Discovery Center Research Articles

Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure-activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.

From conception to fruition: Co-designing a digital exhibit incorporating embodied cognition to encourage young children’s computational thinking in a Science Discovery Centre

From conception to fruition: Co-designing a digital exhibit incorporating embodied cognition to encourage young children’s computational thinking in a Science Discovery Centre

High throughput screening for SARS-CoV-2 helicase inhibitors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for nearly 7 million deaths worldwide since its outbreak in late 2019. Even with the rapid development and production of vaccines and intensive research, there is still a huge need for specific anti-viral drugs that address the rapidly arising new variants. To address this concern, the National Institute of Allergy and Infectious Diseases (NIAID) established nine Antiviral Drug Discovery (AViDD) Centers, tasked with exploring approaches to target pathogens with pandemic potential, including SARS-CoV-2. In this study, we sought inhibitors of SARS-CoV2 non-structural protein 13 (nsP13) as potential antivirals, first developing a HTS-compatible assay to measure SARS-CoV2 nsP13 helicase activity. Here we present our effort in implementing the assay in a 1,536 well-plate format and in identifying nsP13 inhibitor hit compounds from a ∼650,000 compound library. The primary screen was robust (average Z’ = 0.86 ± 0.05) and resulted in 7,009 primary hits. 1,763 of these compounds upon repeated retests were further confirmed, showing consistent inhibition. Following in-silico analysis, an additional orthogonal assay and titration assays, we identified 674 compounds with IC50 <10 μM. We confirmed activity of independent compound batches from de novo powders while also incorporating multiple counterscreen assays. Our study highlights the potential of this assay for use on HTS platforms to discover novel compounds inhibiting SARS-CoV2 nsP13, which merit further development as an effective SARS-CoV2 antiviral.

Simultaneous screening for selective SARS-CoV-2, Lassa, and Machupo virus entry inhibitors

Emerging highly pathogenic viruses can pose profound impacts on global health, the economy, and society. To meet that challenge, the National Institute of Allergy and Infectious Diseases (NIAID) established nine Antiviral Drug Discovery (AViDD) centers for early-stage identification and validation of novel antiviral drug candidates against viruses with pandemic potential. As part of this initiative, we established paired entry assays that simultaneously screen for inhibitors specifically targeting SARS-CoV-2 (SARS2), Lassa virus (LASV) and Machupo virus (MACV) entry. To do so we employed a dual pseudotyped virus (PV) infection system allowing us to screen ∼650,000 compounds efficiently and cost-effectively. Adaptation of these paired assays into 1536 well-plate format for ultra-high throughput screening (uHTS) resulted in the largest screening ever conducted in our facility, with over 2.4 million wells completed. The paired infection system allowed us to detect two PV infections simultaneously: LASV + MACV, MACV + SARS2, and SARS2 + LASV. Each PV contains a different luciferase reporter gene which enabled us to measure the infection of each PV exclusively, albeit in the same well. Each PV was screened at least twice utilizing different reporters, which allowed us to select the inhibitors specific to a particular PV and to exclude those that hit off targets, including cellular components or the reporter proteins. All assays were robust with an average Z’ value ranging from 0.5 to 0.8. The primary screening of ∼650,000 compounds resulted in 1812, 1506, and 2586 unique hits for LASV, MACV, and SARS2, respectively. The confirmation screening narrowed this list further to 60, 40, and 90 compounds that are unique to LASV, MACV, and SARS2, respectively. Of these compounds, 8, 35, and 50 compounds showed IC50 value < 10 μM, some of which have much greater potency and excellent antiviral activity profiles specific to LASV, MACV, and SARS2, and none are cytotoxic. These selected compounds are currently being studied for their mechanism of action and to improve their specificity and potency through chemical modification.

Why Britain needs a national mathematics discovery centre

On the 3rd of January 2023, the UK Prime Minister, Rishi Sunak, first advocated that Mathematics should be a compulsory subject for all students to the age of 18. He was supported in principle by the following statement from the President of the Royal Society, Professor Sir Adrian Smith, issued on the 4th of January 2023: “Maths, data, statistics and numeracy are essential skills for a modern world, whether for the workplace or for playing an active role in society. If we want our economy to thrive and young people to be prepared for well paid jobs, we need a radical overhaul of our education system that will include all young people doing some level of maths to 18 years of age. The PM understands this and today’s announcement is welcome.

Ongoing Implementation and Prospective Validation of Artificial Intelligence/Machine Learning Tools at an African Drug Discovery Center.

Artificial intelligence (AI) and machine learning (ML) are anticipated to accelerate drug discovery programs. Following our development of an end-to-end virtual screening cascade at the University of Cape Town (UCT) Holistic Drug Discovery and Development (H3D) Center, we report the ongoing implementation of open-source AI/ML tools for use in resource-constrained settings.

Dialogue in the Dark Malaysia: reimagining an inclusive society through social innovation

Research methodology This case was developed via primary data collected from personal (one to one) interview with the CEO and founder of Dialogue in the Dark Malaysia (Dialogue Malaysia), Stevens Chan. With Stevens’ contact, the authors also conducted personal interviews with Kaye Chan (co-founder and wife of Stevens Chan), Lynn Foo (project manager since inception until early 2022) and Dr Foo Yin Fah (academic researcher in social entrepreneurship and advisor for Dialogue Malaysia). Secondary data included reports on visually impaired context in Malaysia, Dialogue Malaysia’s annual reports and online articles. Prior to the primary data collection, the authors obtained ethics approval from the University Human Ethics Committee (Project ID: 35461). Case overview/synopsis This case narrative focuses on Stevens Chan, a blind social entrepreneur who champions the empowerment of the disabled and marginalised community. Through a social franchising model, Stevens founded Dialogue in the Dark Malaysia in 2012. As a social start-up, Stevens showcases the strengths of blind and visually impaired individuals through transformative experiential encounters and reimagining future possibilities. Although there are constant challenges in securing financial and human capital, Stevens never lacks psychological capital, characterised by hope, self-efficacy, optimism and resilience. His vision is to educate society on the power of empathy (and not sympathy) and to create a holistic experience of celebrating diversity and inclusion through an innovative discovery centre, where the elderly and the disabled community (including the deaf, mute and those with mobility issues) share their lives with the public through fun activities. However, the future of this social enterprise is uncertain, and this case invites participants to embark on this journey with Stevens to uncover future pathways for growth and social impact. Complexity academic level The case is tailored for higher level undergraduates and entry-level and mid-level managers of executive education programs.

Investigating the Role of TDP-43 Microvasculopathy on Neurovascular unit Function in the Setting of COVID-19 and Alzheimer’s Disease and Related Dementias

Dysfunction of the blood-brain-barrier and the neurovascular unit, comprised of brain endothelial cells, pericytes, neurons, and glia, has been strongly implicated in the neurological manifestations of SARS-CoV-2 and vascular contributions to cognitive impairment and dementia (VCID) in Alzheimer’s disease (AD). A challenging unanswered question is whether the cognitive and neuropsychiatric disturbances of post-acute neurological sequelae of SARS-CoV-2 (Neuro-PASC) or long COVID are potentially linked to the development of AD. The RNA/DNA-binding protein TDP-43 (transactive response DNA-binding protein of 43 kDa) has been implicated in the pathogenesis of several viral infections and is cleaved by the main SARS-CoV-2 protease Nsp5, leading to neurotoxic TDP-43 fragments in mammalian cells. Aggregates composed of phosphorylated, ubiquitinated TDP-43 are also frequently present in AD. While TDP-43 microvasculopathy has been described in a subset of ADRD cases, its impact on blood-brain barrier integrity and neurovascular unit function is unknown. In this study, we investigated whether TDP-43 microvasculopathy is observed in AD and COVID-19 patient brains. We hypothesized that perivascular TDP-43 induces neurovascular unit dysfunction through cell autonomous and non-autonomous effects of pathologic TDP-43 deposition in astrocytic endfeet processes. To test this, hippocampus and dorsolateral prefrontal cortex (dlPFC) from human AD brains (Braak IV-VI; CERAD definite) and cognitively normal age- and sex-matched controls, with and without comorbid COVID-19, were selected from autopsy cases conducted at Yale between 2014-2018 (non-COVID), and COVID-positive cases conducted between April 2020-present; (n=10-12 per group). Our data from COVID-19 and ADRD human brain samples show a distinctive profile of phosphorylated TDP-43 (pTDP-43) and Tau expression compared to COVID-19 negative AD and control brains. Immunofluorescence analysis of hippocampus and cerebral cortex showed perivascular deposits of pTDP-43 found as threads or aggregates in close proximity to capillaries and vascular basal lamina, labeled with type IV collagen. We also observe a subset of pTDP-43 that colocalizes with neuronal tau, suggesting involvement of multiple neurovascular unit cells. Our data also revealed CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) positive cells in the microvessels colocalize with pTDP-43. Interestingly, colocalization of PECAM-1 and pTDP-43 positive cells in the perivascular zone suggests transendothelial migration. Atypical pTDP-43 accumulation was also noted in astrocytic endfeet, and astrocytic hypertrophy was identified. Furthermore the blood-brain barrier may be breached, detected by a downregulation or change in the expression and distribution of Claudin-5 in the blood vessels where pTDP-43 is present. Breakdown of these tight junction proteins has been strongly implicated in the neurological manifestations of SARS-CoV-2 and vascular contributions to cognitive impairment and dementia (VCID) in AD. These findings raise the possibility that perivascular pTDP-43 aggregates impair endothelial, neuronal, and/or astrocytic functions in the neurovascular unit, disrupt blood-brain-barrier, and potentially suggest a novel role for TDP-43 induced microvasculopathy in ADRD and COVID-19. This research and the Center for Human Brain Discovery is supported through philanthropic funds and NIH/NINDS R01NS122907 (to PPG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Improving Children's Rehabilitation Service Quality and Experience Through Innovative Programming: A Developmental Evaluation of the Bright Ideas Program.

Evidence-informed practice (EIP) is a widely accepted approach to providing rehabilitation services, however there are barriers to implementation. Bright Ideas is an innovative program developed by KidsAbility's Rocket Discovery Centre, aiming enhance uptake of EIP through incubating ideas identified by KidsAbility staff linked to organizational priorities of enhancing service access and outcomes. To evaluate Bright Ideas by identifying perceived successes and challenges associated with the program with the aim of supporting clinical innovation and the adoption of evidence-informed practices in children's rehabilitation centres. A developmental evaluation approach was utilized to complete a real-time evaluation of Bright Ideas. Bright Ideas program materials were reviewed to describe the program. A focus group and interview were conducted with staff who led Bright Ideas projects (n = 7) to gain insight into their experiences. Additionally, interviews were conducted with the program coordinators (n = 2) to understand the evolution of the program. Data was analysed using qualitative content analysis. Successes that drive the Bright Ideas program and roadblocks it has encountered were identified across three dimensions: the personal level (involving Bright Ideas project leads), the programmatic level (focusing on the Bright Ideas program), and the organizational level (pertaining to KidsAbility as a whole). Key roadblocks included a lack of knowledge about the program organizationally, restricted time resources, competing organizational priorities, and an absence of infrastructure to scale ideas from Bright Ideas into the organization. Bright Ideas is an innovative program aiming to make impactful change by enabling staff to lead implementation-driven projects. Our findings highlight many successes of the program and use the Theoretical Domains Framework and Behaviour Change Wheel to make recommendations to support its sustained implementation at KidsAbility.

Another decade of antimalarial drug discovery: New targets, tools and molecules.

Malaria remains a devastating but preventable infectious disease that disproportionately affects the African continent. Emerging resistance to current frontline therapies means that not only are new treatments urgently required, but also novel validated antimalarial targets to circumvent cross-resistance. Fortunately, tremendous efforts have been made by the global drug discovery community over the past decade. In this chapter, we will highlight some of the antimalarial drug discovery and development programmes currently underway across the globe, charting progress in the identification of new targets and the development of new classes of drugs to prosecute them. These efforts have been complemented by the development of valuable tools to accelerate target validation such as the NOD scid gamma (NSG) humanized mouse efficacy model and progress in predictive modelling and open-source software. Among the medicinal chemistry programmes that have been conducted over the past decade are those targeting Plasmodium falciparum ATPase4 (ATP4) and acetyl-CoA synthetase (AcAS) as well as proteins disrupting parasite protein translation such as the aminoacyl-tRNA synthetases (aaRSs) and eukaryotic elongation factor 2 (eEF2). The benefits and challenges of targeting Plasmodium kinases will be examined, with a focus on Plasmodium cyclic GMP-dependent protein kinase (PKG), cyclin-dependent-like protein kinase 3 (CLK3) and phosphatidylinositol 4-kinase (PI4K). The chapter concludes with a survey of incipient drug discovery centres in Africa and acknowledges the value of recent international meetings in galvanizing and uniting the antimalarial drug discovery community.

ISU Dairy Farm Open House 2022 - An Opportunity for Education and Engagement

The month of June is known as 'June Dairy Month' and therefore, the Iowa State University (ISU) Dairy Farm Open House took place on June 10th, 2022. The purpose of the ISU Dairy Farm Open House was to invite the public, free of charge, to come and visit the ISU Dairy Research and Teaching Unit in order to learn more about the dairy industry's commitment to animal care, to observe how a modern-day dairy operation functions on a daily basis, and to celebrate and learn about all things dairy. Hence, throughout the event, visitors were able to: consume a variety of safe, wholesome, and nutritious dairy products; learn about cow comfort and the various management practices that are in place on dairy farms to assure that all dairy animals are cared for with the utmost care, view a live milking parlor demonstration and learn about the proper steps dairy farms follow in order to harvest milk properly and safely from dairy cows, and participants received a driving tour of the dairy farm. Tours of the ISU Dairy Farm were provided by research faculty and graduate students who have a deep understanding of dairy production and management and therefore, they were able to further enlighten guests on common feeding strategies used for the dairy herd, discuss the dairy industry's commitment to sustainable farming practices, and environmental stewardship. At the end of the driving tour, guests were transported to the 'Ag Discovery Center' to learn more about agriculture throughout Iowa from a variety of commodity groups within the state. An optional, post-even survey (Table 1) was distributed to gauge visitor perception of the dairy industry. Of those who completed the survey (81 respondents), 94% of visitors indicated having a positive or very positive perception of the dairy industry. Also, 98% of respondents indicated they would attend this event in the future, and respondents unanimously indicated they would recommend this event to someone else. Thus, moving forward, there is a continued desire by the public for ISU to continue planning and hosting the ISU Dairy Farm Open House. Due in part because this event is an excellent opportunity for all in involved to continue educating and promoting dairy to the public in order to ensure a thriving dairy industry in the years to come.

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Kelly Chibale: Learning to Fail Your Way to Success

A portrait is given of Professor Kelly Chibale, the driving force behind H3D, the drug discovery and development centre at the University of Cape Town, South Africa. He is dedicated to the development of new drugs to fight infectious diseases of poverty that are prevalent in Africa, including MMV390048, the first anti-malarial drug ever to be validated in a Phase I trial in Africa. In 2018 he was recognized as one of Fortune magazine’s top 50 ‘World’s Greatest Leaders’.

First fully-automated AI/ML virtual screening cascade implemented at a drug discovery centre in Africa

Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. We present ZairaChem, an artificial intelligence (AI)- and machine learning (ML)-based tool for quantitative structure-activity/property relationship (QSAR/QSPR) modelling. ZairaChem is fully automated, requires low computational resources and works across a broad spectrum of datasets. We describe an end-to-end implementation at the H3D Centre, the leading integrated drug discovery unit in Africa, at which no prior AI/ML capabilities were available. By leveraging in-house data collected over a decade, we have developed a virtual screening cascade for malaria and tuberculosis drug discovery comprising 15 models for key decision-making assays ranging from whole-cell phenotypic screening and cytotoxicity to aqueous solubility, permeability, microsomal metabolic stability, cytochrome inhibition, and cardiotoxicity. We show how computational profiling of compounds, prior to synthesis and testing, can inform progression of frontrunner compounds at H3D. This project is a first-of-its-kind deployment at scale of AI/ML tools in a research centre operating in a low-resource setting.

Price connectedness in U.S. ethanol terminal markets

This article shows, for the first time, the degree of price volatility connectedness across the major regional ethanol markets in the U.S. Connectedness measures are based on forecast error variance decompositions that inform which prices drive system dynamics. We pay special attention to volatility spillovers to and from Chicago, as it is equipped with one of the largest terminals in the U.S. and is widely regarded as the center of ethanol price discovery in the country. Ethanol prices in the Chicago terminal electronic trading platform are also suspected of being manipulated over the 2017‐2019 period. We use Diebold and Yilmaz (2012 and 2014) and a rolling window approach to study the dynamics of price volatility connectedness over time. Using daily data from 2013 to the beginning of 2021, we find that Chicago is the market that generates the most innovations to other market prices. In contrast, Chicago receives the least amount of innovations from all other markets, placing Chicago at the center of price dynamics. We find that price connectedness measures are correlated with market fundamentals, policy, and concentration in the Chicago terminal electronic trading platform, with the latter being associated to an increase in the relevance of Chicago as a central market.

Abstract A018: A top-down proteomic assay to evaluate KRAS4B-compound engagement

Abstract The RAS family of GTPases (HRAS, KRAS, NRAS) continue to present formidable challenges to the design of compounds that successfully and specifically target oncogenic RAS mutant populations in cancer. Although recent advances have led to the successful development of inhibitors specific to KRAS G12C (such as Sotorasib [Amgen] and Adagrasib [Mirati Therapeutics]), ongoing efforts seek to develop additional targeted inhibitors for oncogenic mutants of KRAS. Development of new KRAS targeted inhibitors requires the understanding of how a mutation impacts the accessibility of key residues within the protein, along with how each candidate compound interacts with populations of mutant and wild-type proteins. Proteomic analyses, typically comprising peptide-based methods to confirm compound localization or quantify binding kinetics, represent a key validation step for each phase of the inhibitor development process. However, these methods may not always provide a clear picture of how effectively the compound binds to the protein, how specific the compound is to the target residue, and how concentration or incubation time may impact these factors. To address this, we have developed a novel assay to evaluate target engagement in vitro employing top-down proteomics, which entails the analysis of intact protein molecules and their modified forms (proteoforms). By analyzing intact labeled or compound-treated recombinant KRAS4B proteins, we can directly visualize and precisely characterize each species within a sample. This method allows us to easily detect nonspecific binding, identify targeting of incorrect residues, and characterize unanticipated compound reaction products within a short LC-MS run, all facilitated by targeted MS2 fragmentation. Moreover, we have developed complementary methods for RAS proteoform quantitation, allowing for the evaluation of compound engagement to all proteoforms with greater accuracy than traditional peptide-based methods. We first performed a proof-of-concept experiment using a panel of KRAS4B G12D_C118S proteins with selected residues modified to cysteine to evaluate reactivity to maleimide-biotin over time. We then applied our optimized top-down assay to determine the engagement of targeted covalent inhibitors Sotorasib and Adagrasib with KRAS WT, G12C, or G13C in both the active (GppNHp) and inactive (GDPβS) states. Finally, we selected three compounds from a large-scale screen against a UCSF Small Molecule Discovery Center compound library and evaluated each for specificity to KRAS4B G13C over KRAS4B WT and KRAS4B G12C. Our results show the concentration dependence of target engagement and directly map compound binding location(s) without disrupting the protein’s primary structure. Moreover, our ability to target discrete compound additions for top-down MS2 fragmentation provides context and order of preferential labeling of KRAS4B. Our hope is that this methodology may help accelerate the identification of new successful targeted inhibitors for KRAS and other RAS isoforms by the greater RAS community. Citation Format: Robert A. D'Ippolito, Caroline J. DeHart, Dana Rabara, Maria Abreu Blanco, Emily Alberico, Nitya Ramakrishnan, Stephanie Widmeyer, Simon Messing, David Turner, Michelle Arkin, Anna Maciag, Andrew Stephen, Dominic Esposito, Frank McCormick, Dwight V. Nissley. A top-down proteomic assay to evaluate KRAS4B-compound engagement [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A018.

A hybrid machine learning and embedded IoT-based water quality monitoring system

Since access to clean and safe water is one of life's most basic needs, the exponential growth of the world's population makes it vital to guarantee a workable framework. Manually collecting samples and sending them to a research center for discovery and analysis is the typical approach for gathering information on water qualities. However, this approach is illogical in the long run because it requires a lot of time and labor. This paper aimed to construct, test, and evaluate the usefulness of machine learning and the Internet of Things (IoT) at water storage stations. First, we developed a system prototype and assessed its performance using classifier and reliability matrices. This study considers water's physical and chemical parameters to evaluate the level of water pollutants present in drinking water. The parameters measured include temperature, pH, turbidity, Dissolved Oxygen (DO), Total Dissolved Solids (TDS), Oxidation Reduction Potential (ORP), and electrical conductivity. After analyzing the sensor data, we used Artificial Neural Network (ANN) and Support Vector Machine (SVM) machine learning algorithms to forecast the impurity level of the water measured. The performance showed that the ANN models used have the highest accuracy and are the most suitable to predict water source and status. We also introduced a water treatment method to provide an automated corrective measure based on a specific amount of water contamination. Based on the system's results, we concluded that AI and IoT are more efficient in remotely monitoring safe and harmful water conditions.

Sensory Engagement with the Rhetoric of Science: Creationist Copia at the Discovery Center for Science and Earth History

Abstract The Institute for Creation Research (ICR) opened the Discovery Center for Science and Earth History in Dallas, Texas in September 2019. Through immersive exhibits and advanced technology, the museum communicates what ICR purports to be the truth of creation science. Informed by the rhetorical concept of copia, I argue that the Discovery Center deploys sensory evidence to support creationism through the rhetorical strategies of rotation, immersion, and interruption. These material strategies use the senses as vehicles to communicate multiple arguments simultaneously, direct museumgoers’ attention, and amplify lived experiences as valid ways of knowing and evaluating the science of human origins. I conclude by noting the role of sensory rhetorical strategies in other scientific controversies and encouraging additional scholarship into how sensory evidence offers convincing challenges to scientific knowledge.

Using a contingent valuation method to evaluate an ecotourism site in Borneo, Malaysia: a case of the Rainforest Discovery Centre, Malaysia

ABSTRACT This empirical article intends to examine the conservation value of an ecotourism site in Borneo, Malaysia, specifically the Rainforest Discovery Centre (RDC). The second objective is to determine the visitors’ willingness to pay (WTP) and their heterogeneity with regard to the RDC. In addition to the bid prices and the socio-demographic characteristics of visitors, the dichotomous-contingent valuation analysis takes into account five preferences of visitors for sustainable development in the RDC. These preferences are as follows: (i) Wildlife species population; (ii) Wildlife observation; (iii) Information provision; (iv) Protection level; and (v) Habitat quality. Visitors’ heterogeneity will reveal which factors affect their WTPs. Using the estimated WTP, the total expected increase in economic value in 2017 was about RM 416 323 compared to the actual revenue; which was RM 327 730. In terms of visitors’ heterogeneity, WTP is influenced by income, bid prices, ‘wildlife species population,’ ‘habitat quality,’ and ‘protection level.’ In light of this, emphasis should be given to ways in which these attributes can be enhanced in order to maintain a competitive edge in the travel and tourism business and encourage a greater number of tourists to visit specific locations. This not only helps to preserve the natural world and its various types of flora and fauna, but it also provides the Rainforest Discovery Centre (RDC) and the surrounding community with economic benefits.

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre.

As the so-called “next frontier” in global economic terms, Africa’s disease burden continues to choke and cripple economic growth across the continent. The highest burden is attributable to malaria and tuberculosis (TB), which also remain among the deadliest infectious diseases affecting mankind the world over (Malaria, 627,000 deaths; TB, 1.5 million deaths, in 2020). In achieving self-determination with respect to the health needs of all who live on the continent, Africa must align with global north efforts and be a source of health innovation. This will in part require the creation of an ecosystem of innovative pharmaceutical R&D and expanding it across the continent by scaling up through sustained performance and excellence. To this end, the Holistic Drug Discovery and Development (H3D) Centre at University of Cape Town in South Africa has risen to this challenge. Here, we highlight the innovation experiences gained at H3D, covering the advances made in our quest to contribute to a global pipeline of therapeutic interventions against malaria and TB. We discuss selected chemical series starting from their identification, structure–activity relationships, mode of action, safety, proof-of-concept studies, and lessons learned.