Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Fast and accurate protein function prediction from sequence through pretrained language model and homology-based label diffusion.

Protein function prediction is an essential task in bioinformatics which benefits disease mechanism elucidation and drug target discovery. Due to the explosive growth of proteins in sequence databases and the diversity of their functions, it remains challenging to fast and accurately predict protein functions from sequences alone. Although many methods have integrated protein structures, biological networks or literature information to improve performance, these extra features are often unavailable for most proteins. Here, we propose SPROF-GO, a Sequence-based alignment-free PROtein Function predictor, which leverages a pretrained language model to efficiently extract informative sequence embeddings and employs self-attention pooling to focus on important residues. The prediction is further advanced by exploiting the homology information and accounting for the overlapping communities of proteins with related functions through the label diffusion algorithm. SPROF-GO was shown to surpass state-of-the-art sequence-based and even network-based approaches by more than 14.5, 27.3 and 10.1% in area under the precision-recall curve on the three sub-ontology test sets, respectively. Our method was also demonstrated to generalize well on non-homologous proteins and unseen species. Finally, visualization based on the attention mechanism indicated that SPROF-GO is able to capture sequence domains useful for function prediction. The datasets, source codes and trained models of SPROF-GO are available at https://github.com/biomed-AI/SPROF-GO. The SPROF-GO web server is freely available at http://bio-web1.nscc-gz.cn/app/sprof-go.

DiffDec: Structure-Aware Scaffold Decoration with an End-to-End Diffusion Model.

In molecular optimization, one popular way is R-group decoration on molecular scaffolds, and many efforts have been made to generate R-groups based on deep generative models. However, these methods mostly use information on known binding ligands, without fully utilizing target structure information. In this study, we proposed a new method, DiffDec, to involve 3D pocket constraints by a modified diffusion technique for optimizing molecules through molecular scaffold decoration. For end-to-end generation of R-groups with different sizes, we designed a novel fake atom mechanism. DiffDec was shown to be able to generate structure-aware R-groups with realistic geometric substructures by the analysis of bond angles and dihedral angles and simultaneously generate multiple R-groups for one scaffold on different growth anchors. The growth anchors could be provided by users or automatically determined by our model. DiffDec achieved R-group recovery rates of 69.67% and 45.34% in the single and multiple R-group decoration tasks, respectively, and these values were significantly higher than competing methods (37.33% and 26.85%). According to the molecular docking study, our decorated molecules obtained a better average binding affinity than baseline methods. The docking pose analysis revealed that DiffDec could decorate scaffolds with R-groups that exhibited improved binding affinities and more favorable interactions with the pocket. These results demonstrated the potential and applicability of DiffDec in real-world scaffold decoration for molecular optimization.

GRELinker: A Graph-Based Generative Model for Molecular Linker Design with Reinforcement and Curriculum Learning.

Fragment-based drug discovery (FBDD) is widely used in drug design. One useful strategy in FBDD is designing linkers for linking fragments to optimize their molecular properties. In the current study, we present a novel generative fragment linking model, GRELinker, which utilizes a gated-graph neural network combined with reinforcement and curriculum learning to generate molecules with desirable attributes. The model has been shown to be efficient in multiple tasks, including controlling log P, optimizing synthesizability or predicted bioactivity of compounds, and generating molecules with high 3D similarity but low 2D similarity to the lead compound. Specifically, our model outperforms the previously reported reinforcement learning (RL) built-in method DRlinker on these benchmark tasks. Moreover, GRELinker has been successfully used in an actual FBDD case to generate optimized molecules with enhanced affinities by employing the docking score as the scoring function in RL. Besides, the implementation of curriculum learning in our framework enables the generation of structurally complex linkers more efficiently. These results demonstrate the benefits and feasibility of GRELinker in linker design for molecular optimization and drug discovery.

Notch signalling regulates epibranchial placode patterning and segregation.

Epibranchial placodes are the geniculate, petrosal and nodose placodes that generate parts of cranial nerves VII, IX and X, respectively. How the three spatially separated placodes are derived from the common posterior placodal area is poorly understood. Here, we reveal that the broad posterior placode area is first patterned into a Vgll2+/Irx5+ rostral domain and a Sox2+/Fgf3+/Etv5+ caudal domain relative to the first pharyngeal cleft. This initial rostral and caudal patterning is then sequentially repeated along each pharyngeal cleft for each epibranchial placode. The caudal domains give rise to the neuronal and non-neuronal cells in the placode, whereas the rostral domains are previously unrecognized structures, serving as spacers between the final placodes. Notch signalling regulates the balance between the rostral and caudal domains: high levels of Notch signalling expand the caudal domain at the expense of the rostral domain, whereas loss of Notch signalling produces the converse phenotype. Collectively, these data unravel a new patterning principle for the early phases of epibranchial placode development and a role for Notch signalling in orchestrating epibranchial placode segregation and differentiation.

The Long-Term Outcome of Laparoscopic Resection for Perihilar Cholangiocarcinoma Compared with the Open Approach: A Real-World Multicentric Analysis.

OBJECTIVE: The aim of this study was to compare the short- and long-term outcomes of laparoscopic surgery (LS) and open surgery (OP) for perihilar cholangiocarcinoma (PHC) using a large real-world dataset in China. METHODS: Data of patients with PHC who underwent LS and OP from January 2013 to October 2018, across 10 centers in China, were extracted from medical records. A comparative analysis was performed before and after propensity score matching (PSM) in the LS and OP groups and within the study subgroups. The Cox proportional hazards mixed-effects model was applied to estimate the risk factors for mortality, with center and year of operation as random effects. RESULTS: A total of 467 patients with PHC were included, of whom 161 underwent LS and 306 underwent OP. Postoperative morbidity, such as hemorrhage, biliary fistula, abdominal abscess, and hepatic insufficiency, was similar between the LS and OP groups. The median overall survival (OS) was longer in the LS group than in the OP group (NA vs. 22 months; hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.02-1.39, p = 0.024). Among the matched datasets, OS was comparable between the LS and OP groups (NA vs. 35 months; HR 0.99, 95% CI 0.77-1.26, p = 0.915). The mixed-effect model identified that the surgical method was not associated with long-term outcomes and that LS and OP provided similar oncological outcomes. CONCLUSIONS: Considering the comparable long-term prognosis and short-term outcomes of LS and OP, LS could be a technically feasible surgical method for PHC patients with all Bismuth-Corlett types of PHC.

Laparoscopic versus open surgery for perihilar cholangiocarcinoma: a multicenter propensity score analysis of short- term outcomes.

BACKGROUND: Laparoscopic surgery (LS) has been increasingly applied in perihilar cholangiocarcinoma (pCCA). In this study, we intend to compare the short-term outcomes of LS versus open operation (OP) for pCCA in a multicentric practice in China. METHODS: This real-world analysis included 645 pCCA patients receiving LS and OP at 11 participating centers in China between January 2013 and January 2019. A comparative analysis was performed before and after propensity score matching (PSM) in LS and OP groups, and within Bismuth subgroups. Univariate and multivariate models were performed to identify significant prognostic factors of adverse surgical outcomes and postoperative length of stay (LOS). RESULTS: Among 645 pCCAs, 256 received LS and 389 received OP. Reduced hepaticojejunostomy (30.89% vs 51.40%, P = 0.006), biliary plasty requirement (19.51% vs 40.16%, P = 0.001), shorter LOS (mean 14.32 vs 17.95 d, P < 0.001), and lower severe complication (CD ≥ III) (12.11% vs. 22.88%, P = 0.006) were observed in the LS group compared with the OP group. Major postoperative complications such as hemorrhage, biliary fistula, abdominal abscess, and hepatic insufficiency were similar between LS and OP (P > 0.05 for all). After PSM, the short-term outcomes of two surgical methods were similar, except for shorter LOS in LS compared with OP (mean 15.19 vs 18.48 d, P = 0.0007). A series subgroup analysis demonstrated that LS was safe and had advantages in shorting LOS. CONCLUSION: Although the complex surgical procedures, LS generally seems to be safe and feasible for experienced surgeons. TRIAL REGISTRATION: NCT05402618 (date of first registration: 02/06/2022).

Role of Hippocampal miR-132-3p in Modifying the Function of Protein Phosphatase Mg2+/Mn2+-dependent 1 F in Depression.

Depression is a common, severe, and debilitating psychiatric disorder of unclear etiology. Our previous study has shown that protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) in the hippocampal dentate gyrus (DG) displays significant regulatory effects in depression-related behaviors. miR-132-3p plays a potential role in the etiology of depression. This study explored the effect of miR-132-3p on the onset of depression and the possible underlying mechanism for modulating PPM1F expression during the pathology of depression. We found that miR-132-3p levels in the hippocampus of depressed mice subjected to chronic unpredictable stress (CUS) were dramatically reduced, which were correlated with depression-related behaviors. Knockdown of miR-132-3p in hippocampal DG resulted in depression-related phenotypes and increased susceptibility to stress. miR-132-3p overexpression in hippocampal DG alleviated CUS-induced depression-related performance. We then screened out the potential target genes of miR-132-3p, and we found that the expression profiles of sterol regulatory element-binding transcription factor 1 (Srebf1) and forkhead box protein O3a (FOXO3a) were positively correlated with PPM1F under the condition of miR-132-3p knockdown. Finally, as anticipated, we revealed that the activities of Ca2+/calmodulin-dependent protein kinase II (CAMKII) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) were reduced, which underlies the target signaling pathway of PPM1F. In conclusion, our study suggests that miR-132-3p was designed to regulate depression-related behaviors by indirectly regulating PPM1F and targeting Srebf1 and FOXO3a, which have been linked to the pathogenesis and treatment of depression.

Streptomyces beihaiensis sp. nov., a chitin-degrading actinobacterium, isolated from shrimp pond soil.

A Gram-stain-positive actinobacterium, designated strain GXMU-J5T, was isolated from a sample of shrimp pond soil collected in Tieshangang Saltern, Beihai, PR China. The morphological, chemotaxonomic and phylogenetic characteristics were consistent with its classification in the genus Streptomyces. The organism formed an extensively branched substrate mycelium, with abundant aerial hyphae that differentiated into spores. Phylogenetic analysis of 16S rRNA gene sequences showed that strain GXMU-J5T was most related to Streptomyces kunmingensis DSM 41681T (similarity 97.74 %) and Streptomyces endophyticus YIM 65594T (similarity 96.80 %). However, the values of digital DNA-DNA hybridization, average nucleotide identity and evolutionary distance of multilocus sequence analysis between strain GXMU-J5T and its closest relatives indicated that it represented a distinct species. Strain GXMU-J5T contained ll-diaminopimelic acid and the major whole-cell hydrolysates were xylose and galactose. The predominant menaquinones of strain GXMU-J5T were revealed as MK-9(H4), MK-9(H6) and MK-9(H8). The polar lipids consisted of diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol mannosides and phospholipids of unknown structure containing glucosamine. The predominant cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and anteiso-C17 : 0. The whole genome size of strain GXMU-J5T was 6.79 Mbp with a 71.39 mol% G+C content. Genomic analysis indicated that strain GXMU-J5T had the potential to degrade chitin. On the basis of these genotypic and phenotypic data, it is supported that strain GXMU-J5T represents a novel species of the genus Streptomyces, for which the name Streptomyces beihaiensis sp. nov. is proposed. The type strain is strain GXMU-J5T (=MCCC 1K08064T=JCM 35629T).

Streptomyces fuscus sp. nov., a brown-black pigment producing actinomycete isolated from dry mudflat sand.

A novel Gram-stain-positive, aerobic actinobacterial strain, designated GXMU-J15T, was isolated from dry mudflat sand. A polyphasic approach was employed for its taxonomic characterization. The strain developed extensively branched yellowish white to light yellow substrate mycelia and white aerial mycelia, and produced smooth cylindrical spores in a loose straight spore chain on International Streptomyces Project 2-7 agar media. Strain GXMU-J15T grew at 20-50 °C (optimum, 35 °C), at pH 5.0-8.0 (optimum, pH 7.0) and in the presence of 0-8 % (w/v) NaCl. Analysis of 16S rRNA gene sequences indicated that strain GXMU-J15T represents a member of the genus Streptomyces. Strain GXMU-J15T showed the highest 16S rRNA gene sequence similarity to Streptomyces lusitanus CGMCC 4.1745T (99.1 %) and Streptomyces thermocarboxydus CGMCC 4.1883T (98.8 %). Phylogenetic tree analysis based on multilocus sequence analysis (MLSA) and whole genome sequence construction revealed that strain GXMU-J15T was most closely related to Streptomyces cupreus PSKA01T, Streptomyces cinnabarinus DSM 40467T and Streptomyces davaonensis JCM 4913T. The MLSA and genome-to-genome distances between strain GXMU-J15T and its relatives were 0.0418, 0.0443 and 0.0485 and 0.1237, 0.1188 and 0.1179, respectively. The results of orthologous average nucleotide identity and digital DNA-DNA hybridization analysis corroborated the results of the MLSA and whole genome sequence evolution analysis, indicating that the novel isolate represents a distinct species of the genus Streptomyces. The whole-cell sugars of strain GXMU-J15T were xylose, glucose and galactose. The characteristic diamino acid in the cell-wall hydrolysate was ll-diaminopimelic acid. The lipids contained diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylglycerides, phosphatidylcholine, two phospholipids of an unknown structure containing glucosamine, one unknown phospholipid and two unknown lipids. The major cellular fatty acid components were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0. The main respiratory quinone types were MK-9(H6) and MK-9(H8). The whole genome size of strain GXMU-J15T was 8.68 Mbp, with 71.23 mol% G+C content. Genomic analysis indicated that strain GXMU-J15T has the potential to synthesize polyketides, terpenes and a series of important antibiotics besides the gene cluster for melanin synthesis. Based on these genotypic and phenotypic data, strain GXMU-J15T is proposed to represent a new species of the genus Streptomyces named Streptomyces fuscus sp. nov. The type strain is GXMU-J15T (=MCCC 1K08211T=JCM 35917T).

Drain fluid volume combined with amylase level predicts clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy: A retrospective clinical study.

BACKGROUND AND AIM: Several indicators are recognized in the development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). However, drain fluid volume (DFV) remains poorly studied. We aimed to discover the predictive effects of DFV and guide clinical management. METHODS: We retrospectively reviewed the clinical data of patients that received PD between January 2015 and December 2019 in a high-volume center. DFV was analyzed as a potential risk factor and postoperative short-term outcomes as well as drain removal time were compared stratified by different DFV levels. Receiver operating characteristic curves and area under curves (AUC) were compared for DFV alone and DFV combined with drain fluid amylase (DFA). Subgroup analysis of DFV stratified by DFA evaluated the predictability of CR-POPF. RESULTS: CR-POPF occurred in 19.7% of 841 patients. Hypertension, postoperative day 3 (POD3) DFA ≥ 300 U/L, and POD3 DFV ≥ 30 mL were independent risk factors, while pancreatic main duct diameter ≥ 3 mm was a protective factor. POD3 DFV ≥ 30 mL increased the overall occurrences of CR-POPF and major complications (P = 0.017; P = 0.029). POD3 DFV alone presented a low predictive value (AUC 0.602), while POD3 DFV combined with DFA had a high predictive value (AUC 0.759) for CR-POPF. Subgroup analysis showed that the combination of POD3 DFV ≥ 30 mL and DFA ≥ 300 U/L led to higher incidences of CR-POPF (P = 0.003). CONCLUSION: CR-POPF is common after PD, and high DFV combined with DFA may predict its occurrence and facilitate appropriate management.

LINC00174 Promotes Colon Cancer Progression by Regulating Inflammation and Glycolysis by Targeting the MicroRNA-2467-3p/Enolase 3 Axis.

Objective: To elucidate the mechanism by which LINC00174 promotes colon cancer progression by targeting the microRNA-2467-3p (miR-2467-3p)/enolase 3 (ENO3) axis to regulate inflammation and glycolysis. Methods: The expression of LINC00174 and ENO3 in colon cancer tissues, its relationship with survival rate, and correlation were analyzed using bioinformatic analysis. The effects of LINC00174 overexpression and silencing on the biological behavior of and inflammation in colon cancer cells were analyzed via transfection experiments. The target relationships between miR-2467-3p or LINC00174 and ENO3 were verified using sequence prediction and the dual-luciferase reporter assay, respectively. Furthermore, LINC00174- and/or miR-2467-3p-overexpressing cells were prepared to determine the effects on ENO3 protein levels and glycolysis. Finally, the effects of LINC00174 and/or miR-2467-3p overexpression on colon cancer, ENO3 protein levels, and inflammation were analyzed using a tumor-bearing mice model. Results: LINC00174 and ENO3 were overexpressed and associated with a lower survival rate. LINC00174 was positively correlated with ENO3 in colon cancer tissues. Furthermore, the overexpression of LINC00174 in colon cancer cell lines promoted the proliferation, migration, and invasion of colon cancer cells and inflammation but inhibited apoptosis. The overexpression of miR-2467-3p inhibited ENO3 protein levels, which was attenuated via LINC00174 overexpression. Furthermore, it inhibited the biological behavior of and inflammation and glycolysis in colon cancer cells and blocked their LINC00174-induced promotion. Moreover, using animal experiments, the regulatory effects of LINC00174 on tumor growth, ENO3 protein levels, and inflammation via miR-2467-3p were confirmed. Conclusion: LINC00174 promotes the glycolysis, inflammation, proliferation, migration, and invasion of colon cancer cells and inhibits apoptosis. The cancer-promoting mechanism of LINC00174 is related to targeting miR-2467-3p to promote ENO3 protein levels.

Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID.

α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3ß4 and rα6/α3ß4 nicotinic acetylcholine receptors (nAChRs) with IC50 values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3ß4 and rα6/α3ß4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.

Temporal complementarity between roots and mycorrhizal fungi drives wheat nitrogen use efficiency.

Improving nitrogen (N) use efficiency (NUE) to reduce the application of N fertilisers in a way that benefits the environment and reduces farmers' costs is an ongoing objective for sustainable wheat production. However, whether and how arbuscular mycorrhizal fungi (AMF) affect NUE in wheat is still not well explored. Three independent but complementary experiments were conducted to decipher the contribution of roots and AMF to the N uptake and utilisation efficiency in wheat. We show a temporal complementarity pattern between roots and AMF in shaping NUE of wheat. Pre-anthesis N uptake efficiency mainly depends on root functional traits, but the efficiency to utilise the N taken up during pre-anthesis for producing grains (EN,g ) is strongly affected by AMF, which might increase the uptake of phosphorus and thereby improve photosynthetic carbon assimilation. Root association with AMF reduced the N remobilisation efficiency in varieties with high EN,g ; whilst the overall grain N concentration increased, due to a large improvement in post-anthesis N uptake supported by AMF and/or other microbes. The findings provide evidence for the importance of managing AMF in agroecosystems, and an opportunity to tackle the contradiction between maximising grain yield and protein concentration in wheat breeding.

A Novel Criterion for Lymph Nodes Dissection in Distal Pancreatectomy for Ductal Adenocarcinoma: A Population Study of the US SEER Database.

OBJECTIVE: The aim of this study was to clarify the minimum number of examined lymph nodes (MNELNs) required to ensure the quality of lymph node detection and its impact on long-term survival in distal pancreatectomy for pancreatic ductal adenocarcinoma. METHODS: Clinicopathological characteristics and survival data of patients with resectable pancreatic cancer who underwent distal pancreatectomy between 2004 and 2017 were collected from the Surveillance, Epidemiology, and End Results database. The associations between the number of examined lymph nodes (ELNs) and number of positive lymph nodes (PLNs), stage migration, and overall survival were investigated through adjusted multivariate models with locally weighted scatterplot smoothing smoothing fitting curves and estimation of the structural breakpoints. Kaplan-Meier survival analysis and X-tile software were used to identify the ideal cut-off value for ELNs. RESULTS: In total, 2610 consecutive patients who underwent distal pancreatectomy between 2004 and 2017 were included in this study. The optimal ELN count according to the associations between the number of ELNs and number of PLNs, odds ratio for stage migration, or hazard ratio for overall survival were 19, 17, and 19, respectively. Furthermore, the optimal division of ELN count for maximum overall survival was divided into three populations (ELN ≤ 8, ELN 9-18, ELN ≥ 19) based on X-tile software. CONCLUSION: A minimal count of 19 lymph nodes was demanded to guarantee the quality of lymph node examination in patients with distal pancreatectomy. Long-term survival could be delimited by MNELNs. A sufficient number of ELNs could improve the accuracy of cancer staging and reflect a better overall survival.

Preoperative plasma D-dimer independently predicts survival in patients with pancreatic ductal adenocarcinoma undergoing radical resection.

BACKGROUND: Elevated plasma D-dimer levels have been reported as an unfavorable prognostic indicator in many solid tumors. However, there are limited relevant studies in pancreatic cancer patients following radical surgery, and the clinical significance remains controversial. The aim of this study was to investigate the clinical and prognostic significance of preoperative plasma D-dimer in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection. METHODS: A retrospective analysis was performed on all patients who consecutively underwent radical surgery for PDAC by laparotomy or robotic surgery from December 2011 to December 2018. Baseline clinicopathologic characteristics, preoperative laboratory parameters, and follow-up information were collected. Univariate and multivariate analyses were performed to analyze the prognostic value of preoperative plasma D-dimer. RESULTS: Among 1351 patients, elevated preoperative plasma D-dimer levels (≥ 0.55 ng/mL) were found in 417 (30.9%) patients. Three hundred twelve (23.09%) underwent minimally invasive robotic pancreatectomy. The median overall survival (OS) of patients with elevated D-dimer levels was 6.3 months shorter than that of patients with normal D-dimer levels (15.0 months vs 21.3 months, p < 0.001). Multivariate analysis showed that elevated D-dimer levels independently predicted poorer OS (hazard ratio, 1.33; 95% confidence interval, 1.17-1.51, p < 0.001). Subgroup analysis demonstrated that D-dimer was a reliable prognostic factor in patients who underwent R0 resection. In addition, integration of D-dimer, carbohydrate antigen 19-9 (CA19-9), and NLR provided a better prognostic model for PDAC patients before operation. CONCLUSION: An elevated preoperative plasma D-dimer level was a reliable independent prognostic factor for OS in patients with PDAC undergoing resection. Combination of D-dimer, CA19-9, and NLR can enhance the prognostic accuracy before operation.

Serine peptidase inhibitor Kazal type III (SPINK3) promotes BRL-3A cell proliferation by targeting the PI3K-AKT signaling pathway.

The serine protease inhibitor, Kazal type III (SPINK3), is a trypsin inhibitor associated with liver disease, which highly overexpresses in a variety of cancers. In one of our previous studies of our laboratory, Spink3 was observed to be significantly upregulated in rat liver regeneration (LR) via a gene expression profile. For the current study, rat hepatocyte BRL-3A cells were treated by gene addition/interference, and the addition of the exogenous rat recombinant protein SPINK3. It was revealed that both the overexpression of endogenous Spink3 and addition of exogenous rat recombinant SPINK3 (rrSPINK3) significantly promoted the cell proliferation of BRL-3A cells, whereas cell proliferation was inhibited when Spink3 was interfered. Furthermore, quantitative reverse transcription polymerase chain reaction and western blot results revealed that three signaling pathways, including extracellular-signal-regulated kinase 1/2 (ERK1/2), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT), as well as their related genes, were altered following endogenous Spink3 addition/interference. Also, the PI3K-AKT and SRC-p38 pathways and their related genes were modified following exogenous SPINK3 treatment. Among them, the common signaling pathway was PI3K-AKT pathway. We concluded that SPINK3 could activate the PI3K-AKT pathway by enhancing the expression of AKT1 to regulate the proliferation of BRL-3A cells. This study may contribute to shedding light on the potential mechanisms of SPINK3 that regulate the proliferation of BRL-3A cells.

Dynamic Defense against Stealth Malware Propagation in Cyber-Physical Systems: A Game-Theoretical Framework.

Stealth malware is a representative tool of advanced persistent threat (APT) attacks, which poses an increased threat to cyber-physical systems (CPS) today. Due to the use of stealthy and evasive techniques, stealth malwares usually render conventional heavy-weight countermeasures inapplicable. Light-weight countermeasures, on the other hand, can help retard the spread of stealth malwares, but the ensuing side effects might violate the primary safety requirement of CPS. Hence, defenders need to find a balance between the gain and loss of deploying light-weight countermeasures, which normally is a challenging task. To address this challenge, we model the persistent anti-malware process as a shortest-path tree interdiction (SPTI) Stackelberg game with both static version (SSPTI) and multi-stage dynamic version (DSPTI), and safety requirements of CPS are introduced as constraints in the defender's decision model. The attacker aims to stealthily penetrate the CPS at the lowest cost (e.g., time, effort) by selecting optimal network links to spread, while the defender aims to retard the malware epidemic as much as possible. Both games are modeled as bi-level integer programs and proved to be NP-hard. We then develop a Benders decomposition algorithm to achieve the Stackelberg equilibrium of SSPTI, and design a Model Predictive Control strategy to solve DSPTI approximately by sequentially solving an 1+δ approximation of SSPTI. Extensive experiments have been conducted by comparing proposed algorithms and strategies with existing ones on both static and dynamic performance metrics. The evaluation results demonstrate the efficiency of proposed algorithms and strategies on both simulated and real-case-based CPS networks. Furthermore, the proposed dynamic defense framework shows its advantage of achieving a balance between fail-secure ability and fail-safe ability while retarding the stealth malware propagation in CPS.

Effect of H2 SO4 Solution Treatment on Adhesion, Charge Transfer, and Catalytic Performance of Screen-Printed PEDOT:PSS.

Post-treatment was performed for poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) films screen-printed on fluorine-doped tin oxide (FTO) substrates, to improve their charge transfer efficiency. Different H2 SO4 solutions, including concentrated H2 SO4 and H2 SO4 diluted with H2 O or dimethyl sulfoxide (DMSO), were adopted during the post-treatment. The adhesion of the as-treated films was evaluated by adhesive tape peeling tests, the surface morphology and vertical charge transfer from the films to the substrates were investigated by current-sensing atomic force microscopy, and the catalytic activities toward I3- reduction of PEDOT:PSS films were characterized by electrochemical measurements. It is discovered that selecting proper H2 SO4 solutions is crucial to improve the charge transfer efficiency and catalytic performance while maintaining reliable adhesion of the film on the substrates, with H2 SO4 /DMSO performing best as the solution for post-treatment. A mechanistic explanationis proposed based on different interactions among solution, PEDOT:PSS, and the substrate for various post-treatment solutions.

Effect of Br content on phase stability and performance of H2N=CHNH2Pb(I1-x Br x )3 perovskite thin films.

Pristine and Br-doped H2N = CHNH2Pb(I1-x Br x )3 (FAPb(I1-x Br x )3, Br content x = 0, 0.05, 0.15, 0.2, 0.3, and 0.4) films were prepared. The effect of Br-doping on phase stability, defect density, and performance of FAPb(I1-x Br x )3 was investigated by x-ray diffraction (XRD), scanning electron microscopy, ultraviolet-visible-near infrared absorbance spectroscopy, x-ray photoemission spectroscopy (XPS), Kelvin probe force microscopy (KPFM), positron annihilation spectroscopy, and current density-voltage (J-V) characteristics. The XRD measurements exhibit the enhancement of perovskite phase stability at x = 0.05. However, the phase stability decreases gradually with Br content (x) over 0.05. The increase of Br-doping content leads to the downshifting of both valence band (VB) position (indicated by XPS) and Fermi level (illustrated by KPFM). The energy level shifts are most probably due to the increase of Br 4p orbital content in VB and the change of self-doping levels. Doppler broadening spectra of positron annihilation radiation of the samples reveal that, the defect densities of Br-doped samples are much lower than that of pristine FAPbI3. For FAPb(I0.95Br0.05)3 sample, a high photoelectric conversion efficiency of 17.12% (25.7% higher than that of undoped sample) is successfully achieved. The significant enhancement of photoelectric conversion efficiency realized by Br-doping is attributed to the improvement of morphology, high phase stability, and low defect densities.