Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the last century. The post-genomics era has brought a renaissance in natural product discovery using synthetic biology tools. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging. Here we proposed a resistance gene directed strategy to discover new natural products of desired bioactivity from genomic data. Our approach is based on the co-clustering of a self-resistance gene in the natural product biosynthetic gene cluster, which serves as a window to potential biological activity of the encoded compound. To demonstrate the feasibility, we first successfully located and verified the biosynthetic gene cluster of a glyceraldehyde-3-phosphate dehydrogenase inhibitor heptelidic acid by using a resistance gene. We showed the glyceraldehyde-3-phosphate dehydrogenase homolog hepG, co-localized with biosynthetic genes, is able to confer self-resistance to the producing organism using in vitro biochemical analysis. Next we present the discovery and validation of a highly potent herbicide lead that targets a critical metabolic enzyme that is required for plant survival. We queried dihydroxyacid dehydratase in the branched-chain amino acid biosynthetic pathway in plants, which is often targeted for herbicide development. We also showed that the fungal sesquiterpenoid aspterric acid discovered using this method is a submicromolar inhibitor of DHAD and is effective as an herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements urgent efforts in overcoming weed resistance. Our discovery demonstrates the potential of using a resistance-gene directed approach in the mining of bioactive natural products.

As testing is an incomplete validation of software changes, many developers review code changes before patching the system. Popular source code versioning systems aid review by showing the textual differences between the old and new versions of the source code. This leaves developers with the difficult task of determining whether the differences produced the desired behavior.

We introduce Continuous Semantic Inspection (CSI), which aids code review with inter-version differential semantic analysis. During inspection of a new commit, a developer is presented with not only code differences, but also changes to behaviors, as expressed by likely invariants inferred from testing. We hypothesize that with the extra semantic information developers can more easily determine whether the code changes produced the desired effect.

This dissertation comprises four parts to demonstrate our hypothesis. (1) We present the design and implementation of GETTY, a highly automated tool to support the concept of CSI. (2) To scale the expensive invariant inferences for practical use, we divide GETTY’s analysis into multiple processes distributed to a 16-processor cluster. We achieve substantial performance improvement and show that our approach is feasible for open source projects by enabling a timely repair-compile-review feedback loop. (3) From applying CSI on six open source projects, we found inferred invariants contain the information required to help discover insufficient tests and inconsistent semantic changes at the time of their introduction. (4) We conducted a user study of reviewers using GETTY, which shows that invariant differentials draw attention to information that otherwise often escapes notice, helping developers formulate more focused questions that keep the review moving forward.

Abstract:This dissertation joins the contemporary debate on rewriting the history of Chinese architecture by critically (re-)examining the initial stage of discourse formation during the Republican period. Focusing on the ordinary house in the city, I excavate the popular voice on Chinese architecture from the newspapers and magazines, examine the municipal government’s effort in modernizing the city and life, as well as the professional community’s attempt to establish the authoritative figure of the modern architect to replace that of the traditional craftsman. I show that these different constituencies of Chinese architecture articulated and presented a more vibrant and complex scene of discourse and practice than we have recognized until now. Although each held different forms of power, and focused on different issues, these early interpreters of Chinese architecture nevertheless converged on their understanding of reforming the Chinese house and Chinese architecture. The municipal government’s modernizing projects in the city served to bolster the professional community’s claim to expertise that culminated in writing a new history of Chinese architecture. This history subsequently became the standard historiography, suppressing and subsuming the popular voice and relegating it to history’s dustbin for decades. By retrieving the popular discourse of Chinese architecture from this period, we not only gain a fuller understanding of the formative stage of Chinese architectural historiography, but are also provided with helpful indications pointing to a possible route to rewrite the history of Chinese architecture.

Key words: architectural history, Chinese architecture, historiography, popular discourse, modernity in China, modern China

Developing novel functional materials for applications in energy storage and conservation is essential to solving today’s problems of meeting growing energy demands with minimal environmental impact. The first part of this dissertation describes pseudocapacitive Li-ion electrodes for fast charge storage. Pseudocapacitance, a charge-transfer process that is not diffusion-limited by definition, can be achieved by utilizing short diffusion lengths in nanostructures. In this section, three distinct transitional metal oxides with nanoscale architecture, Nb2O5, MoO2, and LiMn2O4, are examined. We focus on correlating charge storage mechanisms with structural properties, and exploring different aspects of pseudocapacitive charge storage with each system. First, we developed a core/shell Nb2O5/Nb4N5 composite via partial nitridation, achieving specific capacity over 500 C/g within 90 seconds. Our use of the nitride shell provides excellent electronic pathways that connect Nb2O5 nanoparticles and improve the interfacial electrical conductivity. The charge storage mechanism was found to depend on the thickness of the nitride shell. For MoO2, we developed an interconnected porous network that provides facile electrical and ionic pathways for fast charge storage. We also used it as a model system to understand the effects of structural variations on charge storage behavior. Phase transition suppression was found to be associated with highly capacitive systems, and a strong correlation between charge storage properties and crystallite size was established. Last, we developed needle-like nanostructures with selectively engineered surface facets to overcome its capacity loss due to surface Mn dissolution. This unique structure allowed for a higher capacity and less surface Mn dissolution due to a dominant presence of dissolution-resistant facets.

The second part of this dissertation studies thermal transport in mesoporous SiO2. SiO2 is widely used in many thermal insulating applications due to its facile synthesis and easy-to-control of structure. Porous amorphous SiO2 has strong boundary scattering effects that lead to significantly low thermal conductivity. In this section, we examined the effect of porosity, pore size, and framework texture (i.e., continuous or nanoparticulate) on thermal conductivity in mesoporous SiO2 thin films. Sol-gel and nanoparticle-based mesoporous SiO2 thin films were synthesized by evaporation-induced self-assembly using tetraethyl orthosilicate and pre-made SiO2 nanoparticles as the framework precursors, respectively, and a variety of template reagents. The thermal conductivity was measured by time-domain thermoreflectance at room temperature in vacuum. A porosity weighted simple effective medium approximation was employed to explain trends in thermal conductivity. The results give new insight into thermal transport in nanostructured amorphous materials, and suggest design rules of the nanoscale architecture to control the thermal conductivity of mesoporous materials for a wide range of applications.

Perfluoroalkyl Substances (PFASs) are a group of man-made fluorine-containing compounds that are used broadly in industry and commercial products since the 1950s. PFASs are very persistent in the environment and in living organisms, and thus are detected in wildlife and in humans throughout the globe. PFASs can cross the placental barrier and expose the fetus during the most vulnerable period in development. Animal data suggested that PFASs are neurotoxic and have endocrine disruptive properties. A few cross-sectional studies linked current level of PFASs to hyperactivity disorders in children, but finding from prospective studies are lacking. Additional human studies are urgently needed to examine the potential neuro-developmental impacts of these ubiquitous exposures.

We conducted a case-cohort study within the framework of the Danish National Birth Cohort (DNBC) to investigate whether prenatal exposure to PFASs increases the risk of infantile autism, attention-deficit/hyperactivity disorder (ADHD) or congenital cerebral palsy (CP) in children. Among 83,389 mother-child pairs enrolled in the DNBC during 1996-2002, we identified 890 ADHD cases and 301 autism cases in the Danish National Hospital Register and the Danish Psychiatric Central Registry. We also identified 156 CP cases from the Danish National Cerebral Palsy Register. For cost-efficiency, we randomly selected 220 cases of ADHD and autism each, and all 156 CP cases in the three disease groups. In addition, we randomly selected 550 controls from the cohort frequency matched on child's sex. Sixteen` PFASs were measured in maternal plasma samples from early or mid-pregnancy, but in analyses we focus on the six PFASs that were quantifiable in more than 90% of the samples. PFAS concentrations were analyzed as continuous variables (with natural-log transformation) or categorized into quartiles. We estimated Odds Ratios (OR) and Risks Ratios (RR) for the outcomes.

First, we found that prenatal exposures to PFASs may increase the risk for CP in boys. We observed higher risks of CP in boys with increasing maternal PFAS levels (RR=1.74 (95%CI 1.05-2.88) per one unit (natural-log ng/mL) increase in perfluorooctane sulfonate (PFOS) and RR=1.99 (95%CI 1.15-3.44) per unit increase in perfluorooctanoic acid (PFOA)). We also observed a dose-response pattern of CP risks in boys per PFOS and PFOA quartile (p-trend<0.01). Both spastic unilateral or bilateral CP sub-phenotypes were found to be associated with PFASs, but no association between PFASs and CP was found in girls. For ADHD and autism, we found no consistent patterns to suggest that prenatal PFAS exposures increase the risks of ADHD or autism in children, but some observed positive as well as inverse association in secondary analyses should be further explored.

We also conducted a bias analysis to investigate whether conditioning on live-born status may induce sufficiently large bias to explain some of the unexpected inverse associations seen between prenatal PFAS exposures and ADHD in our and previous studies. We employed directed acyclic graphs to present our causal assumptions and the hypothesized scenarios, and used Monte-Carlo techniques to simulate a realistic pregnancy cohort based on the distributions in the DNBC and prior research knowledge. We found that the protective associations of PFAS on ADHD observed in the live-born cohort could possibly be explained by selection bias if PFAS reduces fetal survivals, while PFAS has a true null effect on ADHD. The magnitude of this selection bias due to fetal death are generally small, unless the exposure is a strong determinant of fetal loss and there are one or more strong risk factors of the outcome that also reduce chances of fetal survival. One way to reduce or even eliminate the bias due to conditioning on fetal survival is to adjust for the common causes of the outcome and fetal losses in analyses.

In conclusion, we found that prenatal exposure to PFASs may increases the risks for CP in boys, and no consistent associations were found between maternal PFAS levels and ADHD or autism in children. In additional bias analysis, we quantitatively showed that conditioning on life-born status in observational study can yield a negative bias if an exposure of interests reduces conception or fetal survival among the high risks fetuses for the targeted outcome.