A Flexible Zero-Inflated Poisson-Gamma model with application to microbiome read counts

In microbiome studies, it is of interest to use a sample from a population of microbes, such as the gut microbiota community, to estimate the population proportion of these taxa. However, due to biases introduced in sampling and preprocessing steps, these observed taxa abundances may not reflect true taxa abundance patterns in the ecosystem. Repeated measures including longitudinal study designs may be potential solutions to mitigate the discrepancy between observed abundances and true underlying abundances. Yet, widely observed zero-inflation and over-dispersion issues can distort downstream statistical analyses aiming to associate taxa abundances with covariates of interest. To this end, we propose a Zero-Inflated Poisson Gamma (ZIPG) framework to address the aforementioned challenges. From a perspective of measurement errors, we accommodate the discrepancy between observations and truths by decomposing the mean parameter in Poisson regression into a true abundance level and a multiplicative measurement of sampling variability from the microbial ecosystem. Then, we provide flexible modeling by connecting both mean abundance and the variability to different covariates, and build valid statistical inference procedures for both parameter estimation and hypothesis testing. Through comprehensive simulation studies and real data applications, the proposed ZIPG method provides significant insights into distinguished differential variability and abundance

The effects of concentration, interaction, size distribution and shape anisotropy on rheology of colloidal mixtures

This dissertation studies the rheological properties of dense colloidal mixtures. Particular interest is focused on the role of volume fraction and strength of interactions that lead to glass or gel formation. Variables studied include particle concentration, strength of attraction, particle size distribution, and particle shape, which have effects on dynamic arrest transitions, jamming conditions and steady flow properties of dense suspensions. A special attention is paid to changes in properties at volume fractions exceeding the dynamic arrest transitions and approaching maximum packing fractions. For mixtures of particles, dynamic state diagrams are constructed as functions of large particle volume fraction ratio and total particle volume fraction as particle interactions are varied. The main effort is focused on the system composed of spherical silica particles with different sizes (100nm-1μm) dispersed in low molecular weight polyethylene glycol (PEG) melts with molecular weight 400 and 2000. For this system we explore the impact of the polymer molecular weight on the dynamic arrest transition, linear elasticity, shear thickening, and yielding for both monomodal and bimodal particle size distributions. Data is reported showing a varied dynamic arrest transition volume fraction, weakened shear thickening behavior and augmented shear elasticity in higher molecular weight polymer melt (PEG2000) for single-component system and denoting a stronger particle-particle attraction in higher molecular weight polymer which cannot be a consequence of adsorbed polymer layer entanglement. For bimodal mixtures in PEG400, particles interact with excluded volume potentials and the dynamic arrest transition volume fraction is a non-monotonic function of large particle volume fraction ratio. The dynamic arrest volume fraction is strongly correlated with the maximum packing fraction for each mixture. The data show that rheological properties of dynamic arrested states diverge in a consistent way when approaching maximum packing fractions. When dispersed in PEG2000 where particles are attractive, the dynamic arrest volume fraction is a monotonic function of large particle volume fraction ratio, which is not correlated with maximum packing fraction. Flow properties at this condition are dominated by attractions. In a further study, the flow properties of suspensions of large (diameter~1μm) and small (diameter~300nm) polystyrene particles suspended in an aqueous electrolyte were investigated. Here two types of large particles were investigated: spheres and dumbbell shaped particles. Weak shape anisotropy of the large particles delays the dynamic arrest transition and decreases the viscoelasticity at fixed volume fractions in single-component systems, but enhances the dynamic arrests and alters the jamming conditions in binary mixtures compared to sphere mixtures with bimodal size distributions. A consistent understanding of rheology in dense suspensions is built up based on particle localization effects

Auggie: Encouraging Effortful Communication through Handcrafted Digital Experiences

Digital communication is often brisk and automated. From auto-completed messages to "likes," research has shown that such lightweight interactions can affect perceptions of authenticity and closeness. On the other hand, effort in relationships can forge emotional bonds by conveying a sense of caring and is essential in building and maintaining relationships. To explore effortful communication, we designed and evaluated Auggie, an iOS app that encourages partners to create digitally handcrafted Augmented Reality (AR) experiences for each other. Auggie is centered around crafting a 3D character with photos, animated movements, drawings, and audio for someone else. We conducted a two-week-long field study with 30 participants (15 pairs), who used Auggie with their partners remotely. Our qualitative findings show that Auggie participants engaged in meaningful effort through the handcrafting process, and felt closer to their partners, although the tool may not be appropriate in all situations. We discuss design implications and future directions for systems that encourage effortful communication.Comment: To appear at the 25th ACM Conference On Computer-Supported Cooperative Work And Social Computing (CSCW '22). 25 page

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders

HBV infection-induced liver cirrhosis development in dual-humanized mice with human bone mesenchymal stem cell transplantation

疾病动物模型是现代医学发展的基石，尤其是重大、突发传染病暴发时，适宜的疾病动物模型可为及时发现病原体、制定防控策略提供强大保障，原创的疾病动物模型已成为衡量一个国家生物医药科研水平的标志。我校夏宁邵教授团队和浙江大学附属第一医院李君教授团队历经5年的协同攻关，终于建立了国际上首个高度模拟人类乙肝病毒（HBV）自然感染诱发的慢乙肝肝硬化小鼠模型。厦门大学公共卫生学院袁伦志博士生、浙江大学医学院附属第一医院江静博士和厦门大学公共卫生学院刘旋博士生为该论文共同第一作者。厦门大学夏宁邵教授、浙江大学附属第一医院李君教授和厦门大学程通副教授为该论文共同通讯作者。【Abstract】Objective： Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs). Design： Transplantation of hBMSCs into Fah -/- Rag2 -/- IL-2Rγc -/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanized (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterize the progression of chronic hepatitis and cirrhosis after HBV infection. Results： The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks. Conclusion： This new humanized mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.this work was supported by the national Science and technology Major Project (grant nos. 2017ZX10304402, 2017ZX10203201 and 2018ZX09711003-005-003), the national natural Science Foundation of china(grant nos. 81672023, 81571818 and 81771996), the Scientific research Foundation of the State Key laboratory of Molecular Vaccinology and Molecular Diagnostics (grant no 2016ZY005), Zhejiang Province and State's Key Project of the research and Development Plan of china (grant nos 2017c01026 and 2016YFc1101304/3).该研究获得了传染病防治国家科技重大专项、新药创制国家科技重大专项和国家自然科学基金的资助

Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch

Silver birch (Betula pendula) is a pioneer boreal tree that can be induced to flower within 1 year. Its rapid life cycle, small (440-Mb) genome, and advanced germplasm resources make birch an attractive model for forest biotechnology. We assembled and chromosomally anchored the nuclear genome of an inbred B. pendula individual. Gene duplicates from the paleohexaploid event were enriched for transcriptional regulation, whereas tandem duplicates were overrepresented by environmental responses. Population resequencing of 80 individuals showed effective population size crashes at major points of climatic upheaval. Selective sweeps were enriched among polyploid duplicates encoding key developmental and physiological triggering functions, suggesting that local adaptation has tuned the timing of and cross-talk between fundamental plant processes. Variation around the tightly-linked light response genes PHYC and FRS10 correlated with latitude and longitude and temperature, and with precipitation for PHYC. Similar associations characterized the growth-promoting cytokinin response regulator ARR1, and the wood development genes KAK and MED5A.Peer reviewe

Synthesis and rheology of pH-responsive particles with shape anisotropy

Seeded emulsion polymerization is used to produce large quantities of shape anisotropic, amphoteric particles in a size range of about 1 ??m. Two different kinds of shape anisotropic particles are prepared for comparison to study the effects of incorporating pH-responsive groups on the properties of suspensions containing shape anisotropic colloidal particles. Copolymer dicolloids (CDC) containing pyridine groups are synthesized by swelling spherical, lightly cross linked polystyrene seeds with mixture of styrene and 2-vinyl pyridine (2VP) followed by secondary polymerization. Homopolymer dicolloids (HDC) are made in a similar procedure with only pure styrene swollen into seeds. To investigate the effects of weak attractions, the particles are coated with the nonionic surfactant hexaethylene glycol monododecyl ether (C12E6). As confirmed by electrophoretic mobility measurements as a function of pH, the CDC particles continue to show amphoteric properties. States of aggregation of dilute suspensions are mapped as functions of ionic strength and pH. The CDC particles show amphoteric behavior with strong attractions in medium pH range, while HDC remain stable at all pH???s studied (30.5) with small linear elastic modulus (G0???*) above ??g at different pH conditions and ionic strengths up to 0.5M proving again that the particles experience repulsive or weakly-attractive conditions. The CDC particles behave in a similar manner at high or low pH at an ionic strength, [I] of 0.001M, but gel at a volume fraction of ??g<0.3 and display anomalously large G0???* at the gel transition at intermediate pH or at pH=9 and I=0.5M. The modulus and yielding behavior of these suspensions indicate that even at pH=9 or pH= 3.7 and I=0.001 the CDC particles experience weak attractions that cannot be explained as arising from isotropic repulsions as experienced by the HDC particles. At pH=9 and I=0.5M or pH=4.6 and I=0.001M, these anomalous attractions are accentuated. These anomalous attractions are understood as arising from the chemical anisotropy of the CDC particles where the protrusion created in the second polymerization step is rich in poly-2VP while the seed is rich in negatively charged sulfate groups. These chemical differences can give rise to directional interactions due to differences in charge or due to differences in hydrophobicity. A key conclusion drawn from this work is that the signature of directional interactions comes in the way gels and glasses yield when stressed. Gel points are shifted by anisotropic interactions but the same gel points can be generated with isotropic interactions if the attractions are strong enough. Instead, gel composed of particles experiencing anisotropic chemical interactions yield with multiple constraints under conditions where this is not seen for particles with isotropic interactions

Role of Particle Size and Polymer Length in Rheology of Colloid–Polymer Composites

The effect of particle size on the flow properties of composite melts is explored. We investigate a system composed of silica particles with diameter <i>D</i>_c = 127–730 nm in unentangled poly­(ethylene glycol) of two molecular weights (400 with degree of polymerization ∼9 and 2000 with degree of polymerization of 45). At low concentration, silica particles are stabilized by the adsorbed polymer layer as indicated by intrinsic viscosities slightly larger than the Einstein value of 2.5. Huggins coefficients indicate that at low concentration in PEG400 the particles behave very much like hard spheres, while in PEG2000 the particles experience very weak attractions. At high volume fraction, the absorbed polymer layers begin to interact such that hard-sphere scaling no longer applies to linear and nonlinear rheological responses. In PEG2000, at elevated volume fractions, the particles with stronger attractions experience kinetic arrest with average particle surface separations much larger than the polymer radius of gyration, <i>R</i>_g. We show that the linear rheology, yielding behavior, and shear thickening response of dense composites are varied with <i>R</i>_g/<i>D</i>_c, with volume exclusion glass formation observed at low <i>R</i>_g/<i>D</i>_c and gelation at high <i>R</i>_g/<i>D</i>_c, and with yielding and shear thickening properties changed by <i>R</i>_g and <i>D</i>_c independently. The polymer layers are found to alter the approach to the jamming transition even for <i>R</i>_g/<i>D</i>_c as small as 6 × 10^–3

Synthesis of pH-Responsive Particles with Shape Anisotropy

Seeded emulsion polymerization is used to produce large quantities of shape anisotropic, amphoteric particles in a size range of about 1 μm. Copolymer dicolloids (CDCs) containing pyridine groups are synthesized by swelling spherical, lightly cross-linked polystyrene seeds with a mixture of styrene and pH-responsive monomer 2-vinyl pyridine followed by secondary polymerization to contrast with their analogue homopolymer dicolloids (HDCs) where the swelling step is carried out with styrene alone. After the particles are coated with a nonionic surfactant to minimize van der Waals attractions, surface potentials and aggregation properties of dilute suspensions are studied as functions of pH and ionic strength. Compared to HDCs, which remain stable at all pH values studied (3 < pH < 9) up to an ionic strength of 5 M, the CDC particles show amphoteric behavior with strong attractions under conditions where dipolar interactions are expected to dominate

A Flexible Zero-Inflated Poisson-Gamma Model with Application to Microbiome Sequence Count Data

In microbiome studies, it is of interest to use a sample from a population of microbes, such as the gut microbiota community, to estimate the population proportion of these taxa. However, due to biases introduced in sampling and preprocessing steps, these observed taxa abundances may not reflect true taxa abundance patterns in the ecosystem. Repeated measures, including longitudinal study designs, may be potential solutions to mitigate the discrepancy between observed abundances and true underlying abundances. Yet, widely observed zero-inflation and over-dispersion issues can distort downstream statistical analyses aiming to associate taxa abundances with covariates of interest. To this end, we propose a Zero-Inflated Poisson Gamma (ZIPG) model framework to address these aforementioned challenges. From a perspective of measurement errors, we accommodate the discrepancy between observations and truths by decomposing the mean parameter in Poisson regression into a true abundance level and a multiplicative measurement of sampling variability from the microbial ecosystem. Then, we provide a flexible ZIPG model framework by connecting both the mean abundance and the variability of abundances to different covariates, and build valid statistical inference procedures for both parameter estimation and hypothesis testing. Through comprehensive simulation studies and real data applications, the proposed ZIPG method provides significant insights into distinguished differential variability and mean abundance.</p