Vimentin and tumor-stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer.

Vimentin expression in tumor tissues and the tumor-stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients [three achieved pathological complete response (pCR), three did not]. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin [odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102-0.602, p = 0.002] and TSR (OR 4.971, 95% CI 1.933-15.431, p = 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-low/TSR-low or vimentin-high/TSR-high (OR 5.211, 95% CI 1.248-35.582, p = 0.042) and vimentin-low/TSR-high groups (OR 11.846, 95% CI 3.197-77.079, p = 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290-63.623, p = 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.

Soybean GmSAUL1, a Bona Fide U-Box E3 Ligase, Negatively Regulates Immunity Likely through Repressing the Activation of GmMPK3.

E3 ubiquitin ligases play important roles in plant immunity, but their role in soybean has not been investigated previously. Here, we used Bean pod mottle virus (BPMV)-mediated virus-induced gene silencing (VIGS) to investigate the function of GmSAUL1 (Senescence-Associated E3 Ubiquitin Ligase 1) homologs in soybean. When two closely related SAUL1 homologs were silenced simultaneously, the soybean plants displayed autoimmune phenotypes, which were significantly alleviated by high temperature, suggesting that GmSAUL1a/1b might be guarded by an R protein. Interestingly, silencing GmSAUL1a/1b resulted in the decreased activation of GmMPK6, but increased activation of GmMPK3 in response to flg22, suggesting that the activation of GmMPK3 is most likely responsible for the activated immunity observed in the GmSAUL1a/1b-silenced plants. Furthermore, we provided evidence that GmSAUL1a is a bona fide E3 ligase. Collectively, our results indicated that GmSAUL1 plays a negative role in regulating cell death and immunity in soybean.

MAC3A and MAC3B, Two Core Subunits of the MOS4-Associated Complex, Positively Influence miRNA Biogenesis.

MAC3A and MAC3B are conserved U-box-containing proteins in eukaryotes. They are subunits of the MOS4-associated complex (MAC) that plays essential roles in plant immunity and development in Arabidopsis thaliana However, their functional mechanisms remain elusive. Here, we show that Arabidopsis MAC3A and MAC3B act redundantly in microRNA (miRNA) biogenesis. Lack of both MAC3A and MAC3B in the mac3b mac3b double mutant reduces the accumulation of miRNAs, causing elevated transcript levels of miRNA targets. mac3a mac3b also decreases the levels of primary miRNA transcripts (pri-miRNAs). However, MAC3A and MAC3B do not affect the promoter activity of genes encoding miRNAs (MIR genes), suggesting that they may not affect MIR transcription. This result, together with the fact that MAC3A associates with pri-miRNAs in vivo, indicates that MAC3A and MAC3B may stabilize pri-miRNAs. Furthermore, we find that MAC3A and MAC3B interact with the DCL1 complex that catalyzes miRNA maturation, promote DCL1 activity, and are required for the localization of HYL1, a component of the DCL1 complex. Besides MAC3A and MAC3B, two other MAC subunits, CDC5 and PRL1, also function in miRNA biogenesis. Based on these results, we propose that MAC functions as a complex to control miRNA levels through modulating pri-miRNA transcription, processing, and stability.

Immune-related genes LAMA2 and IL1R1 correlate with tumor sites and predict poor survival in pancreatic adenocarcinoma.

Aims: The aim of this study was to identify the immune- and locus-associated genes in pancreatic ductal adenocarcinoma and evaluate their value in prognosis. Methods: The pancreatic ductal adenocarcinoma stromal and immune scores were calculated with the estimation of stromal and immune cells in malignant tumor tissues using expression data algorithm. The authors screened the differentially expressed genes to generate immune- and stromal-related differentially expressed genes. Next, the authors conducted weighted correlation network analysis to find the gene sets related to tumor sites. Results: IL1R1 and LAMA2 were identified as the site- and immune-related genes in pancreatic ductal adenocarcinoma, and their high expression in pancreatic head cancer exhibited high immune scores and predicted unfavorable prognosis. Conclusion: The authors identified IL1R1 and LAMA2 as immune- and locus-associated genes, and their high expression predicted a poor prognosis.

Lay abstract The prognosis of pancreatic cancer is poor, and pancreatic head carcinoma is different from pancreatic body/tail carcinoma in many respects. In recent years, the role of the immune microenvironment in tumors has been increasingly revealed. The authors wanted to find ways to improve the diagnosis and treatment of patients with pancreatic cancer by analyzing the key genes associated with different immune scores and pancreatic cancer sites. In the authors' study, IL1R1 and LAMA2 were identified as immune- and locus-associated genes, and their high expression predicted a poor prognosis, especially in pancreatic body/tail cancer. Early identification of high IL1R1 expression in pancreatic body/tail carcinoma may improve tumor prognosis.

A 4-gene prognostic signature predicting survival in hepatocellular carcinoma.

OBJECTIVE: To develop an independent prognostic signature for patients with hepatocellular carcinoma (HCC). METHODS: HCC gene expression profile the cancer genome atlas-liver hepatocellular carcinoma and GSE14520 were used as discovery and test set, respectively. Differentially expressed genes (DEGs) were identified between HCC tissues and adjacent normal liver tissues. Univariate Cox proportional hazards regression analysis was performed to identify DEGs correlated with survival of HCC patients. A 4-gene-based signature was constructed based on a least absolute shrinkage and selection operator Cox penalized regression model. The predictive value of the signature was analyzed and validated. RESULTS: Two hundred sixty-three DEGs were identified between HCC and adjacent liver tissues. After univariate survival analysis, 90 DEGs were found to be significantly correlated with the overall survival (OS) of HCC patients, of which 4 genes (KPNA2, CDC20, SPP1, and TOP2A) with non-zero coefficient were used to construct a prognostic signature. The 4-gene signature was significantly associated with the age (P = 0.046), grade ( P = 0.022), and T stage ( P = 0.023) of HCC patients in the discovery set and it also significantly associated with TNM stage ( P = 0.033), and serum alpha-fetoprotein lever ( P = 0.034). Patients in the 4-gene low-risk group were associated with better OS and recurrence-free survival (RFS) than those in the high-risk group in the discovery and test set. Meanwhile, the 4-gene signature is an independent prognostic factor regarding OS and RFS in the discovery and test set. CONCLUSION: We developed a 4-gene-based signature, which could be a candidate prognostic factor for patients with HCC.

Acupuncture Administration Improves Cognitive Functions and Alleviates Inflammation and Nuclear Damage by Regulating Phosphatidylinositol 3 Kinase (PI3K)/Phosphoinositol-Dependent Kinase 1 (PDK1)/Novel Protein Kinase C (nPKC)/Rac 1 Signaling Pathway in Senescence-Accelerated Prone 8 (SAM-P8) Mice.

BACKGROUND Alzheimer's disease (AD) is an age-associated neurodegenerative disorder. This study aimed to investigate effects of acupuncture administration on cognitive function and associated mechanisms. MATERIAL AND METHODS Senescence-accelerated prone 8 (SAM-P8) mice were randomly divided into 3 groups: the SAM-P8 group (P8-CN), the SAM-P8 administrating with acupuncture (P8-Acup) group, and the SAM-P8 administrating without acupuncture (P8-Sham) group. Morris water maze test was conducted to evaluate cognitive functions (memory and learning ability). PDK1, nPKC, and Rac1 inhibitors were used to treat SAM-P8 mice. Transmission electron microscope analysis was used to examine nuclear damage hippocampal tissues. Hematoxylin and eosin (H&E) staining was employed to evaluate inflammation. Western blot was used to detect PI3K, PDK1, nPKC, and Rac 1 expression in hippocampal tissues. RESULTS Acupuncture administration significantly reduced PI3K, PDK1, nPKC, and Rac 1 levels compared to P8-CN group (P<0.05). Both acupuncture and enzyme inhibitors (NSC23766, Rottlerin, OSU03012) significantly improved cognitive functions, reduced inflammation, and alleviated nuclear damages of SAM-P8 mice compared to P8-CN group (P<0.05). Acupuncture significantly enhanced effects of inhibitors on inflammation and nuclear damages compared to inhibitor treatment single (P<0.05). Acupuncture significantly enhanced down-regulative effects of OSU03012 on PI3K and PDK1 levels, increased down-regulative effects of Rottlerin on nPKC and Rac 1 levels and enhanced effects of Rottlerin on Rac 1 compared to P8-CN group (P<0.05). CONCLUSIONS Acupuncture administration improved cognitive functions and alleviated inflammatory response and nuclear damage of SAM-P8 mice, by downregulating PI3K/PDK1/nPKC/Rac 1 signaling pathway. This study could provide potential insight for treating cognitive dysfunction and aging of AD patients.

Genome-wide analysis of genes encoding core components of the ubiquitin system in soybean (Glycine max) reveals a potential role for ubiquitination in host immunity against soybean cyst nematode.

BACKGROUND: Ubiquitination is a major post-translational protein modification that regulates essentially all cellular and physiological pathways in eukaryotes. The ubiquitination process typically involves three distinct classes of enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). To date, a comprehensive identification and analysis of core components comprising of the whole soybean (Glycine max) ubiquitin system (UBS) has not been reported. RESULTS: We performed a systematic, genome-wide analysis of genes that encode core members of the soybean UBS in this study. A total of 1431 genes were identified with high confidence to encode putative soybean UBS components, including 4 genes encoding E1s, 71 genes that encode the E2s, and 1356 genes encoding the E3-related components. Among the E3-encoding genes, 760 encode RING-type E3s, 124 encode U-box domain-containing E3s, and 472 encode F-box proteins. To find out whether the identified soybean UBS genes encode active enzymes, a set of genes were randomly selected and the enzymatic activities of their recombinant proteins were tested. Thioester assays indicated proteins encoded by the soybean E1 gene GmUBA1 and the majority of selected E2 genes are active E1 or E2 enzymes, respectively. Meanwhile, most of the purified RING and U-box domain-containing proteins displayed E3 activity in the in vitro ubiquitination assay. In addition, 1034 of the identified soybean UBS genes were found to express in at least one of 14 soybean tissues examined and the transcript level of 338 soybean USB genes were significantly changed after abiotic or biotic (Fusarium oxysporum and Rhizobium strains) stress treatment. Finally, the expression level of a large number of the identified soybean UBS-related genes was found significantly altered after soybean cyst nematode (SCN) treatment, suggesting the soybean UBS potentially plays an important role in soybean immunity against SCN. CONCLUSIONS: Our findings indicate the presence of a large and diverse number of core UBS proteins in the soybean genome, which suggests that target-specific modification by ubiquitin is a complex and important part of cellular and physiological regulation in soybean. We also revealed certain members of the soybean UBS may be involved in immunity against soybean cyst nematode (SCN). This study sets up an essential foundation for further functional characterization of the soybean UBS in various physiological processes, such as host immunity against SCN.

A Subset of Ubiquitin-Conjugating Enzymes Is Essential for Plant Immunity.

Of the three classes of enzymes involved in ubiquitination, ubiquitin-conjugating enzymes (E2) have been often incorrectly considered to play merely an auxiliary role in the process, and few E2 enzymes have been investigated in plants. To reveal the role of E2 in plant innate immunity, we identified and cloned 40 tomato genes encoding ubiquitin E2 proteins. Thioester assays indicated that the majority of the genes encode enzymatically active E2. Phylogenetic analysis classified the 40 tomato E2 enzymes into 13 groups, of which members of group III were found to interact and act specifically with AvrPtoB, a Pseudomonas syringae pv tomato effector that uses its ubiquitin ligase (E3) activity to suppress host immunity. Knocking down the expression of group III E2 genes in Nicotiana benthamiana diminished the AvrPtoB-promoted degradation of the Fen kinase and the AvrPtoB suppression of host immunity-associated programmed cell death. Importantly, silencing group III E2 genes also resulted in reduced pattern-triggered immunity (PTI). By contrast, programmed cell death induced by several effector-triggered immunity elicitors was not affected on group III-silenced plants. Functional characterization suggested redundancy among group III members for their role in the suppression of plant immunity by AvrPtoB and in PTI and identified UBIQUITIN-CONJUGATING11 (UBC11), UBC28, UBC29, UBC39, and UBC40 as playing a more significant role in PTI than other group III members. Our work builds a foundation for the further characterization of E2s in plant immunity and reveals that AvrPtoB has evolved a strategy for suppressing host immunity that is difficult for the plant to thwart.

Functional analysis of the seven in absentia ubiquitin ligase family in tomato.

Seven in absentia (SINA) protein is one subgroup of ubiquitin ligases possessing an N-terminal cysteine-rich really interesting new gene (RING) domain, two zinc-finger motifs, and a C-terminal domain responsible for substrate-binding and dimerization. In tomato (Solanum lycopersicum), the SINA gene family has six members, and we characterize in this study all tomato SINA (SlSINA) genes and the gene products. Our results show that SlSINA genes are differentially regulated in leaf, bud, stem, flower, and root. All SlSINA proteins possess RING-dependent E3 ubiquitin ligase activity, exhibiting similar specificity towards the E2 ubiquitin-conjugating enzyme. SlSINA1/3/4/5/6 are localized in both cytoplasm and nucleus, whereas SlSINA2 is exclusively localized in the nucleus. Moreover, all SlSINAs can interact with each other for homo- or hetero-dimerization. The functionality of SlSINA proteins has been investigated. SlSINA4 plays a positive role in defense signalling, as manifested by elicitation of E3-dependent hypersensitive response-like cell death; the other SlSINAs are negative regulator and capable to suppress hypersensitive response cell death. Transgenic tomato plants overexpressing SlSINA2 exhibit pale-green leaf phenotype, suggesting SlSINA2 regulates chlorophyll level in plant cells, whereas transgenic tomato plants overexpressing SlSINA5 have altered floral structure with exserted stigma, implicating SlSINA5 plays a role in flower development.

A proof-of-concept study in engineering synthetic protein for selective recognition of substrate-free polyubiquitin.

Similar to substrate-conjugated polyubiquitin, unanchored polyubiquitin chains are emerging as important regulators for diverse biological processes. The affinity purification of unanchored polyubiquitin from various organisms has been reported, however, tools able to distinguish unanchored polyubiquitin chains with different isopeptide linkages have not yet been described. Toward the goal of selectively identifying and purifying unanchored polyubiquitin chains linked through different Lysines, Scott et al. developed a novel strategy in their study [Proteomics 2016, 16, 1961-1969]. They designed a linker-optimized ubiquitin-binding domain hybrid (t-UBD) containing two UBDs, a ZnFCUBP domain, and a linkage-selective UBA domain, to specifically recognize unanchored Lys48-linked polyubiquitin chains. Subsequently, a series of assays has proved the feasibility of this novel strategy for the purification of endogenous substrate-free Lys48-linked polyubiquitin chains from mammalian cell extracts. Their research not only provides a tool for purifying unanchored polyubiquitin with different isopeptide linkages, but also paves the way for generating reagents to study the function of unanchored polyubiquitin chains of different linkages in the future. The design of UBD hybrids for defined unanchored polyubiquitin (Lys48-polyubiquitin) in this study also set an excellent example for future methodology studies regarding monitoring in vivo dynamic changes in the patterns of ubiquitination.

The tomato Fni3 lysine-63-specific ubiquitin-conjugating enzyme and suv ubiquitin E2 variant positively regulate plant immunity.

The activation of an immune response in tomato (Solanum lycopersicum) against Pseudomonas syringae relies on the recognition of E3 ligase-deficient forms of AvrPtoB by the host protein kinase, Fen. To investigate the mechanisms by which Fen-mediated immunity is regulated, we characterize in this study a Fen-interacting protein, Fni3, and its cofactor, S. lycoperiscum Uev (Suv). Fni3 encodes a homolog of the Ubc13-type ubiquitin-conjugating enzyme that catalyzes exclusively Lys-63-linked ubiquitination, whereas Suv is a ubiquitin-conjugating enzyme variant. The C-terminal region of Fen was necessary for interaction with Fni3, and this interaction was required for cell death triggered by overexpression of Fen in Nicotiana benthamiana leaves. Fni3 was shown to be an active E2 enzyme, but Suv displayed no ubiquitin-conjugating activity; Fni3 and Suv together directed Lys-63-linked ubiquitination. Decreased expression of Fni3, another tomato Ubc13 homolog, Sl-Ubc13-2, or Suv in N. benthamiana leaves diminished cell death associated with Fen-mediated immunity and cell death elicited by several other resistance (R) proteins and their cognate effectors. We also discovered that coexpression of Fen and other R proteins/effectors with a Fni3 mutant that is compromised for ubiquitin-conjugating activity diminished the cell death. These results suggest that Fni3/Sl-Ubc13-2 and Suv regulate the immune response mediated by Fen and other R proteins through Lys-63-linked ubiquitination.

The effect of working memory load on selective attention to emotional faces for social anxiety individuals.

Research has confirmed that individuals with social anxiety (SA) show an attentional bias towards threat-related stimuli. However, the extent to which this attentional bias depends on top-down cognitive control processes remains controversial. The present study investigated the effect of working memory (WM) load on selective attention to emotional faces in both high social anxiety (HSA) and low social anxiety (LSA) groups by manipulating WM load through the inclusion of forward counting in multiples of two (low load) or backward counting in multiples of seven (high load) within a modified flanker task. In the flanker task, emotional faces (angry, happy, or neutral faces) were used as targets and distractors. A total of 70 participants (34 HSA participants; 36 LSA participants) completed the flanker task in the laboratory. The results showed that the HSA individuals performed worse when responding to angry targets. Relative to LSA individuals, HSA individuals showed interference from angry distractors in the flanker task, resulting in significantly lower accuracy in identifying angry targets compared to happy targets. These results were unaffected by the manipulation of WM load. The findings imply HSA individuals have impaired attentional control, and that their threat-related attentional bias relies more on the bottom-up automatic attentional process.

A novel mutation in the ABCC8 gene causing maturity-onset diabetes of the young: A case report.

A 34-year-old woman was diagnosed with type 1 diabetes mellitus and treated with insulin for 24 years. The patient has a family history of diabetes in three consecutive generations. Her Whole exon sequencing showed a heterozygous mutation in the ABCC8 gene, and it also found some of her relatives to carry this mutation. She was diagnosed with MODY12 and received glimepiride therapy with the achievement of good glycaemic control.

Synergistic Redox Modulation for High-Performance Nickel Oxide-Based Inverted Perovskite Solar Modules.

Nickel oxide (NiOx)-based inverted perovskite solar cells stand as promising candidates for advancing perovskite photovoltaics towards commercialization, leveraging their remarkable stability, scalability, and cost-effectiveness. However, the interfacial redox reaction between high-valence Ni4+ and perovskite, alongside the facile conversion of iodide in perovskite into I2, significantly deteriorates the performance and reproducibility of NiOx-based perovskite photovoltaics. Here, potassium borohydride (KBH4) is introduced as a dual-action reductant, which effectively avoids the Ni4+/perovskite interface reaction and mitigates the iodide-to-I2 oxidation within perovskite film. This synergistic redox modulation significantly suppresses nonradiative recombination and increases the carrier lifetime. As a result, an impressive power conversion efficiency of 24.17% for NiOx-based perovskite solar cells is achieved, and a record efficiency of 20.2% for NiOx-based perovskite solar modules fabricated under ambient conditions. Notably, when evaluated using the ISOS-L-2 standard protocol, the module retains 94% of its initial efficiency after 2000 h of continuous illumination under maximum power point at 65 °C in ambient air.

A tomato LysM receptor-like kinase promotes immunity and its kinase activity is inhibited by AvrPtoB.

Resistance in tomato (Solanum lycopersicum) to infection by Pseudomonas syringae involves both detection of pathogen-associated molecular patterns (PAMPs) and recognition by the host Pto kinase of pathogen effector AvrPtoB which is translocated into the host cell and interferes with PAMP-triggered immunity (PTI). The N-terminal portion of AvrPtoB is sufficient for its virulence activity and for recognition by Pto. An amino acid substitution in AvrPtoB, F173A, abolishes these activities. To investigate the mechanisms of AvrPtoB virulence, we screened for tomato proteins that interact with AvrPtoB and identified Bti9, a LysM receptor-like kinase. Bti9 has the highest amino acid similarity to Arabidopsis CERK1 among the tomato LysM receptor-like kinases (RLKs) and belongs to a clade containing three other tomato proteins, SlLyk11, SlLyk12, and SlLyk13, all of which interact with AvrPtoB. The F173A substitution disrupts the interaction of AvrPtoB with Bti9 and SlLyk13, suggesting that these LysM-RLKs are its virulence targets. Two independent tomato lines with RNAi-mediated reduced expression of Bti9 and SlLyk13 were more susceptible to P. syringae. Bti9 kinase activity was inhibited in vitro by the N-terminal domain of AvrPtoB in an F173-dependent manner. These results indicate Bti9 and/or SlLyk13 play a role in plant immunity and the N-terminal domain of AvrPtoB may have evolved to interfere with their kinase activity. Finally, we found that Bti9 and Pto interact with AvrPtoB in a structurally similar although not identical fashion, suggesting that Pto may have evolved as a molecular mimic of LysM-RLK kinase domains.

The U-Box/ARM E3 ligase PUB13 regulates cell death, defense, and flowering time in Arabidopsis.

The components in plant signal transduction pathways are intertwined and affect each other to coordinate plant growth, development, and defenses to stresses. The role of ubiquitination in connecting these pathways, particularly plant innate immunity and flowering, is largely unknown. Here, we report the dual roles for the Arabidopsis (Arabidopsis thaliana) Plant U-box protein13 (PUB13) in defense and flowering time control. In vitro ubiquitination assays indicated that PUB13 is an active E3 ubiquitin ligase and that the intact U-box domain is required for the E3 ligase activity. Disruption of the PUB13 gene by T-DNA insertion results in spontaneous cell death, the accumulation of hydrogen peroxide and salicylic acid (SA), and elevated resistance to biotrophic pathogens but increased susceptibility to necrotrophic pathogens. The cell death, hydrogen peroxide accumulation, and resistance to necrotrophic pathogens in pub13 are enhanced when plants are pretreated with high humidity. Importantly, pub13 also shows early flowering under middle- and long-day conditions, in which the expression of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 and FLOWERING LOCUS T is induced while FLOWERING LOCUS C expression is suppressed. Finally, we found that two components involved in the SA-mediated signaling pathway, SID2 and PAD4, are required for the defense and flowering-time phenotypes caused by the loss of function of PUB13. Taken together, our data demonstrate that PUB13 acts as an important node connecting SA-dependent defense signaling and flowering time regulation in Arabidopsis.

A bacterial E3 ubiquitin ligase targets a host protein kinase to disrupt plant immunity.

Many bacterial pathogens of plants and animals use a type III secretion system to deliver diverse virulence-associated 'effector' proteins into the host cell. The mechanisms by which these effectors act are mostly unknown; however, they often promote disease by suppressing host immunity. One type III effector, AvrPtoB, expressed by the plant pathogen Pseudomonas syringae pv. tomato, has a carboxy-terminal domain that is an E3 ubiquitin ligase. Deletion of this domain allows an amino-terminal region of AvrPtoB (AvrPtoB(1-387)) to be detected by certain tomato varieties leading to immunity-associated programmed cell death. Here we show that a host kinase, Fen, physically interacts with AvrPtoB(1-387 )and is responsible for activating the plant immune response. The AvrPtoB E3 ligase specifically ubiquitinates Fen and promotes its degradation in a proteasome-dependent manner. This degradation leads to disease susceptibility in Fen-expressing tomato lines. Various wild species of tomato were found to exhibit immunity in response to AvrPtoB(1-387 )and not to full-length AvrPtoB. Thus, by acquiring an E3 ligase domain, AvrPtoB has thwarted a highly conserved host resistance mechanism.

A deep network embedded with rough fuzzy discretization for OCT fundus image segmentation.

The noise and redundant information are the main reasons for the performance bottleneck of medical image segmentation algorithms based on the deep learning. To this end, we propose a deep network embedded with rough fuzzy discretization (RFDDN) for OCT fundus image segmentation. Firstly, we establish the information decision table of OCT fundus image segmentation, and regard each category of segmentation region as a fuzzy set. Then, we use the fuzzy c-means clustering to get the membership degrees of pixels to each segmentation region. According to membership functions and the equivalence relation generated by the brightness attribute, we design the individual fitness function based on the rough fuzzy set, and use a genetic algorithm to search for the best breakpoints to discretize the features of OCT fundus images. Finally, we take the feature discretization based on the rough fuzzy set as the pre-module of the deep neural network, and introduce the deep supervised attention mechanism to obtain the important multi-scale information. We compare RFDDN with U-Net, ReLayNet, CE-Net, MultiResUNet, and ISCLNet on the two groups of 3D retinal OCT data. RFDDN is superior to the other five methods on all evaluation indicators. The results obtained by ISCLNet are the second only inferior to those obtained by RFDDN. DSC, sensitivity, and specificity of RFDDN are evenly 3.3%, 2.6%, and 7.1% higher than those of ISCLNet, respectively. HD95 and ASD of RFDDN are evenly 6.6% and 19.7% lower than those of ISCLNet, respectively. The experimental results show that our method can effectively eliminate the noise and redundant information in Oct fundus images, and greatly improve the accuracy of OCT fundus image segmentation while taking into account the interpretability and computational efficiency.

Bioinformatics Analysis for Identifying Differentially Expressed MicroRNAs Derived from Plasma Exosomes Associated with Radiotherapy Resistance in Non-Small-Cell Lung Cancer.

Objective: To explore the differentially expressed microRNAs (DEmiRs) derived from plasma exosomes related to radiotherapy resistance and their corresponding pathways in non-small-cell lung cancer (NSCLC). Methods: Plasma samples from NSCLC patients were retrieved and analyzed. The patients were divided into 3 groups based on the tumor regression grade criteria, assessed by radiological imaging after radiotherapy. TRG1 referred to tumor shrinkage of ≤30% after radiotherapy, TRG2 as 30% < TRG < 50%, and TRG3 as TRG ≥ 50%. High-throughput sequencing and bioinformatics analysis were used to compare the DEmiRs between the three groups. The miRanda, PITA, and RNAhybrid software were used to identify potential target genes of the DEmiRs. GO function enrichment and KEGG pathway enrichment analyses were performed on the target gene set. Results: There were 24 DEmiRs (12 were upregulated and 12 downregulated) between the TRG1 and TRG2 groups, 11 between the TRG1 and TRG3 groups (6 upregulated and 5 downregulated), and 35 between the TRG2 and TRG3 groups. The common DEmiRs between the three groups were miR-92a-3p. GO analysis showed that the target genes of the DEmiRs were mainly enriched in unicellular organism processes, cell transformation, cell localization, and their establishment. KEGG enrichment analysis showed that target genes were significantly enriched in the Ras signaling pathway and associated with endocytosis. Among the 135 identified target genes of miR-92a-3p, 4 were involved in the PI3K-Akt signaling pathway (the downstream pathway of the Ras gene) and 3 in the cAMP signaling pathway (the upstream pathway of the Ras gene). Further, 2 other target genes were involved in the Rap1 signaling pathway (the upstream pathway of PI3K-Akt). Conclusion: By assessing the expression and functional profile of DEmiRs in the plasma exosomes of NSCLC patients after radiotherapy, miR-92a-3p was identified as a promising target affecting radiotherapy outcomes through the Ras signaling pathway.

Progressive Feature Fusion Attention Dense Network for Speckle Noise Removal in OCT Images.

Although deep learning for Big Data analytics has achieved promising results in the field of optical coherence tomography (OCT) image denoising, the low recognition rate caused by complex noise distribution and a large number of redundant features is still a challenge faced by deep learning-based denoising methods. Moreover, the network with large depth will bring high computational complexity. To this end, we propose a progressive feature fusion attention dense network (PFFADN) for speckle noise removal in OCT images. We arrange densely connected dense blocks in the deep convolution network, and sequentially connect the shallow convolution feature map with the deep one extracted from each dense block to form a residual block. We add attention mechanism to the network to extract the key features and suppress the irrelevant ones. We fuse the output feature maps from all dense blocks and input them to the reconstruction output layer. We compare PFFADN with the state-of-the-art denoising algorithms on retinal OCT images. Experiments show that our method has better improvement in denoising performance.