Biology subjects

Lee, A.

Publications and source records attributed to Lee, A..

12 recordsLinked to original sources

bioRxiv2018

Does the strength of women’s attraction to male vocal masculinity track changes in steroid hormones?

Recent studies that either used luteinizing hormone tests to confirm the timing of ovulation or measured steroid hormones from saliva have found little evidence that womens preferences for facial or body masculinity track within-subject changes in womens fertility or hormonal status. Fewer studies using these methods have examined womens preferences for vocal masculinity, however, and those that did report mixed results. Consequently, we used a longitudinal design and measured steroid hormones from saliva to test for evidence of hormonal regulation of womens (N=351) preferences for two aspects of male vocal masculinity (low pitch and low formants). Analyses suggested that preferences for masculine pitch, but not masculine formants, may track within-woman changes in estradiol. Although these results present some evidence for the hypothesis that within-subject hormones regulate womens attraction to masculine men, we do not discount the possibility that the effect of estradiol on pitch preferences in the current study is a false positive.

animal behavior and cognition↗

bioRxiv2018

Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells.

Current treatments for heart automaticity disorders still lack a safe and efficient source of stem cells to restore normal biological pacemaking. Since adult Muscle-Derived Stem Cells (MDSC) show multi-lineage differentiation in vitro including into spontaneously beating cardiomyocytes, we questioned whether they could effectively differentiate into cardiac pacemakers, a specific population of cardiomyocytes producing electrical impulses in the sino-atrial node (SAN) of adult heart. We show here that beating cardiomyocytes, differentiated from MDSC in vitro, exhibit typical characteristics of cardiac pacemakers: expression of markers of the SAN lineage Hcn4, Tbx3 and Islet1, as well as spontaneous calcium transients and hyperpolarization-activated "funny" current and L-type Cav1.3 channels. Pacemaker-like myocytes differentiated in vitro from Cav1.3-deficient mouse stem cells produced slower rate of spontaneous Ca2+ transients, consistent with the reduced activity of native pacemakers in mutant mice. In vivo, undifferentiated wild type MDSC migrated and homed with increased engraftment to the SAN of bradycardic mutant Cav1.3-/- within 2-3 days after systemic I.P. injection. The increased homing of MDSCs corresponded to increased levels of the chemokine SDF1 and its receptor CXCR4 in mutant SAN tissue and was ensued by differentiation of MDSCs into Cav1.3-expressing pacemaker-like myocytes within 10 days and a significant improvement of the heart rate maintained for up to 40 days. Optical mapping and immunofluorescence analyses performed after 40 days on SAN tissue from transplanted wild type and mutant mice showed MDSCs integrated as pacemaking cells both electrically and functionally within recipient mouse SAN. These findings identify MDSCs as directly transplantable stem cells that efficiently home, differentiate and improve heart rhythm in mouse models of congenital bradycardia.

cell biology↗

bioRxiv2018

Addition of Degenerate Bases to DNA-based Data Storage for Increased Information Capacity

Introductory paragraphDNA-based data storage has emerged as a promising method to satisfy the exponentially increasing demand for information storage. However, practical implementation of DNA-based data storage remains a challenge because of the high cost of DNA per unit data. Here, we propose the use of eleven degenerate bases as encoding characters in addition to A, C, G, and T, which increases the information capacity (the amount of data that can be stored per length of DNA sequence designed) and reduce the cost of DNA per unit data. Using the proposed method, we experimentally achieved an information capacity of 3.37 bits/character, which is more than twice when compared to the highest information capacity previously achieved. Finally, the platform was projected to reduce the cost of DNA-based data storage by 50%.

synthetic biology↗

bioRxiv2018

Redesign of an Undergraduate General Microbiology Lab to Include Authentic Discovery-Driven Research on Cucumber Fermentations

Many undergraduate introductory microbiology laboratory courses teach basic principles of bacteriology using classical protocol-based experiments, with limited critical thinking and inquiry-based learning practices. We initiated a comprehensive redesign in our General Microbiology Laboratory course to promote scientific critical and creative thinking, while strengthening core microbiology concepts and skills. As part of the redesign, a series of authentic discovery-driven labs, based on cucumber fermentations, were developed as an independent research module within the course curriculum. Integrating discovery-driven labs allowed students to be engaged problem solvers, applying the scientific process to develop hypotheses, design experiments, utilize quantitative reasoning, and effectively communicate results. The inquiry-guided research project was developed to evaluate the minimum concentration of salt (NaCl) required in fermentation brine to safely, and effectively, ferment cucumbers. Over 5 weeks, students assess different aspects of the fermentation process, including quantifying bacterial populations with differential and selective media, measuring pH and glucose concentration of brine solutions, and characterizing the microbial metabolic potential. Additionally, students isolate an unknown bacterium from their fermentations, identifying and characterizing the isolate using 16S rRNA gene sequencing and metabolic tests. Throughout the research project, students collect, graph, and analyze their observations, culminating in students creating and presenting a scientific research poster. With this lab redesign, students generate new knowledge contributing to our understanding of microbial ecology within food fermentations, learn core microbiology skills and techniques, and develop critical and creative thinking skills. The impact of their research is valuable to science educators, researchers, and industry partners.

scientific communication and education↗

bioRxiv2018

Systematic Discovery of the Functional Impact of Somatic Genome Alterations in Individual Tumors through Tumor-specific Causal Inference

We report a tumor-specific causal inference (TCI) framework, which discovers causative somatic genome alterations (SGAs) through inferring causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and identified those SGAs that causally regulate the differentially expressed genes (DEGs) within each tumor. Overall, TCI identified 634 SGAs that cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both well-known and novel candidate drivers. By identifying major candidate drivers and revealing their functional impact in a tumor, TCI shed light on disease mechanisms of each tumor, providing useful information for advancing cancer biology and precision oncology.\n\nSignificance statementsCancer is mainly caused by SGAs. Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. TCI is a novel computational framework for discovering the causative SGAs and their impact on oncogenic processes, thus revealing tumor-specific disease mechanisms. This information can be used to guide precision oncology.

cancer biology↗

bioRxiv2018

Impeding DNA Break Repair Enables Oocyte Quality Control

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death is triggered by defects in chromosome synapsis and recombination, which involve repair of programmed DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocytes elimination in meiotic mutants require RNF212. RNF212 sensitizes cells to DSB-induced apoptosis within a narrow window when chromosomes desynapse during the transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a \"memory\" of meiotic defects that enables quality control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

genetics↗

bioRxiv2018

MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size

Neurons display extreme degrees of polarization, including compartment-specific organelle morphology. In cortical pyramidal neurons, dendritic mitochondria are long and tubular whereas axonal mitochondria display uniformly short length. Here, we explored the functional significance of maintaining small mitochondria for axonal development in vitro and in vivo. We report that the Drp1 receptor Mitochondrial fission factor (MFF) is required for determining the size of mitochondria entering the axon and then for maintenance of their size along the distal portions of the axon without affecting their trafficking properties, presynaptic capture, membrane potential or capacity for ATP production. Strikingly, this increase in presynaptic mitochondrial size upon MFF downregulation augments their capacity for Ca2+ ([Ca2+]m) uptake during neurotransmission, leading to reduced presynaptic [Ca2+]c accumulation, decreased presynaptic release and terminal axon branching. Our results uncover a novel mechanism controlling neurotransmitter release and axon branching through fission-dependent regulation of presynaptic mitochondrial size.

cell biology↗

bioRxiv2018

Generating perfusion maps from structural optical coherence tomography with artificial intelligence

Despite advances in artificial intelligence (AI), its application in medical imaging has been burdened and limited by expert-generated labels. We used images from optical coherence tomography angiography (OCTA), a relatively new imaging modality that measures retinal blood flow, to train an AI algorithm to generate flow maps from standard optical coherence tomography (OCT) images, exceeding the ability and bypassing the need for expert labeling. Deep learning was able to infer flow from single structural OCT images with similar fidelity to OCTA and significantly better than expert clinicians (P < 0.00001). Our model allows generating flow maps from large volumes of previously collected OCT data in existing clinical trials and clinical practice. This finding demonstrates a novel application of AI to medical imaging, whereby subtle regularities between different modalities are used to image the same body part and AI is used to generate detailed inferences of tissue function from structure imaging.

neuroscience↗

bioRxiv2017

The complement system supports normal postnatal development and gonadal function in both sexes

Male and female infertility are clinically managed and classified as distinct diseases, and relatively little is known about mechanisms of gonadal function common to both sexes. We used genome-wide genetic analysis on 74,896 women and men to find rare genetic variants that modulate gonadal function in both sexes. This uncovered an association with variants disrupting CSMD1, a complement regulatory protein located on 8p23, in a genomic region with an exceptional evolution. We found that Csmd1 knockout mice display a diverse array of gonadal defects in both sexes, and in females, impaired mammary gland development that leads to increased offspring mortality. The complement pathway is significantly disrupted in Csmd1 mice, and further disruption of the complement pathway from joint inactivation of C3 leads to more extreme reproductive defects. Our results can explain a novel human genetic association with infertility and implicate the complement system in the normal development of postnatal tissues.

developmental biology↗

bioRxiv2017

Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci

We fine-mapped 76 rheumatoid arthritis (RA) and type 1 diabetes (T1D) loci outside of the MHC. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We fine-mapped1,2 these loci in RA (11,475 cases, 15,870 controls)3, T1D (9,334 cases and 11,111 controls) 4 and combined datasets. We reduced the number of potential causal variants to [≤]5 in 8 RA and 11 T1D loci. We identified causal missense variants in five loci (DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non-coding variants in six loci (MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). Functional analysis confirmed allele specific binding and differential enhancer activity for three variants: the CD28/CTLA4 rs117701653 SNP, the TNFAIP3 rs35926684 indel, and the MEG3 rs34552516 indel. This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.

genetics↗

bioRxiv2017

Integration of visual information in auditory cortex promotes auditory scene analysis through multisensory binding

How and where in the brain audio-visual signals are bound to create multimodal objects remains unknown. One hypothesis is that temporal coherence between dynamic multisensory signals provides a mechanism for binding stimulus features across sensory modalities. Here we report that when the luminance of a visual stimulus is temporally coherent with the amplitude fluctuations of one sound in a mixture, the representation of that sound is enhanced in auditory cortex. Critically, this enhancement extends to include both binding and non-binding features of the sound. We demonstrate that visual information conveyed from visual cortex, via the phase of the local field potential, and is combined with auditory information within auditory cortex. These data provide evidence that early cross-sensory binding provides a bottom-up mechanism for the formation of cross-sensory objects and that one role for multisensory binding in auditory cortex is to support auditory scene analysis.

neuroscience↗

bioRxiv2016

The genome-wide transcriptional response to varying RpoS levels in Escherichia coli K-12

The alternative sigma factor RpoS is a central regulator of a many stress responses in Escherichia coli. The level of functional RpoS differs depending on the stress. The effect of these differing concentrations of RpoS on global transcriptional responses remains unclear. We investigated the effect of RpoS concentration on the transcriptome during stationary phase in rich media. We show that 23% of genes in the E. coli genome are regulated by RpoS level, and we identify many RpoS-transcribed genes and promoters. We observe three distinct classes of response to RpoS by genes in the regulon: genes whose expression changes linearly with increasing RpoS level, genes whose expression changes dramatically with the production of only a little RpoS (\"sensitive\" genes), and genes whose expression changes very little with the production of a little RpoS (\"insensitive\"). We show that sequences outside the core promoter region determine whether a RpoS-regulated gene in sensitive or insensitive. Moreover, we show that sensitive and insensitive genes are enriched for specific functional classes, and that the sensitivity of a gene to RpoS corresponds to the timing of induction as cells enter stationary phase. Thus, promoter sensitivity to RpoS is a mechanism to coordinate specific cellular processes with growth phase, and may also contribute to the diversity of stress responses directed by RpoS.\n\nImportanceThe sigma factor RpoS is a global regulator that controls the response to many stresses in Escherichia coli. Different stresses result in different levels of RpoS production, but the consequences of this variation are unknown. We describe how changing the level of RpoS does not influence all RpoS-regulated genes equally. The cause of this variation is likely the action of transcription factors that bind the promoters of the genes. We show that the sensitivity of a gene to RpoS levels explains the timing of expression as cells enter stationary phase, and that genes with different RpoS sensitivities are enriched for specific functional groups. Thus, promoter sensitivity to RpoS is a mechanism to coordinate specific cellular processes in response to stresses.

microbiology↗