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Conotoxins, isolated from the venom of carnivorous marine snails of the Conus genus, are disulfide-rich peptides and proteins with well-defined three-dimensional structures. Conotoxins' ability to target a wide range of ion channels and receptors, including voltage- and ligand-gated ion channels, G protein-coupled receptors, monoamine transporters, and enzyme, at exquisite potency and selectivity make them valuable research and therapeutic tools. Despite their potentials, Conus venom peptides are present in limited quantities in nature and possess structural complexity that raises significant synthetic challenges for both chemical synthesis and recombinant expression. Here, we document recent advances in the expression and synthesis of conotoxins, particularly focusing on directed formation of disulfide bonds, chemical ligation techniques, and the integration of non-native functional groups. These advances can provide access to even the most complex conotoxins, accelerating conotoxin-based drug discovery and functional analysis, as well as opening new avenues for the development of drug candidates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thao NT Ho reports financial support was provided by Vingroup Big Data Institute (VinBigdata). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence of antimicrobial resistance has led to an urgent and critical situation in developing countries, including Vietnam. This study aimed to investigate the distribution and antimicrobial resistance of bacteria in patients with AE-COPD using both conventional culture and multiplex real-time PCR. Additionally, associations between clinical characteristics and indicators of pneumonia in these patients were examined., Methods: This cross-sectional prospective study included 92 AE-COPD patients with pneumonia and 46 without pneumonia. Sputum specimens were cultured and examined for bacterial identification, and antimicrobial susceptibility was determined for each isolate. Multiplex real-time PCR was also performed to detect ten bacteria and seven viruses., Results: The detection rates of pathogens in AE-COPD patients with pneumonia were 92.39%, compared to 86.96% in those without pneumonia. A total of 26 pathogenic species were identified, showing no significant difference in distribution between the two groups. The predominant bacteria included Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, followed by Acinetobacter baumannii and Streptococcus mitis. There was a slight difference in antibiotic resistance between bacteria isolated from two groups. The frequency of H. influenzae was notably greater in AE-COPD patients who experienced respiratory failure (21.92%) than in those who did not (9.23%). S. pneumoniae was more common in patients with stage I (44.44%) or IV (36.36%) COPD than in patients with stage II (17.39%) or III (9.72%) disease. ROC curve analysis revealed that C-reactive protein (CRP) levels could distinguish patients with AE-COPD with and without pneumonia (AUC = 0.78)., Conclusion: Gram-negative bacteria still play a key role in the etiology of AE-COPD patients, regardless of the presence of pneumonia. This study provides updated evidence for the epidemiology of AE-COPD pathogens and the appropriate selection of antimicrobial agents in Vietnam., (© 2024. The Author(s).)

Objectives: Burkholderia dolosa is a clinically important opportunistic pathogen in inpatients. Here we characterised an extensively drug-resistant and hypervirulent B. dolosa isolate from a patient hospitalised for stroke., Methods: Resistance to 41 antibiotics was tested with the agar disc diffusion, minimum inhibitory concentration, or broth microdilution method. The complete genome was assembled using short-reads and long-reads and the hybrid de novo assembly method. Allelic profiles obtained by multilocus sequence typing were analysed using the PubMLST database. Antibiotic-resistance and virulence genes were predicted in silico using public databases and the 'baargin' workflow. B. dolosa N149 phylogenetic relationships with all available B. dolosa strains and Burkholderia cepacia complex strains were analysed using the pangenome obtained with Roary., Results: B. dolosa N149 displayed extensive resistance to 31 antibiotics and intermediate resistance to 4 antibiotics. The complete genome included three circular chromosomes (6 338 630 bp in total) and one plasmid (167 591 bp). Genotypic analysis revealed various gene clusters (acr, amr, amp, emr, ade, bla and tet) associated with resistance to 35 antibiotic classes. The major intrinsic resistance mechanisms were multidrug efflux pump alterations, inactivation and reduced permeability of targeted antibiotics. Moreover, 91 virulence genes (encoding proteins involved in adherence, formation of capsule, biofilm and colony, motility, phagocytosis inhibition, secretion systems, protease secretion, transmission and quorum sensing) were identified. B. dolosa N149 was assigned to a novel sequence type (ST2237) and formed a mono-phylogenetic clade separated from other B. dolosa strains., Conclusions: This study provided insights into the antimicrobial resistance and virulence mechanisms of B. dolosa., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Deep learning has been studied in recent years to identify periapical lesions- a significant indicator of periapical periodontitis in radiographs. An accurate dataset is essential for constructing an efficient learning model for detecting periapical lesions. In order to achieve this goal, we gathered and created a database of panoramic radiographs containing periapical lesions from the High-quality Dental Treatment Centre, School of Dentistry, Hanoi Medical University, between January 2016 and March 2021. Out of 16,519 radiographs, three experienced dentists identified 3,926 images of periapical lesions and annotated those lesions based on the Periapical Lesions Classification. By applying well-known data processing techniques (e.g. scaling, mirroring, and flipping), the amount of data is increased to 17,004 images through generating additional images for machine learning. The dataset has three folders: one for the original photos, one for the post-augmentation images, and the rest for the annotation of periapical lesions. The information could assist researchers in developing a predictive machine model for detecting periapical lesions in radiographs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Four isolates of the opportunistic pathogen Elizabethkingia anophelis were identified for the first time in a Vietnamese hospital and underwent antimicrobial susceptibility testing and genomic characterization by whole-genome sequencing. Complete, fully circularized genome sequences were obtained for all four isolates. Average Nucleotide Identity analysis and single nucleotide polymorphism phylogenetic analysis on the core genome showed that three of the four isolates were genetically distinct, ruling out the hypothesis of a single strain emergence. Antibiotic susceptibility testing highlighted multi-resistant phenotypes against most antimicrobial families, including beta-lactams, carbapenems, aminoglycosides, quinolones, macrolides, amphenicols, rifamycins and glycopeptides. Additionally, in silico genomic analysis was used to correlate the phenotypic susceptibility to putative resistance determinants, including resistance genes, point mutations and multidrug efflux pumps. Nine different resistance genes were located inside a single resistance pocket predicted to be a putative Integrative and Conjugative Element (ICE). This novel ICE was shared by three isolates from two different lineages and displayed similarity with ICEs previously reported in various Elizabethkingia and Chryseobacterium species. The role of such ICEs in pathogenicity, genome plasticity and antimicrobial resistance gene spread within the Flavobacteriaceae family needs to be further elucidated., (© 2024. The Author(s).)

Background: Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear., Objectives: This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA., Methods: The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRAS G12D /p53 L/L ). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues., Results: AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05)., Conclusions: AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study aims to evaluate the radioprotective effects of liposomes encapsulating curcumin (Lip-CUR), silibinin (Lip-SIL), α-tocopherol (Lip-TOC), quercetin (Lip-QUE) and resveratrol (Lip-RES) in alleviating the adverse effects of ionising irradiation on human lymphoctyes and skin cells in radiotherapy. Liposomes encapsulating the above natural radioprotectants (Lip-NRPs) were prepared by the film hydration method combined with sonication. Their radioprotective effects for the cells against X-irradiation was evaluated using trypan-blue assay and γ-H2AX assay. All prepared Lip-NRPs had a mean diameter less than 240 nm, polydispersity index less than 0.32, and zeta potential more than -23 mV. Among them, the radioprotective effect of Lip-RES was lowest, while that of Lip-QUE was highest. Lip-SIL also exhibited a high radioprotective effect despite its low DPPH-radical scavenging activity (12.9%). The radioprotective effects of Lip-NRPs do not solely depend on the free radical scavenging activity of NRPs but also on their ability to activate cellular mechanisms.

The persistent presence of organic pollutants like dyes in water environment necessitates innovative approaches for efficient degradation. In this research, we developed an advanced hybrid catalyst by combining metal oxides (Cu 2 O, Fe 3 O 4 ) with UiO-66, serving as a heterogeneous Fenton catalyst for for efficient RB19 breakdown in water with H 2 O 2 . The control factors to the catalytic behavior were also quantified by machine learning. Experimental results show that the catalytic performance was much better than its individual components (P < 0.05 & non-zero 95% C.I). The improved catalytic efficiency was linked to the occurrence of active metal centers (Fe, Cu, and Zr), with Cu(I) from Cu 2 O playing a crucial role in promoting increased production of HO • . Also, UiO-66 served as a catalyst support, attracting pollutants to the reaction center, while magnetic Fe 3 O 4 aids catalyst recovery. The optimal experimental parameters for best performance were pH at 7, catalyst loading of 1.6 g/L, H 2 O 2 strength of 0.16 M, and reaction temperature of 25 °C. The catalyst can be magnetically separated and regenerated after five recycling times without significantly reducing catalytic activity. The reaction time and pH were ranked as the most influencing factors on catalytic efficiency via Random Forest and SHapley Additive exPlanations models. The findings show that developed catalyst is a suitable candidate to remove dyes in water by Fenton heterogeneous reaction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Environmental effects of heavy metal pollution are considered as a widespread problem throughout the world, as it jeopardizes human health and also reduces the sustainability of a cleaner environment. Removal of such noxious pollutants from wastewater is pivotal because it provides a propitious solution for a cleaner environment and water scarcity. Adsorption treatment plays a significant role in water remediation due to its potent treatment and low cost of adsorbents. In the last two decades, researchers have been highly focused on the modification of adsorption treatment by functionalized and surface-modified nanomaterials which has spurred intense research. The characteristics of nano adsorbents attract global scientists as it is also economically viable. This review shines its light on the functionalized nanomaterials application for heavy metals removal from wastewater and also highlights the importance of regeneration of nanomaterials in the view of visualizing the economic aspects along with a cleaner environment. The review also focused on the proper disposal of nanomaterials with crucial issues that persist in the adsorption process and also emphasize future research modification at a large-scale application in industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

New wood-based composite materials with thermal conductivity are greatly desired in the fields of packaging materials for electronic components. In this study, a new multifunctional composite material (M@FC) is prepared by simply blending clay-like Ti 3 C 2 T x MXene and delignified wood fibers together, and then followed by an infusing epoxy resin with environmentally friendly vacuum assisted resin transfer molding (VARTM) process. The resulting M@FC (0.92 W m -1 K -1 ) possesses superior thermal conductivity as compared to natural wood (0.099 W m -1 K -1 ) and most polymers. Furthermore, after the VARTM process, the structure of the M@FC is tighter, and thus showing excellent mechanical properties (tensile strength of 93.0 MPa and flexural strength of 172.7 MPa). In addition, good water resistance and excellent flame retardant property are observed for M@FC. The improvement of thermal conductivity provides the possibility for its application for packaging materials in electronic components. This study using waste wood as the important component provides a new idea for carbon cycling and recycling of natural resources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this study, natural core-shell structure activated carbon beads (ACBs) from Litsea glutinosa seeds were successfully produced, characterized, and applied for adsorption of methylene blue (MB). The ACBs were prepared using single-step carbonization-activation with NaHCO 3 at the optimized activation temperature, time, and activating agent concentration of 450 °C, 60 min, and 5%, respectively. Batch experiments were performed to determine the optimum adsorption conditions, suitable kinetic and isotherm models, and thermodynamic parameters for the adsorption of MB onto ACBs. The results showed that the ACBs were displayed as highly porous natural core-shell spheres with a diameter of about 5 mm. The adsorption of MB dye on ACBs was a spontaneous endothermic process, followed the Langmuir isotherm and the pseudo-second-order kinetic models with the rate-controlling step of both external diffusion and intra-particle diffusion. At the optimum conditions (pH of 9, the contact time of 10 h, the temperature of 40 °C, and an adsorbent dosage of 6 g/L), the maximum adsorption capacity reached 29.03 mg/g. The thermal method turned out to be more suitable for regenerating ACBs compared to the chemical method. The ACBs exhibited high reusability and stability, its adsorption efficiency could maintain more than 90% after five consecutive cycles of use. The electrostatic attraction, π-π interaction, hydrogen bonding, and pore-filling were identified as primary contributions to the adsorption mechanism. The overall results revealed that the ACBs could be used as a potential adsorbent for removing MB from water media., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Magnetic activated carbon/chitosan composite (MACCS) beads from spent coffee grounds and shrimp shells were synthesized using green tea extract as a crosslinker. The adsorbent was then applied for removal of Ni(II) ions from aqueous solution after carefully characterizing it by various techniques (XRD, FTIR, FE-SEM, EDX, VSM and BET). The adsorption kinetics, isotherms, thermodynamics, the effects of key adsorption factors such as the pH value, initial Ni(II) concentration, contact time, adsorbent dose and temperature were investigated in detail. A possible adsorption mechanism was proposed. The results indicated that the adsorption process was thermodynamically favourable, spontaneous, endothermic, and was best described by the Langmuir isotherm and pseudo-second-order kinetic models. The MACCS beads with an optimum CS to MAC weight ratio estimated as 60:40 gave the maximum monolayer adsorption capacity for Ni(II) ions of 108.70 mg g -1 at 25°C, pH of 6, adsorbent dose of 1.0g L -1 and a contact time of 6 h. The recycling study confirmed that the adsorption ability of MACCS beads towards Ni(II) ions maintained well after five consecutive cycles with the removal efficiency greater than 86.25%. Eventually, the MACCS beads could be used as an environmentally-friendly and highly efficient adsorbent for removal of Ni(II) ions from wastewater due to the advantages of high efficiency, rapid separation and good reusability.

Resolving late failure of dental implant is difficult and costly; however, only few reviews have addressed the risk factors associated with late failure of dental implant. The aim of this literature review was to summarize the influences of different potential risk factors on the incidence of late dental implant failure. The protocol of this systematic review was prepared and implemented based on the PRISMA (Preferred reporting items for systematic reviews and meta-analyses) guideline. In December 2018, studies published within the previous 10 years on late dental implant failure were selected by fulfilling the eligibility criteria and the risk factors identified in qualified studies were extracted by using a predefined extraction template. Fourteen eligible studies were assessed. The common risk factors for late failure were divided into three groups according to whether they were related to (1) the patient history (radiation therapy, periodontitis, bruxism and early implant failure), (2) clinical parameters (posterior implant location and bone grade 4) or (3) decisions made by the clinician (low initial stability, more than one implant placed during surgery, inflammation at the surgical site during the first year or using an overdenture with conus-type connection). Clinicians should be cautions throughout the treatment process of dental implant-from the initial examination to the treatment planning, surgical operation and prosthesis selection-in order to minimize the risk of late failure of dental implant.

Inotodiol is a lanostane triterpenoid found only in Chaga mushroom. In the previous study investigating anti-allergic effects of fractionated Chaga mushroom extracts, we have found evidence that purified inotodiol holds an activity to suppress the mast cell function in vivo. To address the therapeutic relevance of the finding, in this study, we investigated whether inotodiol could also alleviate allergy symptoms observed in a chicken ovalbumin (cOVA)-induced mouse model of food allergy. Like the crude 70% ethanol extract of Chaga mushroom (320 mg/kg), oral administration of inotodiol (20 mg/kg), regardless of whether that was for preventive or treatment purpose, resulted in a significant improvement in allergic symptoms and inflammatory lesions in the small intestine appearing after repeated oral challenge with cOVA. Despite the results that inotodiol (20 mg/kg) and the Chaga mushroom extract (320 mg/kg) took effect to a similar extent, immunological mechanisms underlying those effects were found to be distinct from each other. That is, the results obtained from several in vivo assays, including mast cell-mediated passive systemic anaphylaxis, activation/proliferation of adoptively transferred antigen-specific T cells and immunoglobulin (IgG1, IgE, IgA) production by antigen-specific B cells, illustrated that inotodiol selectively inhibited the mast cell function without having any noticeable effect on other immune responses while the crude Chaga mushroom extract indiscriminately suppressed diverse immune responses. The strong anti-allergic activity of inotodiol, along with its remarkable selectivity to mast cell, makes it an excellent therapeutic candidate for food allergy with both high efficacy and outstanding safety., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study aimed to compare the in vivo effectiveness between curcumin-oligochitosan nanoplexes (CUR-OCH nanoplexes) and oligochitosan-coated curcumin-encapsulated liposomes (OCH-Lip-CUR) with respect to wound healing and scar treatment. Firstly, CUR-OCH nanoplexes was prepared by drug-polysaccharide complexation method and OCH-Lip-CUR was prepared by a combining method of lipid-film hydration and sonication. Their in vitro cytotoxicity and in vivo wound healing and scar treatment effectiveness were evaluated using 3T3 cells and mice Mus musculus var. Albino, respectively. The resutls indicated that both of them were in nanosize with a moderate PDI (less than 0.3), and exhibited negligible cytotoxicity at low CUR concentration (0.01 mg/mL). Moreover, their application onto wounds resulted in faster healing and higher scar treatment effectiveness than control samples. Interestingly, OCH-Lip-CUR exhibited higher in vivo effectiveness than CUR-OCH nanoplexes. However, based on their own advantages, both of them were good candidates for a commercial formulation for wound healing and scar treatment.

A pilot-scale hybrid constructed wetland with vertical flow and horizontal flow in series was constructed and used to investigate organic material and nutrient removal rate constants for wastewater treatment and establish a practical predictive model for use. For this purpose, the performance of multiple parameters was statistically evaluated during the process and predictive models were suggested. The measurement of the kinetic rate constant was based on the use of the first-order derivation and Monod kinetic derivation (Monod) paired with a plug flow reactor (PFR) and a continuously stirred tank reactor (CSTR). Both the Lindeman, Merenda, and Gold (LMG) analysis and Bayesian model averaging (BMA) method were employed for identifying the relative importance of variables and their optimal multiple regression (MR). The results showed that the first-order-PFR (M 2 ) model did not fit the data (P > 0.05, and R 2  < 0.5), whereas the first-order-CSTR (M 1 ) model for the chemical oxygen demand (COD Cr ) and Monod-CSTR (M 3 ) model for the COD Cr and ammonium nitrogen (NH 4 -N) showed a high correlation with the experimental data (R 2  > 0.5). The pollutant removal rates in the case of M 1 were 0.19 m/d (COD Cr ) and those for M 3 were 25.2 g/m 2 ∙d for COD Cr and 2.63 g/m 2 ∙d for NH 4 -N. By applying a multi-variable linear regression method, the optimal empirical models were established for predicting the final effluent concentration of five days' biochemical oxygen demand (BOD 5 ) and NH 4 -N. In general, the hydraulic loading rate was considered an important variable having a high value of relative importance, which appeared in all the optimal predictive models., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fiber-based sensors integrated on textiles or clothing systems are required for the next generation of wearable electronic platforms. Fiber-based physical sensors are developed, but the development of fiber-based temperature sensors is still limited. Herein, a new approach to develop wearable temperature sensors that use freestanding single reduction graphene oxide (rGO) fiber is proposed. A freestanding and wearable temperature-responsive rGO fiber with tunable thermal index is obtained using simple wet spinning and a controlled graphene oxide reduction time. The freestanding fiber-based temperature sensor shows high responsivity, fast response time (7 s), and good recovery time (20 s) to temperature. It also maintains its response under an applied mechanical deformation. The fiber device fabricated by means of a simple process is easily integrated into fabric such as socks or undershirts and can be worn by a person to monitor the temperature of the environment and skin temperature without interference during movement and various activities. These results demonstrate that the freestanding fiber-based temperature sensor has great potential for fiber-based wearable electronic platforms. It is also promising for applications in healthcare and biomedical monitoring., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. CC treatment options are very limited especially for patients with distant metastasis. Kangai 1 C-terminal interacting tetraspanin (KITENIN) is highly expressed in numerous cancers, but the role of KITENIN in CC remains unknown. Here, we have investigated for the first time the function of KITENIN in human CC cell lines (TFK-1, SZ-1), tissues and a CC mouse model (Alb-Cre/LSL-KRAS G12D /p53 L/L ). KITENIN was expressed in 92.2% of human CC tissues, in murine CC samples and also in human CC cell lines. Knockdown of KITENIN by small interfering RNA (siRNA) effectively reduced proliferation, migration, invasion and colony formation in both intra- and extra-hepatic CC cells. The expression of epithelial-mesenchymal transition (EMT) markers like N-cadherin, Vimentin, Snail and Slug were suppressed in KITENIN knockdown CC cells. Our results indicate that KITENIN is crucial for cholangiocarcinogenesis and it might become a potential therapeutic target for human CC treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Methods for the analysis of chromatin immunoprecipitation sequencing (ChIP-seq) data start by aligning the short reads to a reference genome. While often successful, they are not appropriate for cases where a reference genome is not available. Here we develop methods for de novo analysis of ChIP-seq data. Our methods combine de novo assembly with statistical tests enabling motif discovery without the use of a reference genome. We validate the performance of our method using human and mouse data. Analysis of fly data indicates that our method outperforms alignment based methods that utilize closely related species.

Motivation: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. MiRNAs were shown to play an important role in development and disease, and accurately determining the networks regulated by these miRNAs in a specific condition is of great interest. Early work on miRNA target prediction has focused on using static sequence information. More recently, researchers have combined sequence and expression data to identify such targets in various conditions., Results: We developed the Protein Interaction-based MicroRNA Modules (PIMiM), a regression-based probabilistic method that integrates sequence, expression and interaction data to identify modules of mRNAs controlled by small sets of miRNAs. We formulate an optimization problem and develop a learning framework to determine the module regulation and membership. Applying PIMiM to cancer data, we show that by adding protein interaction data and modeling cooperative regulation of mRNAs by a small number of miRNAs, PIMiM can accurately identify both miRNA and their targets improving on previous methods. We next used PIMiM to jointly analyze a number of different types of cancers and identified both common and cancer-type-specific miRNA regulators., Supplementary Information: Supplementary data are available at Bioinformatics online.

Background: Disease progression in the absence of therapy varies significantly in HIV-1 infected individuals. Both viral and host cellular molecules are implicated; however, the exact role of these factors and/or the mechanism involved remains elusive. To understand how microRNAs (miRNAs), which are regulators of transcription and translation, influence host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative miRNA and mRNA microarray analysis using PBMCs obtained from infected individuals with distinct viral load and CD4 counts., Methods: RNA isolated from PBMCs obtained from HIV-1 seronegative and HIV-1 positive individuals with distinct viral load and CD4 counts were assessed for miRNA and mRNA profile. Selected miRNA and mRNA transcripts were validated using in vivo and in vitro infection model., Results: Our results indicate that HIV-1 positive individuals with high viral load (HVL) showed a dysregulation of 191 miRNAs and 309 mRNA transcripts compared to the uninfected age and sex matched controls. The miRNAs miR-19b, 146a, 615-3p, 382, 34a, 144 and 155, that are known to target innate and inflammatory factors, were significantly upregulated in PBMCs with high viral load, as were the inflammatory molecules CXCL5, CCL2, IL6 and IL8, whereas defensin, CD4, ALDH1, and Neurogranin (NRGN) were significantly downregulated. Using the transcriptome profile and predicted target genes, we constructed the regulatory networks of miRNA-mRNA pairs that were differentially expressed between control, LVL and HVL subjects. The regulatory network revealed an inverse correlation of several miRNA-mRNA pair expression patterns, suggesting HIV-1 mediated transcriptional regulation is in part likely through miRNA regulation., Conclusions: Results from our studies indicate that gene expression is significantly altered in PBMCs in response to virus replication. It is interesting to note that the infected individuals with low or undetectable viral load exhibit a gene expression profile very similar to control or uninfected subjects. Importantly, we identified several new mRNA targets (Defensin, Neurogranin, AIF) as well as the miRNAs that could be involved in regulating their expression through the miRNA-mRNA interaction.

Sequencing of RNAs (RNA-Seq) has revolutionized the field of transcriptomics, but the reads obtained often contain errors. Read error correction can have a large impact on our ability to accurately assemble transcripts. This is especially true for de novo transcriptome analysis, where a reference genome is not available. Current read error correction methods, developed for DNA sequence data, cannot handle the overlapping effects of non-uniform abundance, polymorphisms and alternative splicing. Here we present SEquencing Error CorrEction in Rna-seq data (SEECER), a hidden Markov Model (HMM)-based method, which is the first to successfully address these problems. SEECER efficiently learns hundreds of thousands of HMMs and uses these to correct sequencing errors. Using human RNA-Seq data, we show that SEECER greatly improves on previous methods in terms of quality of read alignment to the genome and assembly accuracy. To illustrate the usefulness of SEECER for de novo transcriptome studies, we generated new RNA-Seq data to study the development of the sea cucumber Parastichopus parvimensis. Our corrected assembled transcripts shed new light on two important stages in sea cucumber development. Comparison of the assembled transcripts to known transcripts in other species has also revealed novel transcripts that are unique to sea cucumber, some of which we have experimentally validated. Supporting website: http://sb.cs.cmu.edu/seecer/.

Host cells respond to exogenous infectious agents such as viruses, including HIV-1. Studies have evaluated the changes associated with virus infection at the transcriptional and translational levels of the cellular genes involved in specific pathways. While this approach is useful, in our view it provides only a partial view of genome-wide changes. Recently, technological advances in the expression profiling at the microRNA (miRNA) and mRNA levels have made it possible to evaluate the changes in the components of multiple pathways. To understand the role of miRNA and its interplay with host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative global miRNA and mRNA microarray using human PBMCs infected with HIV-1. The PBMCs were derived from multiple donors and were infected with virus generated from the molecular clone pNL4-3. The results showed that HIV-1 infection led to altered regulation of 21 miRNAs and 444 mRNA more than 2-fold, with a statistical significance of p<0.05. Furthermore, the differentially regulated miRNA and mRNA were shown to be associated with host cellular pathways involved in cell cycle/proliferation, apoptosis, T-cell signaling, and immune activation. We also observed a number of inverse correlations of miRNA and mRNA expression in infected PBMCs, further confirming the interrelationship between miRNA and mRNA regulation during HIV-1 infection. These results for the first time provide evidence that the miRNA profile could be an early indicator of host cellular dysfunction induced by HIV-1.

Motivation: Expression databases, including the Gene Expression Omnibus and ArrayExpress, have experienced significant growth over the past decade and now hold hundreds of thousands of arrays from multiple species. Since most drugs are initially tested on model organisms, the ability to compare expression experiments across species may help identify pathways that are activated in a similar way in humans and other organisms. However, while several methods exist for finding co-expressed genes in the same species as a query gene, looking at co-expression of homologs or arbitrary genes in other species is challenging. Unlike sequence, which is static, expression is dynamic and changes between tissues, conditions and time. Thus, to carry out cross-species analysis using these databases, we need methods that can match experiments in one species with experiments in another species., Results: To facilitate queries in large databases, we developed a new method for comparing expression experiments from different species. We define a distance metric between the ranking of orthologous genes in the two species. We show how to solve an optimization problem for learning the parameters of this function using a training dataset of known similar expression experiments pairs. The function we learn outperforms previous methods and simpler rank comparison methods that have been used in the past for single species analysis. We used our method to compare millions of array pairs from mouse and human expression experiments. The resulting matches can be used to find functionally related genes, to hypothesize about biological response mechanisms and to highlight conditions and diseases that are activating similar pathways in both species., Availability: Supporting methods, results and a Matlab implementation are available from http://sb.cs.cmu.edu/ExpQ/.

We present efficient cache-oblivious algorithms for some well-studied string problems in bioinformatics including the longest common subsequence, global pairwise sequence alignment and three-way sequence alignment (or median), both with affine gap costs, and RNA secondary structure prediction with simple pseudoknots. For each of these problems, we present cache-oblivious algorithms that match the best-known time complexity, match or improve the best-known space complexity, and improve significantly over the cache-efficiency of earlier algorithms. We present experimental results which show that our cache-oblivious algorithms run faster than software and implementations based on previous best algorithms for these problems.

The purpose of this paper is to investigate the relationship between clinical outcome and the intactness of cagPAI in Helicobacter pylori strains from Vietnam. The presence or absence of 30 cagPAI genes was investigated by polymerase chain reaction (PCR) and dot-blotting. H. pylori-induced interleukin-8 secretion and hummingbird phenotype, and H. pylori adhesion to gastric epithelial cells were examined. The serum concentration of pepsinogen 1, pepsinogen 2, and gastrin was also measured in all patients. cagPAI was present in all 103 Vietnamese H. pylori isolates, of which 91 had intact cagPAI and 12 contained only a part of cagPAI. Infection with the partial cagPAI strains was less likely to be associated with peptic ulcer and chronic gastric mucosal inflammation than infection with strains possessing intact cagPAI. The partial cagPAI strains lacked almost all ability to induce interleukin-8 secretion and the hummingbird phenotype in gastric cells. Their adhesion to epithelial cells was significantly decreased in comparison with intact cagPAI strains. Moreover, for the first time, we found an association between cagPAI status and the serum concentration of pepsinogens 1 and 2 in infected patients. H. pylori strains with internal deletion within cagPAI are less virulent and, thus, less likely to be associated with severe clinical outcomes.

Background: Infections with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging worldwide. We investigated an outbreak of severe CA-MRSA infections in children following out-patient vaccination., Methods and Findings: We carried out a field investigation after adverse events following immunization (AEFI) were reported. We reviewed the clinical data from all cases. S. aureus recovered from skin infections and from nasal and throat swabs were analyzed by pulse-field gel electrophoresis, multi locus sequence typing, PCR and microarray. In May 2006, nine children presented with AEFI, ranging from fatal toxic shock syndrome, necrotizing soft tissue infection, purulent abscesses, to fever with rash. All had received a vaccination injection in different health centres in one District of Ho Chi Minh City. Eight children had been vaccinated by the same health care worker (HCW). Deficiencies in vaccine quality, storage practices, or preparation and delivery were not found. Infection control practices were insufficient. CA-MRSA was cultured in four children and from nasal and throat swabs from the HCW. Strains from children and HCW were indistinguishable. All carried the Panton-Valentine leukocidine (PVL), the staphylococcal enterotoxin B gene, the gene complex for staphylococcal-cassette-chromosome mec type V, and were sequence type 59. Strain HCM3A is epidemiologically unrelated to a strain of ST59 prevalent in the USA, although they belong to the same lineage., Conclusions: We describe an outbreak of infections with CA-MRSA in children, transmitted by an asymptomatic colonized HCW during immunization injection. Consistent adherence to injection practice guidelines is needed to prevent CA-MRSA transmission in both in- and outpatient settings.

Identifying common patterns among area cladograms that arise in historical biogeography is an important tool for biogeographical inference. We develop the first rigorous formalization of these pattern-identification problems. We develop metrics to compare area cladograms. We define the maximum agreement area cladogram (MAAC) and we develop efficient algorithms for finding the MAAC of two area cladograms, while showing that it is NP-hard to find the MAAC of several binary area cladograms. We also describe a linear-time algorithm to identify if two area cladograms are identical.

Background: Recent outbreaks of avian influenza A (H5N1) in poultry throughout Asia have had major economic and health repercussions. Human infections with this virus were identified in Vietnam in January 2004., Methods: We report the clinical features and preliminary epidemiologic findings among 10 patients with confirmed cases of avian influenza A (H5N1) who presented to hospitals in Ho Chi Minh City and Hanoi, Vietnam, in December 2003 and January 2004., Results: In all 10 cases, the diagnosis of influenza A (H5N1) was confirmed by means of viral culture or reverse transcriptase-polymerase chain reaction with primers specific for H5 and N1. None of the 10 patients (mean age, 13.7 years) had preexisting medical conditions. Nine of them had a clear history of direct contact with poultry (median time before onset of illness, three days). All patients presented with fever (temperature, 38.5 to 40.0 degrees C), respiratory symptoms, and clinically significant lymphopenia (median lymphocyte count, 700 per cubic millimeter). The median platelet count was 75,500 per cubic millimeter. Seven patients had diarrhea. In all patients, there were marked abnormalities on chest radiography. There was no definitive evidence of human-to-human transmission. Eight patients died, one patient has recovered, and one is recovering., Conclusions: Influenza A (H5N1) infection, characterized by fever, respiratory symptoms, and lymphopenia, carries a high risk of death. Although in all 10 cases the infection appears to have been acquired directly from infected poultry, the potential exists for genetic reassortment with human influenzaviruses and the evolution of human-to-human transmission. Containment of influenza A (H5N1) in poultry throughout Asia is therefore urgently required., (Copyright 2004 Massachusetts Medical Society)

The aim of this project is to expand DIOGENE with a centralized and integrated patient clinical database system providing a standardized framework for the building of future clinical databases and for the integration of existing heterogeneous ones. The combined 'across time view' and 'across departments view' generated from the integrated clinical data will enable an evolutionary view of the patient state both across time and across medical specialties. For this purpose and to permit the communication and exchange of data, a new controlled vocabulary for representing clinical data has been created. The construction of this vocabulary is based on the international ICD classification, already being used in DIOGENE for encoding patient diagnosis and procedures. A new extension of the ICD is proposed for medical information that goes beyond diagnosis and procedures encoding. The building of a common clinical finding dictionary recording the definition of findings is based on this newly developed clinical vocabulary. This process is incremental, manual, and significant.

The development of Open Systems Architecture and the extensive networked interconnection of Health and Hospital Information Systems (HIS) offer great opportunities for improved care, but simultaneously these facilities pose a great danger to the overall security of the information held. The Geneva University Hospital which has built up it centralized informatics system over the last twenty years must now bring about the conditions for a migration towards open system, for although during the last ten years there have been declarations of intent, this architecture is still a long way from final implementation. Like others, the DIOGENE system (the Geneva HIS) has had to face difficult choices especially due to its own successful situation at the end of the eighties. This paper gives a brief explanation of the technical conditions needed in order to fully migrate towards an open system. The first choices towards obtaining optimum communication standards, operating systems and database management systems were the easiest. The real difficulties occurred when deciding on the choice for management tools in this open environment.