Continuous Discovery Research Articles

“Gemo Ni”: A Grammar Note on Tagabawa Verbs

Tagabawa language’s vitality (bgs) is categorized to be institutional, meaning the language has been developed to the point that it is used and sustained by institutions beyond the home and community. However, the language is still not well documented. Some literature available on the linguistic analysis of Tagabawa is scarce and outdated. There are grammatical descriptions written on Bagobo-Tagabawa; but an updated description is offered by this study as a welcome development to continuous discoveries in the language. Although there is the latest available work on Tagabawa, the Tagabawa-English Dictionary by DuBois in 2016 under the Summer Institute of Linguistics, we believe new literature such as grammatical note would be a great addition to it. To provide further pertinent information in keeping Tagabawa as institutional and well-documented language, this paper documents its variety in Malapangi, Marilog by describing and accounting for its basic linguistic features of Tagabawa language. Furthermore, it provides notes on the salient features of Tagabawa verbs, mainly on its voice, aspects, modes, and transitivity.

Rapid Identification by Resequencing-Based QTL Mapping of a Novel Allele RGA1-FH Decreasing Grain Length in a Rice Restorer Line ‘Fuhui212’

Grain size is one of the most frequently selected traits during domestication and modern breeding. The continued discovery and characterization of new genes and alleles in controlling grain size are important in safeguarding the food supply for the world’s growing population. Previously, a small grain size was observed in a rice restorer line ‘Fuhui212’, while the underlying genetic factors controlling this trait were unknown. In this study, by combining QTL mapping, variant effect prediction, and complementation experiments, we recovered a novel allele RGA1-FH that explains most of the phenotypic changes. The RGA1-FH allele contains an A-to-T splicing site variant that disrupts the normal function of RGA1. While population analysis suggests extremely strong artificial selection in maintaining a functional allele of RGA1, our study is the first, to the best of our knowledge, to prove that a dysfunctional RGA1 allele can also be beneficial in real agricultural production. Future breeding programs would benefit from paying more attention to the rational utilization of those overlooked ‘unfavored’ alleles.

Renin-Angiotensin System: Updated Understanding and Role in Physiological and Pathophysiological States.

The classical view of the renin-angiotensin system (RAS) is that of the circulating hormone pathway involved in salt and water homeostasis and blood pressure regulation. It is also involved in the pathogenesis of cardiac and renal disorders. This led to the creation of drugs blocking the actions of this classical pathway, which improved cardiac and renal outcomes. Our understanding of the RAS has significantly expanded with the discovery of new peptides involved in this complex pathway. Over the last two decades, a counter-regulatory or protective pathway has been discovered that opposes the effects of the classical pathway. Components of RAS are also implicated in the pathogenesis of obesity and its metabolic diseases. The continued discovery of newer molecules also provides novel therapeutic targets to improve disease outcomes. This article aims to provide an overview of an updated understanding of the RAS, its role in physiological and pathological processes, and potential novel therapeutic options from RAS for managing cardiorenal disorders, obesity, and related metabolic disorders.

The Disorazole Z Family of Highly Potent Anticancer Natural Products from Sorangium cellulosum: Structure, Bioactivity, Biosynthesis, and Heterologous Expression.

Myxobacteria serve as a treasure trove of secondary metabolites. During our ongoing search for bioactive natural products, a novel subclass of disorazoles termed disorazole Z was discovered. Ten disorazole Z family members were purified from a large-scale fermentation of the myxobacterium Sorangium cellulosum So ce1875 and characterized by electrospray ionization-high-resolution mass spectrometry (ESI-HRMS), X-ray, nuclear magnetic resonance (NMR), and Mosher ester analysis. Disorazole Z compounds are characterized by the lack of one polyketide extension cycle, resulting in a shortened monomer in comparison to disorazole A, which finally forms a dimer in the bis-lactone core structure. In addition, an unprecedented modification of a geminal dimethyl group takes place to form a carboxylic acid methyl ester. The main component disorazole Z1 shows comparable activity in effectively killing cancer cells to disorazole A1 via binding to tubulin, which we show induces microtubule depolymerization, endoplasmic reticulum delocalization, and eventually apoptosis. The disorazole Z biosynthetic gene cluster (BGC) was identified and characterized from the alternative producer S. cellulosum So ce427 and compared to the known disorazole A BGC, followed by heterologous expression in the host Myxococcus xanthus DK1622. Pathway engineering by promoter substitution and gene deletion paves the way for detailed biosynthesis studies and efficient heterologous production of disorazole Z congeners. IMPORTANCE Microbial secondary metabolites are a prolific reservoir for the discovery of bioactive compounds, which prove to be privileged scaffolds for the development of new drugs such as antibacterial and small-molecule anticancer drugs. Consequently, the continuous discovery of novel bioactive natural products is of great importance for pharmaceutical research. Myxobacteria, especially Sorangium spp., which are known for their large genomes with yet-underexploited biosynthetic potential, are proficient producers of such secondary metabolites. From the fermentation broth of Sorangium cellulosum strain So ce1875, we isolated and characterized a family of natural products named disorazole Z, which showed potent anticancer activity. Further, we report on the biosynthesis and heterologous production of disorazole Z. These results can be stepping stones toward pharmaceutical development of the disorazole family of anticancer natural products for (pre)clinical studies.

Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates

Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous discovery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA).According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development.These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.

Continuous surveillance and viral discovery in animals and humans are a core component of a one-health approach to address recent viral reverse zoonoses.

Contemporary human and animal viruses have a broad or narrow host range-those with a broad host range are potentially transmitted from animals to humans (ie, zoonosis) or humans to animals (ie, reverse zoonosis). This Currents in One Health article reviews the recent reverse zoonoses involving Coronaviridae, Poxviridae, arboviruses, and, for nonhuman primate species, the human respiratory viruses. The prevention and control of reverse zoonoses are also reviewed. Coronaviruses continue to emerge as new zoonotic agents, including a canine coronavirus, CCoV-HuPn-2018, circulating in people at low levels, and a pangolin coronavirus, MjHKU4r-CoV-1, circulating in Malayan pangolins. Moreover, the risk for SARS-CoV-2 variants to mutate in animal reservoirs and reinfect humans is ongoing. In the case of mpox, the risk of reverse zoonosis is low and there are vaccines for use in humans at risk. The situation with arboviruses is as varied as the number of human arboviruses, and only yellow fever virus and dengue virus have licensed vaccines in the Americas. As for reverse zoonoses in endangered species, solutions require changing human behavior and policies at all levels impacting wildlife. Overall, continuous surveillance and viral discovery in humans and animals remain core components of a one-health approach to reduce and, where possible, eliminate zoonotic and reverse zoonotic diseases. Viral zoonosis and viral reverse zoonosis focusing on recent influenza A virus disease events in humans and other species are the subjects of the companion Currents in One Health by Kibenge, AJVR, June 2023.

Structural interaction fingerprints and machine learning for predicting and explaining binding of small molecule ligands to RNA.

Ribonucleic acids (RNAs) play crucial roles in living organisms and some of them, such as bacterial ribosomes and precursor messenger RNA, are targets of small molecule drugs, whereas others, e.g. bacterial riboswitches or viral RNA motifs are considered as potential therapeutic targets. Thus, the continuous discovery of new functional RNA increases the demand for developing compounds targeting them and for methods for analyzing RNA-small molecule interactions. We recently developed fingeRNAt-a software for detecting non-covalent bonds formed within complexes of nucleic acids with different types of ligands. The program detects several non-covalent interactions and encodes them as structural interaction fingerprint (SIFt). Here, we present the application of SIFts accompanied by machine learning methods for binding prediction of small molecules to RNA. We show that SIFt-based models outperform the classic, general-purpose scoring functions in virtual screening. We also employed Explainable Artificial Intelligence (XAI)-the SHapley Additive exPlanations, Local Interpretable Model-agnostic Explanations and other methods to help understand the decision-making process behind the predictive models. We conducted a case study in which we applied XAI on a predictive model of ligand binding to human immunodeficiency virus type 1 trans-activation response element RNA to distinguish between residues and interaction types important for binding. We also used XAI to indicate whether an interaction has a positive or negative effect on binding prediction and to quantify its impact. Our results obtained using all XAI methods were consistent with the literature data, demonstrating the utility and importance of XAI in medicinal chemistry and bioinformatics.

Description of a new montane freshwater crab (Arthropoda, Malacostraca, Decapoda, Potamonautidae) from the Eastern Cape, South Africa.

A new species of freshwater crab, Potamonautesamatholesp. nov., is described from the Winterberg-Amathole mountain range in the Eastern Cape Province, South Africa. Morphologically, P.amathole Peer & Gouws, sp. nov. most closely resembles P.tuerkayi but can be distinguished by key morphological characters including the variation in the shape of the subterminal segment of gonopod 2 between both species. Genetically, P.amathole Peer & Gouws, sp. nov. is placed within the clade of small-bodied, mountain-dwelling crabs including P.parvispina, P.parvicorpus, P.brincki, P.tuerkayi, P.baziya, and P.depressus. The new species is found in slow-moving mountain streams and pools at high altitudes. The continued discovery and description of new freshwater crab species reinforces the need for ongoing research, especially in under-sampled regions.

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening.

The discovery of bioactive natural products lies at the forefront of human medicine. The continued discovery of these molecules is imperative in the fight against infection and disease. While natural products have historically dominated the drug market, discovery in recent years has slowed significantly, partly due to limitations in current discovery methodologies. This work demonstrates a new workflow, deuterium adduct bioactivity screening (DABS), which pairs untargeted isotope labeling with whole cell binding assays for bioactive natural product discovery. DABS was validated and led to the discovery of a new isoprenyl guanidine alkaloid, zillamycin, which showed anti-cancer and anti-microbial activities. DABS thus represents a new workflow to accelerate discovery of natural products with a wide range of bioactive potentials.

Biotization of in vitro oil palm (Elaeis guineensis Jacq.) and its plant-microbe interactions.

Continuous discovery of novel in vitro plant culture practices is always essential to promote better plant growth in the shortest possible cultivation period. An alternative approach to conventional micropropagation practice could be achieved through biotization by inoculating selected Plant Growth Promoting Rhizobacteria (PGPR) into the plant tissue culture materials (e.g., callus, embryogenic callus, and plantlets). Such biotization process often allows the selected PGPR to form a sustaining population with various stages of in vitro plant tissues. During the biotization process, plant tissue culture material imposes developmental and metabolic changes and enhances its tolerance to abiotic and biotic stresses, thereby reducing mortality in the acclimatization and pre-nursery stages. Understanding the mechanisms is, therefore crucial for gaining insights into in vitro plant-microbe interactions. Studies of biochemical activities and compound identifications are always essential to evaluate in vitro plant-microbe interactions. Given the importance of biotization in promoting in vitro plant material growth, this review aims to provide a brief overview of the in vitro oil palm plant-microbe symbiosis system.

Abstract 6564: Biomarker discovery in triple negative breast cancer using RNA-sequencing analysis

Abstract Breast cancer is the most common form of cancer, and afflicted over 2.2 million people in 2020. The sheer volume of patients who suffer from breast cancer warrants continued research and discovery efforts to improve treatment options. Triple negative breast cancer (TNBC) affects 10-15% of breast cancer patients. Unlike other forms of breast cancer, TNBC does not have estrogen or progesterone receptors and makes little to none of the HER2 protein. Due to the lack of these biomarkers that are typical treatment targets for other kinds of breast cancers, the hormone therapies and drugs that target other breast cancers are often ineffective against TNBC. This leaves chemotherapy and radiation therapy as the main treatment options. Although chemotherapy and radiation have treatment benefits, the recurrence rate after treatment is around 40%. Furthermore, these treatment options are very detrimental to the body, resulting in a weaker patient and a necessary recovery time between treatments. In this study, we analyzed publicly available RNA-sequencing (RNA-seq) data to identify the upregulated and downregulated transcriptional mechanism(s) that play a role in TNBC compared to healthy breast tissue. The analysis of the RNA-seq data was completed with the Automated Reproducible Modular Workflow for Preprocessing and Differential Analysis of RNA-seq Data (ARMOR), which trims, maps, and quantifies the mRNA sequencing reads to the human transcriptome for each read. The ARMOR program identified more than 12,000 differentially expressed genes between TNBC and healthy breast tissue samples. We then applied an artificial intelligence-based classification method, a random forest algorithm, to identify new biomarkers that best differentiate TNBC cells from healthy cells. These specific transcriptional biomarkers for TNBC could potentially be used as diagnostic biomarkers or as therapeutic targets. We anticipate that this data may expand the treatment options for TNBC. Citation Format: Jenna B. Poulsen, Mauri E. Dobbs, Naomi Rapier-Sharman, Brett E. Pickett. Biomarker discovery in triple negative breast cancer using RNA-sequencing analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6564.

Precision targeted therapy for EGFR mutation‐positive NSCLC: Dilemmas and coping strategies

The most common driver gene mutation in patients with non-small-cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR) mutation. With the introduction of EGFR-tyrosine kinase inhibitors, the treatment prospects and prognosis of NSCLC patients with EGFR-sensitive mutations have significantly improved. Nonetheless, therapies targeting NSCLC are still associated with a risk of primary or secondary nonclassical drug resistance mutations. In recent years, the research and methodology have led to the continuous discovery of new drugs and drug resistance targets. These explorations have also resulted in continuously discovering new drugs. Consequently, rapid advancements have been made to overcome NSCLC drug resistance. This study aimed to review the current dilemma of targeted therapy for EGFR mutation-positive NSCLC and the coping strategies for these difficulties.

Distinguishing Biotic vs. Abiotic Origins of 'Bio'signatures: Clues from Messy Prebiotic Chemistry for Detection of Life in the Universe.

It is not a stretch to say that the search for extraterrestrial life is possibly the biggest of the cosmic endeavors that humankind has embarked upon. With the continued discovery of several Earth-like exoplanets, the hope of detecting potential biosignatures is multiplying amongst researchers in the astrobiology community. However, to be able to discern these signatures as being truly of biological origin, we also need to consider their probable abiotic origin. The field of prebiotic chemistry, which is aimed at understanding enzyme-free chemical syntheses of biologically relevant molecules, could particularly aid in this regard. Specifically, certain peculiar characteristics of prebiotically pertinent messy chemical reactions, including diverse and racemic product yields and lower synthesis efficiencies, can be utilized in analyzing whether a perceived 'signature of life' could possibly have chemical origins. The knowledge gathered from understanding the transition from chemistry to biology during the origin of life could be used for creating a library of abiotically synthesized biologically relevant organic molecules. This can then be employed in designing, standardizing, and testing mission-specific instruments/analysis systems, while also enabling the effective targeting of exoplanets with potentially 'ongoing' molecular evolutionary processes for robust detection of life in future explorative endeavors.

Revisiting the Ramachandran plot based on statistical analysis of static and dynamic characteristics of protein structures

Ramachandran plots, which describe protein structures by plotting the dihedral angle pairs of the backbone on a two-dimensional plane, have played an important role in structural biology over the past few decades. However, despite continued discovery of new protein structures to date, the Ramachandran plot is still constructed by only a small number of data points, and further it cannot reflect the steric information of proteins. Here, we investigated the secondary structure of proteins in terms of static and dynamic characteristics. As for static feature, the Ramachandran plot was revisited for the dataset consisting of 9,148 non-redundant high-resolution protein structures released in the protein data bank until April 1, 2022. By calculating amino acid propensities, it was found that the proportion of secondary structures with respect to residue depth is directly related to their hydrophobicity. As for dynamic feature, normal mode analysis (NMA) based on an elastic network model (ENM) was carried out for the dataset using our KOSMOS web server (http://bioengineering.skku.ac.kr/kosmos/). All ENM-based NMA results were stored in the KOSMOS database, allowing researchers to use them in various ways. In this process, it was commonly found that high B-factors appeared at the edge of the alpha helix region, which was elucidated by introducing residue depth. In addition, by investigating the change in dihedral angle, it was possible to quantitatively survey the contribution of structural change of protein on the Ramachandran plot. In conclusion, our statistical analysis of protein characteristics will provide insight into a range of protein structural studies.

A critical scientific and policy opinion on reuse and reclamation of contaminated wastewater for agriculture and other purposes

Contaminants of emerging concern and other chemicals are widespread in the environment. While their effects are ambiguous, a wealth of literature now illustrates their ability to induce various effects at concentrations/doses smaller than the toxicological threshold, leading to hormetic biphasic responses. Such responses are increasingly understood, can be positive or negative, and present an issue for wastewater reuse and reclamation for agriculture and other purposes. Considerable efforts have been placed by stakeholders at multiple levels to address the issue of low-dose effects, but there is more that can be done. To effectively address the low-dose issue, treatment/remediation sites for pollutant elimination should be improved, the number and amounts of chemicals released to the environment should be better controlled/prevented, and citizen-science approach with the involvement of NGOs and other organizations should be employed to expand the coverage of assessing pollution and its effects. This Opinion paper summarizes the main challenges introduced by the continuous discovery of emerging contaminants in the environment and the low-dose effects, discusses what has been done by stakeholders to address low-dose effects, and proposes a path forward.

Implementing HL7 FHIR

Fast Healthcare Interoperability Resources (FHIR), created by HL7 more than a decade ago, has become a global standard for exchanging data. Communities of interest have organized under the HL7 FHIR Accelerator Program to develop implementation guides and applications for patient care, health payment systems, public health, patient engagement, clinical and basic research, and social determinants of health. Despite efforts to coordinate the creation of applications in an ever-increasing diversity of use cases, there have been challenges to ensure semantic interoperability, security, privacy, consistent interpretation of the specifications, and the workforce capacity across the industry. In response to these challenges, HL7 created the Standards Implementation Division with the aims of developing a unique ecosystem for continuous testing and discovery, building a global education and certification program, and facilitating advancement across the diverse FHIR implementation communi

Flow As An Operative Methodology Generating The Time Of Intersection Through The Relationship Between Architecture And Artwork In Public Space

Time has always fascinated men for its (apparently) inviolable structure and for the poetic dimension that this concept brings with it. During the history of civilization, time has been a crucial concept to understanding reality. At the beginning of the Twentieth century, thanks to the scientific discoveries, above all, Albert Einstein’s general relativity theory, the notion of time became an important element also for science for understanding the structure of the universe. The continuous and ever-faster scientific discoveries have also dissolved the linearity of time and its very nature, offering new possibilities to rethink space-time, as a series of connected, but not necessarily linear, events. Something we are experiencing today through the multi-temporality of the digital world, but which at the same time also shifts our way of perceiving physical reality.Everything we do and produce is inevitably part of a space-time dimension. We can therefore interpret time - also - as a distinctive structural element of the things that human beings build, whether small or large, from tools to metropolises.In this background, it is very interesting to understand how time works in two of the most symbolic categories of objects of human creation, art, and architecture, focusing more specifically on the category of art in public space. The time that works into the artwork is naturally different from the time that works into architecture, that is, observing art in public space, there are two different times that overlap, or rather the architectural space (and time) houses inside of it, the space (and time) of the work of art. The overlapping of these two different times, inevitably creates a third time, that we will call a “Time of Intersection”, which becomes the subject of this paper.

The Pharmaceutical Market for Biological Products in Latin America: A Comprehensive Analysis of Regional Sales Data.

The global market for biologics and biosimilar pharmaceutical products is experiencing rapid expansion, primarily driven by the continuous discovery of new molecules. However, information regarding Latin America's biological market remains limited.

Government Support of Meaningful Drug and Device Innovation: Pathways and Challenges.

The US government supports drug innovation. It is therefore crucial that it distinguish between high-value and low-value innovation in purchasing expensive prescription drugs and medical devices and ensure the continued discovery of transformative drugs and that patient and taxpayer funds are not wasted.

Research progress on marker-assisted selection pyramiding breeding of disease resistance genes in wheat

Marker-Assisted Selection (MAS) pyramiding breeding combined with traditional breeding techniques has become an important method for molecular breeding in wheat. In recent years, with the continuous discovery of disease-resistance genes and the development of molecular markers associated with related genes in wheat, the research of MAS pyramiding disease-resistance genes has made great progress. The progress on the study of MAS pyramiding resistance genes in wheat powdery mildew, rust, and Fusarium head blight (Fhb) was reviewed. The aims of pyramiding breeding were discussed in order to promote the research on MAS pyramiding breeding in wheat.