A Phytophthora infestans RXLR effector AVR8 suppresses plant immunity by targeting a desumoylating isopeptidase DeSI2.

The potato's most devastating disease is late blight, which is caused by Phytophthora infestans. Whereas various resistance (R) genes are known, most are typically defeated by this fast-evolving oomycete pathogen. However, the broad-spectrum and durable R8 is a vital gene resource for potato resistance breeding. To support an educated deployment of R8, we embarked on a study on the corresponding avirulence gene Avr8. We overexpressed Avr8 by transient and stable transformation, and found that Avr8 promotes colonization of P. infestans in Nicotiana benthamiana and potato, respectively. A yeast-two-hybrid (Y2H) screen showed that AVR8 interacts with a desumoylating isopeptidase (StDeSI2) of potato. We overexpressed DeSI2 and found that DeSI2 positively regulates resistance to P. infestans, while silencing StDeSI2 downregulated the expression of a set of defense-related genes. By using a specific proteasome inhibitor, we found that AVR8 destabilized StDeSI2 through the 26S proteasome and attenuated early PTI responses. Altogether, these results indicate that AVR8 manipulates desumoylation, which is a new strategy that adds to the plethora of mechanisms that Phytophthora exploits to modulate host immunity, and StDeSI2 provides a new target for durable resistance breeding against P. infestans in potato.

Topological alterations in white matter anatomical networks in cervical dystonia.

BACKGROUND: Accumulating neuroimaging evidence indicates that patients with cervical dystonia (CD) have changes in the cortico-subcortical white matter (WM) bundle. However, whether these patients' WM structural networks undergo reorganization remains largely unclear. We aimed to investigate topological changes in large-scale WM structural networks in patients with CD compared to healthy controls (HCs), and explore the network changes associated with clinical manifestations. METHODS: Diffusion tensor imaging (DTI) was conducted in 30 patients with CD and 30 HCs, and WM network construction was based on the BNA-246 atlas and deterministic tractography. Based on the graph theoretical analysis, global and local topological properties were calculated and compared between patients with CD and HCs. Then, the AAL-90 atlas was used for the reproducibility analyses. In addition, the relationship between abnormal topological properties and clinical characteristics was analyzed. RESULTS: Compared with HCs, patients with CD showed changes in network segregation and resilience, characterized by increased local efficiency and assortativity, respectively. In addition, a significant decrease of network strength was also found in patients with CD relative to HCs. Validation analyses using the AAL-90 atlas similarly showed increased assortativity and network strength in patients with CD. No significant correlations were found between altered network properties and clinical characteristics in patients with CD. CONCLUSION: Our findings show that reorganization of the large-scale WM structural network exists in patients with CD. However, this reorganization is attributed to dystonia-specific abnormalities or hyperkinetic movements that need further identification.

Regional structural abnormalities in thalamus in idiopathic cervical dystonia.

BACKGROUND: The thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain largely elusive. Using a structural magnetic resonance imaging (MRI) approach, we examined whether abnormalities differ across thalamic subregions/nuclei in patients with iCD. METHODS: Structural MRI data were collected from 37 patients with iCD and 37 healthy controls (HCs). Automatic parcellation of 25 thalamic nuclei in each hemisphere was performed based on the FreeSurfer program. Differences in thalamic nuclei volumes between groups and their relationships with clinical information were analysed in patients with iCD. RESULTS: Compared to HCs, a significant reduction in thalamic nuclei volume primarily in central medial, centromedian, lateral geniculate, medial geniculate, medial ventral, paracentral, parafascicular, paratenial, and ventromedial nuclei was found in patients with iCD (P < 0.05, false discovery rate corrected). However, no statistically significant correlations were observed between altered thalamic nuclei volumes and clinical characteristics in iCD group. CONCLUSION: This study highlights the neurobiological mechanisms of iCD related to thalamic volume changes.

Where, When, and How Much Should We Pay for Wind Erosion Prevention Services of the Largest Chinese Grassland Reserve?

The large-scale and cross-regional payment for ecosystem services (PES) contributes positively to ecology-economy balance and thus helps prevent environmental challenges such as "sand storm". However, existing PES programs often overlook the connection between service-providing areas (SPAs) and service-benefiting areas (SBAs). Here, we developed an interregional PES framework based on the theory of ecosystem services flow and applied it to the largest Chinese grassland nature reserve, Xilingol Prairie, to quantitatively identify SPAs, SBAs, and flow paths of the ecosystem wind erosion prevention service (WEPS). We showed that, from 2000 to 2020, the grassland ecosystem of Xilingol Prairie had brought an annual WEPS benefit of 1.21 × 108 t/a and economic value of 12.44 × 108 CNY/a, accounting for approximately 107.71% of the GDP in the same area and year and with a slightly increasing trend in most areas. We reveal obvious seasonal (over half in the spring) and interannual variations in the benefit and that Inner Mongolia, Hebei, and Northeast China are the most important beneficiaries of WEPS, rather than Beijing and Tianjin as traditionally thought. Our results warn that the WEPS supply capacity will not last long and call for finer spatial (e.g., among cities) and temporal (e.g., focus on the spring) resolution for PES policy design.

Combined transcriptomic and pangenomic analyses guide metabolic amelioration to enhance tiancimycins production.

Exploration of high-yield mechanism is important for further titer improvement of valuable antibiotics, but how to achieve this goal is challenging. Tiancimycins (TNMs) are anthraquinone-fused enediynes with promising drug development potentials, but their prospective applications are limited by low titers. This work aimed to explore the intrinsic high-yield mechanism in previously obtained TNMs high-producing strain Streptomyces sp. CB03234-S for the further titer amelioration of TNMs. First, the typical ribosomal RpsL(K43N) mutation in CB03234-S was validated to be merely responsible for the streptomycin resistance but not the titer improvement of TNMs. Subsequently, the combined transcriptomic, pan-genomic and KEGG analyses revealed that the significant changes in the carbon and amino acid metabolisms could reinforce the metabolic fluxes of key CoA precursors, and thus prompted the overproduction of TNMs in CB03234-S. Moreover, fatty acid metabolism was considered to exert adverse effects on the biosynthesis of TNMs by shunting and reducing the accumulation of CoA precursors. Therefore, different combinations of relevant genes were respectively overexpressed in CB03234-S to strengthen fatty acid degradation. The resulting mutants all showed the enhanced production of TNMs. Among them, the overexpression of fadD, a key gene responsible for the first step of fatty acid degradation, achieved the highest 21.7 ± 1.1 mg/L TNMs with a 63.2% titer improvement. Our studies suggested that comprehensive bioinformatic analyses are effective to explore metabolic changes and guide rational metabolic reconstitution for further titer improvement of target products. KEY POINTS: • Comprehensive bioinformatic analyses effectively reveal primary metabolic changes. • Primary metabolic changes cause precursor enrichment to enhance TNMs production. • Strengthening of fatty acid degradation further improves the titer of TNMs.

Preventing post-discharge suicides in psychiatric patients: insights from patients, lay healthcare supporters, and mental health professionals-a qualitative analysis.

BACKGROUND: Discharged psychiatric patients are at higher risk of suicide due to various risk factors in their lives compared to the general population. However, specific problems and needs of these patients after discharge remain unclear. This research constitutes a segment of a broader implementation study designed to formulate an interventional strategy targeting post-discharge suicide among Chinese psychiatric patients. The present study seeks to qualitatively investigate the problems and needs from the perspectives of patients, their lay healthcare supporters (LHSs), and mental health professionals (MPs), aiming to enhance the efficacy of the interventional strategy. METHODS: This study is part of a larger implementation study based on Shenzhen Kangning Hospital (SKH) in Shenzhen, Guangdong, China. Under the community-based participatory research framework, we recruited discharged psychiatric patients, their LHSs, and MPs as a collaborative community team, and we conducted individual in-depth interviews for patients and LSHs and focus group interviews with MPs. We utilized a thematic analysis approach to identify sub-themes and themes from interviews through systematically coding and analyzing the data. RESULTS: A total of 45 participants were recruited for interviews, comprising 17 patients, 8 LHSs, and 20 MPs. We conducted 25 individual in-depth interviews and 3 focus group interviews. Through the interviews, we identified three themes of post-discharge problems: problems related to self, family-related problems, societal and community-related problems. We also identified four themes related to reducing post-discharge suicide: proactive self-management, multifunctional relatives, multifunctional MP group, and a warm society. The tangible support from LHSs and emotional support from MPs are strongly emphasized. Follow-up interventions were identified as the most significant way to addressing these unmet needs. Instrumental support from the community and a caring and non-discriminatory environment for individuals with mental disorders are essential for reducing suicide risk. CONCLUSIONS: Establishing an integrated mental health care service network that connects psychiatric patients, LHSs, and MPs cross community and societal sectors, with patient-centered follow-up care at its core, is a practical approach to better address patients' needs and reduce post-discharge suicide. TRIAL REGISTRATION: Registration number: NCT04907669. Date of registration: May 26th,2021.

Generation of DNA Aptamers with Functional Activity in Mammalian Cells by Mimicking Retroviruses.

DNA aptamers are single-stranded DNA oligonucleotide sequences that bind to specific targets with high affinity. Currently, DNA aptamers can be produced only by in vitro synthesis. It is difficult for DNA aptamers to have a sustained impact on intracellular protein activity, which limits their clinical application. In this study, we developed a DNA aptamer expression system to generate DNA aptamers with functional activity in mammalian cells by mimicking retroviruses. Using this system, DNA aptamers targeting intracellular Ras (Ra1) and membrane-bound CD71 (XQ2) were successfully generated in cells. In particular, the expressed Ra1 not only specifically bound to the intracellular Ras protein but also inhibited the phosphorylation of downstream ERK1/2 and AKT. Furthermore, by inserting the DNA aptamer expression system for Ra1 into a lentivirus vector, the system can be delivered into cells and stably produce Ra1 over time, resulting in the inhibition of lung cancer cell proliferation. Therefore, our study provides a novel strategy for the intracellular generation of DNA aptamers with functional activity and opens a new avenue for the clinical application of intracellular DNA aptamers in disease treatment.

Antimicrobial Peptide-Inspired Design of Amino-Modified Lignin with Improved Antimicrobial Activities.

A major challenge to make use of lignin as an antimicrobial material is the weak antimicrobial activity of industrial lignin. Inspired by the antimicrobial mechanism of actions of antimicrobial peptides, alkyldiamines were employed as lysine mimics for lignin modifications. Accordingly, aminoalkyl-modified lignins with different degrees of substitution of amino groups and different hydrophobicity were synthesized. The chemical structure, properties, and antimicrobial activities of the as-prepared aminoalkyl lignins were thoroughly characterized with state-of-the-art technologies. The results indicated that aminobutyl lignin showed enhanced antimicrobial activity against S. aureus and E. coli and performed even better than copper ions. The antimicrobial mechanism of action of the as-prepared aminobutyl lignin was similar to that of polylysine, which damaged the cell membrane, leading to the leakage of intracellular molecules and death of the cell. This study provides a feasible approach to afford modified lignin with enhanced antimicrobial performance, which would facilitate the high-value valorization of lignin as biological materials.

Quantitative synthetic MRI for predicting locally advanced rectal cancer response to neoadjuvant chemoradiotherapy.

OBJECTIVES: To investigate the value of pre-treatment quantitative synthetic MRI (SyMRI) for predicting a good response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer. METHODS: This prospective study enrolled 63 patients with locally advanced rectal cancer scheduled to undergo preoperative chemoradiotherapy from January 2019 to June 2021. T1 relaxation time (T1), T2 relaxation time (T2), proton density (PD) from synthetic MRI, and apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) were measured. Independent-sample t-test, the Mann-Whitney U test, the Delong test, and receiver operating characteristic curve (ROC) analyses were used to predict the pathologic complete response (pCR) and T-downstaging. RESULTS: Among the 63 patients, 19 (30%) achieved pCR and 44 (70%) did not, and 24 (38%) achieved T-downstaging, while 44 (62%) did not. The mean T1 and T2 values were significantly lower in the pCR group compared with those in the non-pCR group and in the T-downstage group compared with those in the non-T-downstage group (all p < 0.05). There were no significant differences in the PD and ADC values between the two groups. There were no significant differences between the mean values of T1 and T2 for predicting pCR after CRT (AUC, 0.767 vs. 0.831, p = 0.37). There were no significant differences between the AUC values of T1 and T2 values for the assessment of post-CRT T-downstaging (AUC, 0.746 vs. 0.820, p = 0.506). CONCLUSIONS: In patients with locally advanced rectal cancer, the synthetic MRI-derived T1 relaxation time and T2 relaxation time values are promising imaging markers for predicting a good response to neoadjuvant chemoradiotherapy. KEY POINTS: • Mean T1 and T2 values were significantly lower in the pathologic complete response group and the T-downstage group. • There were no significant differences in the proton density and apparent diffusion coefficient values between the two groups.

Genomic evaluation for two-way crossbred performance in cattle.

BACKGROUND: Dairy cattle production systems are mostly based on purebreds, but recently the use of crossbreeding has received increased interest. For genetic evaluations including crossbreds, several methods based on single-step genomic best linear unbiased prediction (ssGBLUP) have been proposed, including metafounder ssGBLUP (MF-ssGBLUP) and breed-specific ssGBLUP (BS-ssGBLUP). Ideally, models that account for breed effects should perform better than simple models, but knowledge on the performance of these methods is lacking for two-way crossbred cattle. In addition, the differences in the estimates of genetic parameters (such as the genetic variance component and heritability) between these methods have rarely been investigated. Therefore, the aims of this study were to (1) compare the estimates of genetic parameters for average daily gain (ADG) and feed conversion ratio (FCR) between these methods; and (2) evaluate the impact of these methods on the predictive ability for crossbred performance. METHODS: Bivariate models using standard ssGBLUP, MF-ssGBLUP and BS-ssGBLUP for the genetic evaluation of ADG and FCR were investigated. To measure the predictive ability of these three methods, we estimated four estimators, bias, dispersion, population accuracy and ratio of population accuracies, using the linear regression (LR) method. RESULTS: The results show that, for both ADG and FCR, the heritabilities were low with the three methods. For FCR, the differences in the estimated genetic parameters were small between the three methods, while for ADG, those estimated with BS-ssGBLUP deviated largely from those estimated with the other two methods. Bias and dispersion were similar across the three methods. Population accuracies for both ADG and FCR were always higher with MF-ssGBLUP than with ssGBLUP, while with BS-ssGBLUP the population accuracy was highest for FCR and lowest for ADG. CONCLUSIONS: Our results indicate that in the genetic evaluation for crossbred performance in a two-way crossbred cattle production system, the predictive ability of MF-ssGBLUP and BS-ssGBLUP is greater than that of ssGBLUP, when the estimated variance components are consistent across the three methods. Compared with BS-ssGBLUP, MF-ssGBLUP is more robust in its superiority over ssGBLUP.

Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation.

Previous studies have shown mitochondrial dysfunction in various acute kidney injuries and chronic kidney diseases. Lipoic acid exerts potent effects on oxidant stress and modulation of mitochondrial function in damaged organ. In this study we investigated whether alpha lipoamide (ALM), a derivative of lipoic acid, exerted a renal protective effect in a type 2 diabetes mellitus mouse model. 9-week-old db/db mice were treated with ALM (50 mg·kg-1·d-1, i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels in db/db mice, but restored renal function and significantly improved fibrosis of kidneys. We demonstrated that ALM administration significantly ameliorated mitochondrial dysfunction and tubulointerstitial fibrotic lesions, along with increased expression of CDX2 and CFTR and decreased expression of ß-catenin and Snail in kidneys of db/db mice. Similar protective effects were observed in rat renal tubular epithelial cell line NRK-52E cultured in high-glucose medium following treatment with ALM (200 µM). The protective mechanisms of ALM in diabetic kidney disease (DKD) were further explored: Autodock Vina software predicted that ALM could activate RXRα protein by forming stable hydrogen bonds. PROMO Database predicted that RXRα could bind the promoter sequences of CDX2 gene. Knockdown of RXRα expression in NRK-52E cells under normal glucose condition suppressed CDX2 expression and promoted phenotypic changes in renal tubular epithelial cells. However, RXRα overexpression increased CDX2 expression which in turn inhibited high glucose-mediated renal tubular epithelial cell injury. Therefore, we reveal the protective effect of ALM on DKD and its possible potential targets: ALM ameliorates mitochondrial dysfunction and regulates the CDX2/CFTR/ß-catenin signaling axis through upregulation and activation of RXRα. Schematic figure illustrating that ALM alleviates diabetic kidney disease by improving mitochondrial function and upregulation and activation of RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on ß-catenin activation and nuclear translocation. RTEC renal tubular epithelial cell. ROS Reactive oxygen species. RXRα Retinoid X receptor-α. Mfn1 Mitofusin 1. Drp1 dynamic-related protein 1. MDA malondialdehyde. 4-HNE 4-hydroxynonenal. T-SOD Total-superoxide dismutase. CDX2 Caudal-type homeobox transcription factor 2. CFTR Cystic fibrosis transmembrane conductance regulator. EMT epithelial mesenchymal transition. α-SMA Alpha-smooth muscle actin. ECM extracellular matrix. DKD diabetic kidney disease. Schematic figure was drawn by Figdraw ( www.figdraw.com ).

The investigation of reduced field-of-view diffusion-weighted imaging (DWI) in patients with nasopharyngeal carcinoma: comparison with conventional DWI.

BACKGROUND: Field-of-view optimized and constrained undistorted single-shot imaging (FOCUS) is a new sequence that shows enhanced anatomical details, improving the diffusion-weighted (DW) images. PURPOSE: To investigate the value of FOCUS diffusion-weighted imaging (DWI) in the evaluation of nasopharyngeal carcinoma (NPC) and compare it with the single-shot echo planner imaging (SS-EPI) DWI approach. MATERIAL AND METHODS: A total of 87 patients with NPC underwent magnetic resonance imaging, including FOCUS and SS-EPI DWI sequences. The signal-to-noise ratio (SNR), signal-intensity ratio (SIR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient (ADC) values of the nasopharyngeal lesions were measured and compared. According to the clinical stages of patients, T and N were divided into early and advanced stage groups, respectively. The mean ADC values of the two techniques were computed, and the area under the curve (AUC) was estimated to calculate the diagnostic efficiency. RESULTS: Subjective and objective image qualitative values of FOCUS were significantly higher than those of SS-EPI. The ADC values for FOCUS of early T and N stages were significantly lower than those of the advanced stages. CONCLUSION: FOCUS provides significantly better image quality in NPC compared to SS-EPI, with lower ADC values for early-stage disease than late-stage disease.

Adaptiveness of RGB-image derived algorithms in the measurement of fractional vegetation coverage.

BACKGROUND: Fractional vegetation coverage (FVC) is a crucial parameter in determining vegetation structure. Automatic measurement of FVC using digital images captured by mobile smart devices is a potential direction for future research on field survey methods in plant ecology, and this algorithm is crucial for accurate FVC measurement. However, there is a lack of insight into the influence of illumination on the accuracy of FVC measurements. Therefore, the main objective of this research is to assess the adaptiveness and performance of different algorithms under varying light conditions for FVC measurements and to deepen our understanding of the influence of illumination on FVC measurement. METHODS AND RESULTS: Based on a literature survey, we selected four algorithms that have been reported to have high accuracy in automatic FVC measurements. The first algorithm (Fun01) identifies green plants based on the combination of [Formula: see text], [Formula: see text], and [Formula: see text] ([Formula: see text], [Formula: see text], and [Formula: see text] are the actual pixel digital numbers from the images based on each RGB channel, [Formula: see text] is the abbreviation of the Excess Green index), the second algorithm (Fun02) is a decision tree that uses color properties to discriminate plants from the background, the third algorithm (Fun03) uses [Formula: see text] ([Formula: see text] is the abbreviation of the Excess Red index) to recognize plants in the image, and the fourth algorithm (Fun04) uses [Formula: see text] and [Formula: see text] to separate the plants from the background. [Formula: see text] is an algorithm used to determine a threshold to transform the image into a binary image for the vegetation and background. We measured the FVC of several surveyed quadrats using these four algorithms under three scenarios, namely overcast sky, solar forenoon, and solar noon. FVC values obtained using the Photoshop-assisted manual identification method were used as a reference to assess the accuracy of the four algorithms selected. Results indicate that under the overcast sky scenario, Fun01 was more accurate than the other algorithms and the MAPE (mean absolute percentage error), BIAS, relBIAS (relative BIAS), RMSE (root mean square error), and relRMSE (relative RMSE) are 8.68%, 1.3, 3.97, 3.13, and 12.33%, respectively. Under the scenario of the solar forenoon, Fun02 (decision tree) was more accurate than other algorithms, and the MAPE, BIAS, relBIAS, RMSE, and relRMSE are 22.70%, - 2.86, - 7.70, 5.00, and 41.23%. Under the solar noon scenario, Fun02 was also more accurate than the other algorithms, and the MAPE, BIAS, relBIAS, RMSE, and relRMSE are 20.60%, - 6.39, - 20.67, 7.30, and 24.49%, respectively. CONCLUSIONS: Given that each algorithm has its own optimal application scenario, among the four algorithms selected, Fun01 (the combination of [Formula: see text], [Formula: see text], and [Formula: see text]) can be recommended for measuring FVC on cloudy days. Fun02 (decision tree) is more suitable for measuring the FVC on sunny days. However, it considerably underestimates the FVC in most cases. We expect the findings of this study to serve as a useful reference for automatic vegetation cover measurements.

Genomic Basis of Striking Fin Shapes and Colors in the Fighting Fish.

Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long-fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole-genome sequencing, quantitative trait loci mapping, genome-wide association studies, and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino, and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double-tail mutant was suggested to be caused by a deletion in a zic1/zic4 coenhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

Improvement of genomic prediction in advanced wheat breeding lines by including additive-by-additive epistasis.

KEY MESSAGE: Including additive and additive-by-additive epistasis in a NOIA parametrization did not yield orthogonal partitioning of genetic variances, nevertheless, it improved predictive ability in a leave-one-out cross-validation for wheat grain yield. Additive-by-additive epistasis is the principal non-additive genetic effect in inbred wheat lines and is potentially useful for developing cultivars based on total genetic merit; nevertheless, its practical benefits have been highly debated. In this article, we aimed to (i) evaluate the performance of models including additive and additive-by-additive epistatic effects for variance components (VC) estimation of grain yield in a wheat-breeding population, and (ii) to investigate whether including additive-by-additive epistasis in genomic prediction enhance wheat grain yield predictive ability (PA). In total, 2060 sixth-generation (F6) lines from Nordic Seed A/S breeding company were phenotyped in 21 year-location combinations in Denmark, and genotyped using a 15 K-Illumina-BeadChip. Three models were used to estimate VC and heritability at plot level: (i) "I-model" (baseline), (ii) "I + GA-model", extending I-model with an additive genomic effect, and (iii) "I + GA + GAA-model", extending I + GA-model with an additive-by-additive genomic effects. The I + GA-model and I + GA + GAA-model were based on the Natural and Orthogonal Interactions Approach (NOIA) parametrization. The I + GA + GAA-model failed to achieve orthogonal partition of genetic variances, as revealed by a change in estimated additive variance of I + GA-model when epistasis was included in the I + GA + GAA-model. The PA was studied using leave-one-line-out and leave-one-breeding-cycle-out cross-validations. The I + GA + GAA-model increased PA significantly (16.5%) compared to the I + GA-model in leave-one-line-out cross-validation. However, the improvement due to including epistasis was not observed in leave-one-breeding-cycle-out cross-validation. We conclude that epistatic models can be useful to enhance predictions of total genetic merit. However, even though we used the NOIA parameterization, the variance partition into orthogonal genetic effects was not possible.

EI24 alleviates renal interstitial fibrosis through inhibition of epithelial-mesenchymal transition and fibroblast activation.

Etoposide-induced 2.4 (EI24) exerts tumor suppressor activity through participating in cell apoptosis, autophagy, and inflammation. However, its role in renal diseases has not been elucidated. This study showed that the EI24 level decreased gradually in the kidneys of mice with unilateral ureteral obstruction (UUO) and in another fibrosis model induced by diabetic kidney disease. The overexpression of EI24 was used to investigate the possible role both in vivo and in vitro. The overexpression 1 day after UUO through tail vein injection alleviated the progression of renal interstitial fibrosis (RIF). EI24 inhibited epithelial-mesenchymal transition, excessive deposition of the extracellular matrix, and activation of fibroblasts. Furthermore, administration of EI24-overexpressing plasmids restrained the phosphorylation of nuclear factor-κB (NF-κB) and c-Jun kinase (JNK) through regulating the proteasome-dependent degradation of TRAF2, and then, inhibited the expression of downstream inflammation-associated cytokines (interleukin-6, tumor necrosis factor-α, and monocyte chemotactic protein-1) and infiltration of macrophages and neutrophils in mouse kidney after UUO. In conclusion, the data indicated that EI24, a novel anti-fibrosis regulator, was important in the progression of RIF.

Liposome-Encapsulated Tiancimycin A Is Active against Melanoma and Metastatic Breast Tumors: The Effect of cRGD Modification of the Liposomal Carrier and Tiancimycin A Dose on Drug Activity and Toxicity.

Enediyne natural products, including neocarzinostatin and calicheamicin γ1, are used in the form of a copolymer or antibody-drug conjugate to treat hepatomas and leukemia. Tiancimycin (TNM) A is a novel anthraquinone-fused enediyne that can rapidly and completely kill tumor cells. Herein, we encapsulated TNM A in liposomes (Lip-TNM A) and cyclic arginine-glycine-aspartate (cRGD)-functionalized liposomes (cRGD-Lip-TNM A) and demonstrated its antitumor activity using mouse xenografts. Because TNM A causes rapid DNA damage, cell cycle arrest, and apoptosis, these nanoparticles exhibited potent cytotoxicity against multiple tumor cells for 8 h. In B16-F10 and KPL-4 xenografts, both nanoparticles showed superior potency over doxorubicin and trastuzumab. However, cRGD-Lip-TNM A reduced the tumor weight more significantly than Lip-TNM A in B16-F10 xenografts, in which the αvß3-integrin receptors are significantly overexpressed in this melanoma. Lip-TNM A was slightly more active than cRGD-Lip-TNM A against KPL-4 xenografts, which probably reflected the difference of their in vivo fate in this mouse model. In a highly metastatic 4T1 tumor model, cRGD-Lip-TNM A reduced tumor metastasis induced by losartan, a tumor microenvironment-remodeling agent. These findings suggest that targeted delivery of enediynes with unique modes of action may enable more effective translation of anticancer nanomedicines.

Comparison of linkage disequilibrium estimated from genotypes versus haplotypes for crossbred populations.

BACKGROUND: Linkage disequilibrium (LD) is commonly measured based on the squared coefficient of correlation [Formula: see text] between the alleles at two loci that are carried by haplotypes. LD can also be estimated as the [Formula: see text] between unphased genotype dosage at two loci when the allele frequencies and inbreeding coefficients at both loci are identical for the parental lines. Here, we investigated whether [Formula: see text] for a crossbred population (F1) can be estimated using genotype data. The parental lines of the crossbred (F1) can be purebred or crossbred. METHODS: We approached this by first showing that inbreeding coefficients for an F1 crossbred population are negative, and typically differ in size between loci. Then, we proved that the expected [Formula: see text] computed from unphased genotype data is expected to be identical to the [Formula: see text] computed from haplotype data for an F1 crossbred population, regardless of the inbreeding coefficients at the two loci. Finally, we investigated the bias and precision of the [Formula: see text] estimated using unphased genotype versus haplotype data in stochastic simulation. RESULTS: Our findings show that estimates of [Formula: see text] based on haplotype and unphased genotype data are both unbiased for different combinations of allele frequencies, sample sizes (900, 1800, and 2700), and levels of LD. In general, for any allele frequency combination and [Formula: see text] value scenarios considered, and for both methods to estimate [Formula: see text], the precision of the estimates increased, and the bias of the estimates decreased as sample size increased, indicating that both estimators are consistent. For a given scenario, the [Formula: see text] estimates using haplotype data were more precise and less biased using haplotype data than using unphased genotype data. As sample size increased, the difference in precision and biasedness between the [Formula: see text] estimates using haplotype data and unphased genotype data decreased. CONCLUSIONS: Our theoretical derivations showed that estimates of LD between loci based on unphased genotypes and haplotypes in F1 crossbreds have identical expectations. Based on our simulation results, we conclude that the LD for an F1 crossbred population can be accurately estimated from unphased genotype data. The results also apply for other crosses (F2, F3, Fn, BC1, BC2, and BCn), as long as (selected) individuals from the two parental lines mate randomly.

Long-term impact of conventional and optimal contribution conservation methods on genetic diversity and genetic gain in local pig breeds.

There are rich and vast genetic resources of indigenous pig breeds in the world. Currently, great attention is paid to either crossbreeding or conservation of these indigenous pig breeds, and insufficient attention is paid to the combination of conservation and breeding along with their long-term effects on genetic diversity. Therefore, the objective of this study is to compare the long-term effects of using conventional conservation and optimal contribution selection methods on genetic diversity and genetic gain. A total of 11 different methods including conventional conservation and optimal contribution selection methods were investigated using stochastic simulations. The long-term effects of using these methods were evaluated in terms of genetic diversity metrices such as expected heterozygosity (He) and the rate of genetic gain. The results indicated that the rates of true inbreeding in these conventional conservation methods were maintained at around 0.01. The optimal contribution selection methods based either on the pedigree (POCS) or genome (GOCS) information showed more genetic gain than conventional methods, and POCS achieved the largest genetic gain. Furthermore, the effect of using GOCS methods on most of the genetic diversity metrics was slightly better than the conventional conservation methods when the rate of true inbreeding was the same, but this also required more sires used in OCS methods. According to the rate of true inbreeding, there was no significant difference among these conventional methods. In conclusion, there is no significant difference in different ways of selecting sows on inbreeding when we use different conventional conservation methods. Compared with conventional methods, POCS method could achieve the most genetic gain. However, GOCS methods can not only achieve higher genetic gain, but also maintain a relatively high level of genetic diversity. Therefore, GOCS is a better choice if we want to combine conservation and breeding in actual production in the conservation farms.

Pre-selection against a lethal recessive allele in breeding schemes with optimum-contribution selection or truncation selection.

BACKGROUND: We tested the hypothesis that breeding schemes with a pre-selection step, in which carriers of a lethal recessive allele (LRA) were culled, and with optimum-contribution selection (OCS) reduce the frequency of a LRA, control rate of inbreeding, and realise as much genetic gain as breeding schemes without a pre-selection step. METHODS: We used stochastic simulation to estimate true genetic gain realised at a 0.01 rate of true inbreeding (ΔFtrue) by breeding schemes that combined one of four pre-selection strategies with one of three selection strategies. The four pre-selection strategies were: (1) no carriers culled, (2) male carriers culled, (3) female carriers culled, and (4) all carriers culled. Carrier-status was known prior to selection. The three selection strategies were: (1) OCS in which [Formula: see text] was predicted and controlled using pedigree relationships (POCS), (2) OCS in which [Formula: see text] was predicted and controlled using genomic relationships (GOCS), and (3) truncation selection of parents. All combinations of pre-selection strategies and selection strategies were tested for three starting frequencies of the LRA (0.05, 0.10, and 0.15) and two linkage statuses with the locus that has the LRA being on a chromosome with or without loci affecting the breeding goal trait. The breeding schemes were simulated for 10 discrete generations (t = 1, …, 10). In all breeding schemes, ΔFtrue was calibrated to be 0.01 per generation in generations t = 4, …, 10. Each breeding scheme was replicated 100 times. RESULTS: We found no significant difference in true genetic gain from generations t = 4, …, 10 between breeding schemes with or without pre-selection within selection strategy. POCS and GOCS schemes realised similar true genetic gains from generations t = 4, …, 10. POCS and GOCS schemes realised 12% more true genetic gain from generations t = 4, …, 10 than truncation selection schemes. CONCLUSIONS: We advocate for OCS schemes with pre-selection against the LRA that cause animal suffering and high costs. At LRA frequencies of 0.10 or lower, OCS schemes in which male carriers are culled reduce the frequency of LRA, control rate of inbreeding, and realise no significant reduction in true genetic gain compared to OCS schemes without pre-selection against LRA.