Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

29 records · Page 2Linked to original sources

bioRxiv2018

Altered Reward Processing in Abstinent Dependent Cannabis Users: Social Context Matters

Public perception of cannabis as relatively harmless, alongside claimed medical benefits, have led to moves towards its legalization. Yet, long-term consequences of cannabis dependence, and whether they differ qualitatively from other drugs, are still poorly understood. A key feature of addictive drugs is that chronic use leads to adaptations in reward processing, blunting responsivity to the substance itself and other rewarding stimuli. Against this background, the present study investigated whether cannabis dependence is associated with reductions in hedonic representations by measuring behavioral and neural responses to social reward in 23 abstinent cannabis-dependent men and 24 matched non-using controls. In an interpersonal pleasant touch fMRI paradigm, participants were led to believe they were in physical closeness of or touched (CLOSE, TOUCH) by either a male or female experimenter (MALE, FEMALE), allowing the assessment of touch- and social context-dependent (i.e. female compared to male social interaction) reward dynamics.\n\nUpon female compared to male touch, dependent cannabis users displayed a significantly attenuated increase of reward experience compared to healthy controls. Controls responded to female as compared to male interaction with increased striatal activation whereas cannabis users displayed the opposite activation pattern, with stronger alterations being associated with a higher lifetime exposure to cannabis. Neural processing of pleasant touch in dependent cannabis users remained intact.\n\nThese findings demonstrate that cannabis dependence in men is linked to similar lasting neuroadaptations in striatal responsivity to hedonic stimuli as observed for other drugs of abuse. However, reward processing deficits seem to depend on the social context.

neuroscience↗

bioRxiv2018

Competitive release in tumors

Competitive release is a bedrock principle of coevolutionary ecology and population dynamics. It is also the main mechanism by which heterogeneous tumors develop chemotherapeutic resistance. Understanding, controlling, and exploiting this important mechanism represents one of the key challenges and potential opportunities of current medical oncology. The development of sophisticated mathematical and computational models of coevolution among clonal and sub-clonal cell populations in the tumor ecosystem can guide us in predicting and shaping various responses to perturbations in the fitness landscape which is altered by chemo-toxic agents. This in turn can help us design adaptive chemotherapeutic strategies to combat the release resistant cells.

cancer biology↗

bioRxiv2018

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed and belong to a very few prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death for >3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

cell biology↗

bioRxiv2017

Nonlinear dynamical shaping of the fitness landscape of an evolving tumor to combat competitive release

The development of chemotherapeutic resistance resulting in tumor relapse is largely the consequence of the mechanism of competitive release of pre-existing resistant tumor cells selected for regrowth after chemotherapeutic agents attack the previously dominant chemo-sensitive population. We introduce a prisoners dilemma mathematical model based on the replicator of three competing cell populations: healthy (cooperators), sensitive (defectors), and resistant (defectors) cells. The model is shown to recapitulate prostate-specific antigen measurement data from three clinical trials for metastatic castration-resistant prostate cancer patients treated with 1) prednisone, 2) mitoxantrone and prednisone and 3) docetaxel and prednisone. Continuous maximum tolerated dose schedules reduce the sensitive cell population, initially shrinking tumor volume, but subsequently \"release\" the resistant cells to re-populate and re-grow the tumor in a resistant form. Importantly, a model fit of prostate data shows the emergence of a positive fitness cost associated with a majority of patients for each drug, without predetermining a cost in the model a priori. While the specific mechanism associated with this cost may be very different for each of the drugs, a measurable fitness cost emerges in each. The evolutionary model allows us to quantify responses to conventional therapeutic strategies as well as to design adaptive strategies.

cancer biology↗

bioRxiv2017

Chromatin organization changes during the establishment and maintenance of the postmitotic state

BackgroundGenome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle and existing data suggests a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.\n\nResultsWe focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to re-enter the cell cycle under specific genetic manipulations and a state we call \"robust\", where cells become strongly refractory to cell cycle re-entry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1(HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin associated modifications are restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.\n\nConclusionsHeterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.

developmental biology↗

bioRxiv2017

Comprehensive characterization of pediatric acute myeloid leukemia reveals novel molecular features and age-specific interactions

We present the molecular landscape of pediatric acute myeloid leukemia (AML), characterizing nearly 1,000 participants in Childrens Oncology Group (COG) AML trials. The COG/NCI TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA, miRNA sequencing and CpG methylation profiling. Validated DNA variants revealed diverse, infrequent mutations with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including novel gene fusions and focal MBNL1, ZEB2, and ELF1 deletions, were disproportionately prevalent in young as compared to adult patients. Conversely, DNMT3A and TP53 mutations, common in adults, are conspicuously absent from virtually all pediatric cases. Novel GATA2, FLT3, and CBL mutations, recurrent MYC-ITD, NRAS, KRAS, and WT1 mutations are frequent in pediatric AML. Deletions, mutations, and promoter DNA hypermethylation convergently impact Wnt signaling, Polycomb repression, innate immune cell interactions, and a cluster of zinc finger genes associated with KMT2A rearrangements. These results highlight the need for, and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

cancer biology↗

bioRxiv2017

Simultaneous GCaMP6-based Fiber Photometry and fMRI in Rats

Understanding the relationship between neural and vascular signals is essential for interpretation of functional MRI (fMRI) results with respect to underlying neuronal activity. Simultaneously measuring neural activity using electrophysiology with fMRI has been highly valuable in elucidating the neural basis of the blood oxygenation-level dependent (BOLD) signal. However, this approach is also technically challenging due to the electromagnetic interference that is observed in electrophysiological recordings during MRI scanning. Recording optical correlates of neural activity, such as calcium signals, avoids this issue, and has opened a new avenue to simultaneously acquire neural and BOLD signals. The present study is the first to demonstrate the feasibility of simultaneously and repeatedly acquiring calcium and BOLD signals in animals using a genetically encoded calcium indicator, GCaMP6. This approach was validated with a visual stimulation experiment, during which robust increases of both calcium and BOLD signals in the superior colliculus were observed. In addition, repeated measurement in the same animal demonstrated reproducible calcium and BOLD responses to the same stimuli. Taken together, simultaneous GCaMP6-based fiber photometry and fMRI recording presents a novel, artifact-free approach to simultaneously measuring neural and fMRI signals. Furthermore, given the cell-type specificity of GCaMP6, this approach has the potential to mechanistically dissect the contributions of individual neuron populations with respect to BOLD signal, and ultimately reveal its underlying neural mechanisms.

neuroscience↗

bioRxiv2017

High-content protein localization screening in vivo reveals novel regulators of multiciliated cell development and function

Multiciliated cells (MCCs) drive fluid flow in diverse tubular organs and are essential for development and homeostasis of the vertebrate central nervous system, airway, and reproductive tracts. These cells are characterized by dozens or hundreds of long, motile cilia that beat in a coordinated and polarized manner (Brooks and Wallingford, 2014). In recent years, genomic studies have not only elucidated the transcriptional hierarchy for MCC specification, but also identified myriad new proteins that govern MCC ciliogenesis, cilia beating, or cilia polarization (e.g. (Choksi et al., 2014b; Chung et al., 2014; Hoh et al., 2012; Ma et al., 2014; Treutlein et al., 2014)). Interestingly, this burst of genomic data has also highlighted the obvious importance of the \"ignorome,\" that large fraction of vertebrate genes that remain only poorly characterized (Pandey et al., 2014). Understanding the function of novel proteins with little prior history of study presents a special challenge, especially when faced with large numbers of such proteins. Here, we explored the MCC ignorome by defining the subcellular localization of 260 poorly defined proteins in vertebrate MCCs in vivo. Moreover, functional analyses that arose from results of the screen provide novel insights into the mechanisms by which the actin cytoskeleton simultaneously influences diverse aspects of MCC biology, including basal body docking, and ciliogenesis.

cell biology↗

bioRxiv2017

The Kobresia pygmaea ecosystem of the Tibetan highlands – origin, functioning and degradation of the world’s largest pastoral alpine ecosystem

Kobresia pastures in the eastern Tibetan highlands occupy 450000 km2 and form the worlds largest pastoral alpine ecosystem. The main constituent is an endemic dwarf sedge, Kobresia pygmaea, which forms a lawn with a durable turf cover anchored by a felty root mat, and occurs from 3000 m to nearly 6000 m a.s.l. The existence and functioning of this unique ecosystem and its turf cover have not yet been explained against a backdrop of natural and anthropogenic factors, and thus its origin, drivers, vulnerability or resilience remain largely unknown. Here we present a review on ecosystem diversity, reproduction and ecology of the key species, pasture health, cycles of carbon (C), water and nutrients, and on the paleo-environment. The methods employed include molecular analysis, grazing exclusion, measurements with micro-lysimeters and gas exchange chambers, 13C and 15N labelling, eddy-covariance flux measurements, remote sensing and atmospheric modelling.\n\nThe following combination of traits makes Kobresia pygmaea resilient and highly competitive: dwarf habit, predominantly below-ground allocation of photo assimilates, mixed reproduction strategy with both seed production and clonal growth, and high genetic diversity. Growth of Kobresia pastures is co-limited by low rainfall during the short growing season and livestock-mediated nutrient withdrawal. Overstocking has caused pasture degradation and soil deterioration, yet the extent remains debated. In addition, we newly describe natural autocyclic processes of turf erosion initiated through polygonal cracking of the turf cover, and accelerated by soil-dwelling endemic small mammals. The major consequences of the deterioration of the vegetation cover and its turf include: (1) the release of large amounts of C and nutrients and (2) earlier diurnal formation of clouds resulting in (3) decreased surface temperatures with (4) likely consequences for atmospheric circulation on large regional and, possibly global, scales.\n\nPaleo-environmental reconstruction, in conjunction with grazing experiments, suggests that the present grazing lawns of Kobresia pygmaea are synanthropic and may have existed since the onset of pastoralism. The traditional migratory rangeland management was sustainable over millennia and possibly still offers the best strategy to conserve, and possibly increase, the C stocks in the Kobresia turf, as well as its importance for climate regulation.

ecology↗

bioRxiv2016

HILAQ: A Novel Strategy for Newly Synthesized Protein Quantification

Here we describe a new strategy, HILAQ (Heavy Isotope Labeled Azidohomoalanine Quantification), to rapidly quantify the molecular vulnerability profile to oxytosis. HILAQ quantified more than 1,900 Newly Synthesized Proteins (NSP) after 1h pulse labeling in HEK293T cell line. Compared with the previous published QuaNCAT protocol, the HILAQ strategy simplifies newly synthesized proteome analysis and achieves higher sensitivity.

biochemistry↗

bioRxiv2016

A synthesis of over 9,000 mass spectrometry experiments reveals the core set of human protein complexes

Macromolecular protein complexes carry out many of the essential functions of cells, and many genetic diseases arise from disrupting the functions of such complexes. Currently there is great interest in defining the complete set of human protein complexes, but recent published maps lack comprehensive coverage. Here, through the synthesis of over 9,000 published mass spectrometry experiments, we present hu.MAP, the most comprehensive and accurate human protein complex map to date, containing >4,600 total complexes, >7,700 proteins and >56,000 unique interactions, including thousands of confident protein interactions not identified by the original publications. hu.MAP accurately recapitulates known complexes withheld from the learning procedure, which was optimized with the aid of a new quantitative metric (k-cliques) for comparing sets of sets. The vast majority of complexes in our map are significantly enriched with literature annotations and the map overall shows improved coverage of many disease-associated proteins, as we describe in detail for ciliopathies. Using hu.MAP, we predicted and experimentally validated candidate ciliopathy disease genes in vivo in a model vertebrate, discovering CCDC138, WDR90, and KIAA1328 to be new cilia basal body/centriolar satellite proteins, and identifying ANKRD55 as a novel member of the intraflagellar transport machinery. By offering significant improvements to the accuracy and coverage of human protein complexes, hu.MAP (http://proteincomplexes.org) serves as a valuable resource for better understanding the core cellular functions of human proteins and helping to determine mechanistic foundations of human disease.

systems biology↗