SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer.

Despite progress significant advances in immunotherapy for some solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive poorly responsive to such interventions, largely due to its highly immunosuppressive tumor microenvironment (TME) with limited CD8+ T cell infiltration. This study explores the role of the epigenetic factor Sin3B in the PDAC TME. Using murine PDAC models, we found that tumor cell-intrinsic Sin3B loss reshapes the TME, increasing CD8+ T cell infiltration and cytotoxicity, thus impeding tumor progression and enhancing sensitivity to anti-PD1 treatment. Sin3B-deficient tumor cells exhibited amplified CXCL9/10 secretion in response to Interferon-gamma (IFNγ), creating a positive feedback loop via the CXCL9/10-CXCR3 axis, thereby intensifying the anti-tumor immune response against PDAC. Mechanistically, extensive epigenetic regulation is uncovered by Sin3B loss, particularly enhanced H3K27Ac distribution on genes related to immune responses in PDAC cells. Consistent with the murine model findings, analysis of human PDAC samples revealed a significant inverse correlation between SIN3B levels and both CD8+ T cell infiltration and CXCL9/10 expression. Notebly, PDAC patients with lower SIN3B expression showed a more favorable response to anti-PD1 therapy. The findings suggest that targeting SIN3B can enhance cytotoxic T cell infiltration into the tumor site and improve immunotherapy efficacy in PDAC, offering potential avenues for therapeutic biomarker or target in this challenging disease.

MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. DESIGN: To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. RESULTS: Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy. CONCLUSION: In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.

Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability.

Virus-like particles (VLPs) from bacteriophage MS2 provide a platform to study protein self-assembly and create engineered systems for drug delivery. Here, we aim to understand the impact of intersubunit interface mutations on the local and global structure and function of MS2-based VLPs. In previous work, our lab identified locally supercharged double mutants [T71K/G73R] that concentrate positive charge at capsid pores, enhancing uptake into mammalian cells. To study the effects of particle size on cellular internalization, we combined these double mutants with a single point mutation [S37P] that was previously reported to switch particle geometry from T = 3 to T = 1 icosahedral symmetry. These new variants retained their enhanced cellular uptake activity and could deliver small-molecule drugs with efficacy levels similar to our first-generation capsids. Surprisingly, these engineered triple mutants exhibit increased thermostability and unexpected geometry, producing T = 3 particles instead of the anticipated T = 1 assemblies. Transmission electron microscopy revealed various capsid assembly states, including wild-type (T = 3), T = 1, and rod-like particles, that could be accessed using different combinations of these point mutations. Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.

De novo design of peptides that bind specific conformers of α-synuclein.

Insoluble amyloids rich in cross-ß fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloids in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aß40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis. METHODS: Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays. RESULTS: Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression. CONCLUSION: In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.

The Critical Role of Pyroptosis in Peri-Implantitis.

Background: Peri-implantitis (PI) is a prevalent complication of implant treatment. Pyroptosis, a distinctive inflammatory programmed cell death, is crucial to the pathophysiology of PI. Despite its importance, the pyroptosis-related genes (PRGs) influencing PI's progression remain largely unexplored. Methods: This study conducted histological staining and transcriptome analyze from three datasets. The intersection of differentially expressed genes (DEGs) and PRGs was identified as pyroptosis-related differentially expressed genes (PRDEGs). Functional enrichment analyses were conducted to shed light on potential underlying mechanisms. Weighted Gene Co-expression Network Analysis (WGCNA) and a pyroptotic macrophage model were utilized to identify and validate hub PRDEGs. Immune cell infiltration in PI and its relationship with hub PRDEGs were also examined. Furthermore, consensus clustering was performed to identify new PI subtypes. Protein-protein interaction (PPI) network, competing endogenous RNA (ceRNA) network, mRNA-mRNA binding protein regulatory (RBP) network, and mRNA-drugs regulatory network of hub PRDEGs were also analyzed. Results: Eight hub PRDEGs were identified: PGF, DPEP1, IL36B, IFIH1, TCEA3, RIPK3, NET7, and TLR3, which are instrumental in the PI's progression. Two PI subtypes were distinguished, with Cluster 1 exhibiting higher immune cell activation. The exploration of regulatory networks provided novel mechanisms and therapeutic targets in PI. Conclusion: Our research highlights the critical role of pyroptosis and identifies eight hub PRDEGs in PI's progression, offering insights into novel immunotherapy targets and laying the foundation for advanced diagnostic and treatment strategies. This contributes to our understanding of PI and underscores the potential for personalized clinical management.

Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.

Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders.

De novo Design of Peptides that Bind Specific Conformers of α-Synuclein.

Insoluble amyloids rich in cross-ß fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB database with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aß40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

Gastroblastoma without GLI1 and EWSR1 gene breaks.

OBJECTIVE: To report a rare gastroblastoma; discuss its clinical features, histopathological morphology, diagnosis, differential diagnosis, treatment, and prognosis; and so as to improve the understanding on this disease and provide reference for its diagnosis, treatment, and prognosis. METHODS: The diagnosis and treatment, imaging examination, pathological, and genetic data of a 19-year-old young female patient with gastroblastoma were analyzed retrospectively, and the relevant literature was reviewed and summarized. RESULTS: The patient was found to have a "gastrointestinal stromal tumor" for 3 days by physical examination in another hospital. Abdominal CT and MRI considered "solid pseudopapilloma of pancreas" and clinically planned to perform "radical pancreatoduodenectomy." During the operation, the tumor was observed to bulge from the posterior wall of the gastric antrum, and the root was located in the gastric antrum, so it was changed to "partial gastrectomy + Ronx-y gastrojejunal anastomosis." The postoperative pathology showed that the tumor was bi-differentiated between gastric epithelium and mesenchymal. Combined with the results of IHC and the opinions of several consultation units, the diagnosis of gastric blastoma (low-grade malignancy) was supported. However, the fracture rearrangement of GLI1 and EWSR1 genes was not detected by FISH. After 19 months of follow-up, no signs of tumor recurrence and metastasis were found. CONCLUSION: Combined with existing literature reports, gastroblastoma occurs in young people, equally in men and women, and tends to occur in the gastric antrum. The biological behavior of the tumor tends to be inert, and the prognosis of most cases is good. Postoperative pathology and IHC are reliable methods for the diagnosis of gastric blastoma, and surgical resection of the lesion is the preferred treatment.

Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of the intratumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and the host immune response. Here, we explore whether intervention with butyrate-producing probiotics can limit PDAC progression. METHODS: Based on the TCGA (PAAD) database, we analyzed the differential communities of intratumoral microbiota in PDAC patients with long survival and short survival and explored the relevant mechanisms of Clostridium butyricum and its metabolite butyrate in the treatment of PDAC. Treatment with Clostridium butyricum or butyrate in combination with the ferroptosis inducer RSL3 in a PDAC mouse model has an inhibitory effect on PDAC progression. The potential molecular mechanisms were verified by flow cytometry, RNA-seq, Western blotting, qRT‒PCR and immunofluorescence. RESULTS: We found that the tumoral butyrate-producing microbiota was linked to a better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility in PDAC. CONCLUSION: Our study reveals a novel antitumor mechanism of butyrate and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.

The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity.

IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1hi tumor growth by salvaging the intratumoral cytotoxicity of CD8+ T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer.

Serious Condylar Head Absorption in Children With Intracapsular Condylar Fractures Treated Operatively With Long Screws.

OBJECTIVE: This study was performed to explore bone remodelling in children with intracapsular condylar fractures after the condylar fracture fragments were fixed using long screws and to offer possible explanations about the underlying mechanism. PATIENT AND METHODS: Records of children (less than 12 y old) who sustained intracapsular condylar fractures and fixed with long screws from May 2012 to January 2015 were retrieved. Age, gender, dates of injury, admission, and discharge, mechanism of trauma, location and pattern of fracture, other mandibular fractures, treatment methods, and time of review were recorded and analyzed. Image dates of pretreatments and posttreatments, including the date of review, were also recorded. RESULTS: A total of 8 patients completed their follow-up, and all patients (n=5) who were followed up after more than 3 months showed serious resorption of the condylar head. The condylar head resorbed until the height (or articular surface) dropped and aligned with the surface of the screw. The shortest time of absorption, as shown by the computed tomography scan was 106 days, and the longest time was 171 days (average time of 141.8 d). CONCLUSIONS: Intracapsular condyle fractures in children should be managed conservatively as much as possible. However, if the height of the fracture fragments drops remarkably, open reduction and rigid internal fixation become possible choices.

[Retracted] MicroRNA­18b acts as an oncogene in gastric cancer by directly targeting Kruppel­like factor 6.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration assay data shown in Fig. 2C were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 1926­1934, 2019; DOI: 10.3892/mmr.2019.9830].

Co-transduction of dual-adeno-associated virus vectors in the neonatal and adult mouse utricles.

Adeno-associated virus (AAV)-mediated gene transfer is an efficient method of gene over-expression in the vestibular end organs. However, AAV has limited usefulness for delivering a large gene, or multiple genes, due to its small packaging capacity (< 5 kb). Co-transduction of dual-AAV vectors can be used to increase the packaging capacity for gene delivery to various organs and tissues. However, its usefulness has not been well validated in the vestibular sensory epithelium. In the present study, we characterized the co-transduction of dual-AAV vectors in mouse utricles following inoculation of two AAV-serotype inner ear (AAV-ie) vectors via canalostomy. Firstly, co-transduction efficiencies were compared between dual-AAV-ie vectors using two different promoters: cytomegalovirus (CMV) and CMV early enhancer/chicken ß-actin (CAG). In the group of dual AAV-ie-CAG vectors, the co-transduction rates for striolar hair cells (HCs), extrastriolar HCs, striolar supporting cells (SCs), and extrastriolar SCs were 23.14 ± 2.25%, 27.05 ± 2.10%, 57.65 ± 7.21%, and 60.33 ± 5.69%, respectively. The co-transduction rates in the group of dual AAV-ie-CMV vectors were comparable to those in the dual AAV-ie-CAG group. Next, we examined the co-transduction of dual-AAV-ie-CAG vectors in the utricles of neonatal mice and damaged adult mice. In the neonatal mice, co-transduction rates were 52.88 ± 3.11% and 44.93 ± 2.06% in the striolar and extrastriolar HCs, respectively, which were significantly higher than those in adult mice. In the Pou4f3+/DTR mice, following diphtheria toxin administration, which eliminated most HCs and spared the SCs, the co-transduction rate of SCs was not significantly different to that of normal utricles. Transgene expression persisted for up to 3 months in the adult mice. Furthermore, sequential administration of two AAV-ie-CAG vectors at an interval of 1 week resulted in a higher co-transduction rate in HCs than concurrent delivery. The auditory brainstem responses and swim tests did not reveal any disruption of auditory or vestibular function after co-transduction with dual-AAV-ie vectors. In conclusion, dual-AAV-ie vectors allow efficient co-transduction in the vestibular sensory epithelium and facilitate the delivery of large or multiple genes for vestibular gene therapy.

Establishment and validation of individualized clinical prognostic markers for LUAD patients based on autophagy-related genes.

There is considerable heterogeneity in the genomic drivers of lung adenocarcinoma, which has a dismal prognosis. Bioinformatics analysis was performed on lung adenocarcinoma (LUAD) datasets to establish a multi-autophagy gene model to predict patient prognosis. LUAD data were downloaded from The Cancer Genome Atlas (TCGA) database as a training set to construct a LUAD prognostic model. According to the risk score, a Kaplan-Meier cumulative curve was plotted to evaluate the prognostic value. Furthermore, a nomogram was established to predict the three-year and five-year survival of patients with LUAD based on their prognostic characteristics. Two genes (ITGB1 and EIF2AK3) were identified in the autophagy-related prognostic model, and the multivariate Cox proportional risk model showed that risk score was an independent predictor of prognosis in LUAD patients (HR=3.3, 95%CI= 2.3 to 4.6, P< 0.0001). The Kaplan-Meier cumulative curve showed that low-risk patients had significantly better overall (P<0.0001). The validation dataset GSE68465 further confirmed the nomogram's robust ability to assess the prognosis of LUAD patients. A prognosis model of autophagy-related genes based on a LUAD dataset was constructed and exhibited diagnostic value in the prognosis of LUAD patients. Moreover, real-time qPCR confirmed the expression patterns of EIF2AK3 and ITGB1 in LUAD cell lines. Two key autophagy-related genes have been suggested as prognostic markers for lung adenocarcinoma.

Prediction of elevation of substantial fluctuation in coal seam floor based on surface spline function and its derivative.

With the increasing depth of coal mining, the geological stress and structure becomes more and more complex. The elevation of No.8 coal floor significantly undulates in the studied coal mine. Even though a lot of boreholes have been drilled, it remains difficult to predict the spatial distribution features and it becomes challenging to plan the tunnel for the working face. Consequently, there has been a great loss of production in the coal mine, therefore, it is of great significance to study the prediction method for coal floor elevation of the working face. The surface spline function can be regarded as an infinite flat plate deformation in pure bending. The fluctuation of the coal floor can be considered to be the result of multi-period tectonic stress applied on the coal seam, so, the prediction of elevation of the coal floor with surface spline method is feasible. An advantage of surface spline method is that any order differentiable smooth surface can be obtained without regular known lattice and boundary derivatives. In the paper, the complete expression of surface spline function is derived, which is used to predict the elevation of No.8 coal floor of the coal mine. The results show that the trend of elevation of the coal floor can be extrapolated by known data, and the maximum error is 20 m, the minimum error is 0 m, and the error of 80% of the data is less than 3 m. The general trend of the coal floor has been predicted well. However, local peaks and valleys could not be predicted correctly, therefore, the first and second order derivative are projected to predict the peaks and valleys in the head of the tunneling.

Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia.

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

Machine learning for percolation utilizing auxiliary Ising variables.

Machine learning for phase transition has received intensive research interest in recent years. However, its application in percolation still remains challenging. We propose an auxiliary Ising mapping method for the machine learning study of the standard percolation as well as a variety of statistical mechanical systems in correlated percolation representation. We demonstrate that unsupervised machine learning is able to accurately locate the percolation threshold, independent of the spatial dimension of system or the type of phase transition, which can be first-order or continuous. Moreover, we show that, by neural network machine learning, auxiliary Ising configurations for different universalities can be classified with a high confidence level. Our results indicate that the auxiliary Ising mapping method, despite its simplicity, can advance the application of machine learning in statistical and condensed-matter physics.

Optimization of bifunctional piperidinamide derivatives as σ1R Antagonists/MOR agonists for treating neuropathic pain.

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ1R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ1R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ1R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ1R/MOR ligand, has potential for treating neuropathic pain.

Detection of soybean transgenic event GTS-40-3-2 using electric field-induced release and measurement (EFIRM).

Polymerase chain reaction (PCR) technology has become a standard technique for the detection of genetically modified organisms (GMOs). However, this method requires a PCR amplification process which is both expensive and time-consuming. Herein, we propose electric field-induced release and measurement (EFIRM) technology as an alternative method for GMO screening. The specificity and sensitivity of the EFIRM assay were proven to be comparable to those of the real-time PCR method for detecting genetically modified soybeans. After all the parameters had been evaluated, the actual evaluation of soybean samples from soybean cargoes was performed. An actual EFIRM screening was performed on 157 soybean cargo samples, which had 102 transgenic soybean samples containing the GTS-40-3-2 gene, through a blind trial at the Dalian port of China. Our results showed that 101 transgenic soybean samples were correctly detected, with only one false-negative case, and 55 non-transgenic soybean samples were detected as negative; this demonstrates that the EFIRM assay is an effective, accurate, simple, and economical novel method for detecting transgenic products, which may have a positive impact on the development of rapid on-site GMO monitoring platforms.