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1.
Pediatr Neurol ; 155: 177-181, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38669800

ABSTRACT

BACKGROUND: Despite extensive research on Guillain-Barré syndrome (GBS) in adults and children, there is a lack of comparison regarding short-term outcomes in various age groups. Our study aims to elucidate the differences in clinical features and short-term outcomes in Vietnam. METHODS: After retrospective data collection, we compared clinical features in patients with GBS aged ≤16 years at Children's Hospital 2 and aged >16 years at University Medical Center Ho Chi Minh City from 2017 to 2021. A positive short-term outcome was recorded if patients had a GBS Disability Score of 0 to 2 at hospital discharge. RESULTS: We analyzed 109 adults (58.7% males; mean age 50.6 ± 17.7) and 111 children (58.6% males; mean age 7.2 ± 4.9). Comparable antecedent infection and immunization incidence in both groups were observed (35.8% vs 45.9%, P > 0.05). Pain and sensory disturbance were the most common onset symptom in adults (57.8%), whereas lower limb weakness predominated in children (61.3%). Ophthalmoplegia (18.3% vs 5.4%), pain, sensory disturbance (85.3% vs 67.6%), ataxia (33.0% vs 15.3%) were more prevalent in adults (P < 0.05). The axonal subtype was prominent in both adults (51.4%) and children (53.2%). Patients were classified into: classic GBS (49.5% and 68.5%), GBS variants (11.0% and 15.3%), classic Miller Fisher syndrome (MFS) (1.8% and 1.8%), MFS variants (2.8% and 0%), and GBS/MFS overlap (34.9% and 14.4%). Short-term outcomes did not significantly differ based on age. CONCLUSIONS: Age-related variations in clinical features were observed, but adults and children exhibited similar short-term functional outcomes.


Subject(s)
Guillain-Barre Syndrome , Humans , Guillain-Barre Syndrome/epidemiology , Guillain-Barre Syndrome/physiopathology , Guillain-Barre Syndrome/diagnosis , Vietnam/epidemiology , Male , Female , Retrospective Studies , Child , Adult , Middle Aged , Adolescent , Child, Preschool , Young Adult , Aged , Age Factors
2.
Ann Med Surg (Lond) ; 86(1): 580-587, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38222770

ABSTRACT

Introduction: Mesenchymal chondrosarcoma (MC) is a rapidly progressive sarcoma that predominantly impacts the bones. Making up only 3% of chondrosarcomas, about one-third of these tumours develop in extra-skeletal sites. Case presentation: The authors present a clinical case of a 42-year-old patient who was diagnosed with MC 8 years ago, now admitted to the hospital with a palpable epigastric mass. Clinical and laboratory examinations showed consistent results for MC tumours, with metastasis to the body and tail of the pancreas and invasion of the splenic vein. Surgical resection and systemic screening were performed to ensure that there were no lesions elsewhere. Regular follow-up has found no localized lesions or complications after 15 months. Clinical discussion: Metastatic extra-skeletal mesenchymal chondrosarcoma of the pancreas is exceptionally rare. To our current understanding, only 14 such cases have been documented in medical literature. The symptoms of pancreatic metastasis are diverse and the radiographic features of metastatic mesenchymal chondrosarcoma are not typically distinct. Conclusions: Although MC tumours do not frequently occur in sites other than the axial system, a tumour presenting later in a patient with a history of MC should be reviewed to confirm the diagnosis of metastatic MC. Treatment can vary between surgery, radiation therapy and systemic therapy.

3.
World J Pediatr Congenit Heart Surg ; 15(3): 287-297, 2024 05.
Article in English | MEDLINE | ID: mdl-38263638

ABSTRACT

BACKGROUND: This article aims to demonstrate the morphology of 261 total anomalous pulmonary venous connection (TAPVC) cases operated at Children's Hospital 1 with in-hospital mortality of 19.5% (51/261). METHODS: All the surgical protocols of TAPVC cases repaired between 2008 and June 2023 were reviewed. The descriptions of TAPVC were based on operative findings by surgeons. RESULTS: A total of 261 TAPVC patients were operated, including 124 (47.5%) supra, 83 (31.8%) intra, 41 (15.7%) infra, and 13 (5%) mixed cases. The in-hospital mortality was 19.5% (51/261). Fifteen cases are associated with other anomalies of the heart. Four subtypes of 124 supra TAPVC were found, with 42 (33.9%) obstructed cases. The standard was all pulmonary veins (PVs) forming a common vein (CV) and draining into the innominate veins, then going to the superior vena cava (SVC) (100/124, 80.6%). Eleven supra TAPVC cases were vascular vise type. Ten cases had the vertical vein running from the right of the CV and draining directly into the SVC. Of 83 intracardiac TAPVCs with 9 (10.8%) obstructed cases, the most common was all PVs draining directly into the coronary sinus (60/83, 72.3%). The second was all PVs draining directly into the right atrium (RA) via separated ostia or forming a CV before entering the RA (17/83, 20.5%). Also, there were three cases with rare variants and 100% obstruction when the diagnosis was explored. The in-hospital mortality of intracardiac type was 13.3% (11/83) 41 infra TAPVC with obstructed rate of 61% (25/41) and in-hospital mortality of 29.3% (12/41). Thirteen mixed TAPVCs were repaired, with most cases having three PVs forming a CV. CONCLUSION: This article provides valuable information about the morphology of TAPVC types in Asian patients.


Subject(s)
Hospital Mortality , Pulmonary Veins , Scimitar Syndrome , Humans , Female , Male , Scimitar Syndrome/surgery , Scimitar Syndrome/mortality , Vietnam/epidemiology , Retrospective Studies , Pulmonary Veins/abnormalities , Pulmonary Veins/surgery , Infant , Infant, Newborn , Child, Preschool , Cardiac Surgical Procedures/methods , Child
4.
Polymers (Basel) ; 15(5)2023 Feb 21.
Article in English | MEDLINE | ID: mdl-36904320

ABSTRACT

Injection molding has become an increasingly widely used method in the production of plastic parts. The injection process can be separated into five steps: mold closure, filling, packing, cooling, and product ejection. Before the melted plastic is loaded into the mold, the mold needs to be raised to a specified temperature, in order to increase the mold's filling capacity and improve the resultant product quality. One of the easy methods used to control a mold's temperature is to provide hot water through a cooling channel in the mold, to raise the temperature. In addition, this channel can be used for cooling the mold with cool fluid. This is simple, effective, and cost efficient, involving uncomplicated products. To improve the heating effectiveness of the hot water, a conformal cooling-channel design is considered in this paper. Through heat-transfer simulation using the CFX module in the Ansys software, an optimal cooling channel was defined according to the simulation result, using the Taguchi method integrated with principal component analysis. The comparison of traditional vs. conformal cooling channels revealed higher temperature rises in the first 100 s in both molds. During heating, conformal cooling produced higher temperatures compared with traditional cooling. Conformal cooling demonstrated better performance, with average temperature peaking at 58.78 °C and a range of 63.4 °C (max) to 54.66 °C (min). Traditional cooling resulted in an average steady-state temperature of 56.63 °C and a range of 61.74 °C (max) to 53.18 °C (min). Finally, the simulation results were verified experimentally.

5.
Microorganisms ; 11(2)2023 Feb 16.
Article in English | MEDLINE | ID: mdl-36838456

ABSTRACT

Locus-specific gene amplification and genome-wide endoreplication generate the elevated copy number of ribosomal DNA (rDNA, 9000 C) and non-rDNA (90 C) chromosomes in the developing macronucleus of Tetrahymena thermophila. Subsequently, all macronuclear chromosomes replicate once per cell cycle during vegetative growth. Here, we describe an unanticipated, programmed switch in the regulation of replication initiation in the rDNA minichromosome. Early in development, the 21 kb rDNA minichromosome is preferentially amplified from 2 C to ~800 C from well-defined origins, concurrent with genome-wide endoreplication (2 C to 8-16 C) in starved mating Tetrahymena (endoreplication (ER) Phase 1). Upon refeeding, rDNA and non-rDNA chromosomes achieve their final copy number through resumption of just the endoreplication program (ER Phase 2). Unconventional rDNA replication intermediates are generated primarily during ER phase 2, consistent with delocalized replication initiation and possible formation of persistent RNA-DNA hybrids. Origin usage and replication fork elongation are affected in non-rDNA chromosomes as well. Despite the developmentally programmed 10-fold reduction in the ubiquitous eukaryotic initiator, the Origin Recognition Complex (ORC), active initiation sites are more closely spaced in ER phases 1 and 2 compared to vegetative growing cells. We propose that initiation site selection is relaxed in endoreplicating macronuclear chromosomes and may be less dependent on ORC.

7.
Ann Med Surg (Lond) ; 78: 103785, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35734662

ABSTRACT

Background: Biliary cystadenoma is a rare cystic neoplasm of the liver. The clinical signs and symptoms are nonspecific, and treatment strategy is variable. Case presentation: In this study, we presented a case of a 32-year-old female with multilocular biliary cystadenoma. The patient underwent partial removal of the hepatic cyst two times in two different hospitals for two years and that the histopathological results were biliary cystic adenoma but was successfully treated by radical resection after the second recurrence. The patient underwent a J-shaped laparotomy. The giant cystic mass measuring 20 cm × 15 cm was below the position of the right anterior segment. This lesion pushed the liver parenchyma to both sides and compressed the hepatic hilum, causing dilatation of the intrahepatic bile ducts. The patient underwent complete resection of cystic mass. During the dissection, a 0.5mm-diameter fistula of left hepatic duct with the cyst was found. It was sutured using absorbable polydioxanone (PDS 6.0) and the cystic duct tube (C tube) (6 Fr) was inserted via the cystic duct into the left hepatic duct due to drain the bile fluid. Discussion: A biliary cystadenoma (BCA) primary origin is occasionally rare. Although imaging modalities such as ultrasound, computed tomography and magnetic resonance imaging could be suggestive, however, the definitive diagnosis is depended on the histological examination. Despite of being a benign tumor, it has a high risk of recurrence after conservative treatment. The potential risk for malignant is also present. Therefore, complete resection of the tumors is the treatment of choice. Conclusion: We herein present a report of a rare case with had a giant biliary cystadenoma (BCA) primary origin. This report aims to improve the understanding of the diagnosis and management of this uncommon disease.

8.
J Am Chem Soc ; 144(26): 11608-11619, 2022 07 06.
Article in English | MEDLINE | ID: mdl-35700317

ABSTRACT

NMR spectroscopy is a powerful tool to investigate molecular structure and dynamics. The poor sensitivity of this technique, however, limits its ability to tackle questions requiring dilute samples. Low-concentration photochemically induced dynamic nuclear polarization (LC-photo-CIDNP) is an optically enhanced NMR technology capable of addressing the above challenge by increasing the detection limit of aromatic amino acids in solution up to 1000-fold, either in isolation or within proteins. Here, we show that the absence of NMR-active nuclei close to a magnetically active site of interest (e.g., the structurally diagnostic 1Hα-13Cα pair of amino acids) is expected to significantly increase LC-photo-CIDNP hyperpolarization. Then, we exploit the spin-diluted tryptophan isotopolog Trp-α-13C-ß,ß,2,4,5,6,7-d7 and take advantage of the above prediction to experimentally achieve a ca 4-fold enhancement in NMR sensitivity over regular LC-photo-CIDNP. This advance enables the rapid (within seconds) detection of 20 nM concentrations or the molecule of interest, corresponding to a remarkable 3 ng detection limit. Finally, the above Trp isotopolog is amenable to incorporation within proteins and is readily detectable at a 1 µM concentration in complex cell-like media, including Escherichia coli cell-free extracts.


Subject(s)
Proteins , Tryptophan , Amino Acids , Isotope Labeling , Magnetic Resonance Spectroscopy/methods , Tryptophan/chemistry
9.
BMC Med Genomics ; 14(Suppl 3): 225, 2021 11 17.
Article in English | MEDLINE | ID: mdl-34789252

ABSTRACT

BACKGROUND: Developing efficient and successful computational methods to infer potential miRNA-disease associations is urgently needed and is attracting many computer scientists in recent years. The reason is that miRNAs are involved in many important biological processes and it is tremendously expensive and time-consuming to do biological experiments to verify miRNA-disease associations. METHODS: In this paper, we proposed a new method to infer miRNA-disease associations using collaborative filtering and resource allocation algorithms on a miRNA-disease-lncRNA tripartite graph. It combined the collaborative filtering algorithm in CFNBC model to solve the problem of imbalanced data and the method for association prediction established multiple types of known associations among multiple objects presented in TPGLDA model. RESULTS: The experimental results showed that our proposed method achieved a reliable performance with Area Under Roc Curve (AUC) and Area Under Precision-Recall Curve (AUPR) values of 0.9788 and 0.9373, respectively, under fivefold-cross-validation experiments. It outperformed than some other previous methods such as DCSMDA and TPGLDA. Furthermore, it demonstrated the ability to derive new associations between miRNAs and diseases among 8, 19 and 14 new associations out of top 40 predicted associations in case studies of Prostatic Neoplasms, Heart Failure, and Glioma diseases, respectively. All of these new predicted associations have been confirmed by recent literatures. Besides, it could discover new associations for new diseases (or miRNAs) without any known associations as demonstrated in the case study of Open-angle glaucoma disease. CONCLUSION: With the reliable performance to infer new associations between miRNAs and diseases as well as to discover new associations for new diseases (or miRNAs) without any known associations, our proposed method can be considered as a powerful tool to infer miRNA-disease associations.


Subject(s)
Computational Biology , Genetic Predisposition to Disease , MicroRNAs , Algorithms , Computational Biology/methods , Glaucoma, Open-Angle , Humans , Male , MicroRNAs/genetics
10.
Sci Rep ; 11(1): 21071, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34702958

ABSTRACT

Predicting beneficial and valuable miRNA-disease associations (MDAs) by doing biological laboratory experiments is costly and time-consuming. Proposing a forceful and meaningful computational method for predicting MDAs is essential and captivated many computer scientists in recent years. In this paper, we proposed a new computational method to predict miRNA-disease associations using improved random walk with restart and integrating multiple similarities (RWRMMDA). We used a WKNKN algorithm as a pre-processing step to solve the problem of sparsity and incompletion of data to reduce the negative impact of a large number of missing associations. Two heterogeneous networks in disease and miRNA spaces were built by integrating multiple similarity networks, respectively, and different walk probabilities could be designated to each linked neighbor node of the disease or miRNA node in line with its degree in respective networks. Finally, an improve extended random walk with restart algorithm based on miRNA similarity-based and disease similarity-based heterogeneous networks was used to calculate miRNA-disease association prediction probabilities. The experiments showed that our proposed method achieved a momentous performance with Global LOOCV AUC (Area Under Roc Curve) and AUPR (Area Under Precision-Recall Curve) values of 0.9882 and 0.9066, respectively. And the best AUC and AUPR values under fivefold cross-validation of 0.9855 and 0.8642 which are proven by statistical tests, respectively. In comparison with other previous related methods, it outperformed than NTSHMDA, PMFMDA, IMCMDA and MCLPMDA methods in both AUC and AUPR values. In case studies of Breast Neoplasms, Carcinoma Hepatocellular and Stomach Neoplasms diseases, it inferred 1, 12 and 7 new associations out of top 40 predicted associated miRNAs for each disease, respectively. All of these new inferred associations have been confirmed in different databases or literatures.


Subject(s)
Algorithms , Breast Neoplasms/genetics , Genetic Predisposition to Disease , MicroRNAs/genetics , Models, Genetic , RNA, Neoplasm/genetics , Female , Genetic Association Studies , Humans
11.
Mol Biol Cell ; 32(15): 1335-1346, 2021 07 15.
Article in English | MEDLINE | ID: mdl-34010017

ABSTRACT

Endogenous RNA interference (RNAi) pathways regulate a wide range of cellular processes in diverse eukaryotes, yet in the ciliated eukaryote, Tetrahymena thermophila, the cellular purpose of RNAi pathways that generate ∼23-24 nucleotide (nt) small (s)RNAs has remained unknown. Here, we investigated the phenotypic and gene expression impacts on vegetatively growing cells when genes involved in ∼23-24 nt sRNA biogenesis are disrupted. We observed slower proliferation and increased expression of genes involved in DNA metabolism and chromosome organization and maintenance in sRNA biogenesis mutants RSP1Δ, RDN2Δ, and RDF2Δ. In addition, RSP1Δ and RDN2Δ cells frequently exhibited enlarged chromatin extrusion bodies, which are nonnuclear, DNA-containing structures that may be akin to mammalian micronuclei. Expression of homologous recombination factor Rad51 was specifically elevated in RSP1Δ and RDN2Δ strains, with Rad51 and double-stranded DNA break marker γ-H2A.X localized to discrete macronuclear foci. In addition, an increase in Rad51 and γ-H2A.X foci was also found in knockouts of TWI8, a macronucleus-localized PIWI protein. Together, our findings suggest that an evolutionarily conserved role for RNAi pathways in maintaining genome integrity may be extended even to the early branching eukaryotic lineage that gave rise to Tetrahymena thermophila.


Subject(s)
DNA Repair , RNA, Small Interfering/metabolism , Tetrahymena thermophila/genetics , Tetrahymena thermophila/metabolism , DNA/metabolism , DNA Breaks, Double-Stranded , Evolution, Molecular , Gene Expression Profiling , Gene Expression Regulation , Protozoan Proteins , Rad51 Recombinase/genetics , Recombinational DNA Repair , Sequence Analysis, RNA
12.
Elife ; 102021 04 16.
Article in English | MEDLINE | ID: mdl-33860765

ABSTRACT

The essential Smc5/6 complex is required in response to replication stress and is best known for ensuring the fidelity of homologous recombination. Using single-molecule tracking in live fission yeast to investigate Smc5/6 chromatin association, we show that Smc5/6 is chromatin associated in unchallenged cells and this depends on the non-SMC protein Nse6. We define a minimum of two Nse6-dependent sub-pathways, one of which requires the BRCT-domain protein Brc1. Using defined mutants in genes encoding the core Smc5/6 complex subunits, we show that the Nse3 double-stranded DNA binding activity and the arginine fingers of the two Smc5/6 ATPase binding sites are critical for chromatin association. Interestingly, disrupting the single-stranded DNA (ssDNA) binding activity at the hinge region does not prevent chromatin association but leads to elevated levels of gross chromosomal rearrangements during replication restart. This is consistent with a downstream function for ssDNA binding in regulating homologous recombination.


Subject(s)
Cell Cycle Proteins/metabolism , Chromatin/metabolism , Schizosaccharomyces pombe Proteins/metabolism , Schizosaccharomyces/metabolism , Single Molecule Imaging
13.
Materials (Basel) ; 14(4)2021 Feb 18.
Article in English | MEDLINE | ID: mdl-33670695

ABSTRACT

In the injection molding field, the flow of plastic material is one of the most important issues, especially regarding the ability of melted plastic to fill the thin walls of products. To improve the melt flow length, a high mold temperature was applied with pre-heating of the cavity surface. In this paper, we present our research on the injection molding process with pre-heating by external gas-assisted mold temperature control. After this, we observed an improvement in the melt flow length into thin-walled products due to the high mold temperature during the filling step. In addition, to develop the heating efficiency, a flow focusing device (FFD) was applied and verified. The simulations and experiments were carried out within an air temperature of 400 °C and heating time of 20 s to investigate a flow focusing device to assist with external gas-assisted mold temperature control (Ex-GMTC), with the application of various FFD types for the temperature distribution of the insert plate. The heating process was applied for a simple insert model with dimensions of 50 mm × 50 mm × 2 mm, in order to verify the influence of the FFD geometry on the heating result. After that, Ex-GMTC with the assistance of FFD was carried out for a mold-reading process, and the FFD influence was estimated by the mold heating result and the improvement of the melt flow length using acrylonitrile butadiene styrene (ABS). The results show that the air sprue gap (h) significantly affects the temperature of the insert and an air sprue gap of 3 mm gives the best heating rate, with the highest temperature being 321.2 °C. Likewise, the actual results show that the height of the flow focusing device (V) also influences the temperature of the insert plate and that a 5 mm high FFD gives the best results with a maximum temperature of 332.3 °C. Moreover, the heating efficiency when using FFD is always higher than without FFD. After examining the effect of FFD, its application was considered, in order to improve the melt flow length in injection molding, which increased from 38.6 to 170 mm, while the balance of the melt filling was also clearly improved.

14.
Environ Sci Pollut Res Int ; 28(10): 12131-12143, 2021 Mar.
Article in English | MEDLINE | ID: mdl-32948943

ABSTRACT

Nowadays, together with the economic development, public health activities have gained substantial attention with increasing number of hospitals during the past decades. A multi-method approach involving site visits, questionnaires, and interviews, in combination with secondary data revealed that the healthcare waste (HCW) generation, varied with different specialties (general or pediatric/obstetric hospitals) and different level of hospitals (central, provincial, district levels). The HCW generation from different kinds of surveyed hospitals varied from 0.8 to 1.0 kg/bed/day for domestic waste, 0.15 to 0.25 kg/bed/day for infectious and hazardous waste, and less than 0.1 kg/bed/day for recycled waste. Only 94.3% of central hospitals, 92% of provincial hospitals, and 82% of district hospitals complied with national regulation in hazardous medical waste treatment. For healthcare wastewater treatment, the actual operating rates were 91%, 73%, and 50% for central, provincial, and district hospitals, respectively. The cost for HCW management accounted for only 10-15% of the total budget allocated for the medical facilities. Most of the provincial hospitals spent about $0.2-$0.4/bed/year for HCW management. This is the root cause of ineffective HCW management.


Subject(s)
Medical Waste Disposal , Medical Waste , Waste Management , Child , Delivery of Health Care , Hazardous Waste , Humans , Vietnam
15.
BMC Med Inform Decis Mak ; 20(1): 108, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32546157

ABSTRACT

BACKGROUND: Predictive patient stratification is greatly emerging, because it allows us to prospectively identify which patients will benefit from what interventions before their condition worsens. In the biomedical research, a number of stratification methods have been successfully applied and have assisted treatment process. Because of heterogeneity and complexity of medical data, it is very challenging to integrate them and make use of them in practical clinic. There are two major challenges of data integration. Firstly, since the biomedical data has a high number of dimensions, combining multiple data leads to the hard problem of vast dimensional space handling. The computation is enormously complex and time-consuming. Secondly, the disparity of different data types causes another critical problem in machine learning for biomedical data. It has a great need to develop an efficient machine learning framework to handle the challenges. METHODS: In this paper, we propose a fast-multiple kernel learning framework, referred to as fMKL-DR, that optimise equations to calculate matrix chain multiplication and reduce dimensions in data space. We applied our framework to two case studies, Alzheimer's disease (AD) patient stratification and cancer patient stratification. We performed several comparative evaluations on various biomedical datasets. RESULTS: In the case study of AD patients, we enhanced significantly the multiple-ROIs approach based on MRI image data. The method could successfully classify not only AD patients and non-AD patients but also different phases of AD patients with AUC close to 1. In the case study of cancer patients, the framework was applied to six types of cancers, i.e., glioblastoma multiforme cancer, ovarian cancer, lung cancer, breast cancer, kidney cancer, and liver cancer. We efficiently integrated gene expression, miRNA expression, and DNA methylation. The results showed that the classification model basing on integrated datasets was much more accurate than classification model basing on the single data type. CONCLUSIONS: The results demonstrated that the fMKL-DR remarkably improves computational cost and accuracy for both AD patient and cancer patient stratification. We optimised the data integration, dimension reduction, and kernel fusion. Our framework has great potential for mining large-scale cohort data and aiding personalised prevention.


Subject(s)
Alzheimer Disease , Machine Learning , Alzheimer Disease/diagnostic imaging , Humans , Magnetic Resonance Imaging , Neoplasms/diagnostic imaging
16.
EBioMedicine ; 26: 132-137, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29191560

ABSTRACT

In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.


Subject(s)
Antipsychotic Agents/adverse effects , Medical Informatics/methods , Metoclopramide/adverse effects , Tardive Dyskinesia/pathology , Databases, Factual , Drug Interactions , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Humans , Risk Factors , Tardive Dyskinesia/chemically induced , Tardive Dyskinesia/epidemiology
17.
Nucleic Acids Res ; 45(16): 9481-9502, 2017 Sep 19.
Article in English | MEDLINE | ID: mdl-28934495

ABSTRACT

Developmentally programmed genome rearrangement accompanies differentiation of the silent germline micronucleus into the transcriptionally active somatic macronucleus in the ciliated protozoan Tetrahymena thermophila. Internal eliminated sequences (IES) are excised, followed by rejoining of MAC-destined sequences, while fragmentation occurs at conserved chromosome breakage sequences, generating macronuclear chromosomes. Some macronuclear chromosomes, referred to as non-maintained chromosomes (NMC), are lost soon after differentiation. Large NMC contain genes implicated in development-specific roles. One such gene encodes the domesticated piggyBac transposase TPB6, required for heterochromatin-dependent precise excision of IES residing within exons of functionally important genes. These conserved exonic IES determine alternative transcription products in the developing macronucleus; some even contain free-standing genes. Examples of precise loss of some exonic IES in the micronucleus and retention of others in the macronucleus of related species suggest an evolutionary analogy to introns. Our results reveal that germline-limited sequences can encode genes with specific expression patterns and development-related functions, which may be a recurring theme in eukaryotic organisms experiencing programmed genome rearrangement during germline to soma differentiation.


Subject(s)
Protozoan Proteins/metabolism , Tetrahymena thermophila/genetics , Transposases/metabolism , Chromosomes/genetics , Exons , Gene Rearrangement , Heterochromatin/genetics , Inverted Repeat Sequences , Macronucleus/genetics , Micronucleus, Germline , Protozoan Proteins/genetics , RNA Interference , Transposases/genetics
18.
Nat Commun ; 8: 14011, 2017 01 30.
Article in English | MEDLINE | ID: mdl-28134253

ABSTRACT

The Structural Maintenance of Chromosomes (SMC) complexes: cohesin, condensin and Smc5/6 are involved in the organization of higher-order chromosome structure-which is essential for accurate chromosome duplication and segregation. Each complex is scaffolded by a specific SMC protein dimer (heterodimer in eukaryotes) held together via their hinge domains. Here we show that the Smc5/6-hinge, like those of cohesin and condensin, also forms a toroidal structure but with distinctive subunit interfaces absent from the other SMC complexes; an unusual 'molecular latch' and a functional 'hub'. Defined mutations in these interfaces cause severe phenotypic effects with sensitivity to DNA-damaging agents in fission yeast and reduced viability in human cells. We show that the Smc5/6-hinge complex binds preferentially to ssDNA and that this interaction is affected by both 'latch' and 'hub' mutations, suggesting a key role for these unique features in controlling DNA association by the Smc5/6 complex.


Subject(s)
Cell Cycle Proteins/chemistry , Chromosomal Proteins, Non-Histone/chemistry , DNA Repair/physiology , DNA, Single-Stranded/metabolism , Schizosaccharomyces pombe Proteins/chemistry , Adenosine Triphosphatases/chemistry , Binding Sites , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Survival/physiology , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Crystallography, X-Ray , DNA Damage , DNA-Binding Proteins/chemistry , Humans , Models, Molecular , Multiprotein Complexes/chemistry , Mutagenesis, Site-Directed , Mutation , Phenotype , Protein Binding , Protein Domains/physiology , Protein Multimerization/physiology , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Schizosaccharomyces/physiology , Schizosaccharomyces pombe Proteins/genetics , Schizosaccharomyces pombe Proteins/metabolism , Cohesins
19.
mBio ; 8(1)2017 01 03.
Article in English | MEDLINE | ID: mdl-28049148

ABSTRACT

The basal body shares similar architecture with centrioles in animals and is involved in nucleating flagellar axonemal microtubules in flagellated eukaryotes. The early-branching Trypanosoma brucei possesses a motile flagellum nucleated from the basal body that consists of a mature basal body and an adjacent pro-basal body. Little is known about the basal body proteome and its roles in basal body biogenesis and flagellar axoneme assembly in T. brucei Here, we report the identification of 14 conserved centriole/basal body protein homologs and 25 trypanosome-specific basal body proteins. These proteins localize to distinct subdomains of the basal body, and several of them form a ring-like structure surrounding the basal body barrel. Functional characterization of representative basal body proteins revealed distinct roles in basal body duplication/separation and flagellar axoneme assembly. Overall, this work identified novel proteins required for basal body duplication and separation and uncovered new functions of conserved basal body proteins in basal body duplication and separation, highlighting an unusual mechanism of basal body biogenesis and inheritance in this early divergent eukaryote. IMPORTANCE: The basal body in the early-branching protozoan Trypanosoma brucei nucleates flagellum assembly and also regulates organelle segregation, cell morphogenesis, and cell division. However, the molecular composition and the assembly process of the basal body remain poorly understood. Here, we identify 14 conserved basal body proteins and 25 trypanosome-specific basal body proteins via bioinformatics, localization-based screening, and proximity-dependent biotin identification. We further localized these proteins to distinct subdomains of the basal body by using fluorescence microscopy and superresolution microscopy, discovered novel regulators of basal body duplication and separation, and uncovered new functions of conserved basal body proteins in basal body duplication and separation. This work lays the foundation for dissecting the mechanisms underlying basal body biogenesis and inheritance in T. brucei.


Subject(s)
Basal Bodies/chemistry , Basal Bodies/metabolism , Organelle Biogenesis , Proteome/analysis , Protozoan Proteins/analysis , Trypanosoma brucei brucei/physiology , Axoneme/metabolism , Flagella/metabolism , Locomotion , Trypanosoma brucei brucei/metabolism
20.
Phys Rev Lett ; 115(10): 107003, 2015 Sep 04.
Article in English | MEDLINE | ID: mdl-26382698

ABSTRACT

Density functional plus dynamical mean field calculations are used to show that in transition metal oxides, rotational and tilting (GdFeO(3)-type) distortions of the ideal cubic perovskite structure produce a multiplicity of low-energy optical transitions which affect the conductivity down to frequencies of the order of 1 or 2 mV (terahertz regime), mimicking non-Fermi-liquid effects even in systems with a strictly Fermi-liquid self-energy. For CaRuO(3), a material whose measured electromagnetic response in the terahertz frequency regime has been interpreted as evidence for non-Fermi-liquid physics, the combination of these band structure effects and a renormalized Fermi-liquid self-energy accounts for the low frequency optical response which had previously been regarded as a signature of exotic physics. Signatures of deviations from Fermi-liquid behavior at higher frequencies (∼100 meV) are discussed.

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