Radiosensitizing effect of a novel CTSS inhibitor by enhancing BRCA1 protein stability in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) patients harboring wild-type breast cancer susceptibility gene 1 (BRCA1) account for most TNBC patients but lack adequate targeted therapeutic options. Although radiotherapy (RT) is the primary treatment modality for TNBC patients, radioresistance is one of the major challenges. RT-induced increase in cathepsin S (CTSS) causes radioresistance through suppressing BRCA1-mediated apoptosis of tumor cells, which was induced by CTSS-mediated degradation of BRCA1. Targeting CTSS may provide a novel therapeutic opportunity for TNBC patients. Publicly available data and human tissue microarray slides were analyzed to investigate the relationship between CTSS and BRCA1 in breast cancer patients. A CTSS enzyme assay and in silico docking analysis were conducted to identify a novel CTSS inhibitor. RO5461111 was used first to confirm the concept of targeting CTSS for radiosensitizing effects. The MDA-MB-231 TNBC cell line was used for in vitro and in vivo assays. Western blotting, promoter assay, cell death assay, clonogenic survival assay, and immunohistochemistry staining were conducted to evaluate novel CTSS inhibitors. CTSS inhibitors were further evaluated for their additional benefit of inhibiting cell migration. A novel CTSS inhibitor, TS-24, increased BRCA1 protein levels and showed radiosensitization in TNBC cells with wild-type BRCA1 and in vivo in a TNBC xenograft mouse model. These effects were attributed by BRCA1-mediated apoptosis facilitated by TS-24. Furthermore, TS-24 demonstrated the additional effect of inhibiting cell migration. Our study suggests that employing CTSS inhibitors for the functional restoration of BRCA1 to enhance RT-induced apoptosis may provide a novel therapeutic opportunity for TNBC patients harboring wild-type BRCA1.

A comprehensive review of the characterization, host interactions, and stabilization advancements on probiotics: Addressing the challenges in functional food diversification.

The demand for functional food is rising in tandem with the prevalence of chronic diseases. Probiotics play a crucial role in functional food development, yet their ability to confer health benefits to the host remains a topic of debate according to Food and Agriculture Organization/World Health Organization requirements. The application of culturomics, innovative isolation techniques, within the realm of probiotics is increasingly deemed essential for fully harnessing the latent potential of microbial reservoirs. Nevertheless, its application remains confined predominantly to human fecal sources. Following the integration of probiogenomics, significant advancements have been made in the safety assessment of probiotics. However, the adoption of novel probiotic microorganisms has yet to match the requisite pace. Progress in research concerning host-probiotic interactions by employing omics technologies, particularly in animal models, is notable. Nonetheless, the comprehensive elucidation of mechanisms of action and human trial studies are lagging behind. Additionally, the viability of probiotics, spanning from their production as functional foods to their transit to the human colon, has markedly improved through encapsulation techniques. Nevertheless, opportunities for exploration persist regarding alternative coating materials and diverse encapsulation methodologies. Furthermore, there is a discernible transition in the domain of probiotic-based functional foods, shifting away from a primarily dairy-centric focus toward inclusion in a broader array of food categories. This comprehensive review addresses critical issues ranging from isolation sources and novel techniques to the final functional food developments. while doing so, it explores probiogenomics applications for probiotic characterization, investigations into host-probiotic interactions, and strategies for probiotic stabilization under harsh environmental conditions.

Significance of Soy-Based Fermented Food and Their Bioactive Compounds Against Obesity, Diabetes, and Cardiovascular Diseases.

Soybean-based fermented foods are commonly consumed worldwide, especially in Asia. These fermented soy-products are prepared using various strains of Bacillus, Streptococcus, Lactobacillus, and Aspergillus. The microbial action during fermentation produces and increases the availability of various molecules of biological significance, such as isoflavones, bioactive peptides, and dietary fiber. These dietary bio active compounds are also found to be effective against the metabolic disorders such as obesity, diabetes, and cardiovascular diseases (CVD). In parallel, soy isoflavones such as genistein, genistin, and daidzin can also contribute to the anti-obesity and anti-diabetic mechanisms, by decreasing insulin resistance and oxidative stress. The said activities are known to lower the risk of CVD, by decreasing the fat accumulation and hyperlipidemia in the body. In addition, along with soy-isoflavones fermented soy foods such as Kinema, Tempeh, Douchi, Cheonggukjang/Chungkukjang, and Natto are also rich in dietary fiber (prebiotic) and known to be anti-dyslipidemia, improve lipolysis, and lowers lipid peroxidation, which further decreases the risk of CVD. Further, the fibrinolytic activity of nattokinase present in Natto soup also paves the foundation for the possible cardioprotective role of fermented soy products. Considering the immense beneficial effects of different fermented soy products, the present review contextualizes their significance with respect to their anti-obesity, anti-diabetic and cardioprotective roles.

Holistic Approaches to Plant Stress Alleviation: A Comprehensive Review of the Role of Organic Compounds and Beneficial Bacteria in Promoting Growth and Health.

Plants select microorganisms from the surrounding bulk soil, which act as a reservoir of microbial diversity and enrich a rhizosphere microbiome that helps in growth and stress alleviation. Plants use organic compounds that are released through root exudates to shape the rhizosphere microbiome. These organic compounds are of various spectrums and technically gear the interplay between plants and the microbial world. Although plants naturally produce organic compounds that influence the microbial world, numerous efforts have been made to boost the efficiency of the microbiome through the addition of organic compounds. Despite further crucial investigations, synergistic effects from organic compounds and beneficial bacteria combinations have been reported. In this review, we examine the relationship between organic compounds and beneficial bacteria in determining plant growth and biotic and abiotic stress alleviation. We investigate the molecular mechanism and biochemical responses of bacteria to organic compounds, and we discuss the plant growth modifications and stress alleviation done with the help of beneficial bacteria. We then exhibit the synergistic effects of both components to highlight future research directions to dwell on how microbial engineering and metagenomic approaches could be utilized to enhance the use of beneficial microbes and organic compounds.

Gut Microbes in Polycystic Ovary Syndrome and Associated Comorbidities; Type 2 Diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), Cardiovascular Disease (CVD), and the Potential of Microbial Therapeutics.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine anomalies among females of reproductive age, highlighted by hyperandrogenism. PCOS is multifactorial as it can be associated with obesity, insulin resistance, low-grade chronic inflammation, and dyslipidemia. PCOS also leads to dysbiosis by lowering microbial diversity and beneficial microbes, such as Faecalibacterium, Roseburia, Akkermenisa, and Bifidobacterium, and by causing a higher load of opportunistic pathogens, such as Escherichia/Shigella, Fusobacterium, Bilophila, and Sutterella. Wherein, butyrate producers and Akkermansia participate in the glucose uptake by inducing glucagon-like peptide-1 (GLP-1) and glucose metabolism, respectively. The abovementioned gut microbes also maintain the gut barrier function and glucose homeostasis by releasing metabolites such as short-chain fatty acids (SCFAs) and Amuc_1100 protein. In addition, PCOS-associated gut is found to be higher in gut-microbial enzyme ß-glucuronidase, causing the de-glucuronidation of conjugated androgen, making it susceptible to reabsorption by entero-hepatic circulation, leading to a higher level of androgen in the circulatory system. Overall, in PCOS, such dysbiosis increases the gut permeability and LPS in the systemic circulation, trimethylamine N-oxide (TMAO) in the circulatory system, chronic inflammation in the adipose tissue and liver, and oxidative stress and lipid accumulation in the liver. Thus, in women with PCOS, dysbiosis can promote the progression and severity of type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). To alleviate such PCOS-associated complications, microbial therapeutics (probiotics and fecal microbiome transplantation) can be used without any side effects, unlike in the case of hormonal therapy. Therefore, this study sought to understand the mechanistic significance of gut microbes in PCOS and associated comorbidities, along with the role of microbial therapeutics that can ease the life of PCOS-affected women.

Impact of propiconazole fungicide on soil microbiome (bacterial and fungal) diversity, functional profile, and associated dehydrogenase activity.

Pesticides, protect crops but can harm the environment and human health when used without caution. This study evaluated the impact of propiconazole, a fungicide that acts on fungal cell membranes, on soil microbiome abundance, diversity, and functional profile, as well as soil dehydrogenase activity (DHA). The study conducted microcosm experiments using soil samples treated with propiconazole and employed next-generation sequencing (MiSeq) and chromatographic approaches (GC-MS/MS) to analyze the shift in microbial communities and propiconazole level, respectively. The results showed that propiconazole significantly altered the distribution of microbial communities, with notable changes in the abundance of various bacterial and fungal taxa. Among soil bacterial communities, the relative abundance of Proteobacteria and Planctomycetota increased, while that of Acidobacteria decreased after propiconazole treatment. In the fungal communities, propiconazole increased the abundance of Ascomycota and Basidiomycota in the treated soil, while that of Mortierellomycota was reduced. Fungicide application further triggered a significant decrease in DHA over time. Analysis of the functional profile of bacterial communities showed that propiconazole significantly affected bacterial cellular and metabolic pathways. The carbon degradation pathway was upregulated, indicating the microbial detoxification of the contaminant in the treated soil. Our findings suggest that propiconazole application has a discernible impact on soil microbial communities, which could have long-term consequences for soil health, quality, and function.

3D-integrated multilayered physical reservoir array for learning and forecasting time-series information.

A wide reservoir computing system is an advanced architecture composed of multiple reservoir layers in parallel, which enables more complex and diverse internal dynamics for multiple time-series information processing. However, its hardware implementation has not yet been realized due to the lack of a high-performance physical reservoir and the complexity of fabricating multiple stacks. Here, we achieve a proof-of-principle demonstration of such hardware made of a multilayered three-dimensional stacked 3 × 10 × 10 tungsten oxide memristive crossbar array, with which we further realize a wide physical reservoir computing for efficient learning and forecasting of multiple time-series data. Because a three-layer structure allows the seamless and effective extraction of intricate three-dimensional local features produced by various temporal inputs, it can readily outperform two-dimensional based approaches extensively studied previously. Our demonstration paves the way for wide physical reservoir computing systems capable of efficiently processing multiple dynamic time-series information.

Comparative Analysis of Gut Microbiota between Captive and Wild Long-Tailed Gorals for Ex Situ Conservation.

The long-tailed goral is close to extinction, and ex situ conservation is essential to prevent this phenomenon. Studies on the gut microbiome of the long-tailed goral are important for understanding the ecology of this species. We amplified DNA from the 16S rRNA regions and compared the microbiomes of wild long-tailed gorals and two types of captive long-tailed gorals. Our findings revealed that the gut microbiome diversity of wild long-tailed gorals is greatly reduced when they are reared in captivity. A comparison of the two types of captive long-tailed gorals confirmed that animals with a more diverse diet exhibit greater gut microbiome diversity. Redundancy analysis confirmed that wild long-tailed gorals are distributed throughout the highlands, midlands, and lowlands. For the first time, it was revealed that the long-tailed goral are divided into three groups depending on the height of their habitat, and that the gut bacterial community changes significantly when long-tailed gorals are raised through ex situ conservation. This provides for the first time a perspective on the diversity of food plants associated with mountain height that will be available to long-tailed goral in the future.

Whole-genome sequencing of Beauveria bassiana KNU-101 using the hybrid assembly approach.

In this report, we present the whole-genome sequences of Beauveria bassiana KNU-101, a widely recognized entomopathogenic fungus used as a biopesticide. The genome was assembled using a hybrid assembly approach, resulting in 13 scaffolds with a total size of 35,638,224 bp.

The preventive effect of Gastrodia elata Blume extract on vancomycin-induced acute kidney injury in rats.

BACKGROUND: Gastrodia elata Blume (GEB), a traditional medicinal herb, has been reported to have pharmacological effect including protection against liver, neuron and kidney toxicity. However, explanation of its underlying mechanisms remains a great challenge. This study investigated the protective effects of GEB extract on vancomycin (VAN)-induced nephrotoxicity in rats and underlying mechanisms with emphasis on the anti-oxidative stress, anti-inflammation and anti-apoptosis. The male Sprague-Dawley rats were randomly divided three groups: control (CON) group, VAN group and GEB group with duration of 14 days. RESULTS: The kidney weight and the serum levels of blood urea nitrogen and creatinine in the GEB group were lower than the VAN group. Histological analysis using hematoxylin & eosin and periodic acid Schiff staining revealed pathological changes of the VAN group. Immunohistochemical analysis revealed that the expression levels of N-acetyl-D-glucosaminidase, myeloperoxidase and tumor necrosis factor-alpha in the GEB group were decreased when compared with the VAN group. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, phosphohistone and malondialdehyde levels were lower in the GEB group than VAN group. The levels of total glutathione in the GEB group were higher than the VAN group. CONCLUSIONS: The findings of this study suggested that GEB extract prevents VAN-induced renal tissue damage through anti-oxidation, anti-inflammation and anti-apoptosis.

Fungal Microbiome of Alive and Dead Korean Fir in its Native Habitats.

A rapid decline of Abies koreana has been reported in most of the natural alpine habitats in Korea. It is generally accepted that this phenomenon is due to climate change even though no clear conclusions have been drawn. Most research has focused on abiotic environmental factors, but studies on the relationships between A. koreana and soil fungal microbiomes are scarce. In this study, the rhizoplane and rhizosphere fungal communities in the alive and dead Korean fir trees from its three major natural habitats including Mt. Deogyu, Mt. Halla, and Mt. Jiri in Korea were investigated to identify specific soil fungal groups closely associated with A. koreana. Soil fungal diversity in each study site was significantly different from another based on the beta diversity calculations. Heat tree analysis at the genus level showed that Clavulina, Beauveria, and Tomentella were most abundant in the healthy trees probably by forming ectomycorrhizae with Korean fir growth and controlling pests and diseases. However, Calocera, Dacrymyces, Gyoerffyella, Hydnotrya, Microdochium, Hyaloscypha, Mycosymbioces, and Podospora were abundant in the dead trees. Our findings suggested that Clavulina, Beauveria, and Tomentella are the major players that could be considered in future reforestation programs to establish ectomycorrhizal networks and promote growth. These genera may have played a significant role in the survival and growth of A. koreana in its natural habitats. In particular, the genus Gyoerffyella may account for the death of the seedlings. Our work presented exploratory research on the specific fungal taxa associated with the status of A. koreana.

Increase of the indoor concentration of volatile organic compounds after the use of incense and scented candle in studio apartments determined using passive sampling.

Burning incenses and scented candles may provide harmful chemicals. Although many studies have evaluated volatile organic chemicals emitted by their use and related health risks, extension of our understanding for guiding appropriate use under various use conditions is necessary. In this study, emission characteristics of commercial incenses and scented candles were evaluated in a laboratory chamber using real-time measurement and the time-weighted average exposure concentrations of monoaromatic compounds and monoterpenes were assessed using passive samplers while volunteers living in a studio apartment use them. After burning incense, the average levels of benzene increased from 1.4 to 100 µg m-3. The presence of a wood core in commercial incense products was the main cause of high benzene emission by burning them although the increase in benzene was also influenced by factors such as the brand of the products, the number of incense sticks burned, the duration of each burning session, and ventilation period. Electrical warming of scented candles increased the levels of monoterpenes by factors of 16-30 on average. Considering the emission characteristics found in this study, exposure to benzene and monoterpenes could be mitigated by cautious use of those products in residential areas.

Determination of personal exposure to volatile organic compounds and their health risks after the use of mosquito repellents in residential environments using passive sampling.

The ubiquitous use of mosquito repellents in homes across Asia, Africa, and South America is related with human exposure to indoor volatile organic compounds (VOCs). There are three primary types of mosquito repellents: those in the form of coils, mats, and liquids. The repellent mechanisms of these products are distinct, resulting in the generation of varying types of VOCs during the repellent process. In this study, the emission characteristics of commercial coil-, mat-, and liquid-type mosquito repellents were observed in a laboratory chamber using real-time measurement. A previously developed personal passive sampler, ePTFE PS, was used to quantify personal exposure to indoor VOCs while 86 volunteers habitually used those three representative types for 3 h in their residence. Notable increase of indoor benzene was observed for coil- and mat-type mosquito repellents, while α-pinene concentration increased significantly following the use of liquid-type mosquito repellent. The average incremental cancer risks for benzene were 10-6 to 10-4 for adults following the use of coil- and mat-type mosquito repellents. The average non-cancer risks for all chemicals were <1 after the use of three types of mosquito repellents. Considering the potential human health risks associated with byproducts (e.g., particulate matter or carbon monoxide from incomplete combustion) emitted after mosquito coil use, further research on this topic is warranted.

Microbial dysbiosis index for assessing colitis status in mouse models: A systematic review and meta-analysis.

Although countless gut microbiome studies on colitis using mouse models have been carried out, experiments with small sample sizes have encountered reproducibility limitations because of batch effects and statistical errors. In this study, dextran-sodium-sulfate-induced microbial dysbiosis index (DiMDI) was introduced as a reliable dysbiosis index that can be used to assess the state of microbial dysbiosis in DSS-induced mouse models. Meta-analysis of 189 datasets from 11 independent studies was performed to construct the DiMDI. Microbial dysbiosis biomarkers, Muribaculaceae, Alistipes, Turicibacter, and Bacteroides, were selected through four different feature selection methods and used to construct the DiMDI. This index demonstrated a high accuracy of 82.3% and showed strong robustness (88.9%) in the independent cohort. Therefore, DiMDI may be used as a standard for assessing microbial imbalance in DSS-induced mouse models and may contribute to the development of reliable colitis microbiome studies in mouse experiments.

Human Circulatory/Respiratory-Inspired Comprehensive Air Purification System.

The circulatory and respiratory systems in humans are marvels of biological engineering that exhibit competence in maintaining homeostasis. These systems not only shield the organism from external contaminants but also orchestrate the vital gases via the bloodstream to sustain cellular respiration and metabolic processes across diverse tissues. It is noticed that spaces inhabited encounter challenges akin to those of the human body: protecting the indoor air from external pollutants while removing anthropogenic byproducts like carbon dioxide (CO2), particulate matters (PM), and volatile organic compounds (VOCs) tooutside. A biomimetic approach, composed of a microbubble-based gas exchanger and circulating liquid inspired by alveoli, capillary beds, and bloodstream of the human circulatory/respiratory system, offer an innovative solution for comprehensive air purification of hermetic spaces. Circulatory/respiratory-inspired air purification system (CAPS) ensure both continuous removal of PM and exchange of gas species between indoor and outdoor environments to maintain homeostasis. The effectiveness of this system is also supported by animal behavior experiments with and without CAPS, showing an effect of reducing CO2 concentration by 30% and increasing mice locomotor activity by 53%. CAPS is expected to evolve into robust and comprehensive air purification schemes through the networked integration of plural internal and external environments.

Effect of Regdanvimab on Mortality in Patients Infected with SARS-CoV-2 Delta Variants: A Propensity Score-Matched Cohort Study.

INTRODUCTION: Regdanvimab, a monoclonal antibody pharmaceutical, is the first Korean drug approved for treating coronavirus disease 2019 (COVID-19). We analyzed the therapeutic efficacy of regdanvimab in patients with the COVID-19 delta variant infection. METHODS: We retrospectively reviewed the electronic medical records of patients hospitalized at two Korean tertiary COVID-19 hospitals with COVID-19 delta variant infection between May 26, 2021, and January 30, 2022. To analyze the therapeutic efficacy of regdanvimab, the patients were divided into regdanvimab and non-regdanvimab groups and were 1:1 propensity-score (PS)-matched on age, severity at admission, and COVID-19 vaccination history. RESULTS: Of 492 patients, 262 (53.3%) and 230 (46.7%) were in the regdanvimab and non-regdanvimab groups, respectively. After PS matching the groups on age, severity at admission, and COVID-19 vaccination history, each group comprised 189 patients. The 30-day hospital mortality rates (0.0% vs. 1.6%, p = 0.030), proportions of patients with exacerbated conditions to severe/critical/died (9.5% vs. 16.4%, p = 0.047), proportions who received oxygen therapy because of pneumonia exacerbation (7.4% vs. 16.4%, p = 0.007), and proportions with a daily National Early Warning Score ≥ 5 from hospital day 2 were significantly lower in the regdanvimab group. CONCLUSIONS: We showed that regdanvimab reduced the exacerbation rates of conditions and mortality in patients with the COVID-19 delta variant infection. Thus, it is recommended to streamline the drug approval system during epidemics of new variant viruses to improve the availability and usage of therapeutics for patients. To facilitate this, relevant institutional support is required.

Molybdenum Disulfide-Assisted Spontaneous Formation of Multistacked Gold Nanoparticles for Deep Learning-Integrated Surface-Enhanced Raman Scattering.

Several fabrication methods have been developed for label-free detection in various fields. However, fabricating high-density and highly ordered nanoscale architectures by using soluble processes remains a challenge. Herein, we report a biosensing platform that integrates deep learning with surface-enhanced Raman scattering (SERS), featuring large-area, close-packed three-dimensional (3D) architectures of molybdenum disulfide (MoS2)-assisted gold nanoparticles (AuNPs) for the on-site screening of coronavirus disease (COVID-19) using human tears. Some AuNPs are spontaneously synthesized without a reducing agent because the electrons induced on the semiconductor surface reduce gold ions when the Fermi level of MoS2 and the gold electrolyte reach equilibrium. With the addition of polyvinylpyrrolidone, a two-dimensional large-area MoS2 layer assisted in the formation of close-packed 3D multistacked AuNP structures, resembling electroless plating. This platform, with a convolutional neural network-based deep learning model, achieved outstanding SERS performance at subterascale levels despite the microlevel irradiation power and millisecond-level acquisition time and accurately assessed susceptibility to COVID-19. These results suggest that our platform has the potential for rapid, low-damage, and high-throughput label-free detection of exceedingly low analyte concentrations.

Flash-within-flash synthesis of gram-scale solid-state materials.

Sustainable manufacturing that prioritizes energy efficiency, minimal water use, scalability and the ability to generate diverse materials is essential to advance inorganic materials production while maintaining environmental consciousness. However, current manufacturing practices are not yet equipped to fully meet these requirements. Here we describe a flash-within-flash Joule heating (FWF) technique-a non-equilibrium, ultrafast heat conduction method-to prepare ten transition metal dichalcogenides, three group XIV dichalcogenides and nine non-transition metal dichalcogenide materials, each in under 5 s while in ambient conditions. FWF achieves enormous advantages in facile gram scalability and in sustainable manufacturing criteria when compared with other synthesis methods. Also, FWF allows the production of phase-selective and single-crystalline bulk powders, a phenomenon rarely observed by any other synthesis method. Furthermore, FWF MoSe2 outperformed commercially available MoSe2 in tribology, showcasing the quality of FWF materials. The capability for atom substitution and doping further highlights the versatility of FWF as a general bulk inorganic materials synthesis protocol.

Deciphering key factors in pathogen-suppressive microbiome assembly in the rhizosphere.

In a plant-microbe symbiosis, the host plant plays a key role in promoting the association of beneficial microbes and maintaining microbiome homeostasis through microbe-associated molecular patterns (MAMPs). The associated microbes provide an additional layer of protection for plant immunity and help in nutrient acquisition. Despite identical MAMPs in pathogens and commensals, the plant distinguishes between them and promotes the enrichment of beneficial ones while defending against the pathogens. The rhizosphere is a narrow zone of soil surrounding living plant roots. Hence, various biotic and abiotic factors are involved in shaping the rhizosphere microbiome responsible for pathogen suppression. Efforts have been devoted to modifying the composition and structure of the rhizosphere microbiome. Nevertheless, systemic manipulation of the rhizosphere microbiome has been challenging, and predicting the resultant microbiome structure after an introduced change is difficult. This is due to the involvement of various factors that determine microbiome assembly and result in an increased complexity of microbial networks. Thus, a comprehensive analysis of critical factors that influence microbiome assembly in the rhizosphere will enable scientists to design intervention techniques to reshape the rhizosphere microbiome structure and functions systematically. In this review, we give highlights on fundamental concepts in soil suppressiveness and concisely explore studies on how plants monitor microbiome assembly and homeostasis. We then emphasize key factors that govern pathogen-suppressive microbiome assembly. We discuss how pathogen infection enhances plant immunity by employing a cry-for-help strategy and examine how domestication wipes out defensive genes in plants experiencing domestication syndrome. Additionally, we provide insights into how nutrient availability and pH determine pathogen suppression in the rhizosphere. We finally highlight up-to-date endeavors in rhizosphere microbiome manipulation to gain valuable insights into potential strategies by which microbiome structure could be reshaped to promote pathogen-suppressive soil development.