New Citation 25 July 2019

【】1.Analytical results for a generalized model of bursty gene expression with molecular memory
Huahai Qiu, Bengong Zhang, and Tianshou Zhou
Phys. Rev. E 100, 012128 – Published 19 July 2019

ABSTRACT
The activation of a gene is a complex biochemical process and could involve small steps, creating a memory between individual events. However, the effect of this molecular memory was often neglected in previous work. How the molecular memory affects gene expression remains not fully explored. We analyze a stochastic model（随机模型） of bursty gene expression, where the waiting time from inactivation to activation is assumed to follow a nonexponential distribution(非指数分布)(in fact, Erlang). We derive the analytical expression for the gene-product distribution, which explicitly traces the effect of molecule memory. Interestingly, we find that the effect of molecular memory is equivalent to the introduction of feedback. In addition, we analytically show that the stationary distribution is always super-Poissonian,(泊松) independent of the detail of the waiting-time distribution, and there is the optimal step size that minimizes the Fano factor for any given mean burst size and is a decreasing function of the mean burst size. These analytical results indicate that molecular memory is an unneglectable factor affecting gene expression.

2.STEADY STATE AND SENSITIVITY ANALYSIS OF A NOTCH–DELTA SIGNALING SYSTEM OF ONE SINGLE CELL INTERACTING WITH FIXED ENVIRONMENT

Abstract
The Notch–Delta signaling pathway is a highly conserved signaling system that partakes（分担） in a diverse process of growth, patterns and differentiation. Experiments have shown that Delta from different cells activates this pathway (trans-activation) while Delta from the same cell inhibits this pathway (cis-inhibition). The Notch–Delta interactions could switch a cell to one of the two opposite fates: either Sender (high Delta/low Notch) or Receiver (low Delta/high Notch). We studied a Notch–Delta signaling model from Sprinzak et al., (2010), to investigate the cell fate through steady state analysis. The focus was placed on a fundamental case of one single cell with fixed external Delta and Notch supplies. First, we proved there exists a unique steady state which is asymptotically stable（渐进稳定）. Second, we derived the increasing/decreasing and asymptotic properties of the steady state with respect to all the parameters. Third, we studied the sensitivity and discovered the cell fate is only sensitive to the production rates of Notch and Delta under strong cis-inhibition. Finally, we applied this model to multi-cellular cases and found that the lateral inhibition pattern could be created with the spatially varied Delta production rate. The Hopf bifurcation（霍普夫分歧） is not observed in the current model.

3. Approaches for Protein Function Prediction and Candidate Discovery for Gene Regulatory Network Expansion
Biology is experiencing a paradigm shift since the advent of next generation sequencing
technologies. The retrieved data largely exceeds the capability of biologists
to investigate all possibilities in the laboratories, hence predictive tools able to guide
the research are now a fundamental component of their workflow. Given the central
role of proteins in living organisms, in this thesis we focus on their functional
analysis and the intrinsic multi-target nature of this task. To this end, we propose
different predictive methods, specifically developed to exploit side knowledge among
target variables and examples.

As a first contribution we face the task of protein-function prediction and more in general of hierarchical-multilabel classification (HMC). We present Ocelot a predictivepipeline for genome-wide protein characterization. It relies on a statisticalrelational-learning tool, where the knowledge on the input examples is coded by thecombination of multiple kernel matrices, while relations among target variables are expressed as logical constraints. Both, the mislabeling of examples and the infringement of logical rules are penalized by the loss function, but Ocelot do not forces
hierarchical consistency. To overcome this limitation, we present AWX, a neuralnetworks output-layer that guarantees the formal consistency of HMC predictions.

The second contribution is VSC, a binary classifier designed to incorporate the
concepts of subsampling(二次抽样、分层抽样) and locality in the definition of features to be used as the input of a perceptron. A locality-based confidence measure is used to weight the contribution of maximum-margin hyper-planes built by subsampling pairs of examples of opposite class. The rationale is that local methods can be exploited when a multitargettask is expected, but not reflected in the annotation space.

The third and last contribution are NES2RA and OneGenE, two approaches
for finding candidates to expand known gene regulatory networks. NES2RA adopts variable-subsetting strategies, enabled by volunteer distributed computing, and the PCalgorithm to discover candidate causal relationships within each subset of variables.Then, ranking aggregators combine the partial results into a single ranked candidategenes list. OneGenE overcomes the main limitation of NES2RA, i.e. latency, by precomputing candidate expansion lists for each transcript of an organism that are
then aggregated on-demand.