The increased concentration of 4-Hydroxynonenal in aldh3a1 zebrafish mutants disrupts pancreas development, leading to hyperglycaemia and retina hyaloid vasculature alteration

Background and Aim: The increased formation of methylglyoxal (MG) under hyperglycaemia is associated with the development of microvascular complications in patients with diabetes. However, in zebrafish, a permanent knock out of glyoxalase 1(Glo1), the central MG detoxifying system, only led to a two-fold elevation of endogenous MG levels. Importantly, a two-fold increase in aldehyde dehydrogenases (ALDH) activity, a group of enzymes which catalyse the oxidation of aldehydes, was observed. Besides, RT-qPCR based results identified elevated aldh3a1 mRNA level in glo1-/- mutants. Thus, this dissertation aims to generate Aldh3a1 knockout zebrafish and analyse its function in glucose homeostasis and diabetes. Materials and Methods: aldh3a1-/- zebrafish were generated by using CRISPR/Cas9. Vasculature, pancreatic and β-Cell mass area size were analysed in Tg(fli1:EGFP), Tg(hb9:GFP) and Tg(ins:nfsB-mCherry)zebrafish larvae. mRNA expression was examined by RT-qPCR and RNA-seq analysis. 4-Hydroxynonenal (4-HNE) amount was measured by ELISA (BioVision) and whole-body glucose was measured by Glucose Assay Kit (Merck). Results: Aldh3a1 knockout zebrafish were successfully generated and validated by significantly decreased ALDH activity. In Tg(fli1:EGFP) zebrafish larvae, loss of Aldh3a1 increased abnormal intersegmental vessels formation in the trunk and widened branch diameters in retina hyaloid vasculature, which can be further enhanced via pancreatic and duodenal homeobox 1 (pdx1) expression silencing. A combination of Aldh3a1 knockout and knockdown strategies identified a decreased pancreatic size in Tg(hb9:GFP) and reduced β-Cell mass dimension in Tg(ins:nfsB-mCherry) zebrafish larvae. Also, mRNA expression of pdx1 and insulin were decreased and RNA-seq data have further confirmed disruption of the endocrine pancreas development in the alda3a1 mutants. Consequently, aldh3a1 –/– larvae exhibited hyperglycaemia by 40% whole-body glucose elevation. Moreover, disruption of the pancreas in alda3a1mutants is driven by an increased 4-HNE amount and external 4-HNE in wild type zebrafish larvae mimics the phenotype in aldh3a1 mutants. Conclusion: Overall, this dissertation provided patent evidence for the contribution of deficient 4-HNE detoxification and subsequent increased 4-HNE concentration to the development of hyperglycaemia via pancreas dysfunction in aldh3a1 mutants, as a novel direction for future research regarding diabetic pathophysiology and therapy

Artificial Intelligence and Drug Innovation

We study how artificial intelligence (AI) can influence the drug development process in the global pharmaceutical industry. Despite considerable effort made in developing drugs, pharmaceutical firms experience declines in novelty for drugs they produced. As AI becomes an important general purpose technology (GPT), it could be used to address some known challenges in the drug development process. Using two large-scale datasets that contain detailed historical records of global drug development and patents, we identify AI-related patents to approximate firms’ AI capabilities and construct a relatively new similarity-based metric to measure drug novelty based on their chemical structure. We find that AI can primarily affect the earliest stage in drug discovery when tasks are heavily dependent on automatic data processing and reasoning. However, it may not necessarily help with the more expensive and risky clinical trial stages that require substantial human engagements and interventions. Additionally, AI can facilitate the development for drugs at the medium level of chemical novelty more than at the extreme ends of the spectrum. Our study sheds light on the understanding of the roles and limitations modern technology can have on drug development, one of the most complex innovation processes in the world

Artificial Intelligence, CEO Turnover, and Directional Change in Firm Innovation

We examine the role of artificial intelligence (AI) in facilitating a change in innovation directions after a leadership change. Using patent data for firms that have gone through a CEO turnover, we find that firms with greater AI investment are more successful in changing their innovation directions. The effect of AI is driven principally by the continued development of innovation in areas that are modestly different from the past. Further analyses show that this effect is likely due to firms with AI investment that can enable strategic change in cultivating culture of exploring frontiers in innovation and managing R&D. A new CEO can direct more resources to the acquisition of employees with greater technological capabilities such as AI skills to facilitate the innovation change. Overall, our study sheds light on the value of AI in fostering the change in innovation directions during uncertain and turbulent times

Thinking about Strategic Thinking:Putting Top Management Teams' Strategic Decision-Making Processes into a Double-Layered Contextual Model

In the past three decades, upper echelon studies have generated inconclusive findings regarding the direct link between top management team (TMT) characteristics and various organisational outcomes. The heterogeneous results have hinted at a missing link between the "who", describing the characteristics of decision-makers, and organisational outcomes, labelled as a "black box" problem. It is the missing theoretical constructs to explain "relationships between demographic variables and organisational outcomes" (Lawrence, 1997: 1). The process by which a strategic decision is made by a TMT, the strategic decision-making process (SDMP), could be a critical explanation for the "black box" problem. So far, SDMP studies primarily see strategic decisions as the outcome of rational processes but overlook intuitive elements. Therefore, the current research draws upon the dual-process theory to investigate a TMT's SDMP from a cognitive perspective. However, TMT's SDMP is not free of constraints, highlighting the relevance of contingency theory. By combining dual-process theory and contingency theory, this study develops a double-layered contextual model of SDMP to understand the upstream development and downstream application of TMT's SDMP, which contributes to a richer understanding of the effects of upper echelons on organisational performance.Mergers and Acquisitions (M&A), as rare and complex strategic decisions, have been selected as the research context. The conceptual model was examined empirically across a sample of 109 M&A transactions. The data was collected via cross-sectional primary data research from British firms that made acquisition decisions between 2014 to 2018 and analysed with partial least square (PLS) structural equation modelling (SEM). The findings indicate the duality of TMT's SDMPs (i.e. procedural rationality and collective intuition). This research also finds that most of TMT social-psychological characteristics (i.e. cohesion, behavioural integration and transactive memory system) affect the development of SDMP only if considering the organisational contexts (i.e. organisational structure and board strategic involvement). Similarly, the effect of SDMP on M&A performance is largely contextual and depends on decision-making contexts (i.e. environmental dynamism and the importance of strategic decision). In light of those findings, this research identifies important implications for SDMP and M&A research and practices.  Keywords: Upper Echelon Theory, Top Management Team, Strategic Decision-making Process, Dual-Process Theory, Contingency Theory, Mergers and Acquisitions (M&A

Evoke: Evoking Critical Thinking Abilities in LLMs via Reviewer-Author Prompt Editing

Large language models (LLMs) have made impressive progress in natural language processing. These models rely on proper human instructions (or prompts) to generate suitable responses. However, the potential of LLMs are not fully harnessed by commonly-used prompting methods: many human-in-the-loop algorithms employ ad-hoc procedures for prompt selection; while auto prompt generation approaches are essentially searching all possible prompts randomly and inefficiently. We propose Evoke, an automatic prompt refinement framework. In Evoke, there are two instances of a same LLM: one as a reviewer (LLM-Reviewer), it scores the current prompt; the other as an author (LLM-Author), it edits the prompt by considering the edit history and the reviewer's feedback. Such an author-reviewer feedback loop ensures that the prompt is refined in each iteration. We further aggregate a data selection approach to Evoke, where only the hard samples are exposed to the LLM. The hard samples are more important because the LLM can develop deeper understanding of the tasks out of them, while the model may already know how to solve the easier cases. Experimental results show that Evoke significantly outperforms existing methods. For instance, in the challenging task of logical fallacy detection, Evoke scores above 80, while all other baseline methods struggle to reach 20

Fast and high-quality decision-making:The role of behavioral integration

Decision speed and quality are both vital for organizational survival and prosperity. However, they are assumed to be in tension, and there has been limited theory development concerning whether, and if so how, both are attainable. To address this gap, we turn to behavioral integration which captures the intensity of intra-team interactions. While behavioral integration is considered an antecedent of decision quality, it is presumed to slow decision-making, and overall, there remains a “black box” surrounding the mechanisms, behaviors, and processes which transmit behavioral integration to decision outcomes. Our theoretical account challenges the notion of behavioral integration being an impediment to decision speed, and we present new theory and evidence—comprising a mixed-method field study—explaining how behavioral integration acts as a key driver of both decision speed and quality, while theorizing decision uncertainty as a new and important boundary condition

National Outbreak of Salmonella Serotype Saintpaul Infections: Importance of Texas Restaurant Investigations in Implicating Jalapeño Peppers

BACKGROUND: In May 2008, PulseNet detected a multistate outbreak of Salmonella enterica serotype Saintpaul infections. Initial investigations identified an epidemiologic association between illness and consumption of raw tomatoes, yet cases continued. In mid-June, we investigated two clusters of outbreak strain infections in Texas among patrons of Restaurant A and two establishments of Restaurant Chain B to determine the outbreak's source. METHODOLOGY/PRINCIPAL FINDINGS: We conducted independent case-control studies of Restaurant A and B patrons. Patients were matched to well controls by meal date. We conducted restaurant environmental investigations and traced the origin of implicated products. Forty-seven case-patients and 40 controls were enrolled in the Restaurant A study. Thirty case-patients and 31 controls were enrolled in the Restaurant Chain B study. In both studies, illness was independently associated with only one menu item, fresh salsa (Restaurant A: matched odds ratio [mOR], 37; 95% confidence interval [CI], 7.2-386; Restaurant B: mOR, 13; 95% CI 1.3-infinity). The only ingredient in common between the two salsas was raw jalapeño peppers. Cultures of jalapeño peppers collected from an importer that supplied Restaurant Chain B and serrano peppers and irrigation water from a Mexican farm that supplied that importer with jalapeño and serrano peppers grew the outbreak strain. CONCLUSIONS/SIGNIFICANCE: Jalapeño peppers, contaminated before arrival at the restaurants and served in uncooked fresh salsas, were the source of these infections. Our investigations, critical in understanding the broader multistate outbreak, exemplify an effective approach to investigating large foodborne outbreaks. Additional measures are needed to reduce produce contamination

Braces for idiopathic scoliosis in adolescents. A cochrane review

STUDY DESIGN. Cochrane systematic review. OBJECTIVE. To evaluate the efficacy of bracing in adolescent patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA. AIS is a 3-dimensional deformity of the spine. Although AIS can progress during growth and cause a surface deformity, it is usually not symptomatic. However, in adulthood, if the final spinal curvature surpasses a certain critical threshold, the risk of health problems and curve progression is increased. Braces are traditionally recommended to stop curvature progression in some countries and criticized in others. They generally need to be worn full time, with treatment extending over years. METHODS. The following databases (up to July 2008) were searched with no language limitations: the Cochrane Central Register of Controlled Trials, MEDLINE (from January 1966), EMBASE (from January 1980), and CINHAL (from January 1982), and reference lists of the articles. An extensive handsearch of the gray literature was also conducted. Randomized controlled trials (RCTs) and prospective cohort studies were searched for comparing braces with no treatment, other treatment, surgery, and different types of braces. Two review authors independently assessed trial quality and extracted data. RESULTS. We included 2 studies. There was very low quality evidence from 1 prospective cohort study with 286 girls that a brace curbed curve progression at the end of growth (success rate, 74 95% confidence interval {CI}: 52%-84%), better than observation (success rate, 34% 95% CI: 16%-49%) and electrical stimulation (success rate, 33% 95% CI: 12%-60%). There is low-quality evidence from 1 RCT with 43 girls that a rigid brace is more successful than an elastic one (SpineCor) at curbing curve progression when measured in Cobb degrees, but there were no significant differences between the 2 groups in the subjective perception of daily difficulties associated with wearing the brace. CONCLUSION. There is very low quality evidence in favor of using braces, making generalization very difficult. Further research could change the actual results and our confidence in them; in the meantime, patients' choices should be informed by multidisciplinary discussion. Future research should focus on short- and long-term patient-centered outcomes, in addition to measures such as Cobb angles. RCTs and prospective cohort studies should follow both the Scoliosis Research Society and Society on Scoliosis Orthopedic and Rehabilitation Treatment criteria for bracing studies. © 2010, Lippincott Williams & Wilkins

Arsenic-phosphorus interactions in the soil-plant-microbe system: dynamics of uptake, suppression and toxicity to plants

High arsenic (As) concentrations in the soil, water and plant systems can pose a direct health risk to humans and ecosystems. Phosphate (Pi) ions strongly influence As availability in soil, its uptake and toxicity to plants. Better understanding of As(V)-Pi interactions in soils and plants will facilitate a potential remediation strategy for As contaminated soils, reducing As uptake by crop plants and toxicity to human populations via manipulation of soil Pi content. However, the As(V)-Pi interactions in soil-plant systems are complex, leading to contradictory findings among different studies. Therefore, this review investigates the role of soil type, soil properties, minerals, Pi levels in soil and plant, Pi transporters, mycorrhizal association and microbial activities on As-Pi interactions in soils and hydroponics, and uptake by plants, elucidate the key mechanisms, identify key knowledge gaps and recommend new research directions. Although Pi suppresses As uptake by plants in hydroponic systems, in soils it could either increase or decrease As availability and toxicity to plants depending on the soil types, properties and charge characteristics. In soil, As(V) availability is typically increased by the addition of Pi. At the root surface, the Pi transport system has high affinity for Pi over As(V). However, Pi concentration in plant influences the As transport from roots to shoots. Mycorrhizal association may reduce As uptake via a physiological shift to the mycorrhizal uptake pathway, which has a greater affinity for Pi over As(V) than the root epidermal uptake pathway