Combined Set Research Articles

Abstract 4060: Characterization of MDNA113, a tumor-targeting anti-PD1-IL-2SK immunocytokine with conditional activation to increase tolerability and maximize efficacy

Abstract Background-MDNA113 consists of an IL-13 decoy receptor-binding domain (MDNA213) fused to anti-PD1-IL-2SK (MDNA223) immunocytokine using a matrix metalloprotease (MMP) sensitive linker (PSL). MDNA213 is an IL-13 superkine with high selectivity towards IL-13Rα2, a tumor associated antigen overexpressed in numerous aggressive solid tumors with limited expression in normal tissues. IL-13Rα2 overexpression is associated with MMPs abundancy in tumor microenvironment (TME) and poor clinical outcomes. MDNA223, a fusion of ‘not-alpha, beta enhanced’ IL-2 superkine with anti-PD1 is designed to facilitate cis-binding to PD1 and IL-2Rβγ on CD8+ T cells. MDNA223 is superior to co-administration of anti-PD1 and IL-2 agonist at inhibiting both immunologically ‘hot’ and ‘cold’ tumors in mice. MDNA113 is designed to target and accumulate in tumors via the MDNA213 domain, which also attenuates immune stimulation by hindering IL-2R activation to reduce peripheral activity. The dual targeting/masking MDNA213 domain is released within tumor microenvironment following MMP cleavage of PSL to fully restore IL-2R agonism while maintaining PD1/PDL-1 blockade. Methods-In vitro signaling studies were performed in reporter cell assays and human PBMCs. Tolerability and pharmacodynamic studies were conducted in mice. Tumor growth inhibition was assessed in syngeneic mouse tumor models in monotherapy and combination settings. Results-MDNA113 showed reduced IL-2R agonism (~38-fold) while maintaining PD1/PD-L1 blockade compared to MDNA223 (non-masked) in cell-based reporter assays. Capacity to stimulate human PBMC proliferation was reduced while potency in CD8+ T cell p-STAT5 signaling also decreased. MMP cleavage of MDNA113 to release MDNA213 domain fully restored IL-2R signaling. Systemic delivery of MDNA113 to mice showed reduction, but not complete blockade, of lymphocyte expansion compared to equimolar dose of MDNA223. A 3x increase in MDNA113 restored lymphocyte expansion to a similar level achieved with MDNA223, indicating a ‘partial masking’ effect of MDNA213 domain. Accordingly, MDNA113 was better tolerated than MDNA223 in viability studies in mice. In syngeneic tumor models, equimolar treatment with MDNA113 and MDNA223 (non-mask version) resulted in similar extent of tumor growth inhibition. In contrast, in vivo activity was partially compromised when mice were treated with a non-cleavable version of MDNA113, consistent with a role for MMP-cleavage to restore full anti-tumor effect within TME. Conclusion-MDNA113 is a tumor-targeting and conditional-activatable anti-PD1/IL-2SK fusion characterized with potent PD1/PDL1 blockade and ‘not-alpha, beta enhanced’ IL-2R agonism. MDNA113 is better tolerated than the non-mask version while achieving similar effect on tumor control, therefore offering a much broader therapeutic index. Citation Format: Aanchal Sharma, Minh D. To, Qian Liu, Fahar Merchant. Characterization of MDNA113, a tumor-targeting anti-PD1-IL-2SK immunocytokine with conditional activation to increase tolerability and maximize efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4060.

Abstract 1230: MTX-531, a first-in-class pan-PI3K inhibitor spares hyperinsulinemia yielding durable tumor regressions and resilience to adaptive resistance

Abstract Adaptive resistance mechanisms compromise the long-term effectiveness of kinase-targeted agents dictating the need for strategic combination approaches. MTX-531 was computationally designed to selectively target both PI3K and wild type EGFR. MTX-531 exhibits low nanomolar potency against the PI3K isoform family and EGFR with a high degree of specificity predicted by co-crystal structural analyses. Full kinome screening confirmed that MTX-531 is exquisitely selective for its intended targets. We evaluated the pharmacological profile of MTX-531, whereupon single agent treatment with this lead molecule elicited a high incidence of durable tumor regressions in a broad panel of PIK3CA mutant CDX and PDX squamous head and neck (HNSCC) models. The combination of MTX-531 with RAS pathway inhibitors, including agents directed against KRAS G12C, led to durable regressions of KRAS mutant colorectal and pancreatic xenografts, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to hyperglycemia and hyperinsulinemia commonly seen with predecessor pan PI3K inhibitors. MTX-531 acts as an agonist of PPARγ, a structural feature of the molecule that is thought to mitigate hyperglycemia induced by PI3K inhibition. This unique attribute of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors. To the best of our knowledge, MTX-531 is the first reported pan-PI3K inhibitor that does not lead to hyperglycemia. The pharmaceutical profile of MTX-531 includes favorable cross-species oral bioavailability, microsomal stability, and a facile 3 step chemical synthesis. MTX-531, which has the unique capability of concurrently and selectively inhibiting PI3K and EGFR, illustrates the power of rational computational drug design to target multiple adaptive resistance mechanisms in a single molecule. The versatility of MTX-531 in both the single agent and combination settings offers a breadth of development strategies that continue to evolve as new combination candidates become available. MTX-531 is currently undergoing advanced preclinical development for anticipated first in human clinical trials in late 2024. Citation Format: Christopher E. Whitehead, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Rachel A. Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Michelle Norris, Scott Kopetz, Veera Baladandayuthapani, Melinda Hollingshead, Sharad Verma, Judith S. Sebolt-Leopold. MTX-531, a first-in-class pan-PI3K inhibitor spares hyperinsulinemia yielding durable tumor regressions and resilience to adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1230.

Abstract 2491: The Oxford Classic can identify HGSOC patients who may benefit from EMT-targeting therapies

Abstract Introduction: Despite development of novel targeted therapies such as PARP inhibitors and anti-angiogenic drugs, there is a clear lack of treatment options for High Grade Serous Ovarian Cancer (HGSOC) patients who are Homologous Recombination Repair proficient (50% of cases) and those with intrinsic resistance to these drugs. In this study we demonstrate the ability of the Oxford Classic (OxC)1,2, a non-genetic classifier, to identify HGSOC patients who may benefit from EMT targeting drugs. Methods: 139 HGSOC diagnostic tumor tissue (Brescia cohort) underwent RNA sequencing. Scottish cohort3 was used for external validation and TCGA, AOCS & OVCAD datasets were used for meta-analysis. Deconvolution of tumor RNAseq data, survival analyses, differential gene expression (DGE) analysis, gene pathway analyses in R and tumor immune profiling using CIBERSORT were performed. Results: Risk stratification of HGSOC using the Oxford Classic Patients with a higher OxC-EMT score had 3.6 times increased risk of death (95%CI: 1.6-8.0; p=2e-03) compared to patients with a lower OxC-EMT score by a multivariable cox regression analysis of Brescia cohort. By Kaplan-Meier survival analyses, a significant difference in overall survival in Brescia cohort (p=9e-06), Scottish cohort (p=2e-03) and a combined set of 1023 cases (p=1e-04), was observed between EMT-low risk patients (OxC-EMT score-0) and EMT-high risk patients (OxC-EMT score>0). Notably, 5-year median survival of EMT-low risk and EMT-high risk group was 50% and 13%, resp. (95%CI: 36.1%-69.3% vs 7.1%-23.5%) in Brescia cohort. Therapeutic options for OxC-EMT-high risk group DGE analysis of EMT-low patients and EMT-very high patients (OxC-EMT score>0.5) identified 404 differentially expressed genes common to the datasets. These included genes related to extracellular matrix organisation (VCAN, TGFβI), epithelial cell proliferation (RUNX2, FABP4, SERPINF1), cell chemotaxis (CCL19, DUSP1), angiogenic factors (VEGFC, CXCL12) and transmembrane kinase signalling pathways (TGFβ1/3, PDGFRα/β, IGFBP4/5/6, Wnt11). Of note, key EMT transcription factors, TWIST1/2, SNAI1/2, ZEB1/2, and stemness marker, ALDH1A3, were 2-7 times overexpressed in EMT-very high group. Furthermore, immune modulators, IL6 and IL10 were significantly upregulated and M2 macrophages were significantly more abundant in EMT-very high patients. Multiplex IHC is currently underway to confirm the abundance of TAMs and CD8-positive TRM in the two risk groups. Conclusions: 1) The Oxford Classic-based EMT is a robust prognostic biomarker of overall survival in HGSOC, that faithfully represents the complex circuitry of pathways which are a hallmark of Epithelial to Mesenchymal Transition. 2) OxC-EMT risk stratification can identify HGSOC patients who may benefit from EMT-targeting therapies. Reference: 1) Hu Z. Cancer Cell 2020 2) Hu Z. Clin Cancer Res 2021 3) Hollis R. Clin Cancer Res 2022 Citation Format: Lena Rai, Antonella Ravaggi, Eliana Bignotti, Robb Hollis, Joel Nulsen, Leticia Campo, Alistair Easton, Mara Artibani, Mike Churchman, Federico Ferrari, Christopher Yau, Charlie Gourley, Franco Odicino, Ahmed Ahmed. The Oxford Classic can identify HGSOC patients who may benefit from EMT-targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2491.

A novel mathematical model for predicting a sustainable selective laser melting and controlled densification

ABSTRACT We introduce the innovative concept of Sustainable Laser Energy Consumption (SLEC, ε) that promotes sustainable metal additive manufacturing practices while maintaining productivity and tailored densification in the Selective Laser Melting (SLM) process. This study focuses on deriving analytical expressions through dimensional analysis and Buckingham’s π theorem to predict bulk density with high precision across studied materials: In718, W, AlSi10Mg, Ti6Al4V, and SS316L. This approach provides valuable insights and allows the setting of an appropriate combination of scanning speed and hatch distance for a range of laser power, enabling sustainable manufacturing of SLMed components with tailored density. Furthermore, the mathematical expression introduced as SLEC facilitates the tradeoff between energy consumption and productivity, promoting a greener and more sustainable future of metal additive manufacturing. Furthermore, the underlying fractal nature of SLM is explored through the investigation of the influence of fractal structures, present in the powder bed, on densification that provides information on how powder morphology and homogeneity (i.e. fractal dimension and lacunarity) of the powder bed are linked to a sustainable SLM process.

Motor unit modes in the calf muscles during a submaximal isometric contraction are changed by brief stretches.

The purpose of our study was to investigate the influence of a stretch intervention on the common modulation of discharge rate among motor units in the calf muscles during a submaximal isometric contraction. The current report comprises a computational analysis of a motor unit dataset that we published previously (Mazzo etal., 2021). Motor unit activity was recorded from the three main plantar flexor muscles while participants performed an isometric contraction at 10% of the maximal voluntary contraction force before and after each of two interventions. The interventions were a control task (standing balance) and static stretching of the plantar flexor muscles. A factorization analysis on the smoothed discharge rates of the motor units from all three muscles yielded three modes that were independent of the individual muscles. The composition of the modes was not changed by the standing-balance task, whereas the stretching exercise reduced the average correlation in the second mode and increased it in the third mode. A centroid analysis on the correlation values showed that most motor units were associated with two or three modes, which were presumed to indicate shared synaptic inputs. The percentage of motor units adjacent to the seven centroids changed after both interventions: Control intervention, mode 1 decreased and the shared mode 1+2 increased; stretch intervention, shared modes either decreased (1+2) or increased (1+3). These findings indicate that the neuromuscular adjustments during both interventions were sufficient to change the motor unit modes when the same task was performed after each intervention. KEY POINTS: Based on covariation of the discharge rates of motor units in the calf muscles during a submaximal isometric contraction, factor analysis was used to assign the correlated discharge trains to three motor unit modes. The motor unit modes were determined from the combined set of all identified motor units across the three muscles before and after each participant performed a control and a stretch intervention. The composition of the motor unit modes changed after the stretching exercise, but not after the control task (standing balance). A centroid analysis on the distribution of correlation values found that most motor units were associated with a shared centroid and this distribution, presumably reflecting shared synaptic input, changed after both interventions. Our results demonstrate how the distribution of multiple common synaptic inputs to the motor neurons innervating the plantar flexor muscles changes after a brief series of stretches.

When one logic is not enough: Integrating first-order annotations in OWL ontologies

In ontology development, there is a gap between domain ontologies which mostly use the Web Ontology Language, OWL, and foundational ontologies written in first-order logic, FOL. To bridge this gap, we present Gavel, a tool that supports the development of heterogeneous ‘FOWL’ ontologies that extend OWL with FOL annotations, and is able to reason over the combined set of axioms. Since FOL annotations are stored in OWL annotations, FOWL ontologies remain compatible with the existing OWL infrastructure. We show that for the OWL domain ontology OBI, the stronger integration with its FOL top-level ontology BFO via our approach enables us to detect several inconsistencies. Furthermore, existing OWL ontologies can benefit from FOL annotations. We illustrate this with FOWL ontologies containing mereotopological axioms that enable additional, useful inferences. Finally, we show that even for large domain ontologies such as ChEBI, automatic reasoning with FOL annotations can be used to detect previously unnoticed errors in the classification.

Functional Implications of the Prosomeric Brain Model.

Brain models present a viewpoint on the fundamental structural components of the brain and their mutual organization, generally relative to a particular concept of the brain axis. A model may be based on adult brain structure or on developmental morphogenetic aspects. Brain models usually have functional implications, depending on which functional properties derive from the postulated organization. This essay examines the present scenario about brain models, emphasizing the contrast between columnar or other longitudinal models and transverse subdivisional neuromeric models. In each case, the main functional implications and apparent problems are explored and commented. Particular attention is given to the modern molecularly based 'prosomeric model', which postulates a set of 20 transverse prosomeres as the developmental units that serve to construct all the cerebral parts and the particular typology of many different neuronal populations within the forebrain and the hindbrain, plus a number of additional spinal cord units. These metameric developmental units (serially repeated, but with unique molecular profiles) confer to this model remarkable functional properties based mainly on its multiplicity and modularity. Many important brain functions can be decomposed into subfunctions attended to by combined sets of neuronal elements derived from different neuromeres. Each neuromere may participate in multiple functions. Most aspects related to creation of precise order in neural connections (axonal navigation and synaptogenesis) and function is due to the influence of neuromeric anteroposterior and dorsoventral positional information. Research on neuromeric functionality aspects is increasing significantly in recent times.

Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.

Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance. Using a training/validation study design, FUT2/FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay. In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2. Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

Improved empirical formula for spontaneous fission half-lives

The spontaneous fission (SF) half-lives of all 96 experimentally accessible SF emitters were examined. The SF emitters are classified as even Z-even A, odd Z-even A, odd Z-odd A and even Z-odd A. A plot of [Formula: see text] versus [Formula: see text] demonstrates a straight line, where k is variable. The [Formula: see text] values produced in this study are compared to all other semi-empirical relations such as Ren et al., [Nucl. Phys. A 759, 64 (2005)], Xu et al., [Phys. Rev. C 78, 044329 (2008)], Santhosh et al., [Nucl. Phys. A 832, 220 (2010)] and Karpov et al., [Int. J. Mod. Phys. E 21, 1250013 (2012)] available in the literature. When compared to earlier semi-empirical equations accessible in the literature, the new formula shows reduced uncertainty in standard deviation in the case of Odd Z-even A and even Z-Odd A nuclei. When compared to other sets of combinations (even Z-even A, and odd Z-odd A nuclei), this study more accurately reproduces the experimental SF half-lives for even Z-odd A and odd Z-even A nuclei with smaller [Formula: see text] in the atomic number range 9[Formula: see text]12 and mass number range 23[Formula: see text]84.

Measuring the Queen Bee Phenomenon in technically efficient firms: implications from Southeast Asian manufacturers

This study examines the “Queen Bee Phenomenon,” that is, Southeast Asian manufacturers having female CEOs and owners. In addition, the buffering effect of female CEOs and owners on manufacturers seeking higher technical efficiencies is also examined in this research. This study uses the fractional regression and two-limit Tobit regression models to examine a combined set of cross-sectional data from surveys conducted by the World Bank, consisting of 3471 manufacturers in Southeast Asia, including those in Thailand, the Philippines, Indonesia, Malaysia, and Vietnam. Our results find that the “Queen Bee Phenomenon” does not exist in Southeast Asian manufacturing enterprises. Furthermore, manufacturers with higher technical efficiency levels are likely to hire fewer female workers; nevertheless, if female CEOs and owners run these technically efficient firms, hiring more female workers can be noticed. This research demonstrates that globalization through FDI and exports may promote female labor force participation among Southeast Asian enterprises and those seeking greater technical efficiencies.

Multicomponent (bio)markers for obesity risk prediction: a scoping review protocol

IntroductionDespite international efforts, the number of individuals struggling with obesity is still increasing. An important aspect of obesity prevention relates to identifying individuals at risk at early stage, allowing for...

Experimental Investigation of the Surface Roughness for Aluminum Alloy AA6061 in Milling Operation by Taguchi Method with the ANOVA Technique

The surface roughness of the machined parts is the most important parameter to predict the performance of mechanical components. Moreover, predicting the optimal machining parameters conditions is the preferable method for cost reduction and achieving the desired surface quality of the product. This study investigates three cutting parameters, such as depth of cut, spindle speed, and feed for the milling aluminium alloy AA6061, to predict the surface roughness quality. The experimental work utilized a manual milling machine with a coated carbide cutter. Furthermore, the experiments were arranged using the Taguchi L9 orthogonal array (OA) method. The average surface roughness (Ra) was measured and converted to signal-to-noise (S/N) ratio and then analyzed in the statistical method of analysis of variance (ANOVA). Finally, the optimal combination set speed, feed, and depth of cut was 2400 rpm, 30 mm/min, and 0.5 mm, respectively. Also, according to the ANOVA test, the most influential parameter was the spindle speed among the selected parameters, with the highest P value of (66.42%). In comparison, the lowest P value is a depth of cut (5.34%). Furthermore, spindle speed was the only significant factor statistically. By selecting a high spindle speed (2400 rpm), surface quality was enhanced, but the preferable level was low for depth of cut and feed.

Teak (Tectona grandis Linn. f) and Edaphic Factors Affecting the Regeneration of Woody Species and Their Functional Traits in Economic Forest Plantation, Northern Thailand

Improved understanding of relationships among plant traits, stand characteristics, and soil properties can provide insights into the regenerating tree communities of commercial teak plantations. We investigated whether plant traits could be used to predict the natural regeneration of woody species in teak plantations with different soil and stand conditions. Data were collected in fifty 20 m × 20 m plots that were established in teak plantations of varying ages in northern Thailand. We analyzed differences in stand characteristics, soil properties, and community-level functional traits among sites. The RLQ analysis was performed to explore the associations among species abundances, plant traits, and a combined set of soil variables and stand characteristics. Our results showed that tree species with high leaf dry matter contents and high wood density dominated communities in an older teak plantation and were associated with high OM and N concentrations. Trees with larger leaves are increased in plantations that had experienced their first teak thinning, and were rich in organic matter. Species with high specific leaf areas increased in sites with high teak basal areas and which had experienced more intense thinning on fertile soils. Thick-leaved species had high importance values on sites with high densities of teak and infertile soils. Our results indicated that tree communities with similar conspecific traits were associated with specific soil and stand conditions in teak plantations. A knowledge of these regeneration dynamics may allow forest managers to encourage increased natural regeneration and enhanced diversity in commercial teak plantations.

Investigating the readability of test code

ContextThe readability of source code is key for understanding and maintaining software systems and tests. Although several studies investigate the readability of source code, there is limited research specifically on the readability of test code and related influence factors.ObjectiveIn this paper, we aim at investigating the factors that influence the readability of test code from an academic perspective based on scientific literature sources and complemented by practical views, as discussed in grey literature.MethodsFirst, we perform a Systematic Mapping Study (SMS) with a focus on scientific literature. Second, we extend this study by reviewing grey literature sources for practical aspects on test code readability and understandability. Finally, we conduct a controlled experiment on the readability of a selected set of test cases to collect additional knowledge on influence factors discussed in practice.ResultsThe result set of the SMS includes 19 primary studies from the scientific literature for further analysis. The grey literature search reveals 62 sources for information on test code readability. Based on an analysis of these sources, we identified a combined set of 14 factors that influence the readability of test code. 7 of these factors were found in scientific and grey literature, while some factors were mainly discussed in academia (2) or industry (5) with only limited overlap. The controlled experiment on practically relevant influence factors showed that the investigated factors have a significant impact on readability for half of the selected test cases.ConclusionOur review of scientific and grey literature showed that test code readability is of interest for academia and industry with a consensus on key influence factors. However, we also found factors only discussed by practitioners. For some of these factors we were able to confirm an impact on readability in a first experiment. Therefore, we see the need to bring together academic and industry viewpoints to achieve a common view on the readability of software test code.

Comparative quantitative trait loci analysis framework reveals relationships between salt stress responsive phenotypes and pathways.

Soil salinity is a complex abiotic stress that involves several biological pathways. Hence, focusing on a specific or a few salt-tolerant phenotypes is unlikely to provide comprehensive insights into the intricate and interwinding mechanisms that regulate salt responsiveness. In this study, we develop a heuristic framework for systematically integrating and comprehensively evaluating quantitative trait loci (QTL) analyses from multiple stress-related traits obtained by different studies. Making use of a combined set of 46 salinity-related traits from three independent studies that were based on the same chromosome segment substitution line (CSSL) population of rice (Oryza sativa), we demonstrate how our approach can address technical biases and limitations from different QTL studies and calling methods. This allows us to compile a comprehensive list of trait-specific and multi-trait QTLs, as well as salinity-related candidate genes. In doing so, we discover several novel relationships between traits that demonstrate similar trends of phenotype scores across the CSSLs, as well as the similarities between genomic locations that the traits were mapped to. Finally, we experimentally validate our findings by expression analyses and functional validations of several selected candidate genes from multiple pathways in rice and Arabidopsis orthologous genes, including OsKS7 (ENT-KAURENE SYNTHASE 7), OsNUC1 (NUCLEOLIN 1) and OsFRO1 (FERRIC REDUCTASE OXIDASE 1) to name a few. This work not only introduces a novel approach for conducting comparative analyses of multiple QTLs, but also provides a list of candidate genes and testable hypotheses for salinity-related mechanisms across several biological pathways.

Studying the adsorption of emerging organic contaminants in zeolites with dispersion-corrected density functional theory calculations: From numbers to recommendations.

Adsorption energies obtained from dispersion-corrected density functional theory (DFT) calculations show a considerable dependence on the choice of exchange-correlation functional and dispersion correction. A number of investigations have employed different approaches to compute adsorption energies of small molecules in zeolites, using reference values from high-level calculations and/or experiments. Such comparative studies are lacking for larger functional organic molecules such as pharmaceuticals or personal care products, despite their potential relevance for applications, e. g., in contaminant removal or drug delivery. The present study aims to fill this gap by comparing adsorption energies and, for selected cases, equilibrium structures of emerging organic contaminants adsorbed in MOR- and FAU-type all-silica zeolites. A total of 13 dispersion-corrected DFT approaches are compared, including methods using a pairwise dispersion correction as well as non-local van der Waals density functionals. While absolute values of adsorption energies vary widely, qualitative trends across the set of zeolite-guest combinations are not strongly dependent on the choice of functional. For selected cluster models, DFT adsorption energies are compared to reference values from coupled cluster (DLPNO-CCSD(T)) calculations. Although all DFT approaches deliver systematically more negative adsorption energies than the coupled cluster reference, this tendency is least pronounced for the rev-vdW-DF2 functional.

A Weighted multi-objective evolutionary algorithm optimization

Weight Based Genetic Algorithms (WBGA) have a computational efficacy and non-cumbersome for multi-objective optimization. The solutions obtained in the converged region do not always produce maximum optimization for all the objective functions simultaneously. But, the combination of the solutions from different iteration may yield optimized values for all the objective functions to a satisfactory level. The paper attempts to find a method which keeps the simplicity and computational efficiency of WBGA intact, but at the same time counters the problem of inferior pareto-optimal solutions. This is done by finding such a combinational set of solutions which yields strong values for all the objectives. The paper proposes neutrosophic logic (NL) as a postprocessor to the outcome of the WBGA. The NL assigns a percentage of truth, false and indeterminant value to the obtained solutions. The proposed postprocessor operation has been demonstrated with hand calculations on a test problem, and a complex practical example. The results obtained as compared to WBGA show the emergence of a superior solution-set and reaches in close agreement with NSGA-II, while maintaining the computational efficiency.

Suberin deficiency and its effect on the transport physiology of young poplar roots.

The precise functions of suberized apoplastic barriers in root water and nutrient transport physiology have not fully been elucidated. While lots of research has been performed with mutants of Arabidopsis, little to no data are available for mutants of agricultural crop or tree species. By employing a combined set of physiological, histochemical, analytical, and transport physiological methods as well as RNA-sequencing, this study investigated the implications of remarkable CRISPR/Cas9-induced suberization defects in young roots of the economically important gray poplar. While barely affecting overall plant development, contrary to literature-based expectations significant root suberin reductions of up to 80-95% in four independent mutants were shown to not evidently affect the root hydraulic conductivity during non-stress conditions. In addition, subliminal iron deficiency symptoms and increased translocation of a photosynthesis inhibitor as well as NaCl highlight the involvement of suberin in nutrient transport physiology. The multifaceted nature of the root hydraulic conductivity does not allow drawing simplified conclusions such as that the suberin amount must always be correlated with the water transport properties of roots. However, the decreased masking of plasma membrane surface area could facilitate the uptake but also leakage of beneficial and harmful solutes.

Evaluating vegetation vulnerability under compound dry and hot conditions using vine copula across global lands

With global warming, climate extremes are intensifying, particularly compound dry and hot events (CDHEs), which would severely impact vegetation growth. However, quantitatively evaluating vegetation vulnerability to CDHEs remains challenging in global lands. A conditional probability model was constructed using the vine copula function to evaluate responses of vegetation to CDHEs based on the Standardized Moisture Anomaly Index (SZI), the Standardized Temperature Index (STI), and the kernel Normalized Difference Vegetation Index (kNDVI). The results show that vegetation growth is more susceptible to dry and hot conditions in arid and semi-arid regions than in sub-humid and humid regions. In terms of vegetation types, shrubs, savanna, grass, and crops are more susceptible to CDHEs than to individual dry or hot events, especially in water-limited regions. In arid regions, the vegetation vulnerability for open shrubs, closed shrubs, savanna, and grass under extreme CDHEs would correspondingly increase by 45%, 23%, 15%, and 12% compared with dry conditions, indicating the necessity to consider both dry and hot conditions simultaneously when evaluating vegetation dynamics to climatic extremes. In semi-arid and sub-humid regions, broadleaf forests show higher vulnerability to CDHEs than needleleaf forests. However, evergreen broadleaf forests show the lowest vulnerability and higher resistance to CDHEs in humid regions. The Analysis of Variance (ANOVA)-based uncertainty decomposition results show that copula combination sets in vine copula trees and vine copula structures are the two main uncertainty sources, accounting for about 60%. Despite with uncertainty, the modeling results show consistent vegetation loss probability patterns simulated with different structures of the vine copula model, indicating the robustness and reliability of the results. The findings provide a profound comprehension of ecosystems’ response mechanisms to compound extremes, which are essential to developing effective mitigation and adaptation strategies against the impact of future climate change.

A Methodology for Rating Electricity Transmission Lines to Assess the Most Important or Critical Lines

The proposed method, based on three combined criteria—Sn—design capacity of the power line, LF, (line flow)—power flow in an electric transmission line, MVA, and the ratio of LF/Sn—allows for ranking electric transmission lines when calculations are performed in normal/pre-emergency modes. A combined set of criteria used to study critical/post-emergency N-k modes is developed. The simulations were performed on the real Baltic 330 kV electricity transmission system. The results reveal that when the power system operates in different load modes, most of the critical power lines determined by our method fall into the actual set of important/“critical” power transmission lines. This allows us to significantly reduce the number of simulated combinations and shorten the calculation time required for it. During the study of the Baltic electricity system, it was found that the developed method was accurate and efficient and suitable for the assessment of the reliability of real electricity transmission networks when planning operational and perspective work modes. The simulations results revealed the high reliability of the Baltic electricity system. The 330 kV electricity transmission network of the Baltic countries fully meets the N-2 criterion (usually, electricity transmission networks are designed to meet the N-1 criterion).