More and more disordered regions have been discovered in protein sequences, and many of them are found to be functionally significant. Previous studies reveal that disordered regions of a protein can ...be predicted by its primary structure, the amino acid sequence. One observation that has been widely accepted is that ordered regions usually have compositional bias toward hydrophobic amino acids, and disordered regions are toward charged amino acids. Recent studies further show that employing evolutionary information such as position specific scoring matrices (PSSMs) improves the prediction accuracy of protein disorder. As more and more machine learning techniques have been introduced to protein disorder detection, extracting more useful features with biological insights attracts more attention.
This paper first studies the effect of a condensed position specific scoring matrix with respect to physicochemical properties (PSSMP) on the prediction accuracy, where the PSSMP is derived by merging several amino acid columns of a PSSM belonging to a certain property into a single column. Next, we decompose each conventional physicochemical property of amino acids into two disjoint groups which have a propensity for order and disorder respectively, and show by experiments that some of the new properties perform better than their parent properties in predicting protein disorder. In order to get an effective and compact feature set on this problem, we propose a hybrid feature selection method that inherits the efficiency of uni-variant analysis and the effectiveness of the stepwise feature selection that explores combinations of multiple features. The experimental results show that the selected feature set improves the performance of a classifier built with Radial Basis Function Networks (RBFN) in comparison with the feature set constructed with PSSMs or PSSMPs that adopt simply the conventional physicochemical properties.
Distinguishing disordered regions from ordered regions in protein sequences facilitates the exploration of protein structures and functions. Results based on independent testing data reveal that the proposed predicting model DisPSSMP performs the best among several of the existing packages doing similar tasks, without either under-predicting or over-predicting the disordered regions. Furthermore, the selected properties are demonstrated to be useful in finding discriminating patterns for order/disorder classification.
The pathophysiology of alcohol use disorder (AUD) is not totally clear. The aim of this study was to investigate the serum levels of brain-derived neurotrophic factor (BDNF) and oxidative stress ...markers in AUD patients during alcohol detoxification. Evaluation of changes in BDNF, glutathione peroxidase (GPX), catalase, superoxide dismutase, thiobarbituric acid reactive substances, 8-hydroxy 2'-deoxyguanosine, PCC and S100B were carried out.14 AUD inpatients and 20 healthy control subjects were recruited for this study. The serum BDNF, S100B and oxidative stress markers were measured with assay kits.Serum levels of catalase, GPX, PCC and 8-hydroxy 2'-deoxyguanosine were significantly higher in the AUD group subjects than in the controls (P < .05). However, BDNF levels were lower in the AUD group than in the controls (P < .05). After alcohol detoxification treatment, the GPX levels in the AUD group dropped (P < .05) and the BDNF levels rose (P < .05).The results suggest that serum BDNF and GPX levels might be state biomarkers for AUD patients undergoing alcohol detoxification.
PURPOSEPerfluoroalkyl and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals used in the manufacture of many everyday products. Previous reports have shown PFAS exposure may ...contribute to cardiovascular diseases (CVD). Recent studies have also identified a critical role for DNA methylation, a model of epigenetic regulation, in the pathogenesis of CVD. Additionally, PFAS has been shown to affect DNA methylation. Our previous study reported the positive association between serum perfluorooctane sulfonate (PFOS) levels and mean carotid intima-media thickness (CIMT), a biomarker of arteriosclerosis, in a cohort composed of adolescent and young adult Taiwanese. However, the contribution of DNA methylation in the mechanism of PFOS-induced arteriosclerosis has never been explored in previous literature. APPROACH AND RESULTSIn this cross-sectional study, we included 1425 young and middle-aged Taiwanese individuals (12-63 years) to investigate the correlation between serum PFOS levels, 5mdC/dG (a global DNA methylation marker) and the mean CIMT. We showed that the positive association between serum PFOS levels, 5mdC/dG, and mean CIMT. The regression coefficients of mean CIMT with a one-unit increase in ln-PFOS concentration were higher when the levels of 5mdC/dG were above the 50th percentile in the multiple regression analysis. In the structural equation model (SEM), the results showed that serum PFOS levels were directly correlated with mean CIMT and indirectly correlated with CIMT through 5mdC/dG. CONCLUSIONSOur results showed that PFOS exposure has direct associations on arteriosclerosis and indirect direct associations on arteriosclerosis through DNA methylation. The results suggest that DNA methylation might regulate the relationship between PFOS and arteriosclerosis in the study subjects. Additional works are required to understand the causal inference between PFOS, DNA methylation, and arteriosclerosis.
Targeted temperature management (TTM) is recommended for comatose out-of-hospital cardiac arrest (OHCA) survivors. Several prediction models have been proposed; however, most of these tools require ...data conversion and complex calculations. Early and easy predictive model of neurological prognosis in OHCA survivors with TTM warrant investigation.
This multicenter retrospective cohort study enrolled 408 non-traumatic adult OHCA survivors with TTM from the TaIwan network of targeted temperature ManagEment for CARDiac arrest (TIMECARD) registry during January 2014 to June 2019. The primary outcome was unfavorable neurological outcome at discharge. The clinical variables associated with unfavorable neurological outcomes were identified and a risk prediction score—TIMECARD score was developed. The model was validated with data from National Taiwan University Hospital.
There were 319 (78.2%) patients presented unfavorable neurological outcomes at hospital discharge. Eight independent variables, including malignancy, no bystander cardiopulmonary resuscitation (CPR), non-shockable rhythm, call-to-start CPR duration >5 min, CPR duration >20 min, sodium bicarbonate use during resuscitation, Glasgow Coma Scale motor score of 1 at return of spontaneous circulation, and no emergent coronary angiography, revealed a significant correlation with unfavorable neurological prognosis in TTM-treated OHCA survivors. The TIMECARD score was established and demonstrated good discriminatory performance in the development cohort (area under the receiver operating characteristic curve AUC = 0.855) and validation cohorts (AUC = 0.918 and 0.877, respectively).
In emergency settings, the TIMECARD score is a practical and simple-to-calculate tool for predicting neurological prognosis in OHCA survivors, and may help determine whether to initiate TTM in indicated patients.
Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for ...insulin-regulated glucose metabolism, while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β cells. Using a mouse model with inducible β-cell-specific deletion of the Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high-fat-diet (HFD)-induced growth and survival of β cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with an intact Akt1 gene. When metabolic stress was induced by HFD, β cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that AKT1 protein deficiency caused endoplasmic reticulum (ER) stress and potentiated β cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to the induction of eukaryotic initiation factor 2 α subunit (eIF2α) signaling and ER stress markers under normal-chow-fed conditions, indicating chronic low-level ER stress. Together, these data established a role for AKT1 as a growth and survival factor for adaptive β-cell response and suggest that ER stress induction is responsible for this effect of AKT1.
Background
Culture of Helicobacter pylori with previous eradication failure has been emphasized in clinical guidelines. The current unmet need to manage previously treated H pylori is one tool with ...diagnostic accuracy and ability for antibiotics susceptibility. Gastric juice PCR can provide diagnosis and antibiotics susceptibility; however, whether treatment failure affects its accuracy remains uninvestigated. Our study aimed to investigate diagnostic accuracy and antibiotics susceptibility of juice PCR in previously treated H pylori and to compare with the current standard of culture.
Methods
We categorized all 547 patients into treatment‐naïve, post‐1st treatment, post‐2nd treatment, and post‐3rd treatment. Helicobacter pylori infection was confirmed using gold standards. Sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and area under ROC curve (AUC) of juice PCR and culture were calculated. Intra‐gastric H pylori density was evaluated. Lastly, the antibiotics susceptibility results of gastric juice and culture were compared.
Results
Our findings demonstrated AUC was higher in juice PCR than culture in all patients (96.7% vs 91.3%, P < 0.0001). The superiority of juice PCR was statistically significant in previously treated patients (P < 0.0001) but not in treatment‐naïve patients (P = 0.13). Antral H pylori density was less marked in previously treated patients (P = 0.014). The comparisons of PCR‐RFLP and E‐test for Clarithromycin resistance showed reliable AUC = 89.8%.
Conclusion
Compared with the current standard of culture, the gastric juice PCR contains the strengths of performing the antibiotics susceptibility and overcomes the shortcomings of low accuracy. Consequently, gastric juice PCR suits the unmet need to manage previously treated H pylori.
Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed ...case of virologic breakthrough (VBT) in a pediatric case has been reported.
Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy.
Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.
Preparation of substituent-diverse, triazole-iduronic acid hybrid molecules by click reaction of an azido iduronic acid derivative with randomly chosen alkynes is described. Library members were ...screened for their ability to inhibit α-l-iduronidase, and hit molecules and analogues were then investigated for their ability to stabilize rh-α-IDUA in a thermal denaturation study. This work resulted in the discovery of the first small molecules that can be used to stabilize exogenous rh-α-IDUA protein in vitro.
► A new species of thermoloterant reddish pigment producing microalga was isolated. ► Morphological and molecular evidences suggest this microalga belongs to Coelastrella. ► Doubling time of this ...Coelastrella at 35/45°C bi-phasic cultivation was about 40h. ► Salt and high light stress accelerated pigment and oil production in this microalga. ► The pigment contains astaxanthin, lutein, canthaxanthin and β-carotene.
Microalgae are good crops to produce natural pigments because of their high growth rates. Tropical zones are better locations than temperate areas for microalgal cultivation because they have longer duration of daylight and more stable temperatures throughout the year, but the high temperatures pose a challenge to microalgal cultivation. A newly isolated thermotolerant microalga produces reddish pigments under environmental stress. Morphological and molecular evidence including meridional ribs on the cell wall, pigment production, and its 18S rDNA sequence suggests that this microalga belongs to the genus Coelastrella. Salt stress and high light intensity accelerated biosynthesis of the pigments, and significant quantities of oil accumulated as the cells experienced stress due to nutrient deficiency. This microalga could withstand temperature of 50°C for more than 8h, which is a necessary trait for outdoor cultivation in tropical areas. The pigments contain astaxanthin, lutein, canthaxanthin, and β-carotene as analysed by using HPLC.
Telisotuzumab vedotin is a
MET
-targeting antibody–drug conjugate that has demonstrated a good treatment response in patients with
EGFR
wild-type MET-overexpressing non-squamous non-small cell lung ...cancer. However, patients have been reported to acquire resistance to this drug, and the subsequent therapy has not been standardized. Here, we present a case of a 56-year-old woman diagnosed with
KIF5B-MET
fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.
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