal state.

neuroscience↗

bioRxiv2020

Molecular characterization of selectively vulnerable neurons in Alzheimer's Disease

Alzheimers disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus - brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively - from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

neuroscience↗

bioRxiv2020

The Power of Citizen Science to Quantify Ecological Risks in Cities

Urbanization is an extreme form of habitat modification that can alter ecological relationships among organisms, but these can be hard to study because much of the urban landscape is inaccessible private property. We show that citizen science can be a powerful tool to overcome this challenge. We used photo-vouchered observations submitted to the citizen science platform iNaturalist to assess predation and parasitism across urbanization gradients in a secretive yet widespread species, the Southern Alligator Lizard (Elgaria multicarinata), in Southern California, USA. From photographs, we quantified predation risk by assessing tail injuries and quantified parasitism rates by counting tick loads on lizards. We estimated urbanization intensity by determining percent impervious surface around each lizard observation. We found that tail injuries increased with age of the lizard and with urbanization, suggesting that urban areas are riskier habitats, likely because of elevated populations of predators such as outdoor cats. Conversely, parasitism decreased with urbanization likely due to a loss of mammalian hosts and anti-tick medications used on companion animals. Moreover, our citizen science approach allowed us to generate a large dataset on a secretive species extremely rapidly and at an immense spatial scale that facilitated quantitative measures of urbanization (e.g. percent impervious surface cover) as opposed to qualitative measures (e.g. urban vs rural). This study demonstrates that citizen science is allowing researchers to answer ecological questions that otherwise would go unanswered.

ecology↗

bioRxiv2019

Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury

Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By transcriptionally profiling sensory ganglia at single-cell resolution, we find that different somatosensory neuronal subtypes undergo a remarkably consistent and dramatic transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. Successful axonal regeneration leads to a restoration of neuronal cell identity and the deactivation of the growth program. This injury-induced transcriptional reprogramming requires Atf3, a transcription factor which is induced rapidly after injury and is necessary for axonal regeneration and functional recovery. While Atf3 and other injury-induced transcription factors are known for their role in reprogramming cell fate, their function in mature neurons is likely to facilitate major adaptive changes in cell function in response to damaging environmental stimuli.

neuroscience↗

bioRxiv2019

Bayesian Modeling Reveals Ultrasensitivity Underlying Metabolic Compensation in the Cyanobacterial Circadian Clock

Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near-24-h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly-detailed but mechanistically agnostic model of the KaiA-KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide-bound states of KaiC. We argue that the ultrasensitive stimulus-response relation is critical to metabolic compensation by suppressing premature phosphorylation at nighttime. SynopsisThis study takes a data-driven kinetic modeling approach to characterizing the interaction between KaiA and KaiC in the cyanobacterial circadian oscillator and understanding how the oscillator responds to changes in cellular metabolic conditions. O_LIAn extensive dataset of KaiC autophosphorylation measurements was gathered and fit to a detailed yet mechanistically agnostic kinetic model within a Bayesian parameter estimation framework. C_LIO_LIKaiA concentration tunes the sensitivity of KaiC autophosphorylation and the period of the full oscillator to %ATP. C_LIO_LIThe model reveals an ultrasensitive dependence of KaiC phosphorylation on KaiA concentration as a result of differential KaiA binding affinity to ADP- vs. ATP-bound KaiC. C_LIO_LIUltrasensitivity in KaiC phosphorylation contributes to metabolic compensation by suppressing premature phosphorylation at nighttime. C_LI

systems biology↗

bioRxiv2019

Temperature accounts for the biodiversity of a hyperdiverse group of insects in urban Los Angeles

The urban heat island effect is a worldwide phenomenon that has been linked to species distributions and abundances in cities. However, effects of urban heat on biotic communities are nearly impossible to disentangle from effects of land cover in most cases because hotter urban sites also have less vegetation and more impervious surfaces than cooler sites within cities. We sampled phorid flies, one of the largest, most biologically diverse families of true flies (Insecta: Diptera: Phoridae), at 30 sites distributed within the central Los Angeles Basin, where we found that temperature and the density of urban land cover are decoupled. Abundance, richness, and community composition of phorids inside urban Los Angeles were most parsimoniously accounted for by mean air temperature in the week preceding sampling. Sites with intermediate mean temperatures had more phorid fly individuals and higher richness. Communities were more even at urban sites with lower minimum temperatures and sites located further away from natural areas, suggesting that communities separated from natural source populations may be more homogenized. Species composition was best explained by minimum temperature. Inasmuch as warmer areas within cities can predict future effects of climate change, phorid fly communities are likely to shift non-linearly under future climates in more natural areas. Exhaustive surveys of biotic communities within cities, such as the one we describe here, can provide baselines for determining the effects of urban and global climate warming as they intensify.

ecology↗

bioRxiv2018

QuBiT: A quantitative tool for epithelial tubes reveals cell dynamics and unexpected patterns of organization during Drosophila tracheal morphogenesis

Biological tubes are essential for animal survival, and their functions are critically dependent on tube shape. Analyzing the contributions of cell shape and organization to the morphogenesis of small tubes has been hampered by the limitations of existing programs in quantifying cell geometry on highly curved tubular surfaces and calculating tube-specific parameters. We therefore developed QuBiT (Quantitative Tool for Biological Tubes) and used it to analyze morphogenesis during embryonic Drosophila tracheal (airway) development. We find that there are previously unknown anterior-to-posterior (A-P) gradients of cell orientation and aspect ratio, and that there is periodicity in the organization of cells in the main tube. Furthermore, cell intercalation during development dampens an A-P gradient of the number of the number of cells per cross-section of the tube, but these intercalation events do not change the patterns of cell connectivity. These unexpected findings demonstrate the importance of a computational tool for analyzing the morphogenesis of small diameter biological tubes.

cell biology↗

bioRxiv2018

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

BackgroundMalignant Peritoneal Mesothelioma (PeM) is a rare but frequently fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM yet exist. In the search for novel therapeutic target candidates in PeM, we performed a comprehensive integrative multi-omics analysis of 19 treatment-naive PeM tumors.\n\nResultsThe analysis identified PeM tumors with BAP1 loss to form a distinct molecular subtype characterized by distinct expression patterns of genes involved in chromatin remodeling, DNA repair pathway, and immune checkpoint receptor activation. This PeM subtype could potentially benefit from immune checkpoint, PARP, or HDAC inhibition therapies.\n\nConclusionsOur findings uncover BAP1 as a trackable prognostic and predictive biomarker, and refine PeM disease classification. This integrated molecular characterization provides a comprehensive foundation for developing PeM precision medicine.

cancer biology↗