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1.
J Clin Med ; 12(13)2023 Jun 30.
Article in English | MEDLINE | ID: mdl-37445446

ABSTRACT

BACKGROUND: There is little research in the literature comparing the efficacy of coblation nucleoplasty with conservative treatment in the treatment of cervical discogenic dizziness and reporting the achieved rate of minimal clinically important differences (MCID) and patient acceptable symptom state (PASS) after surgery. This retrospective study aims to explore the patient-reported outcome measures (PROM) following coblation nucleoplasty for cervical discogenic dizziness and to compare the therapeutic effect of coblation nucleoplasty with prolonged conservative treatment. METHODS: Sixty-one patients with cervical discogenic dizziness and a positive intradiscal diagnostic test eligible for single-level cervical coblation nucleoplasty were included in the study. Among these 61 patients, 40 patients underwent cervical coblation nucleoplasty, while the remaining 21 patients refused surgery and received continued conservative treatment. The primary PROMs were the intensity and frequency of dizziness and secondary PROMs were related to the neck disability index (NDI) and visual analog scale (VAS) for neck pain (VAS-neck) during a 12-month follow-up period. Moreover, the achieved rate of MCID and PASS in both groups was assessed 12 months after surgery. RESULTS: Dizziness intensity, dizziness frequency, VAS-neck score, and NDI score were significantly improved from the baseline at all follow-up time points in both treatment groups, except for showing no significant improvement in dizziness frequency in the conservative treatment group at 6 and 12 months after surgery. However, at each follow-up time point, the above indexes were lower in the surgery group than in the conservative treatment group. In addition, the achieved rates for PASS and MCID in all indexes in the surgery group were significantly higher than those in the conservative treatment group at 12 months after surgery. CONCLUSIONS: Cervical coblation nucleoplasty significantly improved the intensity and frequency of dizziness, neck pain, and NDI in patients with cervical discogenic dizziness, and the results were superior to those from prolonged conservative treatment. Meanwhile, cervical coblation nucleoplasty is a good choice for patients with chronic neck pain and refractory cervical discogenic dizziness who have not demonstrated the indications for open surgery and have not responded well to conservative treatment.

2.
Orthop Surg ; 15(1): 133-140, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36394075

ABSTRACT

OBJECTIVE: Cervical spondylosis is often accompanied by tinnitus. Up to now, there is a lack of large samples and prospective studies to investigate the effect of anterior cervical decompression and fusion (ACDF) on tinnitus associate with cervical spondylosis. To this end, we performed a prospective cohort study to assess the effectiveness of ACDF on the relief of tinnitus. METHODS: This was a multicenter, prospective, cohort clinical study. Between August 2017 and August 2018, 174 patients with cervical spondylosis accompanied by tinnitus were enrolled, with a follow-up of 12 months. Among the 174 patients, 142 received anterior cervical surgery (surgery group) and 32 received conservative treatment (conservative group). The primary end point was the mean change in scores on the tinnitus functional index (TFI). The secondary end points included tinnitus loudness, modified Japanese orthopaedic association scores (mJOA) for spinal cord function, and visual analogue scale (VAS) for neck pain. All the above indexes were measured before treatments and at 1, 3, 6, and 12 months after treatments. One-way analysis of variance and paired samples t-test was adopted for statistical analysis. RESULTS: The TFI score was reduced immediately after cervical decompression surgery (from 54.7 ± 15.6 to 32.3 ± 12.5, P < 0.001) and this was sustained at 12 months (P < 0.001). The TFI score of the conservative group also decreased (from 53.9 ± 16.8 to 45.2 ± 13.6, P < 0.001), but the effect was not maintained at 12 months (P = 0.069). There was a significant improvement in tinnitus loudness (from 5.2 ± 1.6 to 2.6 ± 1.9, P < 0.001), mJOA (from 12.0 ± 1.6 to 14.2 ± 1.6, P < 0.001), and VAS for neck pain (from 58.5 ± 9.6 to 22.0 ± 16.4, P < 0.001) in the surgical group. Improvements in the surgical group were statistically significantly greater than that in the conservative group (P < 0.001). CONCLUSION: This study indicates that anterior cervical surgery can relieve tinnitus in patients with cervical spondylosis and that tinnitus is an accompanying manifestation of cervical spondylosis.


Subject(s)
Spinal Fusion , Spondylosis , Tinnitus , Humans , Prospective Studies , Diskectomy , Neck Pain/surgery , Treatment Outcome , Tinnitus/surgery , Tinnitus/complications , Cervical Vertebrae/surgery , Spondylosis/complications , Spondylosis/surgery , Decompression, Surgical , Retrospective Studies
3.
Front Neurol ; 13: 1064976, 2022.
Article in English | MEDLINE | ID: mdl-36504652

ABSTRACT

Background: Cervicogenic headache (CEH) has long been recognized as a referred pain deriving from pathological changes in the upper cervical nerves. However, previous clinical studies found that anterior lower cervical discectomy for the treatment of cervical myelopathy and/or radiculopathy can also help relieve associated headaches. To date, there is still a lack of large sample and prospective study to investigate the effect of anterior cervical decompression and fusion (ACDF) on CEH associated with cervical spondylosis. Methods: A total of 656 patients with cervical radiculopathy and/or myelopathy were enrolled in three spinal centers. Among them, 221 patients who were diagnosed with CEH were collected in this study, and 204 completed a 1-year follow-up. The primary endpoint was headache intensity during a 12-month follow-up period measured by the numeric pain rating scale (NPRS). The secondary outcome measures included headache frequency, headache duration, and the neck disability index (NDI). Results: Among all 204 patients with CEH who completed a 1-year follow-up, 166 received anterior cervical surgery (surgery group) and 38 received conservative treatment (conservative group). There were statistically significant lower NPRS in the surgical group during follow-up. Between-group differences showed that NPRS in the surgery group was significantly greater improvement at 1 month (2.8, 95% CI: 2.0, 3.6), 3 months (2.6, 95% CI: 1.8, 3.4), 6 months (2.4, 95% CI: 1.6, 3.2), and 12 months (1.5, 95% CI: 0.7, 2.4) (p < 0.05 for all). There were statistically significant lower NDI, less frequent headaches, and lower headache duration in the surgery group during follow-up (p < 0.05 for all). Conclusion: This study indicates that ACDF can effectively relieve CEH associated with cervical myelopathy and/or radiculopathy.

4.
PLoS One ; 16(10): e0257072, 2021.
Article in English | MEDLINE | ID: mdl-34597305

ABSTRACT

Liver cancer morbidity and mortality rates differ among ethnic groups. In the United States, the burden of liver cancer in Asian Americans (AS) is higher compared to Caucasian Americans (CA). Research on liver cancer health disparities has mainly focused on environmental and socioeconomic factors yet has ignored the genotypic differences among various racial/ethnic groups. This lack of molecular level understanding has hindered the development of personalized medical approaches for liver cancer treatment. To understand the genetic heterogeneity of liver cancer between AS and CA, we performed a systematic analysis of RNA-seq data of AS and CA patients from The Cancer Genome Atlas (TCGA). We used four differential gene expression analysis packages; DESeq2, limma, edgeR, and Superdelta2, to identify the differentially expressed genes. Our analysis identified cytochrome P450-2D6 enzyme (CYP2D6) as the gene with the greatest differential expression with higher levels in AS compared to CA. To scrutinize the underlying mechanism of CYP2D6, Ingenuity Pathway Analysis (IPA) and Cytoscape were conducted and found hepatocyte nuclear factor-4α (HNF4A) and interleukin-6 (IL6) in direct association with CYP2D6. IL6 is downregulated in AS compared to CA, while HNF4A is not significantly different. Herein, we report that CYP2D6 may serve as a putative biomarker in liver cancer health disparities. Its negative association with IL6 proclaims an intricate relationship between CYP2D6 and inflammation in the ethnic differences seen in AS and CA liver cancer patients. The goal of the present study was to understand how genetic factors may contribute to the interethnic variability of liver cancer prevalence and outcomes in AS and CA patients. Identifying ethnic-specific genes may help ameliorate detection, diagnosis, surveillance, and treatments of liver cancer, as well as reduce disease-related incidence and mortality rates in the vulnerable population.


Subject(s)
Carcinoma, Hepatocellular/genetics , Cytochrome P-450 CYP2D6/genetics , Gene Expression Regulation, Neoplastic , Genotype , Liver Neoplasms/genetics , Polymorphism, Genetic , Alleles , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Databases, Genetic , Gene Expression Profiling , Gene Regulatory Networks , Health Status Disparities , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology
5.
J Affect Disord ; 293: 484-491, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34280772

ABSTRACT

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a widely recognized mental health problem in developed countries but remains under-investigated in developing settings. This study examines the prevalence, correlates, and consequences of ADHD symptoms among elementary school students in rural China. METHODS: Cross-sectional data were collected from 6,719 students across 120 rural primary schools in China on ADHD symptoms, demographic characteristics, and academic performance in reading and math. ADHD symptoms were evaluated using the caregiver-reported ADHD Rating Scale-IV. RESULTS: The prevalence of ADHD symptoms was 7.5% in our sample. Male students, students in lower grade levels, and students with lower cognitive ability showed a significantly higher prevalence of ADHD symptoms (ORs = 2.56, 2.06, and 1.84, respectively; p<0.05). Left-behind children showed a significantly lower prevalence of ADHD symptoms than did children who were living with their parents (OR = 0.74, p < 0.05). Adjusted regressions show that students with ADHD symptoms scored 0.12 standardized deviations lower in reading (p < 0.05) and 0.19 standardized deviations lower in math (p < 0.01). LIMITATIONS: The ADHD Rating Scale-IV is a screening scale rather than a diagnostic test. Caregiver self-report measures also may underestimate ADHD symptoms for our sample. CONCLUSIONS: ADHD is a common disorder among rural students in China and appears to be contributing to poor academic outcomes. The higher prevalence of ADHD among students with low cognitive ability also suggests that many rural children in China face multifactorial learning challenges. Taken together, the findings indicate a need for educators and policymakers in rural China to develop programs to reduce risk and support students with ADHD symptoms.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Attention Deficit Disorder with Hyperactivity/epidemiology , Child , China/epidemiology , Cross-Sectional Studies , Humans , Male , Prevalence , Students
6.
Cereb Cortex ; 31(4): 1998-2012, 2021 03 05.
Article in English | MEDLINE | ID: mdl-33230530

ABSTRACT

Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.


Subject(s)
DNA Methyltransferase 3A/metabolism , Locomotion/physiology , Prefrontal Cortex/enzymology , Stress, Psychological/enzymology , Stress, Psychological/psychology , Synapses/enzymology , Animals , Chronic Disease , DNA Methyltransferase 3A/antagonists & inhibitors , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Locomotion/drug effects , Male , Mice , Phthalimides/pharmacology , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley , Tryptophan/analogs & derivatives , Tryptophan/pharmacology
7.
J Pain Res ; 13: 2783-2789, 2020.
Article in English | MEDLINE | ID: mdl-33173327

ABSTRACT

STUDY DESIGN: Retrospective study. OBJECTIVE: To report the efficacy of anterior cervical surgery for the relief of cervicogenic headache (CEH) caused by cervical spondylosis. METHODS: From January 2014 to December 2016, a total of 166 cases of cervical radiculopathy and/or myelopathy received anterior cervical decompression and fusion (ACDF) in our institution, among which 50 cases (mean age 44.7 years) were accompanied by CEH and followed up at 3, 6, 12, and 24 months postoperatively, respectively. Neck pain and headache scores according to neck disability index (NDI) were documented for all patients at regular intervals. The results measured at different follow-up time point were compared statistically. RESULTS: All 50 patients reported neck pain and headache at the same time before surgery. The average NDIs for neck pain before and after surgery were 2.86 (95% CI: 2.7-3.0) preoperatively, 0.98 (95% CI: 0.8-1.1) at 3 months, 0.68 (95% CI: 0.5-0.9) at 6 months, 0.62 (95% CI: 0.5-0.8) at 12 months, and 0.60 (95% CI: 0.4-0.8) at 24 months postoperatively, respectively. The average NDIs for CEH before and after surgery were 2.32 (95% CI: 2.2-2.5) preoperatively, 0.62 (95% CI: 0.5-0.8) at 3 months, 0.60 (95% CI: 0.4-0.8) at 6 months, 0.56 (95% CI: 0.4-0.7) at 12 months, and 0.50 (95% CI: 0.3-0.7) at 24 months postoperatively, respectively. The neck pain and headache improved in all cases and the NDI score of neck pain or headache at each follow-up point after surgery was significantly different from that before surgery (P <0.001). The simple correlation analysis between neck pain and headache was performed, and the Pearson coefficient r was 0.71, indicating a positive correlation between neck pain NDI and headache NDI. No serious surgical complications were found. CONCLUSION: Our study suggests that patients with cervical spondylosis complicated with CEH are always accompanied by neck pain. ACDF can not only relieve neck pain but also improve the accompanying CEH.

8.
PLoS Comput Biol ; 16(11): e1007450, 2020 11.
Article in English | MEDLINE | ID: mdl-33156882

ABSTRACT

Reusability is part of the FAIR data principle, which aims to make data Findable, Accessible, Interoperable, and Reusable. One of the current efforts to increase the reusability of public genomics data has been to focus on the inclusion of quality metadata associated with the data. When necessary metadata are missing, most researchers will consider the data useless. In this study, we developed a framework to predict the missing metadata of gene expression datasets to maximize their reusability. We found that when using predicted data to conduct other analyses, it is not optimal to use all the predicted data. Instead, one should only use the subset of data, which can be predicted accurately. We proposed a new metric called Proportion of Cases Accurately Predicted (PCAP), which is optimized in our specifically-designed machine learning pipeline. The new approach performed better than pipelines using commonly used metrics such as F1-score in terms of maximizing the reusability of data with missing values. We also found that different variables might need to be predicted using different machine learning methods and/or different data processing protocols. Using differential gene expression analysis as an example, we showed that when missing variables are accurately predicted, the corresponding gene expression data can be reliably used in downstream analyses.


Subject(s)
Data Curation , Gene Expression , Metadata , Computational Biology
9.
Mol Oncol ; 14(11): 2775-2786, 2020 11.
Article in English | MEDLINE | ID: mdl-32920960

ABSTRACT

It is well known that different racial groups have significantly different incidence and mortality rates for certain cancers. It has been suggested that biological factors play a major role in these cancer racial disparities. Previous studies on the biological factors contributing to cancer racial disparity have generated a very large number of candidate factors, although there is modest agreement among the results of the different studies. Here, we performed an integrative analysis using genomic data of 21 cancer types from TCGA, GTEx, and the 1000 Genomes Project to identify biological factors contributing to racial disparity in cancer. We also built a companion website with additional results for cancer researchers to freely mine. Our study identified genes, gene families, and pathways displaying similar differential expression patterns between different racial groups across multiple cancer types. Among them, XKR9 gene expression was found to be significantly associated with overall survival for all cancers combined as well as for several individual cancers. Our results point to the interesting hypothesis that XKR9 could be a novel drug target for cancer immunotherapy. Bayesian network modeling showed that XKR9 is linked to important cancer-related genes, including FOXM1, cyclin B1, and RB1CC1 (RB1 regulator). In addition, metabolic pathways, neural signaling pathways, and several cancer-related gene families were found to be significantly associated with cancer racial disparities for multiple cancer types. Single nucleotide polymorphisms (SNPs) discovered through integrating data from the TCGA, GTEx, and 1000 Genomes databases provide biologists the opportunity to test highly promising, targeted hypotheses to gain a deeper understanding of the genetic drivers of cancer racial disparity and cancer biology in general.


Subject(s)
Neoplasms/genetics , Apoptosis Regulatory Proteins/genetics , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Genomics , Humans , Incidence , Membrane Proteins/genetics , Neoplasms/epidemiology , Polymorphism, Single Nucleotide , Race Factors , Transcriptome
10.
World J Clin Cases ; 8(10): 1958-1965, 2020 May 26.
Article in English | MEDLINE | ID: mdl-32518787

ABSTRACT

BACKGROUND: In recent years, the mechanical concept of intervertebral disc regeneration has become more and more popular due to the increasing awareness of the importance of preservation of spine movement. Interestingly, there is increasing evidence, however, that dynamic stabilization systems may compensate non-physiological loads, limit pathological movement, normalize disc height and intradiscal pressure, and provide an adaptive environment for disc regeneration. CASE SUMMARY: The patient was a 54-year-old man, who presented with a 10-year history of mechanical back pain, which had become progressively serious and radiated into the left lower limb with numbness 3 mo prior. He had decreased muscle strength (class IV) of the left dorsal extensor and plantar flexor. Magnetic resonance imaging scans showed L3-S1 disc degeneration and L4-L5 disc herniation. Because the patient did not respond to various conservative treatments, he underwent a posterior L4-5 discectomy with fixation of the BioFlex dynamic stabilization system (Bio-Spine, Seoul, Korea). Preoperative symptoms were relieved and lumbar function was markedly improved after the operation. L4-L5 disc rehydration of instrumented segment was noted on magnetic resonance imaging at the 2-year follow-up. CONCLUSION: Rehydration of the degenerated disc in our patient indicates that the BioFlex dynamic stabilization system may promote disc regeneration. Further research is needed to provide more evidence to support lumbar disc rehydration in the bridged segment using this system.

11.
EMBO Mol Med ; 11(11): e10659, 2019 11 07.
Article in English | MEDLINE | ID: mdl-31559706

ABSTRACT

CULLIN3-based E3 ubiquitin ligase substrate-binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient-derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non-hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti-cancer efficacy of NEO2734 in SPOP-mutated PCa patients.


Subject(s)
Antineoplastic Agents/pharmacology , E1A-Associated p300 Protein/metabolism , Mutant Proteins/metabolism , Nuclear Proteins/metabolism , Peptide Fragments/metabolism , Prostatic Neoplasms/pathology , Repressor Proteins/metabolism , Sialoglycoproteins/metabolism , Transcription Factors/metabolism , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Disease Models, Animal , E1A-Associated p300 Protein/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Heterografts , Humans , Male , Mutant Proteins/genetics , Mutation, Missense , Neoplasm Transplantation , Nuclear Proteins/genetics , Peptide Fragments/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Repressor Proteins/genetics , Sialoglycoproteins/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors
12.
Biophys J ; 116(6): 1075-1084, 2019 03 19.
Article in English | MEDLINE | ID: mdl-30819568

ABSTRACT

Protein dynamics in crowded environments is important for understanding protein functions in vivo and is especially relevant for membrane proteins because of the roles of protein-protein interactions in membrane protein functions and their regulation. Here, using solid-state NMR spectroscopy in combination with coarse-grained molecular dynamics simulations, we report that the rotational correlation time for the transmembrane domain of the influenza A M2 proton channel in lipid bilayers increases dramatically at an elevated protein/lipid ratio. This increase is attributable to persistent protein-protein interactions, thus revealing for the first time, to the best of our knowledge, extensive cluster formation of the M2 tetrameric channel. Such clustering appears to have direct biological relevance during budding of the nascent influenza virus, which does not use the endosomal sorting complexes required for transport machinery. Indeed, initial coarse-grained molecular dynamics simulations of the longer M2 construct known as the conductance domain suggest clustering-induced membrane curvature formation.


Subject(s)
Influenza A virus/physiology , Lipid Metabolism , Viral Matrix Proteins/metabolism , Virus Release , Amino Acid Sequence , Diffusion , Models, Molecular , Protein Conformation , Rotation , Viral Matrix Proteins/chemistry
13.
World Neurosurg ; 119: e686-e693, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30092465

ABSTRACT

OBJECTIVES: Dizziness often happens in patients with chronic neck pain with only cervical disc degeneration but without cervical radiculopathy or myelopathy. We prospectively selected a series of patients who showed cervical disc degeneration with concomitant chronic neck pain and intractable dizziness who did not respond to conservative treatment to test a new diagnostic method for this dizziness, to analyze the results of anterior cervical discectomy and fusion (ACDF) surgery based on the test, and to explore its pathogenesis. METHODS: Seventy-seven patients who had a transient neck pain and dizziness relief after injection of bupivacaine into a suspected disc were included in the study. In total, 52 underwent ACDF as surgery group, and 25 refused surgery and accepted conservative treatments as conservative group from June, 2015 to October, 2016 with subsequent follow-up to 1 year. The outcomes were visual analogue scale for neck pain, Neck Disability Index, and intensity and frequency of dizziness. During ACDF, the 72 specimens of degenerative cervical discs were collected to determine the innervation in degenerative cervical discs immunohistochemically. RESULTS: After surgery, the patients experienced a significant reduction in neck pain and dizziness. Symptomatic relief in surgery group was obviously better than conservative group at each time point of follow-up (P = 0.001). Ruffini corpuscles and substance P-positive free nerve fibers were obviously increased in the number and deeply ingrown into the inner degenerative cervical discs. CONCLUSIONS: Current clinical and immunohistochemical studies strongly suggest that chronic neck pain and intractable dizziness in this series of patients stem from the degenerative cervical discs.


Subject(s)
Cervical Vertebrae/surgery , Diskectomy/methods , Dizziness/etiology , Intervertebral Disc Degeneration/complications , Neck Pain/etiology , Spinal Fusion/methods , Adolescent , Adult , Aged , Disability Evaluation , Dizziness/pathology , Dizziness/surgery , Female , Humans , Immunohistochemistry , Intervertebral Disc Degeneration/pathology , Intervertebral Disc Degeneration/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Neck Pain/pathology , Neck Pain/surgery , Prospective Studies , Range of Motion, Articular/physiology , Treatment Outcome , Young Adult
14.
Chem Rev ; 118(4): 1691-1741, 2018 02 28.
Article in English | MEDLINE | ID: mdl-29319301

ABSTRACT

Charged and polar groups, through forming ion pairs, hydrogen bonds, and other less specific electrostatic interactions, impart important properties to proteins. Modulation of the charges on the amino acids, e.g., by pH and by phosphorylation and dephosphorylation, have significant effects such as protein denaturation and switch-like response of signal transduction networks. This review aims to present a unifying theme among the various effects of protein charges and polar groups. Simple models will be used to illustrate basic ideas about electrostatic interactions in proteins, and these ideas in turn will be used to elucidate the roles of electrostatic interactions in protein structure, folding, binding, condensation, and related biological functions. In particular, we will examine how charged side chains are spatially distributed in various types of proteins and how electrostatic interactions affect thermodynamic and kinetic properties of proteins. Our hope is to capture both important historical developments and recent experimental and theoretical advances in quantifying electrostatic contributions of proteins.


Subject(s)
Proteins/chemistry , Static Electricity , Kinetics , Protein Binding , Protein Conformation , Protein Folding , Thermodynamics
15.
FEBS J ; 284(20): 3381-3391, 2017 10.
Article in English | MEDLINE | ID: mdl-28805312

ABSTRACT

Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and-coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites. Here, by a combination of experiment and computation, we determined the precise form of dock-and-coalesce operating in the association between the intrinsically disordered GTPase-binding domain (GBD) of the Wiskott-Aldrich Syndrome protein and the Cdc42 GTPase. The association rate constants (ka ) were measured by stopped-flow fluorescence under various solvent conditions. ka reached 107 m-1 ·s-1 at physiological ionic strength and had a strong salt dependence, suggesting that an electrostatically enhanced, diffusion-controlled docking step may be rate limiting. Our computation, based on the transient-complex theory, identified the N-terminal basic region of the GBD as the docking segment. However, several other changes in solvent conditions provided strong evidence that the coalescing step also contributed to determining the magnitude of ka . Addition of glucose and trifluoroethanol and an increase in temperature all produced experimental ka values much higher than expected from the effects on the docking rate alone. Conversely, addition of urea led to ka values much lower than expected if only the docking rate was affected. These results all pointed to ka being approximately two-thirds of the docking rate constant under physiological solvent conditions.


Subject(s)
Intrinsically Disordered Proteins/metabolism , Wiskott-Aldrich Syndrome Protein/metabolism , cdc42 GTP-Binding Protein/metabolism , Humans , Intrinsically Disordered Proteins/chemistry , Protein Binding , Wiskott-Aldrich Syndrome Protein/chemistry , cdc42 GTP-Binding Protein/chemistry
16.
J Struct Biol ; 200(3): 369-375, 2017 12.
Article in English | MEDLINE | ID: mdl-28739483

ABSTRACT

NMDA receptors are tetrameric ligand-gated ion channels that are crucial for neurodevelopment and higher order processes such as learning and memory, and have been implicated in numerous neurological disorders. The lack of a structure for the channel open state has greatly hampered the understanding of the normal gating process and mechanisms of disease-associated mutations. Here we report the structural modeling for the open state of an NMDA receptor. Staring from the crystal structure of the closed state, we repacked the pore-lining helices to generate an initial open model. This model was modified to ensure tight packing between subunits and then refined by a molecular dynamics simulation in explicit membrane. We identify Cα-H…O hydrogen bonds, between the Cα of a conserved glycine in one transmembrane helix and a carbonyl oxygen of a membrane-parallel helix, at the extracellular side of the transmembrane domain as important for stabilizing the open state. This observation explains why mutations of the glycine are associated with neurological diseases and lead to significant decrease in channel open probability.


Subject(s)
Models, Molecular , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Cell Membrane/chemistry , Glycine/chemistry , Molecular Dynamics Simulation , Phosphatidylcholines/chemistry , Protein Conformation , Protein Domains
17.
Annu Rev Biophys ; 46: 105-130, 2017 05 22.
Article in English | MEDLINE | ID: mdl-28375732

ABSTRACT

Whereas protein-ligand binding affinities have long-established prominence, binding rate constants and binding mechanisms have gained increasing attention in recent years. Both new computational methods and new experimental techniques have been developed to characterize the latter properties. It is now realized that binding mechanisms, like binding rate constants, can and should be quantitatively determined. In this review, we summarize studies and synthesize ideas on several topics in the hope of providing a coherent picture of and physical insight into binding kinetics. The topics include microscopic formulation of the kinetic problem and its reduction to simple rate equations; computation of binding rate constants; quantitative determination of binding mechanisms; and elucidation of physical factors that control binding rate constants and mechanisms.


Subject(s)
Proteins/chemistry , Algorithms , Humans , Kinetics , Ligands , Molecular Dynamics Simulation , Protein Binding
18.
Case Rep Med ; 2017: 7317289, 2017.
Article in English | MEDLINE | ID: mdl-29362566

ABSTRACT

INTRODUCTION: Hemolymphangioma is an extremely rare malformation of the lymphatic and blood vessels. A limited number of hemolymphangioma cases occurring in the pancreas, extremities, spleen, and other organs have been reported until September 2017. To the best of our knowledge, no cases of hemolymphangioma in the occipitocervical region have been reported in the literature. CASE PRESENTATION: We reported the case of a 23-year-old male patient with an occipitocervical lesion presenting atypically as neck pain and stiffness over a period of five months. Although hemolymphangioma has historically demonstrated a female predilection (2.25 : 1 female to male) and presentation in the third to fourth decades of life, this case is an atypical manifestation occurring in a young male patient. The clinical characteristics and management choices of this uncommon case of hemolymphangioma in the occipitocervical region are discussed, and a review based on the available literature is also presented. CONCLUSION: Hemolymphangioma of the occipitocervical region is an uncommon presentation of a rare lesion. Although rare, hemolymphangioma should be considered a differential diagnosis for masses occurring in the occipitocervical region. Complete surgical resection is the treatment of choice and affords a good prognosis.

19.
Spine (Phila Pa 1976) ; 42(12): 903-908, 2017 Jun 15.
Article in English | MEDLINE | ID: mdl-27792119

ABSTRACT

STUDY DESIGN: We performed decompression surgery or conservative treatments on 135 cervical spondylotic myelopathy (CSM) patients with concomitant hypertension and did follow-up assessments up to 1 year to examine the change of blood pressure, spinal cord function, and cervical pain. OBJECTIVE: The aim of this study was to determine whether concomitant hypertension is relieved after decompression surgery, and whether it is related to the improvement of spinal cord function or cervical pain. SUMMARY OF BACKGROUND DATA: In clinical practice, we often found that some patients with CSM have concomitant hypertension. Interestingly, after CSM was treated successfully by decompression surgery, some patients' high blood pressure returned to normal range even without oral medications. METHODS: We enrolled 135 CSM patients with hypertension, 103 of whom received decompression surgery, and remaining 32 patients accepted conservative treatments. We did follow-up assessments at 3, 6, and 12 months. The primary endpoints were changes of blood pressure, and secondary endpoints were changes of modified Japanese Orthopedic Association (mJOA) score and cervical pain visual analogue scale (VAS). Spearman correlation coefficients were calculated between changes in systolic blood pressure (SBP) and mJOA scores, VAS scores. RESULTS: In patients with decompression surgery, the significant decrease in both SBP and diastolic blood pressure (DBP) that was seen 3 months and sustained through subsequent visit at 12 months. Paired-samples t test showed that both SBP and DBP were significantly lower than baseline blood pressure at all time points after procedure (P < 0.001). Significant correlation was found between the improvement rates of mJOA score and changes in SBP (r = -0.579, P < 0.001). But the correlation between changes in VAS score and changes in SBP was not significant (r = 0.58, P = 0.571). CONCLUSION: Cervical decompression surgery could reduce concomitant high blood pressure in CSM patients, indicating a significant association between the decrease in blood pressure and the improvement of spinal cord function. LEVEL OF EVIDENCE: 2.


Subject(s)
Cervical Vertebrae/surgery , Decompression, Surgical , Hypertension/surgery , Spinal Cord Diseases/surgery , Spondylosis/surgery , Aged , Female , Humans , Hypertension/complications , Male , Middle Aged , Prospective Studies , Spinal Cord Diseases/etiology , Spondylosis/complications
20.
Spine (Phila Pa 1976) ; 42(8): 540-546, 2017 Apr 15.
Article in English | MEDLINE | ID: mdl-27438387

ABSTRACT

STUDY DESIGN: We collected the samples of cervical intervertebral discs from patients with vertigo to examine the distribution and types of mechanoreceptors in diseased cervical disc. OBJECTIVE: The aim of this study was to determine whether mechanoreceptors are distributed more abundantly in cervical discs from patients with cervical spondylosis, and whether they are related to vertigo. SUMMARY OF BACKGROUND DATA: Previous limited studies have found that normal cervical intervertebral discs are supplied with mechanoreceptors that have been considered responsible for proprioceptive functions. Several clinical studies have indicated that the patients with cervical spondylosis manifested significantly impaired postural control and subjective balance disturbance. METHODS: We collected 77 samples of cervical discs from 62 cervical spondylosis patients without vertigo, 61 samples from 54 patients with vertigo, and 40 control samples from 8 cadaveric donors to investigate distribution of mechanoreceptors containing neurofilament (NF200) and S-100 protein immunoreactive nerve endings. RESULTS: The immunohistochemical investigation revealed that the most frequently encountered mechanoreceptors were the Ruffini corpuscles in all groups of cervical disc samples. They were obviously increased in the number and deeply ingrown into inner annulus fibrosus and even into nucleus pulposus in the diseased cervical discs from patients with vertigo in comparison with the discs from patients without vertigo and control discs. Only three Golgi endings were seen in the three samples from patients with vertigo. No Pacinian corpuscles were found in any samples of cervical discs. CONCLUSION: The diseased cervical discs from patients with vertigo had more abundant distribution of Ruffini corpuscles than other discs. A positive association between the increased number and ingrowth of Ruffini corpuscles in the diseased cervical disc and the incidence of vertigo in the patients with cervical spondylosis was found, which may indicate a key role of Ruffini corpuscles in the pathogenesis of vertigo of cervical origin. LEVEL OF EVIDENCE: 1.


Subject(s)
Cervical Vertebrae/physiology , Intervertebral Disc/pathology , Mechanoreceptors/pathology , Spondylosis/pathology , Vertigo/pathology , Adult , Aged , Cervical Vertebrae/metabolism , Female , Humans , Immunohistochemistry , Intervertebral Disc/metabolism , Male , Mechanoreceptors/metabolism , Middle Aged , Neurofilament Proteins/metabolism , Radiculopathy/metabolism , Radiculopathy/pathology , S100 Proteins/metabolism , Spinal Cord Diseases/metabolism , Spinal Cord Diseases/pathology , Spondylosis/complications , Spondylosis/metabolism , Vertigo/complications , Vertigo/metabolism
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