Thymic Rosai-Dorfmann disease: a case report.

BACKGROUND: Rosai-Dorfman disease (RDD), known as sinus histiocytosis with massive lymphadenopathy, commonly involves lymph nodes in the neck or mediastinum, although extranodal involvement is observed in approximately 40% of RDD patients. RDD involving only the thymus has rarely been reported. Here, we report a case of RDD originating in the thymus. The lesion was surgically removed, and a cure was finally achieved. There was no recurrence after telephone follow-up for 3 years. CASE PRESENTATION: A 52-year-old male was accidentally found to have a 7 × 6 cm anterior mediastinum lump by chest computed tomography (CT). The mediastinal lesion was resected by surgery, and postoperative pathology revealed RDD originating from the thymus. Regular telephone follow-up after surgery lasted 3 years and showed that the patient remained in good condition without any relevant symptoms. CONCLUSIONS: RDD originating in the thymus cannot be characterized from CT images and is easily misdiagnosed as a traditional mediastinal tumor. This is mainly because there is so little disease in this area that physicians are not aware of it. We report this case with the hope that clinicians will have a better understanding of this disease. According to our follow-up results, surgery is an effective means of treatment.

Riddle of the Sphinx: Emerging role of circular RNAs in cervical cancer.

Cervical cancer is a prominent cause of cancer-related mortality among women, with recent attention directed toward exploring the involvement of circular RNAs (circRNAs) in this particular cancer. CircRNAs, characterized by a covalently closed loop structure, belong to a class of single-stranded non-coding RNA (ncRNA) molecules that play crucial roles in cancer development and progression through diverse mechanisms. The abnormal expression of circRNAs in vivo is significantly associated with the development of cervical cancer. Notably, circRNAs actively interact with miRNAs in cervical cancer, leading to the regulation of diverse signaling pathways, and they can contribute to cancer hallmarks such as self-sufficiency in growth signals, insensitivity to antigrowth signals, limitless proliferation, evading apoptosis, tissue invasion and metastasis, and sustained angiogenesis. Moreover, the distinctive biomedical attributes exhibited by circRNAs, including their abundance, conservation, and stability in body fluids, position them as promising biomarkers for various cancers. In this review, we elucidate the tremendous potential of circRNAs as diagnostic markers or therapeutic targets in cervical cancer by expounding upon their biogenesis, characteristics, functions, and databases, highlighting the novel advances in the signaling pathways associated with circRNAs in cervical cancer.

Bakuchiol inhibits lung cancer by modulating tumor microenvironment and the expression of PD-L1.

Immune checkpoint therapy is an emerging frontier in cancer therapy. With the aim to develop an efficient herb derived compound to facilitate immune checkpoint therapy, here we investigate if a herb-derived compound, Bakuchiol (BAK), can be used to treat lung cancer and elucidate if BAK could serve as a PD-L1 regulator. To this end, a murine lung cancer model was established by subcutaneously inoculating murine Lewis lung carcinoma (LLC) cells. BAK of 5 to 40 mg/kg was used for treatment in vivo for 15 days. On Day 15, the population of CD4+ and CD8+ T cells, Treg cells. BAK could effectively inhibit tumor growth by starting treatment either on Day 0 or 6 after tumor inoculation at doses of 5-40 mg/kg. BAK treatment increased the population of cytotoxic immune cells (i.e., CD8+ T cells, and M1 macrophages), meanwhile decreasing pro-tumor immune cells (i.e., CD3+ T cells, Treg cells, and M2 macrophages). Anti-inflammatory cytokines, including IL1ß, IL2, IFNγ, TNF-α, IL4 and IL10 were upregulated by BAK. PD-L1 expression in the tumor was also lowered by BAK. AKT and STAT3 signaling were inhibited by BAK. BAK is an efficient agent in reducing LLC tumor growth. These data support the potential of BAK as a new drug for treating lung cancer by serving as a PD-L1 inhibitor that suppresses the activation of AKT and STAT3.

The three steps method for uniportal video-assisted thoracoscopic right upper lobectomy.

BACKGROUND: The uniportal video-assisted thoracoscopic right upper lobectomy (UVATRUL), as a common procedure for thoracic surgeons, is difficult to manipulate and has some inherent challenges. To solve both of problems, we summarized a series of techniques as the three steps method and investigated its feasibility on the patients of right upper lung cancer. METHODS: Forty-eight patients with right upper lobe lung cancer who underwent the three steps method UVATRUL in our hospital from January 2020 to May 2022 were selected as the three steps method group. Forty-seven patients who underwent the traditional UVATRUL were selected as the traditional method group. The intraoperative condition and postoperative condition of the two groups were retrospectively analysed. Multiple linear regression analysis was carried out to analyze the relationship between positive results and surgical method. RESULTS: All patients had successfully completed their surgeries. There was no significant difference between the two groups in respect of intraoperative blood loss, rate of conversion, day one thoracic drainage volume, chest tube indwelling time, incidence of postoperative complications, number of lymph node, and postoperative hospital stay (P > 0.05). Operative time of the three steps method group was significantly shorter than the traditional method group (P < 0.001), and number of reloads used was also significantly less than the traditional method group (P = 0.014). Multiple linear regression analysis showed that operative time (ß = - 0.470, P < 0.001), and number of reloads (ß = - 0.254, P = 0.007) correlated with surgical method. CONCLUSION: Compared with the traditional UVATRUL, the three steps method trims the surgery procedures, shortens the operative time, and reduces the use of reloads which makes it an effective procedure for UVATRUL.

Single-port thoracoscopic removal of an azygos vein aneurysm: a case report and literature review.

BACKGROUND: Azygos vein aneurysms (AVAs) are extremely rare. The majority of patients have no obvious clinical symptoms, so they are found by physical examination or by chance. There is limited clinical treatment experience that can be referred to, and there are no clear guidelines or research evidence standardizing the surgical and interventional therapy. Here, we report a patient with idiopathic AVA whose three-dimensional reconstruction of the tumor was completed before surgery. On the basis of three-dimensional reconstruction, single-port thoracoscopic resection of the AVA was successfully completed and reported for the first time. The previously reported cases are summarized to provide guidance for the diagnosis and treatment of patients with AVAs. CASE PRESENTATION: A 56-year-old man was transferred to our hospital due to "dysphagia". The diagnosis of AVA was made after enhanced computed tomography, gastroscopy, fiberoptic bronchoscopy, and three-dimensional reconstruction. Congenital weakness or degenerative changes causes the vein walls to be extremely thin that the AVA had the risk of ruptur. Furthermore, the patient had symptoms of dysphagia, he received single-port thoracoscopic surgery. After the operation, his dysphagia disappeared. The postoperative pathology confirmed hemangioma. The patient was discharged 3 days after surgery without any complications. CONCLUSIONS: AVAs are rare. Preoperative three-dimensional reconstruction can greatly help surgeons clarify the disease diagnosis, formulate the surgical plan, avoid damage to the surrounding vital organs, and reduce intraoperative bleeding. Thoracoscopic surgery to remove AVAs is difficult and has a high risk of bleeding, while more minimally invasive single-port thoracoscopic surgery is also safe and effective for the treatment of AVAs.

Synergism Effect of Dendrobine on Cisplatin in Treatment of H1299 by Modulating the Balance of Treg/Th17.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancers. Cisplatin is a broad-spectrum anti-cancer drug and is often used in combination with other drugs. Research suggests that dendrobine, a pyrrolizidine derivative alkaloid, exhibits antitumor activity in various cancers. This study explores the effect of dendrobine combined with cisplatin on NSCLC and its underlying molecular mechanism. METHODS: The effects of dendrobine combined with cisplatin on tumor progression were evaluated by xenograft model (in vivo) and clonogenic survival assay (in vitro) using H1299 cell line. Annexin V staining was used for detecting apoptotic cells. The population of T cells, B cells and other subpopulations in the peripheral blood was determined by flow cytometry. RESULTS: Dendrobine combined with cisplatin prolonged the survival of mice implanted with H1299 cells and reduced tumor volume compared with single drug application. However, dendrobine exhibited no effect on H1299 cells in clonal survival assays with or without cisplatin treatment and did not promote cisplatin-induced apoptosis in vitro. Importantly, dendrobine suppressed the regulatory T cells (Treg cells) and enhanced the T helper 17 cells (Th17 cells). Treatment of dendrobine significantly reduced Foxp3, and increased the level of IL-17 in serum. CONCLUSION: Dendrobine displayed a synergistic effect with cisplatin to exert anti-tumor effect in vivo, which might be achieved by modulating the balance of Treg/Th17 cells rather than regulating cell apoptosis.

Overexpressed SNRPB/D1/D3/E/F/G correlate with poor survival and immune infiltration in hepatocellular carcinoma.

BACKGROUND: Prior reports have indicated that the abnormal expression of small nuclear ribonucleoproteins (snRNPs) genes is related to malignant tumors. However, in hepatocellular carcinoma (HCC), the precise role of snRNPs is not well understood. Therefore, the purpose of this study was to evaluate the prognostic roles of SNRPB/D1/D2/D3/E/F/G and their correlation to immune infiltration in HCC. METHODS: The study was carried out via the following databases, software, and experimental validation: ONCOMINE, GEPIA2, UALCAN, The Cancer Genome Atlas, Gene Expression Omnibus, ArrayExpress, Kaplan-Meier plotter, cBioPortal, STRING, DAVID 6.8, TIMER, Cytoscape software, and immunohistochemistry experiments. RESULTS: Overexpressed SNRPB/D1/D2/D3/E/F/G proteins were found in HCC tissues. The transcription levels of 7 snRNPs genes were related to the TP53 mutation and tumor grades. SNRPB/D1/D2/D3/F/G expression was significantly correlated with cancer staging, whereas SNRPE was not. Moreover, Kaplan-Meier survival analysis showed that upregulation of SNRPB/D1/D2/E/G was relevant to worse OS in HCC patients, especially in patients with alcohol consumption and those without viral hepatitis. Multivariate Cox regression analysis indicated that expression of SNRPB/D1/D3/E/F/G were independent prognostic factors for unfavorable OS in HCC. In addition, a high mutation rate of snRNPs genes (44%) was also found in HCC. The mRNA expression levels of snRNPs were meaningfully and positively related to six types of infiltrating immune cells (B cells, CD4+ T cells, CD8+ T cells, neutrophil, macrophage, and dendritic cells). Also, SNRPB/D1/G genes were significantly associated with molecular markers of various immune cells in HCC. CONCLUSIONS: SNRPB/D1/D3/E/F/G are potential prognostic biomarkers for a short OS in HCC, and SNRPB/D1/G were novel immune therapy targets in HCC patients.

Genetic Variants Associated with Chronic Obstructive Pulmonary Disease Risk: Cumulative Epidemiological Evidence from Meta-Analyses and Genome-Wide Association Studies.

Background: Last two decades, many association studies on genetic variants and chronic obstructive pulmonary disease (COPD) risk have been published. But results from different studies are inconsistent. Therefore, we performed this article to systematically evaluate results from previous meta-analyses and genome-wide association studies (GWASs). Material and Methods. Firstly, we retrieved meta-analyses in PubMed, Embase, and China National Knowledge Infrastructure and GWASs in PubMed and GWAS catalog on or before April 7th, 2022. Then, data were extracted and screened. Finally, two main methods-Venice criteria and false-positive report probability test-were used to evaluate significant associations. Results: As a result, eighty-eight meta-analyses and 5 GWASs were deemed eligible for inclusion. Fifty variants in 26 genes obtained from meta-analyses were significantly associated with COPD risk. Cumulative epidemiological evidence of an association was graded as strong for 10 variants in 8 genes (GSTM1, CHRNA, ADAM33, SP-D, TNF-α, VDBP, HMOX1, and HHIP), moderate for 6 variants in 5 genes (PI, GSTM1, ADAM33, TNF-α, and VDBP), and weak for 40 variants in 23 genes. Five variants in 4 genes showed convincing evidence of no association with COPD risk in meta-analyses. Additionally, 29 SNPs identified in GWASs were proved to be noteworthy based on the FPRP test. Conclusion: In summary, more than half (52.38%) of genetic variants reported in previous meta-analyses showed no association with COPD risk. However, 13 variants in 9 genes had moderate to strong evidence for an association. This article can serve as a useful reference for further studies.

SNRPD1/E/F/G Serve as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

Objectives: Sm proteins (SNRPB/D1/D2/D3/E/F/G), involved in pre-mRNA splicing, were previously reported in the tumorigenesis of several cancers. However, their specific role in lung adenocarcinoma (LUAD) remains obscure. Our study aims to feature abnormal expressions and mutations of genes for Sm proteins and assess their potential as therapeutic targets via integrated bioinformatics analysis. Methods: In this research, we explored the expression pattern and prognostic worth of genes for Sm proteins in LUAD across TCGA, GEO, UALCAN, Oncomine, Metascape, David 6.8, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via univariate and multivariate cox regression analysis. Meanwhile, their expression patterns were validated by RT-qPCR. Gene mutations and co-expression of genes for Sm proteins were analyzed by the cBioPortal database. The PPI network for Sm proteins in LUAD was visualized by the STRING and Cytoscape. The correlations between genes for Sm proteins and immune infiltration were analyzed by using the "GSVA" R package. Results: Sm proteins genes were found upregulated expression in both LUAD tissues and LUAD cell lines. Moreover, highly expressed mRNA levels for Sm proteins were strongly associated with short survival time in LUAD. Genes for Sm proteins were positively connected with the infiltration of Th2 cells, but negatively connected with the infiltration of mast cells, Th1 cells, and NK cells. Importantly, Cox regression analysis showed that high SNRPD1/E/F/G expression were independent risk factors for the overall survival of LUAD. Conclusion: Our study showed that SNRPD1/E/F/G could independently predict the prognostic outcome of LUAD and was correlated with immune infiltration. Also, this report laid the foundation for additional exploration on the potential treatment target's role of SNRPD1/E/F/G in LUAD.

PRPS2 Enhances Resistance to Cisplatin via Facilitating Exosomes-mediated Macrophage M2 Polarization in Non-small Cell Lung Cancer.

BACKGROUND: Phosphoribosyl pyrophosphate synthetases 2 (PRPS2) is reported as an oncogene in various cancers. However, the role of PRPS2 in cisplatin (DDP) resistance of non-small cell lung cancer (NSCLC) remains unclear. The present study aimed to explore the effect of PRPS2 in DDP resistance of NSCLC. METHODS: mRNA expression levels of genes were detected by RT-PCR. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used to detect protein expression levels. Cell viability was determined by the MTT assay and colony formation assay. Cell apoptosis was detected using nucleosome ELISA assay and caspase-3 activity assay. PRPS2 silencing was achieved using siRNA transfection. Exosomes of cultured cells were isolated through ultracentrifugation. RESULTS: Elevated PRPS2 was correlated with DDP resistance and poor prognosis in NSCLC patients. PRPS2 silencing enhanced sensitivity of DDP-resistant cells to DDP treatment. NSCLC cell-derived exosome induced M2 macrophage polarization. PRPS2 was enriched in the exosomes of NSCLC cells. Exosomal PRPS2 mediated M2 macrophage polarization to promote DDP resistance of NSCLC cells. CONCLUSIONS: In conclusion, PRPS2 potentiates resistance to DDP by promoting exosome-mediated macrophage M2 polarization in NSCLC.

Massive hemothorax caused by intercostal artery pseudoaneurysm:a case report.

BACKGROUND: Intercostal artery pseudoaneurysm is rare and at the risk of rupture. The aetiology is always reported to be iatrogenic and traumatic injury. Embolisation is the most common therapeutic method. Here, we report a case of spontaneous intercostal artery pseudoaneurysm and cured by combining covered stent grafting and surgical management. CASE PRESENTATION: A 60-year-old man complained of acute right back pain for 5 h. Computed tomography showed right massive hemothorax and a giant mass with distinct feeding vessel originated from the thoracic aorta within the right hemithorax. Thoracocentesis was performed, and then a covered stent was positioned across the origin of the feeding vessel. The patient was diagnosed with intercostal artery pseudoaneurysm. Finally, we successfully resected the pseudoaneurysm and ligated the proximal part of the artery. Histologic examination have proved the diagnosis. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. There is no recurrence reported during follow-up. CONCLUSIONS: Spontaneous intercostal artery pseudoaneurysm is extremly rare. Delayed hemothorax due to rupture of the pseudoaneurysm may occur years after the formation. Early diagnosis is important and a combined treatment of endovascular intervention and surgical management is feasible, especially for the case of ruptured large tumour-like mass presentation of the pseudoaneurysm.

A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins.

The extraterminal (ET) domain of BRD3 is conserved among BET proteins (BRD2, BRD3, BRD4), interacting with multiple host and viral protein-protein networks. Solution NMR structures of complexes formed between the BRD3 ET domain and either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN329-408) or its 22-residue IN tail peptide (IN386-407) alone reveal similar intermolecular three-stranded ß-sheet formations. 15N relaxation studies reveal a 10-residue linker region (IN379-388) tethering the SH3 domain (IN329-378) to the ET-binding motif (IN389-405):ET complex. This linker has restricted flexibility, affecting its potential range of orientations in the IN:nucleosome complex. The complex of the ET-binding peptide of the host NSD3 protein (NSD3148-184) and the BRD3 ET domain includes a similar three-stranded ß-sheet interaction, but the orientation of the ß hairpin is flipped compared with the two IN:ET complexes. These studies expand our understanding of molecular recognition polymorphism in complexes of ET-binding motifs with viral and host proteins.

Matrix metalloproteinase family gene polymorphisms and lung cancer susceptibility: an updated meta-analysis.

BACKGROUND: Many studies have investigated the association between matrix metalloproteinase polymorphisms and lung cancer susceptibility. However, the results are still controversial. To clarify these associations, we conducted a meta-analysis. METHODS: A systematic search of studies was conducted in PubMed, Embase, and China National Knowledge Infrastructure. Overall and subgroup analysis stratified by ethnicity was conducted. OR with 95% CI was used to assess the strength of the association. Furthermore, false-positive report probability (FPRP) tests were also performed for associations obtained in this meta-analysis. RESULTS: Twenty-four studies, including 10,099 cases and 9,395 controls, were analyzed. Nine polymorphisms were reported. For MMP1 -1607 1G/2G and MMP7 -181 A/G, increased lung cancer risk was found in Asians. For MMP2 -1306 C/T and MMP2 -735 C/T, decreased lung cancer risk was found in both "diverse populations" and Asians. For MMP9 -1562, C/T decreased lung cancer risk was found in both "diverse populations" and Caucasians. For MMP13 -77A/G, the A/G genotype decreased lung cancer risk in Asians. However, only associations between MMP1 -1607 1G/2G, MMP2 -1306 C/T, MMP2 -735 C/T, and MMP7 -181 A/G and lung cancer risk were considered noteworthy according to FPRP tests. There was no association between MMP3 -1171 5A/6A, MMP9 R279Q, and MMP12 -82A/G and lung cancer risk. CONCLUSIONS: Our meta-analysis suggested that MMP1 -1607 1G/2G and MMP7 -181 A/G were risk factors for lung cancer, while MMP2 -1306 C/T, MMP2 -735 C/T, MMP9 -1562 C/T, and MMP13 -77A/G might be protective factors. However, results for MMP9 -1562 C/T and MMP13 -77A/G should be interpreted with caution due to the probability of false-positive reports.

Nerve growth factor against PTSD symptoms: Preventing the impaired hippocampal cytoarchitectures.

Although exogenous nerve growth factor (NGF) demonstrated great potential for post-traumatic stress disorder (PTSD) treatment, its therapeutic effect and underlying cytological mechanism were not fully elucidated so far. We employed a controlled, prospectively designed modified single prolonged stress mice model to investigate the role of exogenous NGF on the modified single prolonged stress induced PTSD-like symptoms and hippocampal cytoarchitecture impairment, as well as the potential neuronal signaling modulation. We discovered that the modified single prolonged stress-exposure induced significant PTSD-like symptoms as well as mildly impaired hippocampal Cornu Ammonis 1 (CA1) subregion cytoarchitecture, but not dentate gyrus neurogenesis, together with a gradual inhibition of TrkA-CREB-ERK signalings in hippocampal CA1 subregion. NGF treatment dose-dependently ameliorated the modified single prolonged stress induced PTSD-like symptoms. NGF increased the cytoplasm/nucleus ratio and improved the neuronal plasticity, mainly via the TrkA-ERK-CREB pathway. Our study offered the translational evidence for the potential application of exogenous NGF for treating or early preventing PTSD after stress exposure.

De novo protein design by citizen scientists.

Online citizen science projects such as GalaxyZoo1, Eyewire2 and Phylo3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson-Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now-starting from an extended polypeptide chain-generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds-including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.

Antiparallel Coiled-Coil Interactions Mediate the Homodimerization of the DNA Damage-Repair Protein PALB2.

Deficits in DNA damage-repair pathways are the root cause of several human cancers. In mammalian cells, DNA double-strand break repair is carried out by multiple mechanisms, including homologous recombination (HR). The partner and localizer of BRCA2 (PALB2), which is an essential factor for HR, binds to the breast cancer susceptibility 1 (BRCA1) protein at DNA double-strand breaks. At the break site, PALB2 also associates with the breast cancer susceptibility 2 (BRCA2) protein to form a multiprotein complex that facilitates HR. The BRCA1-PALB2 interaction is mediated by association of predicted helical coiled-coil regions in both proteins. PALB2 can also homodimerize through the formation of a coiled coil by the self-association of helical elements at the N-terminus of the PALB2 protein, and this homodimerization has been proposed to regulate the efficiency of HR. We have produced a segment of PALB2, designated PALB2cc (PALB2 coiled coil segment) that forms α-helical structures, which assemble into stable homodimers. PALB2cc also forms heterodimers with a helical segment of BRCA1, called BRCA1cc (BRCA1 coiled coil segment). The three-dimensional structure of the homodimer formed by PALB2cc was determined by solution NMR spectroscopy. This PALB2cc homodimer is a classical antiparallel coiled-coil leucine zipper. NMR chemical-shift perturbation studies were used to study dimer formation for both the PALB2cc homodimer and the PALB2cc/BRCA1cc heterodimer. The mutation of residue Leu24 of PALB2cc  significantly reduces its homodimer stability, but has a more modest effect on the stability of the heterodimer formed between PALB2cc and BRCA1cc. We show that mutation of Leu24 leads to genomic instability and reduced cell viability after treatment with agents that induce DNA double-strand breaks. These studies may allow the identification of distinct mutations of PALB2cc that selectively disrupt homodimeric versus heterodimeric interactions, and reveal the specific role of PALB2cc homodimerization in HR.

Inhibitor Bound Dengue NS2B-NS3pro Reveals Multiple Dynamic Binding Modes.

Dengue virus poses a significant global health threat as the source of increasingly deleterious dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. As no specific antiviral treatment exists for dengue infection, considerable effort is being applied to discover therapies and drugs for maintenance and prevention of these afflictions. The virus is primarily transmitted by mosquitoes, and infection occurs following viral endocytosis by host cells. Upon entering the cell, viral RNA is translated into a large multisubunit polyprotein which is post-translationally cleaved into mature, structural and nonstructural (NS) proteins. The viral genome encodes the enzyme to carry out cleavage of the large polyprotein, specifically the NS2B-NS3pro cofactor-protease complex-a target of high interest for drug design. One class of recently discovered NS2B-NS3pro inhibitors is the substrate-based trifluoromethyl ketone containing peptides. These compounds interact covalently with the active site Ser135 via a hemiketal adduct. A detailed picture of the intermolecular protease/inhibitor interactions of the hemiketal adduct is crucial for rational drug design. We demonstrate, through the use of protein- and ligand-detected solution-state 19F and 1H NMR methods, an unanticipated multibinding mode behavior of a representative of this class of inhibitors to dengue NS2B-NS3pro. Our results illustrate the highly dynamic nature of both the covalently bound ligand and protease protein structure, and the need to consider these dynamics when designing future inhibitors in this class.

rTMS Ameliorates PTSD Symptoms in Rats by Enhancing Glutamate Transmission and Synaptic Plasticity in the ACC via the PTEN/Akt Signalling Pathway.

Repetitive transcranial magnetic stimulation (rTMS) is a novel physiological therapy that has been adopted to clinically treat psychiatric disorders. Our previous study indicated the potential therapeutic effect of rTMS on posttraumatic stress disorder (PTSD). However, the exact molecular mechanism is elusive. Currently, using the single prolonged stress (SPS) rat model for PTSD, we investigated the glutamatergic transmission and neural plasticity changes in the anterior cingulate cortex (ACC) after SPS induction and explored the protective effects and mechanism of rTMS treatment. We found that high-frequency rTMS (HrTMS, 15 Hz) treatment significantly relieved the impaired glutamatergic receptors in the ACC after SPS treatment by significantly increasing NMDAR and AMPAR expression. Simultaneously, HrTMS blocked inhibited neuronal phosphatase and tensin homologue on chromosome 10 (PTEN)/Akt signalling in the ACC after SPS treatment by decreasing PTEN expression and increasing Akt phosphorylation, which is critically involved in the regulation of memory and synaptic plasticity. The PTEN inhibitors bpV and small interfering RNA and the Akt inhibitor wortmannin were stereotaxically administered to the ACC after SPS treatment to advance the mechanistic study. Analysis by Western blot, double immunofluorescence, Golgi staining and behavioural tests demonstrated that the effects of rTMS on PTEN/Akt activation, glutamatergic receptor expression, neuronal synaptic plasticity and PTSD-related behaviours induced by SPS treatment were enhanced by PTEN inhibition and blocked by Akt inhibition in the ACC. Our study provides convincing evidence for the effectiveness of rTMS treatment on PTSD and suggests that its potential mechanism involves remodelling neuronal synaptic plasticity via the PTEN/Akt signalling pathway.

Structural/Functional Properties of Human NFU1, an Intermediate [4Fe-4S] Carrier in Human Mitochondrial Iron-Sulfur Cluster Biogenesis.

Human mitochondrial NFU1 functions in the maturation of iron-sulfur proteins, and NFU1 deficiency is associated with a fatal mitochondrial disease. We determined three-dimensional structures of the N- and C-terminal domains of human NFU1 by nuclear magnetic resonance spectroscopy and used these structures along with small-angle X-ray scattering (SAXS) data to derive structural models for full-length monomeric apo-NFU1, dimeric apo-NFU1 (an artifact of intermolecular disulfide bond formation), and holo-NFUI (the [4Fe-4S] cluster-containing form of the protein). Apo-NFU1 contains two cysteine residues in its C-terminal domain, and two apo-NFU1 subunits coordinate one [4Fe-4S] cluster to form a cluster-linked dimer. Holo-NFU1 consists of a complex of three of these dimers as shown by molecular weight estimates from SAXS and size-exclusion chromatography. The SAXS-derived structural model indicates that one N-terminal region from each of the three dimers forms a tripartite interface. The activity of the holo-NFU1 preparation was verified by demonstrating its ability to activate apo-aconitase.

Quetiapine Ameliorates Schizophrenia-Like Behaviors and Protects Myelin Integrity in Cuprizone Intoxicated Mice: The Involvement of Notch Signaling Pathway.

BACKGROUND: White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown. METHODS: The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period. RESULTS: Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167. CONCLUSIONS: The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone-induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs.