Biology subjects

Yan, S.

Publications and source records attributed to Yan, S..

100 records · Page 6Linked to original sources

bioRxiv2019

GPU-accelerated mesh-based Monte Carlo photon transport simulations

The mesh-based Monte Carlo (MMC) algorithm is increasingly used as the gold-standard for developing new biophotonics modeling techniques in 3-D complex tissues, including both diffusion-based and various Monte Carlo (MC) based methods. Compared to multi-layered and voxel-based MCs, MMC can utilize tetrahedral meshes to gain improved anatomical accuracy, but also results in higher computational and memory demands. Previous attempts of accelerating MMC using graphics processing units (GPUs) have yielded limited performance improvement and are not publicly available. Here we report a highly efficient MMC - MMCL - using the OpenCL heterogeneous computing framework, and demonstrate a speedup ratio up to 420x compared to state-of-the-art single-threaded CPU simulations. The MMCL simulator supports almost all advanced features found in our widely disseminated MMC software, such as support for a dozen of complex source forms, wide-field detectors, boundary reflection, photon replay and storing a rich set of detected photon information. Furthermore, this tool supports a wide range of GPUs/CPUs across vendors and is freely available with full source codes and benchmark suites at http://mcx.space/#mmc.

bioengineering↗

bioRxiv2019

Classification of platelet aggregates by agonist type

Platelets are anucleate cells in blood whose principal function is to stop bleeding by forming aggregates for hemostatic reactions. In addition to their participation in physiological hemostasis, platelet aggregates are also involved in pathological thrombosis and play an important role in inflammation, atherosclerosis, and cancer metastasis. The aggregation of platelets is elicited by various agonists, but these platelet aggregates have long been considered indistinguishable and impossible to classify. Here we present an intelligent method for classifying them by agonist type. It is based on a convolutional neural network trained by high-throughput imaging flow cytometry of blood cells to identify and differentiate subtle yet appreciable morphological features of platelet aggregates activated by different types of agonists. The method is a powerful tool for studying the underlying mechanism of platelet aggregation and is expected to open a window on an entirely new class of clinical diagnostics, pharmacometrics, and therapeutics.

cell biology↗

bioRxiv2019

Direct microRNA sequencing using Nanopore Induced Phase-Shift Sequencing (NIPSS)

MicroRNAs (miRNAs) are a class of short non-coding RNAs that function in RNA silencing and post-transcriptional gene regulation. Besides their participation in regulating normal physiological activities, specific miRNA types could act as oncogenes, tumor suppressors or metastasis regulators, which are critical biomarkers for cancer. However, direct characterization of miRNA is challenging due to its unique properties such as its low abundance, sequence similarities and short length. Nanopore Induced Phase Shift Sequencing (NIPSS), which is a variant form of nanopore sequencing, could directly sequence any short analytes including miRNA. In practice, NIPSS clearly discriminates between different identities, isoforms and epigenetic variants of model miRNA sequences. This work demonstrates the first report of direct miRNA sequencing, which serves as a complement to existing miRNA sensing routines by the introduction of single molecule resolution. Future engineering of this technique may assist miRNA based early stage diagnosis or inspire novel cancer therapeutics.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC=\"FIGDIR/small/747113v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (33K):\norg.highwire.dtl.DTLVardef@216b4borg.highwire.dtl.DTLVardef@b1e88org.highwire.dtl.DTLVardef@1b04aorg.highwire.dtl.DTLVardef@dcdbb7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2019

Inland-coastal bifurcation of southern East Asians revealed by Hmong-Mien genomic history

The early history of the Hmong-Mien language family and its speakers is elusive. A good variety of Hmong-Mien-speaking groups distribute in Central China. Here, we report 903 high-resolution Y-chromosomal, 624 full-sequencing mitochondrial, and 415 autosomal samples from 20 populations in Central China, mainly Hunan Province. We identify an autosomal component which is commonly seen in all the Hmong-Mien-speaking populations, with nearly unmixed composition in Pahng. In contrast, Hmong and Mien respectively demonstrate additional genomic affinity to Tibeto-Burman and Kra-Dai speakers. We also discover two prevalent uniparental lineages of Hmong-Mien speakers. Y-chromosomal haplogroup O2a2a1b1a1b-N5 diverged [~]2,330 years before present (BP), approximately coinciding with the estimated time of Proto-Hmong-Mien ([~]2,500 BP), whereas mitochondrial haplogroup B5a1c1a significantly correlates with Pahng and Mien. All the evidence indicates a founding population substantially contributing to present-day Hmong-Mien speakers. Consistent with the two distinct routes of agricultural expansion from southern China, this Hmong-Mien founding ancestry is phylogenetically closer to the founding ancestry of Neolithic Mainland Southeast Asians and present-day isolated Austroasiatic-speaking populations than Austronesians. The spatial and temporal distribution of the southern East Asian lineage is also compatible with the scenario of out-of-southern-China farming dispersal. Thus, our finding reveals an inland-coastal genetic discrepancy related to the farming pioneers in southern China and supports an inland southern China origin of an ancestral meta-population contributing to both Hmong-Mien and Austroasiatic speakers.

genetics↗

bioRxiv2019

MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autism

MECP2 gain- and loss-of-function in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that MECP2 coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in MECP2 overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map MECP2-related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.\n\nOne sentence summaryWe identify shared circuit-level abnormalities between MECP2 transgenic monkeys and a stratified subgroup of human autism, and demonstrate the translational need of a multimodal approach to capture multifaceted effects triggered by a single genetic event in a genetically-engineered primate model.

neuroscience↗

bioRxiv2019

The olfactory co-receptor IR8a governs larval-frass mediated competition avoidance in a hawkmoth

Finding a suitable oviposition site is a challenging task for a gravid female moth. At the same time, it is of paramount importance considering the limited capability of most caterpillars to relocate to alternative host plants. The hawkmoth, Manduca sexta (Sphingidae), oviposits on solanaceous plants. Larvae hatching on a plant that is already attacked by conspecific caterpillars can face food competition, as well as an increased exposure to predators and induced plant defenses. Here, we show that frass from conspecific caterpillars is sufficient to deter a female M. sexta from ovipositing on a plant and that this deterrence is based on the frass-emitted carboxylic acids 3-methylpentanoic acid and hexanoic acid. Using a combination of genome editing (CRISPR/Cas9), electrophysiological recordings, calcium imaging and behavioral analyses we demonstrate that the ionotropic co-receptor IR8a is essential for acid-mediated frass avoidance in ovipositing hawkmoths.

neuroscience↗

bioRxiv2019

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

cancer biology↗

bioRxiv2018

Stabilizing Obligatory Non-native Intermediates Along Co-transcriptional Folding Trajectories of SRP RNA Affects Cell Viability

Signal recognition particle (SRP) in Escherichia coli comprises protein Ffh and SRP RNA. Its essential functionality--co-translational protein-targeting/delivery to cellular membranes-- hinges on the RNA attaining a native long-hairpin fold that facilitates protein conformational rearrangements within the SRP complex. Since RNA folds co-transcriptionally on RNA polymerase, we use high-resolution optical tweezers to first characterize the mechanical unfolding/refolding of incrementally lengthened RNAs from stalled transcription complexes until reaching the full-length transcript. This analysis allows identification of folding intermediates adopted during the real-time co-transcriptional folding of SRP RNA. The co-transcriptional folding trajectories are surprisingly invariant to transcription rates, and involve formation of an obligatory non-native hairpin intermediate that eventually resolves into the native fold. SRP RNA variants designed to stabilize this non-native intermediate--likely sequestering the SRP ribonucleoprotein complex in an inactive form--greatly reduce cell viability, indicating that the same co-transcriptional folding mechanism operates in vivo and possible alternative antibiotic strategies.\n\nHighlightsO_LIFolding pathway of an essential functional RNA has been resolved co-transcriptionally.\nC_LIO_LIThe co-transcriptional folding pathway of SRP RNA is invariant to transcription rates.\nC_LIO_LINascent SRP RNA obligatorily forms a non-native intermediate before adopting the native fold.\nC_LIO_LIModulating transitions from the non-native to native SRP RNA hairpin fold alters cell viability.\nC_LI

biophysics↗

bioRxiv2018

ATP-dependent force generation and membrane scission by ESCRT-III and Vps4

The ESCRTs catalyze reverse-topology scission from the inner face of membrane necks in HIV budding, multivesicular endosome biogenesis, cytokinesis, and other pathways. We encapsulated a minimal ESCRT module consisting of ESCRT-III subunits Snf7, Vps24, and Vps2, and the AAA+ ATPase Vps4 such that membrane nanotubes reflecting the correct topology of scission could be pulled from giant vesicles. Upon ATP release by photo-uncaging, this system was capable of generating forces within the nanotubes in a manner dependent upon Vps4 catalytic activity, Vps4 coupling to the ESCRT-III proteins, and membrane insertion by Snf7. At physiological concentrations, single scission events were observed that correlated with forces of ~6 pN, verifying predictions that ESCRTs are capable of exerting forces on membranes. Imaging of scission with subsecond resolution revealed Snf7 puncta at the sites of membrane cutting, directly verifying longstanding predictions for the ESCRT scission mechanism.\n\nOne Sentence SummaryESCRT-III and Vps4 were reconstituted from within the interior of nanotubes pulled from giant vesicles, revealing that this machinery couples ATP-dependent force production for membrane scission.

biophysics↗

bioRxiv2017

Prediction (Or Not) During Language Processing. A Commentary On Nieuwland et al. (2017) And Delong et al. (2005)

The extent to which language processing involves prediction of upcoming inputs remains a question of ongoing debate. One important data point comes from DeLong et al. (2005) who reported that an N400-like event-related potential correlated with a probabilistic index of upcoming input. This result is often cited as evidence for gradient probabilistic prediction of form and/or semantics, prior to the bottom-up input becoming available. However, a recent multi-lab study reports a failure to find these effects (Nieuwland et al., 2017). We review the evidence from both studies, including differences in the design and analysis approach between them. Building on over a decade of research on prediction since DeLong et al. (2005)s original study, we also begin to spell out the computational nature of predictive processes that one might expect to correlate with ERPs that are evoked by a functional element whose form is dependent on an upcoming predicted word. For paradigms with this type of design, we propose an index of anticipatory processing, Bayesian surprise, and apply it to the updating of semantic predictions. We motivate this index both theoretically and empirically. We show that, for studies of the type discussed here, Bayesian surprise can be closely approximated by another, more easily estimated information theoretic index, the surprisal (or Shannon information) of the input. We re-analyze the data from Nieuwland and colleagues using surprisal rather than raw probabilities as an index of prediction. We find that surprisal is gradiently correlated with the amplitude of the N400, even in the data shared by Nieuwland and colleagues. Taken together, our review suggests that the evidence from both studies is compatible with anticipatory semantic processing. We do, however, emphasize the need for future studies to further clarify the nature and degree of form prediction, as well as its neural signatures, during language comprehension.

neuroscience↗