Mechanistic Models of Neural Computation in the Fruit Fly Brain

Understanding the operating principles of the brain functions is the key to building novel computing architectures for mimicking human intelligence. Neural activities at different scales lead to different levels of brain functions. For example, cellular functions, such as sensory transduction, occur in the molecular reactions, and cognitive functions, such as recognition, emerge in neural systems across multiple brain regions. To bridge the gap between neuroscience and artificial computation, we need systematic development of mechanistic models for neural computation across multiple scales. Existing models of neural computation are often independently developed for a specific scale and hence not compatible with others. In this thesis, we investigate the neural computations in the fruit fly brain and devise mechanistic models at different scales in a systematic manner so that models at one scale constitute functional building blocks for the next scale. Our study spans from the molecular and circuit computations in the olfactory system to the system-level computation of the central complex in the fruit fly. First, we study how the two key aspects of odorant, identity and concentration, are encoded by the odorant transduction process at the molecular scale. We mathematically quantify the odorant space and propose a biophysical model of the olfactory sensory neuron (OSN). To validate our modeling approaches, we examine the OSN model with a multitude of odorant waveforms and demonstrate that the model output reproduces the temporal responses of OSNs obtained from in vivo electrophysiology recordings. In addition, we evaluate the model at the OSN population level and quantify the combinatorial complexity of the transformation taking place between the odorant space and the OSNs. The resulting concentration-dependent combinatorial code determines the complexity of the input space driving olfactory processing in the downstream neuropil, the antennal lobe. Second, we investigate the neural information processing in the antennal lobe across the molecule scale and the circuit scale. The antennal lobe encodes the output of the OSN population from a concentration-dependent code into a concentration-independent combinatorial code. To study the transformation of the combinatorial code, we construct a computational model of the antennal lobe that consists of two sub circuits, a predictive coding circuit and an on-off circuit, realized by two distinct local neuron networks, respectively. By examining the entire circuit model with both monomolecular odorant and odorant mixtures, we demonstrate that the predictive coding circuit encodes the odorant identity into concentration invariant code and the on-off circuit encodes the onset and the offset of a unique odorant identity. Third, we investigate the odorant representation inherent in the Kenyon cell activities in the mushroom body. The Kenyon cells encodes the output of the antennal lobe into a high-dimensional, sparse neural code that is immediately used for learning and memory formation. We model the Kenyon cell circuitry as a real-time feedback normalization circuit converting odorant information into a time-dependent hash codes. The resultant real-time hash code represents odorants, pure or mixture alike, in a way conducive to classifications, and suggests an intrinsic partition of the odorant space with similar hash codes. Forth, we study at the system scale the neural coding of the central complex. The central complex is a set of neuropils in the center of the fly brain that integrates multiple sensory information and play an important role in locomotor control. We create an application that enables simultaneous graphical querying and construction of executable model of the central complex neural circuitry. By reconfiguring the circuitry and generating different executable models, we compare the model response of the wild type and mutant fly strains. Finally, we show that the multi-scale study of the fruit fly brain is made possible by the Fruit Fly Brain Observatory (FFBO), an open-source platform to support open, collaborative fruit fly neuroscience research. The software architecture of the FFBO and its key application are highlighted along with several examples

Functional identification of an antennal lobe DM4 projection neuron of the fruit fly

A rich set of genetic tools and extensive anatomical data make the olfactory system of the fruit fly a neural circuit of choice for studying function in sensory systems. Though a substantial amount of work has been published on the neural coding of olfactory sensory neurons (OSNs) of the fruit fly, yet little is known how projection neurons (PNs) encode time-varying odor stimuli. Here we address this question with in vivo experiments coupled with a phenomenological characterization of the spiking activity of PNs. Recently, a new class of identification algorithms called Channel Identification Machines (CIMs) was proposed for identifying dendritic processing in simple neural circuits using conditional phase response curves (cPRCs). By combining cPRCs with the reduced project-integrated-and-fire neuron (PIF) model, the CIM algorithms identify a complete phenomenological description of spike generation of a biological neuron for weak to moderately strong stimuli. Moreover, the identification method employed does not require white noise stimuli nor an infinitesimal pulse injection protocol as widely used in the past. Here we identify the PNs both in silico and in vivo. Starting with simulations, we investigate the feasibility of the CIM method on PNs modeled as pseudo uni-polar neurons in silico, as shown in Figures 1.(B) and 1.(C). We then systematically convert the CIM method into a step-by-step experimental protocol, and carry it out in vivo by injecting currents into PNs using the patch clamping technique

Elevated Krüppel-like factor 4 transcription factor in canine mammary carcinoma

<p>Abstract</p> <p>Background</p> <p>Krüppel-like factors (KLFs) are critical regulators of biological and physiological systems and have been extensively studied for their roles in cell proliferation, differentiation and survival in the context of cancer. Among the KLFs, KLF4 is highly expressed in human breast cancers and plays an oncogenic role. The present study examined the expression of KLF4 and assessed its significance in canine mammary carcinoma.</p> <p>Results</p> <p>Immunohistochemistry was employed to investigate the expression of KLF4 in 142 cases of canine mammary tumor. 75 of the 142 (52.8%) cases were histologically confirmed as mammary carcinoma. Quantification of immunohistochemistry was carried out using Quick score which multiply the staining intensity by the percentage of positive cells. High KLF4 expression was identified in 44 of the 75 (59%) dogs with mammary carcinoma and none in the benign cases. High KLF4 expression occurred only in the tumor cells and not the adjacent normal cells in mammary carcinoma (P < 0.001). Moreover, the high expression level of KLF4 expression was statistically associated with poor grade, late stage, histological subtypes of simple and complex carcinoma, and shorter 24-month survival. The Kaplan-Meier survival analysis also indicated that dogs with high nuclear KLF4 expression had a significantly shorter survival than those with low/moderate KLF4 expression (P = 0.011).</p> <p>Conclusions</p> <p>KLF4 is highly and frequently expressed in canine mammary carcinoma and correlates with a more aggressive phenotype.</p

Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells

<p>Abstract</p> <p>Background</p> <p>Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-κB. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells.</p> <p>Results</p> <p>Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. The pharmacological inhibition of NF-κB, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells.</p> <p>Conclusions</p> <p>This study is the first to directly address the role Stat3 plays on the autocrine production of IL-6, which occurs through a positive-feedback loop. Our biochemical and genetic studies clearly demonstrated that Jak2/Stat3, in combination with other IL-6 downstream pathways, contributed frequently and substantially to IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples. Our findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance.</p

Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells

<p>Abstract</p> <p>Background</p> <p>Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-κB. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells.</p> <p>Results</p> <p>Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. The pharmacological inhibition of NF-κB, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells.</p> <p>Conclusions</p> <p>This study is the first to directly address the role Stat3 plays on the autocrine production of IL-6, which occurs through a positive-feedback loop. Our biochemical and genetic studies clearly demonstrated that Jak2/Stat3, in combination with other IL-6 downstream pathways, contributed frequently and substantially to IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples. Our findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance.</p

Ferroelectric Control of the Conduction at the LaAlO 3 /SrTiO 3 Hetero-interface

Abstract The LaAlO 3 /SrTiO 3 (LAO/STO) interface serves as a model system in which a highly mobile quasi-twodimensional electron gas (2DEG) forms between two band insulator

Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

<p>Abstract</p> <p>Background</p> <p>A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.</p> <p>Methods</p> <p>Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients.</p> <p>Results</p> <p>A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α <it>in vitro </it>was through a <it>ras</it>- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (<it>p </it>< 0.05), and overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival (<it>p </it>< 0.01).</p> <p>Conclusions</p> <p>In addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.</p

Clinical Efficacy and Post-Treatment Seromarkers Associated with the Risk of Hepatocellular Carcinoma among Chronic Hepatitis C Patients

This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004–2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22–0.63) for those without cirrhosis and 0.54 (0.31–0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored