Children consider informants' explanation quality with their social dominance in seeking novel explanations.

Identifying high-quality causal explanations is key to scientific understanding. This research (N = 202; 50% girls; Mage: 5.82 years; 64% Asian, 33% White, and 3% multiracial; data collected from 2018 to 2024) examined how explanation circularity and informants' social dominance impact children's learning preferences for causal explanations. Raised in a culture valuing circular logic, Chinese children still preferred non-circular explanations and learning from informants providing non-circular explanations (d ≥ 0.50). When informants with non-circular explanations were subordinate to those with circular explanations, Chinese and American children preferred non-circular over circular explanations (d = 1.10), but did not prefer learning new information from either informant. Although children weigh explanation quality over informant dominance when seeking explanations for given questions, they consider both cues when evaluating informants' credibility.

Miraculous, magical, or mundane? The development of beliefs about stories with divine, magical, or realistic causation.

Children's naïve theories about causal regularities enable them to differentiate factual narratives describing real events and characters from fictional narratives describing made-up events and characters (Corriveau, Kim, Schwalen, & Harris, Cognition 113 (2): 213-225, 2009). But what happens when children are consistently presented with accounts of miraculous and causally impossible events as real occurrences? Previous research has shown that preschoolers with consistent exposure to religious teaching tend to systematically judge characters involved in fantastical or religious events as real (Corriveau et al., Cognitive Science, 39 (2), 353-382, 2015; Davoodi et al., Developmental Psychology, 52 (2), 221, 2016). In the current study, we extended this line of work by asking about the scope of the impact of religious exposure on children's reality judgments. Specifically, we asked whether this effect is  domain-general or domain-specific. We tested children in Iran, where regular exposure to uniform religious beliefs might influence children's reasoning about possibility in non-religious domains, in addition to the domain of religion. Children with no or minimal schooling (5- to 6-year-olds) and older elementary school students (9- to 10-year-olds) judged the reality status of different kinds of stories, notably realistic, unusual (but nonetheless realistic), religious, and magical stories. We found that while younger children were not systematic in their judgments, older children often judged religious stories as real but rarely judged magical stories as real. This developmental pattern suggests that the impact of religious exposure on children's reality judgments does not extend beyond their reasoning about divine intervention. Children's justifications for their reality judgments provided further support for this domain-specific influence of religious teaching.

Concentrations, seasonal trends, sources, health risk and subchronic toxicity to the respiratory and immune system of PAHs in PM2.5 in Xi'an.

PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) have been proved to be hazardous to health. Previous studies have focused on the distribution and sources of PAHs, whereas there is little knowledge of the damage to organs. Here we sought to investigate the pollution level and seasonal variation characteristics of PAHs in PM2.5 in Xi'an and assess the health risk, to establish a PAHs exposure model, and investigate the toxicological effects of PAHs on the respiratory and immune functions. A sub-chronic exposure model of PAHs was established by inhalation. The pathological changes of lung tissues were observed with a light microscope. Inflammatory reactions in alveolar lavage fluid were determined using the corresponding kit. The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) were detected with enzyme linked immunosorbent assay (ELISA) kit; the proliferation of lymphocytes in spleen was detected with methyl tetrazolium (MTT); DNA immune damage was determined with DNA gel electrophoresis. The results showed that (1) the total concentration of 16 PAHs ranged from 41.1 to 387 ng/m3, with a mean value of 170 ng/m3, and the concentration of PAHs in PM2.5 was higher in winter than in other seasons. (2) The sources of PAHs in the atmosphere of Xi'an urban area were mainly coal combustion, and the equivalent carcinogenic concentration of PAHs in PM2.5 was 3.9 ng/m3. (3) Foreign body granuloma formation and inflammatory cell damage were observed in the lungs of rats infected with toxin; the levels of reactive oxygen species (ROS) and mobile device assistant (MDA) increased while nitric oxide synthase (NOS) decreased with the increase of dose; the expression levels of IL-6 and IL-8 elevated with the increase of toxin dose, showing an obvious dose-effect relationship; the level of PAHs damage to cells showed a dose-effect relationship. Sub-chronic exposure to PAHs could cause sustained inflammatory injury to the organism. Measures should be taken to counter the problems of PAHs in PM2.5 in Xi'an and relevant health promotion strategies should be developed.

Melatonin prevents diabetes-associated cognitive dysfunction from microglia-mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway.

Cognitive dysfunction often occurs in diabetes mellitus patients. This study aimed to investigate the efficacy of melatonin (MLT) in improving diabetes-associated cognitive decline and the underlying mechanism involved. Type 2 diabetic mice and palmitic acid (PA)-stimulated BV-2 cells were treated by MLT, and the potential mechanisms among MLT, cognition, and autophagy were explored. The results showed that type 2 diabetic mice showed obvious learning and memory impairments in the Morris water maze test compared with normal controls, which could be ameliorated by MLT treatment. Meanwhile, MLT administration significantly improved neuroinflammation and regulated microglial apoptosis. Furthermore, autophagy inhibitor 3-methyladenine (3-MA) increased the microglial inflammation and apoptosis, indicating that the treatment effect of MLT was mediated by autophagy. Lastly, MLT treatment significantly decreased the levels of toll-like receptors 4 (TLR4), phosphorylated-protein kinase B (Akt), and phosphorylated-mechanistic target of rapamycin (mTOR), indicating that blocking TLR4/Akt/mTOR pathway might be an underlying basis for the anti-inflammatory and anti-apoptosis effects of MLT. Collectively, our study suggested that MLT could improve learning and memory in type 2 diabetic mice by activating autophagy via the TLR4/Akt/mTOR pathway, thereby inhibiting neuroinflammation and microglial apoptosis.

Association between mixed dietary B vitamin intake and insulin resistance in US middle-aged and older adults without diabetes: The Bayesian kernel machine regression approach.

BACKGROUND AND OBJECTIVES: In daily life, the intake of dietary nutrients is mixed. However, evidence for the association between mixed dietary B vitamin intake and insulin resistance is limited. In this study, we estimated the joint effect of intake of various dietary B vitamins on insulin resistance. METHODS AND STUDY DESIGN: This cross-sectional study used data from the National Health and Nutrition Examination Survey 2011-2018. We included 1,628 middle-aged and 1,058 older adults without diabetes. Multivariable logistic regression and Bayesian kernel machine regression models were constructed. RESULTS: In the multivariable logistic regression, when all B vitamins were included in the model, the ORs (95% CIs) of insulin resistance were 3.06 (1.00-9.37) and 0.42 (0.19- 0.93) for the highest quartile of vitamin B-1 and B-12 intake in the middle-aged group when the lowest quartile was the reference. In the older group, no significant association was observed. In the Bayesian kernel machine regression analysis, a negative trend was noted between mixed B vitamin intake and insulin resistance in both examined groups. The univariate exposure-response function indicated that vitamin B-12 intake was negatively associated with insulin resistance in the middle-aged group, and that vitamin B-6 and dietary folate equivalent intakes were negatively associated with insulin resistance in older group. The bivariate exposure-response function indicated a potential interaction effect between dietary intake of vitamin B-12 and those of vitamin B-1, B-2, niacin, and dietary folate equivalent on insulin resistance in older people. CONCLUSIONS: Our results suggest that mixed dietary B vitamin intake tends to decrease the OR of insulin resistance both in middle-aged and older people.

Mesenchymal stem cell-conditioned medium improved mitochondrial function and alleviated inflammation and apoptosis in non-alcoholic fatty liver disease by regulating SIRT1.

Non-alcoholic fatty liver disease (NAFLD), an emerging risk factor for diabetes, is now recognized as the most common liver disease worldwide. Mesenchymal stem cells (MSCs), a promising tool in regenerative medicine, release abundant molecules into the conditioned medium (CM). Increasing evidence showed that MSC-CM is beneficial for diabetes-associated NAFLD. However, the mechanism of how MSC-CM improves NAFLD remains uncertain. In this study, to determine the effects of MSC-CM on NAFLD, streptozotocin (STZ) and high-fat diet (HFD) induced T2DM mice model and palmitic acid (PA)-stimulated L-O2 cells were used and treated with MSC-CM. Our results demonstrated that MSC-CM improved insulin resistance in diabetic mice, amended the pathological structure of the liver, enhanced the liver's total antioxidant capacity and mitochondrial function, reduced inflammation and cell apoptosis. We further verified that SIRT1 played a key role in mediating the protective effect of MSC-CM. These findings provide novel evidence that MSC-CM has the potential to treat T2DM patients with NAFLD clinically.

Combining quantitative trait locus and co-expression analysis allowed identification of new candidates for oil accumulation in rapeseed.

In crops there are quantitative trait loci (QTLs) in which some of the causal quantitative trait genes (QTGs) have not been functionally characterized even in the model plant Arabidopsis. We propose an approach to delineate QTGs in rapeseed by coordinating expression of genes located within QTLs and known orthologs related to traits from Arabidopsis. Using this method in developing siliques 15 d after pollination in 71 lines of rapeseed, we established an acyl-lipid metabolism co-expression network with 21 modules composed of 270 known acyl-lipid genes and 3503 new genes. The core module harbored 76 known genes involved in fatty acid and triacylglycerol biosynthesis and 671 new genes involved in sucrose transport, carbon metabolism, amino acid metabolism, seed storage protein processes, seed maturation, and phytohormone metabolism. Moreover, the core module closely associated with the modules of photosynthesis and carbon metabolism. From the co-expression network, we selected 12 hub genes to identify their putative Arabidopsis orthologs. These putative orthologs were functionally analysed using Arabidopsis knockout and overexpression lines. Four knockout mutants exhibited lower seed oil content, while the seed oil content in 10 overexpression lines was significantly increased. Therefore, combining gene co-expression network analysis and QTL mapping, this study provides new insights into the detection of QTGs and into acyl-lipid metabolism in rapeseed.

Both overlapping and independent loci underlie seed number per pod and seed weight in Brassica napus by comparative quantitative trait loci analysis.

Seed number per pod (SNPP) and seed weight (SW) are two components of seed yield in rapeseed (Brassica napus). Here, a natural population of rapeseed was employed for genome-wide association analysis for SNPP and SW across multi-years. A total of 101 and 77 SNPs significantly associated with SNPP and SW with the phenotypic variances (R2) ranging from 1.35 to 29.47% and from 0.78 to 34.58%, respectively. And 43 and 33 homologs of known genes from model plants were located in the 65 and 49 haplotype blocks (HBs) for SNPP and SW, respectively. Notably, we found 5 overlapping loci and 3 sets of loci with collinearity for both SNPP and SW, of which 4 overlapping loci harbored the haplotypes with the same direction of genetic effects on SNPP and SW, indicating high possibility to simultaneously improve SNPP and SW in rapeseed. Our findings revealed both overlapping and independent loci controlling seed number per pod and seed weight in rapeseed. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01232-1.

Correction to: Both overlapping and independent loci underlie seed number per pod and seed weight in Brassica napus by comparative quantitative trait loci analysis.

[This corrects the article DOI: 10.1007/s11032-021-01232-1.].

GWAS and co-expression network combination uncovers multigenes with close linkage effects on the oleic acid content accumulation in Brassica napus.

BACKGROUND: Strong artificial and natural selection causes the formation of highly conserved haplotypes that harbor agronomically important genes. GWAS combination with haplotype analysis has evolved as an effective method to dissect the genetic architecture of complex traits in crop species. RESULTS: We used the 60 K Brassica Infinium SNP array to perform a genome-wide analysis of haplotype blocks associated with oleic acid (C18:1) in rapeseed. Six haplotype regions were identified as significantly associated with oleic acid (C18:1) that mapped to chromosomes A02, A07, A08, C01, C02, and C03. Additionally, whole-genome sequencing of 50 rapeseed accessions revealed three genes (BnmtACP2-A02, BnABCI13-A02 and BnECI1-A02) in the A02 chromosome haplotype region and two genes (BnFAD8-C02 and BnSDP1-C02) in the C02 chromosome haplotype region that were closely linked to oleic acid content phenotypic variation. Moreover, the co-expression network analysis uncovered candidate genes from these two different haplotype regions with potential regulatory interrelationships with oleic acid content accumulation. CONCLUSIONS: Our results suggest that several candidate genes are closely linked, which provides us with an opportunity to develop functional haplotype markers for the improvement of the oleic acid content in rapeseed.

A Self-Assembled ATP Probe for Melanoma Cell Imaging.

In this investigation, a new terpyridine metal complex was developed as a probe for selective detection of ATP and imaging of melanoma cells. The probe takes advantage of the ability of the metal complex to be transformed to its imaging competent turn-on state through assembly with ATP.

Serum Levels of Meteorin-Like (Metrnl) Are Increased in Patients with Newly Diagnosed Type 2 Diabetes Mellitus and Are Associated with Insulin Resistance.

BACKGROUND Meteorin-like (Metrnl) is a novel adipomyokine that may improve glucose tolerance and affect insulin resistance. This study aimed to investigate the association between serum levels of Metrnl with blood glucose status and to its association with insulin resistance. MATERIAL AND METHODS The study included 160 subjects with normal glucose tolerance (NGT) (n=40), impaired fasting glucose (IFG) (n=40), impaired glucose tolerance (IGT) (n=40), and newly diagnosed type 2 diabetes mellitus (T2DM) (n=40). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of Metrnl. Partial correlation analysis was used to analyze the relationship between serum levels of Metrnl and metabolic parameters. Multiple logistic regression analysis was performed to identify the association between serum levels of Metrnl with the risk of diabetes. RESULTS Serum levels of Metrnl was highest in patients with T2DM and significantly increased in patients with prediabetes compared with individuals with NGT. After adjusting for age, gender, and body mass index (BMI), serum Metrnl level was significantly correlated with lipid profile, glucose profile, and insulin resistance. Multiple logistic regression analysis showed that Metrnl significantly increased the risk of T2DM (OR=1.727; P=0.008) before adjusting for the homeostatic model assessment of insulin resistance (HOMA-IR). When further adjusted for HOMA-IR, Metrnl was no longer associated with an increased OR for T2DM (OR=1.491; P=0.066), while the HOMA-IR significantly increased the risk of T2DM (OR=1.935; P=0.008). CONCLUSIONS Serum levels of Metrnl were significantly increased in patients with T2DM and may increase the risk of T2DM independent of insulin resistance.

The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between?

The depression incidence is much higher in patients with diabetes mellitus (DM), and the majority of these cases remain under-diagnosed. Type 1 diabetes mellitus (T1D) is now widely thought to be an organ-specific autoimmune disease. As a chronic autoimmune condition, T1D is characterized by T cell-mediated selective loss of insulin-producing ß-cells. The age of onset of T1D is earlier than T2D, and T1D patients have an increased vulnerability to depression due to its diagnosis and treatment burden occurring in a period when the individuals are young. The literature has suggested that inflammatory cytokines play a wide role in both diseases. In this review, the mechanisms behind the initiation and propagation of the autoimmune response in T1D and depression are analyzed, and the contribution of cytokines to both conditions is discussed. This review outlines the immunological mechanism of T1D and depression, with a particular emphasis on the role of tumor necrosis factor-α (TNF-α), IL-1ß, and interferon-γ (IFN-γ) cytokines and their signaling pathways. The purpose of this review is to highlight the possible pathways of the cytokines shared by these two diseases via deciphering their cytokine cascades. They may provide a basic groundwork for future study of the possible mechanism that links these two diseases and to develop new compounds that target the same pathway but can conquer two diseases.

Phosphorus removal and recovery from fosfomycin pharmaceutical wastewater by the induced crystallization process.

The excessive release of phosphorus is a main cause of eutrophication, but phosphorus itself is an important non-renewable resource. If phosphorus could be recovered from wastewater, it can not only reduce the pollution, but also reach the aim of resource recycle. An induced crystallization process was combined with the schorl/H2O2 system to remove and recover phosphorus from the fosfomycin pharmaceutical wastewater. Firstly, in the schorl/H2O2 heterogeneous Fenton system, the organic phosphorus (OP) in fosfomycin pharmaceutical wastewater was transformed to the inorganic phosphorus (IP), and then IP was recovered by hydroxyapatite (HAP) induced crystallization process. In sequence batch reactors (SBR), the entire crystallization process went through 60 cycles, and each of the cycle lasted for 12 h, including 2 h for reaction and 10 h for sedimentation. The influence of different initial pH values, which were 8, 9, 10 and 11, on the induced crystallized product was investigated. The morphology and structure of the induced crystallized product were analysed. The results indicated that when the pH value was about 8, most of the recovery products was in the form of dicalcium phosphate anhydrous (DCP, CaHPO4). At pH 9 the recovery products were mainly DCP and HAP. As pH increased to 10 or 11, most of the recovery products would be HAP and calcium carbonate. Carbonate involved in the crystallization reaction, especially at pH 11.

Genome-wide identification of loci affecting seed glucosinolate contents in Brassica napus L.

Glucosinolates are amino acid-derived secondary metabolites that act as chemical defense agents against pests. However, the presence of high levels of glucosinolates severely diminishes the nutritional value of seed meals made from rapeseed (Brassica napus L.). To identify the loci affecting seed glucosinolate content (SGC), we conducted genome-wide resequencing in a population of 307 diverse B. napus accessions from the three B. napus ecotype groups, namely, spring, winter, and semi-winter. These resequencing data were used for a genome-wide association study (GWAS) to identify the loci affecting SGC. In the three ecotype groups, four common and four ecotype-specific haplotype blocks (HBs) were significantly associated with SGC. To identify candidate genes controlling SGC, transcriptome analysis was carried out in 36 accessions showing extreme SGC values. Analyses of haplotypes, genomic variation, and candidate gene expression pointed to five and three candidate genes in the common and spring group-specific HBs, respectively. Our expression analyses demonstrated that additive effects of the three candidate genes in the spring group-specific HB play important roles in the SGC of B. napus.

Genetic characterization and fine mapping for multi-inflorescence in Brassica napus L.

KEY MESSAGE: A major QTL for multi-inflorescence was mapped to a 27.18-kb region on A05 in Brassica napus by integrating QTL mapping, microarray analysis and whole-genome sequencing. Multi-inflorescence is a desirable trait for the genetic improvement of rapeseed (Brassica napus L.). However, the genetic mechanism underlying the multi-inflorescence trait is not well understood. In the present study, a doubled haploid (DH) population derived from a cross between single- and multi-inflorescence lines was investigated for the penetrance of multi-inflorescence across 3 years and genotyped with 257 simple sequence repeat and sequence-related amplified polymorphism loci. A major quantitative trait locus (QTL) for penetrance of multi-inflorescence was mapped to a 9.31-Mb region on chromosome A05, explaining 45.81% of phenotypic variance on average. Subsequently, 13 single-inflorescence and 15 multi-inflorescence DH lines were genotyped with the Brassica microarray, and the QTL interval of multi-inflorescence was narrowed to a 0.74-Mb region with 37 successive single nucleotide polymorphisms between single- and multi-inflorescence groups. A 27.18-kb QTL interval was detected by screening 420 recessive F2 individuals with genome-specific markers. These results will be valuable for gene cloning and molecular breeding of multi-inflorescence in rapeseed.

A genome-wide survey with different rapeseed ecotypes uncovers footprints of domestication and breeding.

Rapeseed (Brassica napus L.) is an important oilseed crop. Despite a short period of domestication and breeding, rapeseed has formed three diverse ecotype groups, namely spring, winter, and semi-winter. However, the genetic changes among the three ecotype groups have remained largely unknown. To detect selective signals, a set of 327 accessions from a worldwide collection were genotyped using a Brassica array, producing 33 186 high-quality single nucleotide polymorphisms (SNPs). Linkage disequilibrium (LD) was unevenly distributed across the genome. A total of 705 (78.2%) weak LD regions were found in the A subgenome, whereas 445 (72.6%) strong LD regions were in the C subgenome. By calculating the nucleotide diversity and population differentiation indices, a total of 198 selective sweeps were identified across ecotype groups, spanning 5.91% (37.9 Mb) of the genome. Within these genome regions, a few known functional genes or loci were found to be in association with environmental adaptability and yield-related traits. In particular, all 12 SNPs detected in significant association with flowering time among accessions were in the selection regions between ecotype groups. These findings provide new insights into the structure of the B. napus genome and uncover the footprints of domestication and breeding.

Involvement of TLRs/NF-κB/ESE-1 signaling pathway in T-2 toxin-induced cartilage matrix degradation.

T-2 toxin, a highly toxic type A monotrichothecene mycotoxin, has been found in many different types of cereals and is considered to be one of the most dangerous naturally occurring forms of food contamination. Globally, consuming grain-based food tainted with T-2 toxin poses significant risks to animal and human health. Prior research has indicated that the presence of T-2 toxin may lead to the demise of chondrocytes and the deterioration of the extracellular matrix of cartilage in degenerative bone and joint conditions, such as Kashin-Beck disease. However, the mechanisms by which T-2 toxin exerts its biological toxicity on the degradation of the extracellular matrix in cartilage are not well understood. In the current study, we found original results that demonstrate an upregulation of Toll-Like Receptors (TLR-2, TLR-4) and ESE-1 expression levels in the articular cartilage of a rat model subjected to T-2 toxin exposure. Furthermore, it was revealed that the exposure to T-2 toxin resulted in an increase in the expression of TLR-2, TLR-4, and ESE-1 in human C28/I2 chondrocytes. The findings of this study indicate that the increased expression of TLR-2, TLR-4, and ESE-1 may contribute to the development of degenerative osteoarthritic disease caused by T-2 toxin. Consistent with our hypotheses, we discovered that T-2 toxin increased the expression of MMP-1 and MMP-13 in human C28/I2 chondrocytes. We used a luciferase reporter gene assay to measure the activity of the ESE-1 promoter and transfected cells with plasmids encoding TLR-2 and TLR-4 to investigate their effects on this activity. TLR-2 and TLR-4 can activate ESE-1 transcriptional gene expression, and this expression is mediated through the NF-κB pathway, additional evidence is provided for the participation of the TLRs/NF-κB/ESE-1 signaling pathway in T-2 toxin-induced cartilage matrix degradation. Together, the findings indicated that the TLRs/NF-κB/ESE-1 signaling pathway played an essential part in T-2 toxin-induced cartilage matrix degradation.

Low expression of selenoprotein S induces oxidative damage in cartilages.

Low levels of the indispensable trace element selenium (Se) can cause oxidative stress and disrupt environmental homeostasis in humans and animals. Selenoprotein S (Selenos), of which Se is a key component, is a member of the selenoprotein family involved in various biological processes. This study aimed to investigate whether low-level SELENOS gene expression can induce oxidative stress and decrease the antioxidative capacity of chondrocytes. Compared with control cells, SELENOS-knockdown ATDC5 cells showed substantially higher dihydroethidium, reactive oxygen species and malondialdehyde levels, and lower superoxide dismutase (SOD) expression. Knockout of the gene in C57BL/6 mice increased the 8-hydroxy-2-deoxyguanosine level considerably and decreased SOD expression in cartilages relative to the levels in wild-type mice. The results showed that the increased nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling mediated by low-level SELENOS expression was involved in oxidative damage. The proliferative zone of the cartilage growth plate of SELENOS-knockout mice was shortened, suggesting cartilage differentiation dysfunction. In conclusion, this study confirmed that low-level Selenos expression plays a role in oxidative stress in cartilages.

Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly.

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 µM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.