PERK, as one of the principle unfolded
protein response signal
transducers, is believed to be associated with many human diseases,
such as cancer and type-II diabetes. There has been increasing effort
to discover potent PERK inhibitors due to its potential therapeutic
interest. In this study, a computer-based virtual screening approach
is employed to discover novel PERK inhibitors, followed by experimental
validation. Using a focused library, we show that a consensus approach,
combining pharmacophore modeling and docking, can be more cost-effective
than using either approach alone. It is also demonstrated that the
conformational flexibility near the active site is an important consideration
in structure-based docking and can be addressed by using molecular
dynamics. The consensus approach has further been applied to screen
the ZINC lead-like database, resulting in the identification of 10
active compounds, two of which show IC50 values that are
less than 10 μM in a dose–response assay.
Total intravenous anesthesia (TIVA) is used widely in spinal surgery because inhalational anesthetics are known to decrease the amplitude of motor evoked potentials. Presently, dexmedetomidine is used as an adjuvant for propofol-based TIVA. We compared the effects of remifentanil and dexmedetomidine on pain intensity as well as the analgesic requirements after post-anesthesia care unit (PACU) discharge in patients undergoing spinal surgery.
Forty patients scheduled for posterior lumbar interbody fusion (PLIF) surgery under general anesthesia were enrolled. Anesthesia was maintained using propofol at 3–12 mg/kg/h and remifentanil at 0.01–0.2 μg/kg/min in Remifentanil group or dexmedetomidine at 0.01–0.02 μg/kg/min in Dexmedetomidine group, keeping the bispectral index between 40 and 60. Patient-controlled analgesia (PCA) made of hydromophone was applied once the patients opened their eyes in the PACU. The visual analog scale (VAS) score, PCA dosage administered, and postoperative nausea and vomiting (PONV) were recorded at the time of discharge from the PACU (T1) and at 2 (T2), 8 (T3), 24 (T4), and 48 hours (T5) after surgery.
The VAS score in Remifentanil group was significantly higher than that in Dexmedetomidine group at immediate and late postoperative period (4.1 ± 2.0 vs. 2.3 ± 2.2 at T1, and 4.0 ± 2.2 vs. 2.6 ± 1.7 at T5; P < 0.05). Dexmedtomidine group had a statistically significantly lower PCA requirement at every time point after surgery except directly before discharge from the PACU (3.0 ± 1.2 ml vs. 2.3 ± 1.4 ml at T1; P > 0.05, but 69.7 ± 21.4 ml vs. 52.8 ± 10.8 ml at T5; P < 0.05). Patients in Remifentanil group displayed more PONV until 24 hours post-surgery.
Dexmedetomidine displayed superior efficacy in alleviating pain and in postoperative pain management for 48 hours after PLIF. Therefore, dexmedetomidine may be used instead of remifentanil as an adjuvant in propofol-based TIVA.
Clinical Research Information Service (CRiS) Identifier: KCT0001041.
Dexmedetomidine; Remifentanil; Total intravenous anesthesia; Postoperative pain
De-identification of personal health information is essential in order not to require written patient informed consent. Previous de-identification methods were proposed using natural language processing technology in order to remove the identifiers in clinical narrative text, although these methods only focused on narrative text written in English. In this study, we propose a regular expression-based de-identification method used to address bilingual clinical records written in Korean and English. To develop and validate regular expression rules, we obtained training and validation datasets composed of 6,039 clinical notes of 20 types and 5,000 notes of 33 types, respectively. Fifteen regular expression rules were constructed using the development dataset and those rules achieved 99.87% precision and 96.25% recall for the validation dataset. Our de-identification method successfully removed the identifiers in diverse types of bilingual clinical narrative texts. This method will thus assist physicians to more easily perform retrospective research.
De-identification; Anonymization; Clinical Text; Bilingual Text; Patient Privacy; Medical Informatics; Text Mining
The inherent attenuation of a homogeneous viscous medium limits radiation propagation, thereby restricting the use of many high-frequency acoustic devices to only short-range applications. Here, we design and experimentally demonstrate an acoustic metamaterial localization cavity which is used for sound pressure level (SPL) gain using double coiled up space like structures thereby increasing the range of detection. This unique behavior occurs within a subwavelength cavity that is 1/10th of the wavelength of the incident acoustic wave, which provides up to a 13 dB SPL gain. We show that the amplification results from the Fabry-Perot resonance of the cavity, which has a simultaneously high effective refractive index and effective impedance. We also experimentally verify the SPL amplification in an underwater environment at higher frequencies using a sample with an identical unit cell size. The versatile scalability of the design shows promising applications in many areas, especially in acoustic imaging and underwater communication.
Extended-spectrum beta-lactamase; Klebsiella pneumoniae; Endocarditis
Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly.
Adipocyte differentiation is a complex developmental process forming adipocytes from various precursor cells. The murine 3T3-L1 preadipocyte cell line has been most frequently used in the studies of adipocyte differentiation. Differentiation of 3T3-L1 preadipocytes includes a medium containing fetal bovine serum (FBS) with hormonal induction. In this study, we observed that differentiation medium containing adult bovine serum (ABS) instead of FBS did not support differentiation of preadipocytes. Impaired adipocyte differentiation was due to the presence of a serum protein factor in ABS that suppresses differentiation of preadipocytes. Using a proteomic analysis, alpha-2-macroglobulin and paraoxonase/arylesterase 1, which were previously shown to suppress differentiation of preadipocytes, were identified as anti-adipogenic proteins. Although their functional mechanisms have not yet been elucidated, the anti-adipogenic effects of these proteins are discussed. [BMB Reports 2013; 46(12): 582-587]
Adipocyte; Alpha-2-macroglobulin; Differentiation; Paraoxonase; Serum
The JNK–JIP1 interaction represents an attractive
for the selective inhibition of JNK-mediated signaling. We report
a virtual screening (VS) workflow, based on a combination of three-dimensional
shape and electrostatic similarity, to discover novel scaffolds for
the development of non-ATP competitive inhibitors of JNK targeting
the JNK–JIP interaction. Of 352 (0.13%) compounds selected
from the NCI Diversity Set, more than 22% registered as hits in a
biochemical kinase assay. Several compounds discovered to inhibit
JNK activity under standard kinase assay conditions also impeded JNK
activity in HEK293 cells. These studies led to the discovery that
the lignan (−)-zuonin A inhibits JNK–protein interactions
with a selectivity of 100-fold over ERK2 and p38 MAPKα. These
results demonstrate the utility of a virtual screening protocol to
identify novel scaffolds for highly selective, cell-permeable inhibitors
of JNK–protein interactions.
virtual screening; JNK; non-ATP competitive
inhibitor; JNK−JIP interaction; molecular
docking and dynamics
The JNK-JIP1 interaction represents an attractive target for the selective inhibition of JNK-mediated signaling. We report a virtual screening (VS) workflow, based on a combination of three-dimensional shape and electrostatic similarity to discover novel scaffolds for the development of non-ATP competitive inhibitors of JNK targeting the JNK-JIP interaction. Of 352 (0.13%) compounds selected from the NCI diversity set more than 22% registered as hits in a biochemical kinase assay. Several compounds discovered to inhibit JNK activity under standard kinase assay conditions also impeded JNK activity in HEK293 cells. These studies led to the discovery that the lignan (−)-zuonin A inhibits JNK-protein interactions with a selectivity of 100-fold over ERK2 and p38 MAPKα. These results demonstrate the utility of a virtual screening protocol to identify novel scaffolds for highly selective, cell-permeable inhibitors of JNK-protein interactions.
virtual screening; JNK; non-ATP competitive inhibitor; JIP-JNK interaction; molecular docking and dynamics
The Korean government has enacted two laws, namely, the Personal Information Protection Act and the Bioethics and Safety Act to prevent the unauthorized use of medical information. To protect patients' privacy by complying with governmental regulations and improve the convenience of research, Asan Medical Center has been developing a de-identification system for biomedical research.
We reviewed Korean regulations to define the scope of the de-identification methods and well-known previous biomedical research platforms to extract the functionalities of the systems. Based on these review results, we implemented necessary programs based on the Asan Medical Center Information System framework which was built using the Microsoft. NET Framework and C#.
The developed de-identification system comprises three main components: a de-identification tool, a search tool, and a chart review tool. The de-identification tool can substitute a randomly assigned research ID for a hospital patient ID, remove the identifiers in the structured format, and mask them in the unstructured format, i.e., texts. This tool achieved 98.14% precision and 97.39% recall for 6,520 clinical notes. The search tool can find the number of patients which satisfies given search criteria. The chart review tool can provide de-identified patient's clinical data for review purposes.
We found that a clinical data warehouse was essential for successful implementation of the de-identification system, and this system should be tightly linked to an electronic Institutional Review Board system for easy operation of honest brokers. Additionally, we found that a secure cloud environment could be adopted to protect patients' privacy more thoroughly.
Access to Information; Information Systems; Research Design; Research Ethics; Biomedical Research
The human B12 trafficking chaperone hCblC is well conserved in mammals and non-mammalian eukaryotes. However, the C-terminal ∼40 amino acids of hCblC vary significantly and are predicted to be deleted by alternative splicing of the encoding gene. In this study, we examined the thermostability of the bovine CblC truncated at the C-terminal variable region (t-bCblC) and its regulation by glutathione. t-bCblC is highly thermolabile (Tm = ∼42℃) similar to the full-length protein (f-bCblC). However, t-bCblC is stabilized to a greater extent than f-bCblC by binding of reduced glutathione (GSH) with increased sensitivity to GSH. In addition, binding of oxidized glutathione (GSSG) destabilizes t-bCblC to a greater extent and with increased sensitivity as compared to f-bCblC. These results indicate that t-bCblC is a more sensitive form to be regulated by glutathione than the full-length form of the protein. [BMB Reports 2013; 46(3): 169-174]
B12 trafficking chaperone; Glutathione; Thermostability; Vitamin B12
Community coalitions are increasingly recognized as important strategies for addressing health disparities. By providing the opportunity to pool resources, they provide a means to develop and sustain innovative approaches to affect community health.
This article describes the challenges and lessons learned in building the Asian American Hepatitis B Program (AAHBP) coalition to conduct a community-based participatory research (CBPR) initiative to address hepatitis B (HBV) among New York City Asian-American communities.
Using the stages of coalition development as a framework, a comprehensive assessment of the process of developing and implementing the AAHBP coalition is presented.
Findings highlight the importance of developing a sound infrastructure and set of processes to foster a greater sense of ownership, shared vision, and investment in the program.
Grassroots community organizing and campus–community partnerships can be successfully leveraged to address and prevent a significant health disparity in an underserved and diverse community.
Asian Americans; community-based participatory research; community health services; healthcare disparities; hepatitis B
The hang-back surgery is a useful technique in the field of strabismus surgery. The aim of this study is to determine the stabilizing effects of fibrin glue as an adjuvant to hang-back surgery.
Materials and methods
Four (4)-mm hang-back recessions of the superior rectus muscle was performed in 32 eyes of 16 rabbits. Only in the left eye of the 16 rabbits, fibrin glue was applied between the recessed muscle bed and the sclera at the end of hang-back surgery (fibrin glue group). After 6 weeks, we compared the stability of the recessed rectus muscle between the fibrin glue group and the control group by evaluating the displacement of the muscle.
The frequency of stable insertion of the recessed muscle at the intended site was greater in the fibrin glue group (9 eyes) compared to the control group (3 eyes) (p = 0.028). In the control group, 5 eyes showed anterior displacement and 8 eyes showed posterior displacement and in the fibrin glue group, 1 eye showed anterior displacement, and 6 eyes showed posterior displacement. Anterior displacement was more common in the control group (6.3% Vs 31.3%). The control group and the fibrin glue group showed similar histological findings on microscopic examination.
Fibrin glue is effective in stabilizing the new rectus muscle insertion and decreasing the displacement in the hang-back surgery.
Fibrin glue; Hang-back surgery; Rabbit