Protein-protein interactions (PPIs) are central to most biological processes. Although efforts have been devoted to the development of methodology for predicting PPIs and protein interaction networks, the application of most existing methods is limited because they need information about protein homology or the interaction marks of the protein partners. In the present work, we propose a method for PPI prediction using only the information of protein sequences. This method was developed based on a learning algorithm-support vector machine combined with a kernel function and a conjoint triad feature for describing amino acids. More than 16,000 diverse PPI pairs were used to construct the universal model. The prediction ability of our approach is better than that of other sequence-based PPI prediction methods because it is able to predict PPI networks. Different types of PPI networks have been effectively mapped with our method, suggesting that, even with only sequence information, this method could be applied to the exploration of networks for any newly discovered protein with unknown biological relativity. In addition, such supplementary experimental information can enhance the prediction ability of the method.conjoint triad ͉ support vector machine T he molecular bases of cellular operations are sustained largely by different types of interactions among proteins. Thus, a major goal of functional genomics is to determine protein interaction networks for whole organisms (1). However, only recently has it become possible to combine the traditional study of proteins as isolated entities with the analysis of large protein interaction networks by using microarray and proteomic approaches (2, 3). Such kinds of studies are significantly important because many of the functions of complex systems seem to be more closely determined by their interactions rather than by the characteristics of their individual components (4). For example, metabolic pathways, signaling cascades, and transcription control processes involve complicated interaction networks (5). Recently, interaction networks have begun to be appreciated because it is necessary to address the general principles of biological systems by means of systems biology (6). Moreover, the study of protein interaction networks has been driven by potentially practical applications in drug discovery, because it might provide great insights into mechanisms of human diseases. This study may revolutionize the pipeline of drug discovery, because drugs discovered based on the protein interaction network may specifically modulate the disease-related pathway rather than simply inhibit or activate the functions of an individual target protein (7,8). Determining accurate cellular protein interaction networks with experimental methods in combination with computational approaches therefore has become a major theme of functional genomics and proteomics efforts (9).An impressive set of experimental techniques has been developed for the systematic analysis of protein-protein interactions (...

Fatty acid binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and modulates inflammatory and metabolic response. Studies in FABP4-deficient mice have shown that this lipid carrier has a significant role within the field of metabolic syndrome, inflammation and atherosclerosis; thus, its inhibition may open up new opportunities to develop novel therapeutic agents. A number of potent small molecule inhibitors of FABP4 have been identified and found to have the potential to prevent and treat metabolic diseases such as type-2 diabetes and atherosclerosis. Due to the ubiquity of endogenous fatty acids and the high intracellular concentration of FABP4, the inhibitors need to have significantly greater intrinsic potency than endogenous fatty acids. Furthermore, heart-type FABP (FABP3), which is expressed in both heart and skeletal muscle, is involved in active fatty acid metabolism where it transports fatty acids from the cell membrane to mitochondria for oxidation. However, FABP3 shares high overall sequence identity and similar 3D structure with FABP4, but has a potential problem with selectivity. In this review, we would like to analyze the main inhibitors that have appeared in the literature in the last decade, focusing on chemical structures, biological properties, selectivity and structure-activity relationships.

Chitinases belong to family 18 glycosyl hydrolases that can hydrolyze chitin by cleaving β-1,4-glycosidic bond, and are at key points in the life cycles of organism. The inhibitors of chitinases not only have chemotherapeutic potential against fungi, insects, but also hold anti-inflammatory efficacy against asthma and allergic disease in human. This review summarizes the structural characters of chitinases, the proposed catalytic mechanism, furthermore, also gives descriptions of currently existing inhibitors. In addition, computational studies of the interaction modes of chitinases with different inhibitors and substrates, as well as the inhibitor design of chitinases, are summarized so as to obtain an overall understanding for chitinases.Keywords: Chitinases, chitinase inhibitors, computer-aided approach. CHITIN AND CHITINASESChitin (C 8 H 13 O 5 N) n (shown in Fig. 1a), a linear insoluble homopolymer of N-acetyl-D-glucosamine (GlcNAc), is the second most abundant polysaccharide on the earth next to the cellulose [1, 2] and has been found in a wide range of organism, including bacteria, fungi, insects, and viruses [3][4][5].Accumulation of chitin in an organism is modulated by chitin synthase-mediated biosynthesis and chitinases-mediated hydrolytic degradation [6]. Since chitin synthases have become an ideal target for the development of pesticides and fugicides in agriculture, the design of chitin synthase's inhibitors has attracted much more attention [7,8]. Recently, some chitin synthase inhibitors have been successfully designed and synthesized in the group of Dr. Qing Yang [6,9], and these synthesized inhibitors were claimed to be novel potential agents due to their bioactivities. Chitinases (EC 3.2.1.14) play a key role in hydrolyzing β-1,4-glycosidic bond of the chitin into low molecular weight, soluble oligomers of GlcNAc [10,11]. Chitinases are currently classified into two different families of glycosyl hydrolases, namely family 18 and family 19 [12][13][14], and this review mainly focuses on family 18 chitinases studies, information available from their three-dimensional structures and the biochemistry of reaction. Chitinases are also widespread, and perform different functions in the different organism [15][16][17][18][19][20]. Although chitin does not exist in mammals, human chitinase family members, such as acidic mammalian chitinase (AMCase), have also been described in previous Therefore, the design of chitinases inhibitors is of great interest. The well-known inhibitor allosamidin (shown in Fig. 1b) is the most potent broad-spectrum inhibitor of chitinases. It inhibits chitinases by mimicing the reaction intermediate [24], but unfortunately, the synthesis of allosamidin and its derivatives are very difficult and expensive, which makes it a less suitable candidate targating a common chemotherapeutical therapy [25]. Izumida et al. found another effective chitinases inhibitor, the cyclic dipeptide [cyclo-(L-Arg-D-pro)] CI-4 (shown in Fig. 1c) [26]. CI-4 shows relatively weak inhibition ...

Background: When liver metastasis in patients with breast cancer is diagnosed, treatment is generally palliative and usually consists of systemic therapies only. This study aimed to evaluate the efficacy and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy in patients with breast carcinoma liver metastases (BCLM). Methods: From January 2012 to December 2019, HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 19 patients with BCLM. All patients received systemic chemotherapy and HAI gemcitabine plus floxuridine (FUDR). Methods: The overall response rate (ORR) of intrahepatic lesions was 73.7%, including 2 patients (10.5%) with complete remission (CR) and 12 patients (63.2%) with partial remission (PR). Additionally, we found that young patients (age < 55 years) had a higher ORR than the older (100% vs 44.4%, P = .011). The median overall survival (mOS) was 13.1 months. Kaplan-Meier survival curves demonstrated that the mOS was not significantly different between patients with < 9 intrahepatic lesions and those with ≥ 9 lesions (13.7 months vs 10.9 months, P = .225). The mOS was 14.3 and 10.6 months for patients without extrahepatic metastases and with extrahepatic metastases, respectively ( P = .016). None of the patients had grade 4 toxicity. The grade 3 toxicities included leucopenia, neutropenia and diarrhea. Conclusions: HAI gemcitabine plus FUDR combined with systemic chemotherapy is effective in achieving a high local response and prolonging mOS for patients with BCLM and is associated with a relatively low rate of toxicity.

Figure 1. A. Chiari's network wrapped around the tip of J wire; B. Complete Chiari's network was shown in the water.A 35-year-old female patient was diagnosed with sick sinus syndrome and needed a pacemaker implantation. During the operation, the left subclavian vein was punctured when a J wire was attempting to be placed into the inferior vena cava to ensure entry to the venous system. In the process of adjusting position of the J wire, it was found that the J wire was entrapped in the junctional area of the lower right atrium and inferior vena cava. The J wire was rotated and was attempted to be pulled out, but it failed. Finally, the wire was forcefully pulled out, and it was found that the tip of J wire was wrapped completely around Chiari's network (Fig. 1).Although it has never been reported that the wire was entrapped in Chiari's network was pulled out by force, it is not encouraged in consideration of the high risk of tearing the inferior vena cava. With the development of devices, new choices will be available to deal with this problem. It has been reported that an entrapped pacing lead was pulled out successfully with the use of a laser sheath and intracardiac echocardiogram. This method should be considered a good choice with less risk of injury. Above all, during cardiac intervention, rotating the J wire, lead or catheter in the junctional area of the lower right atrium and inferior vena cava should be avoided.

Rationale: Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in genes encoding sarcomeric proteins. One of the most commonly mutated HCM genes is the MYBPC3 gene. Mutations in this gene lead mainly to truncation of the protein, which gives rise to a relatively severe phenotype. Analyses of gene mutations associated with HCM are valuable for molecular diagnosis, genetic counseling, and management of familial HCM. Patient concerns: A 12-year-old boy presented with palpitations and dyspnea after exercise for 1 year. Echocardiography showed myocardial asymmetric hypertrophy of the ventricular septum, the anterior wall, and the lateral wall of the left ventricle. The thickness of the interventricular septum was estimated to be 33 mm. ECG showed left ventricular high voltage and ST-T changes. He had been diagnosed with HCM 3 months previously. Diagnoses: Due to his clinical presentation, he was determined to have HCM via a molecular analysis, revealing compound heterozygotes (p.R597W and p.Q1012Sfs∗8) in the MYBPC3 gene. Interventions: The patient was prescribed metoprolol to slow the heart rate and increase diastolic filling time. Outcomes: The boy was treated with metoprolol 6.75 mg b.i.d. Approximately 3 months later, review of the echocardiography showed that the peak velocity across the LVOT dropped to 2.3 m/seconds and that the pressure gradient dropped to 21 mm Hg. Lessons: A custom next-generation sequencing (NGS) technology for the HCM panel allowed us to identify compound heterozygous mutations in the MYBPC3 gene, confirming NGS as a molecular diagnostic tool.

Pan-cancer study can uncover cell- and tissue-specific genomic loci and regions with underlying biological functions, as one of fundamental procedures toward precision medicine. We utilized the online curated resource of DNA methylation annotation knowledgebase, to implement the cross-cell interrogation of pan-cancer study of breast cancer. The study revealed genome-wide differentially-methylated loci and regions by the reduced representation bisulfite sequencing profiling. The knowledgebase contains three level of curated information across multiple cancer and normal cells from the ENCODE Consortium. The reference base covers all identified differentially-methylation CpG sites and regions of interest, further annotated gene information, together with tumor suppressor gene and methylation level. Lastly, it includes the inferred functional association network and related Gene Ontology analysis results based on all the tumor suppressor genes identified from the differentially-methylated regions of interest. Our knowledgebase and analysis results provide a thorough reference source for biomedical researchers and clinicians. The cross-cell analysis results are deposited at: http://github.com/gladex/DMAK.