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Hepatology (Baltimore, Md.) Sep 2023Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a... (Review)
Review
Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future. The adaptations to clinical trial operations in response to the disruptions by the COVID-19 pandemic and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant-derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem. The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.
Topics: Humans; COVID-19; Pandemics; Ecosystem; Data Collection
PubMed: 37140242
DOI: 10.1097/HEP.0000000000000436 -
Journal of Integrative Plant Biology Mar 2024Excess soil salinity affects large regions of land and is a major hindrance to crop production worldwide. Therefore, understanding the molecular mechanisms of plant salt... (Review)
Review
Excess soil salinity affects large regions of land and is a major hindrance to crop production worldwide. Therefore, understanding the molecular mechanisms of plant salt tolerance has scientific importance and practical significance. In recent decades, studies have characterized hundreds of genes associated with plant responses to salt stress in different plant species. These studies have substantially advanced our molecular and genetic understanding of salt tolerance in plants and have introduced an era of molecular design breeding of salt-tolerant crops. This review summarizes our current knowledge of plant salt tolerance, emphasizing advances in elucidating the molecular mechanisms of osmotic stress tolerance, salt-ion transport and compartmentalization, oxidative stress tolerance, alkaline stress tolerance, and the trade-off between growth and salt tolerance. We also examine recent advances in understanding natural variation in the salt tolerance of crops and discuss possible strategies and challenges for designing salt stress-resilient crops. We focus on the model plant Arabidopsis (Arabidopsis thaliana) and the four most-studied crops: rice (Oryza sativa), wheat (Triticum aestivum), maize (Zea mays), and soybean (Glycine max).
Topics: Crops, Agricultural; Arabidopsis; Glycine max; Salt Tolerance; Salinity
PubMed: 38108117
DOI: 10.1111/jipb.13599 -
Ageing Research Reviews Nov 2023This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of... (Review)
Review
This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of numerous degenerative diseases and debilitating effects of aging. It proposes that the most fundamental, evolutionary-based integrative strategy to sustain and protect health is based on the concept of hormesis. This concept integrates anti-oxidant, anti-inflammatory and cellular repair responses at all levels of biological organization (i.e., cell, organ and organism) within the framework of biphasic dose responses that describe the quantitative limits of biological plasticity in all cells and organisms from bacteria and plants to humans. A major feature of the hormetic concept is that low levels of biological, chemical, physical and psychological stress upregulate adaptive responses that not only precondition, repair and restore normal functions to damaged tissues/organs but modestly overcompensate, reducing ongoing background damage, thereby enhancing health beyond that in control groups, lacking the low level "beneficial" stress. Higher doses of such stress often become counterproductive and eventually harmful. Hormesis is active throughout the life-cycle and can be diminished by aging processes affecting the onset and severity of debilitating conditions/diseases, especially in elderly subjects. The most significant feature of the hormetic dose response is that the limits of biological plasticity for adaptive processes are less than twice that of control group responses, with most, at maximum, being 30-60 % greater than control group values. Yet, these modest increases can make the difference between health or disease and living or dying. The quantitative features of these adaptive hormetic dose responses are also independent of mechanism. These features of the hormetic dose response determine the capacity to which systems can adapt/be protected, the extent to which biological performance (e.g., memory, resistance to injury/disease, wound healing, hair growth or lifespan) can be enhanced/extended and the extent to which synergistic interactions may occur. Hormesis defines the quantitative rules within which adaptive processes operate and is central to evolution and biology and should become transformational for experimental concepts and study design strategies, public health practices and a vast range of therapeutic strategies and interventions.
Topics: Humans; Aged; Hormesis; Longevity; Aging; Adaptation, Physiological; Antioxidants
PubMed: 37709054
DOI: 10.1016/j.arr.2023.102074 -
Molecular Plant Sep 2023The shoot meristem generates the entire shoot system and is precisely maintained throughout the life cycle under various environmental challenges. In this study, we...
The shoot meristem generates the entire shoot system and is precisely maintained throughout the life cycle under various environmental challenges. In this study, we identified a prion-like domain (PrD) in the key shoot meristem regulator SHOOT MERISTEMLESS (STM), which distinguishes STM from other related KNOX1 proteins. We demonstrated that PrD stimulates STM to form nuclear condensates, which are required for maintaining the shoot meristem. STM nuclear condensate formation is stabilized by selected PrD-containing STM-interacting BELL proteins in vitro and in vivo. Moreover, condensation of STM promotes its interaction with the Mediator complex subunit MED8 and thereby enhances its transcriptional activity. Thus, condensate formation emerges as a novel regulatory mechanism of shoot meristem functions. Furthermore, we found that the formation of STM condensates is enhanced upon salt stress, which allows enhanced salt tolerance and increased shoot branching. Our findings highlight that the transcription factor partitioning plays an important role in cell fate determination and might also act as a tunable environmental acclimation mechanism.
Topics: Salt Tolerance; Arabidopsis; Meristem; Salt Stress; Cell Differentiation; Homeodomain Proteins; Arabidopsis Proteins
PubMed: 37674313
DOI: 10.1016/j.molp.2023.09.005 -
The New Phytologist Mar 2024Salt stress is a major challenge that has a negative impact on soybean growth and productivity. Therefore, it is important to understand the regulatory mechanism of salt...
Salt stress is a major challenge that has a negative impact on soybean growth and productivity. Therefore, it is important to understand the regulatory mechanism of salt response to ensure soybean yield under such conditions. In this study, we identified and characterized a miR160a-GmARF16-GmMYC2 module and its regulation during the salt-stress response in soybean. miR160a promotes salt tolerance by cleaving GmARF16 transcripts, members of the Auxin Response Factor (ARF) family, which negatively regulates salt tolerance. In turn, GmARF16 activates GmMYC2, encoding a bHLH transcription factor that reduces salinity tolerance by down-regulating proline biosynthesis. Genomic analysis among wild and cultivated soybean accessions identified four distinct GmARF16 haplotypes. Among them, the GmARF16 haplotype is preferentially enriched in localities with relatively saline soils, suggesting GmARF16 was artificially selected to improve salt tolerance. Our findings therefore provide insights into the molecular mechanisms underlying salt response in soybean and provide valuable genetic targets for the molecular breeding of salt tolerance.
Topics: Glycine max; Salt Tolerance; Haplotypes; Base Sequence; Gene Expression Regulation, Plant
PubMed: 38135657
DOI: 10.1111/nph.19503 -
Annual Review of Marine Science Jan 2024For decades, multiple-driver/stressor research has examined interactions among drivers that will undergo large changes in the future: temperature, pH, nutrients, oxygen,... (Review)
Review
For decades, multiple-driver/stressor research has examined interactions among drivers that will undergo large changes in the future: temperature, pH, nutrients, oxygen, pathogens, and more. However, the most commonly used experimental designs-present-versus-future and ANOVA-fail to contribute to general understanding or predictive power. Linking experimental design to process-based mathematical models would help us predict how ecosystems will behave in novel environmental conditions. We review a range of experimental designs and assess the best experimental path toward a predictive ecology. Full factorial response surface, fractional factorial, quadratic response surface, custom, space-filling, and especially optimal and sequential/adaptive designs can help us achieve more valuable scientific goals. Experiments using these designs are challenging to perform with long-lived organisms or at the community and ecosystem levels. But they remain our most promising path toward linking experiments and theory in multiple-driver research and making accurate, useful predictions.
Topics: Ecosystem; Ecology; Nutrients; Oxygen; Temperature
PubMed: 37625127
DOI: 10.1146/annurev-marine-041823-095913 -
Angewandte Chemie (International Ed. in... Aug 2023The rapidly growing importance of green hydrogen and renewable carbon resources as essential feedstocks for sustainable chemical value chains opens room for disruptive... (Review)
Review
The rapidly growing importance of green hydrogen and renewable carbon resources as essential feedstocks for sustainable chemical value chains opens room for disruptive innovations regarding chemical production processes. The fluctuation and variability associated with non-fossil energy and raw material supply holds many challenges for catalysts to cope with the resulting dynamics. However, many new opportunities also arise once catalyst design starts to aim at performance that is "adaptive" rather than "task-specific". In this Scientific Perspective, we propose to define adaptivity in catalysis on the basis of three essential properties that are reversibility, rapidity, and robustness (R rule). Promising design strategies and selected examples are described to substantiate the scientific concept and to highlight its potential for chemical energy conversion.
PubMed: 37345624
DOI: 10.1002/anie.202301956 -
The American Surgeon Nov 2023Historically, surgical instruments were designed by men for male surgeons. Although instrumentation has changed with the changing paradigms of surgery, it has failed to... (Review)
Review
Historically, surgical instruments were designed by men for male surgeons. Although instrumentation has changed with the changing paradigms of surgery, it has failed to adapt to the changing surgical workforce. Almost 30% of surgeons are female and nearly 90% of surveyed female surgeons report poor instrument design and associated musculoskeletal injuries from use. Understanding the current state of handheld surgical instrument design, published literature was reviewed, surgical instrument collections were contacted, and the U.S. Patent and Trademark databases were queried to identify public patents and pre-granted applications of female inventors of handheld surgical instruments. Twenty-five female inventors were identified from published literature and 1551 unique females hold patents. This number pales when the denominator of male inventors is considered. Hence, to address the female surgeon's lack of instrumentation and design, there is a critical need for participatory ergonomics whereby both the female surgeon and engineer collaborate on design.
Topics: Humans; Male; Female; Inventors; Surveys and Questionnaires; Musculoskeletal Diseases; Ergonomics; Surgical Instruments; Surgeons
PubMed: 37148253
DOI: 10.1177/00031348231172164 -
Translational and Clinical Pharmacology Dec 2023An adaptive design is a clinical trial design that allows for modification of a structured plan in a clinical trial based on data accumulated during pre-planned interim...
An adaptive design is a clinical trial design that allows for modification of a structured plan in a clinical trial based on data accumulated during pre-planned interim analyses. This flexible approach to clinical trial design improves the success rate of clinical trials while reducing time, cost, and sample size compared to conventional methods. The purpose of this study is to identify the current status of adaptive design and present key considerations for planning an appropriate adaptive design based on specific circumstances. We searched for clinical trials conducted between January 2006 to July 2021 in the Clinical Trials Registry (ClinicalTrials.gov) using keywords specified in the Food and Drug Administration Adaptive Design Clinical Trial Guidelines. In order to analyze the adaptive designs used in selected cases, we classified the results according to the phase of the clinical trial, type of indication, and the specific adaptation method employed. A total of 267 clinical trials were identified on ClinicalTrials.gov. Among them, 236 clinical trials actually applied adaptive designs and were classified according to phase, indication types, and adaptation methods. Adaptive designs were most frequently used in phase 2 clinical trials and oncology research. The most commonly used adaptation method was the adaptive treatment selection design. In the case of coronavirus disease 2019, the most frequently used designs were adaptive platform design and seamless design. Through this study, we expect to provide valuable insights and considerations for the implementation of adaptive design clinical trials in different diseases and stages.
PubMed: 38197001
DOI: 10.12793/tcp.2023.31.e21 -
An Overview of Adaptive Designs and Some of Their Challenges, Benefits, and Innovative Applications.Journal of Medical Internet Research Oct 2023Adaptive designs are increasingly developed and used to improve all phases of clinical trials and in biomedical studies in various ways to address different statistical...
Adaptive designs are increasingly developed and used to improve all phases of clinical trials and in biomedical studies in various ways to address different statistical issues. We first present an overview of adaptive designs and note their numerous advantages over traditional clinical trials. In particular, we provide a concrete demonstration that shows how recent adaptive design strategies can further improve an adaptive trial implemented 13 years ago. Despite their usefulness, adaptive designs are still not widely implemented in clinical trials. We offer a few possible reasons and propose some ways to use them more broadly in practice, which include greater availability of software tools and interactive websites to generate optimal adaptive trials freely and effectively, including the use of metaheuristics to facilitate the search for an efficient trial design. To this end, we present several web-based tools for finding various adaptive and nonadaptive optimal designs and discuss nature-inspired metaheuristics. Metaheuristics are assumptions-free general purpose optimization algorithms widely used in computer science and engineering to tackle all kinds of challenging optimization problems, and their use in designing clinical trials is just emerging. We describe a few recent such applications and some of their capabilities for designing various complex trials. Particle swarm optimization is an exemplary nature-inspired algorithm, and similar to others, it has a simple definition but many moving parts, making it hard to study its properties analytically. We investigated one of its hitherto unstudied issues on how to bring back out-of-range candidates during the search for the optimum of the search domain and show that different strategies can impact the success and time of the search. We conclude with a few caveats on the use of metaheuristics for a successful search.
Topics: Humans; Research Design; Algorithms; Software
PubMed: 37843888
DOI: 10.2196/44171