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1.
Med Eng Phys ; 127: 104158, 2024 05.
Article in English | MEDLINE | ID: mdl-38692761

ABSTRACT

BACKGROUND: The intervertebral disc exhibits not only strain rate dependence (viscoelasticity), but also significant asymmetry under tensile and compressive loads, which is of great significance for understanding the mechanism of lumbar disc injury under physiological loads. OBJECTIVE: In this study, the strain rate sensitive and tension-compression asymmetry of the intervertebral disc were analyzed by experiments and constitutive equation. METHOD: The Sheep intervertebral disc samples were divided into three groups, in order to test the strain rate sensitive mechanical behavior, and the internal displacement as well as pressure distribution. RESULTS: The tensile stiffness is one order of magnitude smaller than the compression stiffness, and the logarithm of the elastic modulus is approximately linear with the logarithm of the strain rate, showing obvious tension-compression asymmetry and rate-related characteristics. In addition, the sensitivity to the strain rate is the same under these two loading conditions. The stress-strain curves of unloading and loading usually do not coincide, and form a Mullins effect hysteresis loop. The radial displacement distribution is opposite between the anterior and posterior region, which is consistent with the stress distribution. By introducing the damage factor into ZWT constitutive equation, the rate-dependent viscoelastic and weakening behavior of the intervertebral disc can be well described.


Subject(s)
Compressive Strength , Intervertebral Disc , Stress, Mechanical , Animals , Intervertebral Disc/physiology , Sheep , Biomechanical Phenomena , Tensile Strength , Weight-Bearing , Elasticity
2.
Oxid Med Cell Longev ; 2022: 8729398, 2022.
Article in English | MEDLINE | ID: mdl-36035210

ABSTRACT

Cerebral ischemia/reperfusion (I/R) injury is a clinical event associated with high morbidity and mortality. Neuroinflammation plays a crucial role in the pathogenesis of I/R-induced brain injury and cognitive decline. Low-density lipoprotein receptor-related protein-1 (LRP1) can exert strong neuroprotection in experimental intracerebral hemorrhage. However, whether LRP1 can confer neuroprotective effects after cerebral I/R is yet to be elucidated. The present study is aimed at investigating the effects of LRP1 activation on cerebral I/R injury and deducing the underlying mechanism involving TXNIP/NLRP3 signaling pathway. Cerebral I/R injury was induced in mice by bilateral common carotid artery occlusion. LPR1 ligand, apoE-mimic peptide COG1410, was administered intraperitoneally. To elucidate the underlying mechanism, overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, Western blot, enzyme-linked immunosorbent assay, HE, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of endogenous LRP1, TXNIP, NLRP3, procaspase-1, and cleaved caspase-1 were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 inhibited microglia proinflammatory polarization and promoted anti-inflammatory polarization, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were abolished by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially related to modulating microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 treatment might serve as a promising therapeutic approach in the management of cerebral I/R patients.


Subject(s)
Brain Ischemia , Cognitive Dysfunction , Low Density Lipoprotein Receptor-Related Protein-1 , Oxidative Stress , Reperfusion Injury , Animals , Carrier Proteins , Caspase 1 , Cognitive Dysfunction/prevention & control , Inflammasomes , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , Neuroinflammatory Diseases , Reperfusion Injury/prevention & control , Signal Transduction , Thioredoxins
3.
RSC Adv ; 12(17): 10835-10845, 2022 Mar 31.
Article in English | MEDLINE | ID: mdl-35424975

ABSTRACT

In the last decade, transition-metal-catalyzed direct C-H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp2)-H and C(sp3)-H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C-H functionalization of thioethers from 2010 to 2021.

4.
RSC Adv ; 10(66): 40365-40372, 2020 Nov 02.
Article in English | MEDLINE | ID: mdl-35520828

ABSTRACT

Furfurylamine and furfuryl alcohol are known as important furfural-upgrading derivatives in the production of pharmaceuticals, fibers, additives, polymers, etc. In a one-pot manner, the catalysis of biomass into furan-based chemicals was established in a tandem reaction with sulfonated Sn-graphite catalysts and biocatalysts. Using a raw bamboo shoot shell (75.0 g L-1) as the feedstock, a high furfural yield of 41.1% (based on xylan) was obtained using the heterogeneous Sn-graphite catalyst (3.6 wt% dosage) in water (pH 1.0) for 30 min at 180 °C. Under the optimum bioreaction conditions, the biomass-derived furfural could be transformed into furfuryl alcohol (0.310 g furfuryl alcohol per g xylan in biomass) by a reductase biocatalyst or furfurylamine (0.305 g furfurylamine per g xylan in biomass) using an ω-transaminase biocatalyst. Such one-pot chemoenzymatic processes combined the merits of both heterogeneous catalysts and biocatalysts, and sustainable processes were successfully constructed for synthesizing key bio-based furans.

5.
Phytomedicine ; 43: 11-20, 2018 Apr 01.
Article in English | MEDLINE | ID: mdl-29747742

ABSTRACT

BACKGROUND: Genistein (GEN), a phytoestrogen that is extracted from leguminous plants, can bind to estrogen receptor and exert biological effects. G protein-coupled estrogen receptor (GPER), a novel membrane estrogen receptor, has been reported to be involved in the anti-inflammatory process. In the present study, using BV2 microglial cell line and primary microglial culture, we evaluated the involvement of GPER in the anti-inflammatory effects of genistein against lipopolysaccharide (LPS)-induced microglia activation. METHODS: The anti-inflammatory effects of genistein were investigated in LPS-induced microglial activation in murine BV2 microglial cell line and primary microglial culture. Anti-inflammatory properties of genistein were determined by MTT, real time PCR, ELISA and western blot analysis. The pharmacological blockade and lentivirus-mediated siRNA knockdown of GPER were used to study the underlying mechanism. RESULTS: The results showed that genistein exerted inhibitory effects on LPS-induced expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1 ß (IL-1ß) and interleukin-6 (IL-6). Pre-treatment with GPER antagonist G15 could significantly block the anti-inflammatory effects of genistein. Moreover, the inhibitory effects of genistein on LPS-induced activation of MAPKs and NF-κB signaling pathways could also be blocked by G15. Lentivirus-mediated siRNA knockdown of GPER significantly inhibited the anti-inflammatory effects of genistein in BV2 cells. Further study revealed that genistein treatment could increase the gene and protein expressions of GPER in BV2 cells. CONCLUSION: Taken together, these data provide the first evidence that genistein exerts anti-inflammatory effects in microglial cells via GPER activation. These beneficial effects of genistein may represent a new strategy for the treatment of neuroinflammatory diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Genistein/pharmacology , Microglia/drug effects , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Cell Line , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Gene Expression Regulation/drug effects , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Mice , Microglia/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Rats, Sprague-Dawley , Receptors, Estrogen/genetics , Receptors, G-Protein-Coupled/genetics , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism
6.
Zhonghua Yi Xue Za Zhi ; 92(31): 2214-8, 2012 Aug 21.
Article in Chinese | MEDLINE | ID: mdl-23158430

ABSTRACT

OBJECTIVE: To explore the effects of ferric ion on the differentiation from both RAW264.7 and bone marrow macrophages to osteoclast in vitro and bone resorption in vivo. METHODS: In the presence of 50 ng/ml receptor activator of nuclear factor kappa-B ligand (RANKL), RAW264.7 was treated with ferric ammonium citrate (FAC). The formation of osteoclast was observed by staining of tartrate-resistant acid phosphatase (TRAP) and the TRAP positive cell counted. The expression levels of TRAP, cathepsin-K, nuclear factor of activated T cells c1 (NFATc1) and (receptor activator of NF-κB) RANK were measured by reverse transcription-polymerase chain reaction (RT-PCR).The control and iron overload groups were established by the intraperitoneal injection of normal saline and FAC. In vivo imaging system was employed to determine the bone density of femoral midportion and the fourth lumbar vertebra. After that, the bone marrow cells of femurs were used for osteoclast culture. The serum levels of ferritin, TRAP-5b, RANKL, osteoprotegerin (OPG) and C-terminal cross-linking telopeptide (CTX) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Ferric ion could stimulate the formation of TRAP positive cells in a dose-dependent manner. The expression levels of TRAP, cathepsin-K and NFATc1 in the FAC treated group were significantly higher those of the control group (P < 0.05) while the expression of RANK showed no statistical difference among these groups (P = 0.967). The bone marrow density of femoral midportion and the fourth lumbar vertebra of the iron-overload group decreased significantly versus the control group. The concentrations of ferritin, TRAP-5b, RANKL and CTX of the iron overload group were markedly higher than those of the control group (P < 0.05). Moreover, the concentration of ferritin showed a positive correlation with TRAP-5b and CTX respectively in the iron-overload group (r = 0.65, r = 0.76, P < 0.05). But no significant differences existed in the concentration of OPG for two groups (P > 0.05). CONCLUSION: Ferric ion may enhance the differentiation of osteoclast in vitro as well as bone resorption in vivo.


Subject(s)
Cell Differentiation/drug effects , Ferric Compounds/pharmacology , Osteoclasts/drug effects , Quaternary Ammonium Compounds/pharmacology , Acid Phosphatase/metabolism , Animals , Bone Resorption , Cell Line , Collagen Type I/metabolism , Isoenzymes/metabolism , Macrophages/cytology , Macrophages/drug effects , Mice , Mice, Inbred ICR , NFATC Transcription Factors/metabolism , Osteoclasts/cytology , Osteoprotegerin/metabolism , Peptides/metabolism , RANK Ligand/metabolism , Tartrate-Resistant Acid Phosphatase
7.
Bioorg Med Chem ; 18(14): 5039-47, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20598556

ABSTRACT

Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a-z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N+Y181C RT HIV-1 strains than efavirenz.


Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Infections/drug therapy , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Cell Line , Cell Survival/drug effects , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , Humans , Models, Molecular , Nitriles , Protein Binding , Pyridazines/chemistry , Pyridazines/pharmacology , Pyrimidines , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity Relationship
8.
Bioorg Med Chem ; 18(13): 4601-5, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-20570527

ABSTRACT

Nine newly 6-cyano-2-naphthyl substituted diarylpyrimidines (DAPY) were synthesized as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. The antiviral and cytotoxicity evaluation indicated that these compounds displayed strong activity against wild-type HIV-1 at nanomolar concentrations with selectivity index SI greater than 23 779. The most active compounds 3c and 3e exhibited activity against the double mutant (103N+181C) strains at an EC50 of 0.16 and 0.15 µM, and were more activity than that of efavirenz.


Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Naphthols/chemistry , Pyrimidines/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/toxicity , Benzoxazines/pharmacology , Binding Sites , Cell Line , Computer Simulation , Cyclopropanes , HIV Reverse Transcriptase/metabolism , Humans , Naphthols/chemical synthesis , Naphthols/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/toxicity
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 30(4): 838-41, 2010 Apr.
Article in Chinese | MEDLINE | ID: mdl-20423861

ABSTRACT

OBJECTIVE: To analyze the risk factors of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation for beta-thalassemia in children. METHODS: The clinical records of 30 children with beta-thalassemia undergoing allogeneic hematopoietic stem cell transplantation between December, 2008 and November, 2009 were analyzed. RESULTS: Hemorrhagic cystitis occurred in 8 of the 33 patients with an incidence of 24.24%, including 1 with grade I, 6 with grade II and 1 with grade III hemorrhagic cystitis. The median time of hemorrhagic cystitis onset was 22.9 days (range 6-35 days) and the median duration was 11.9 days(range 3-27 days). Univariate analysis indicated that the different types of transplantation and acute graft-versus-host disease affect the occurrence of hemorrhagic cystitis. The children with Allo-PBSCT had higher incidence than those receiving Allo-PBSCT+Allo-UBT and Allo-BMT (P<0.05). The children at an age >or=6 years had obviously higher incidence of hemorrhagic cystitis than those at younger ages. CONCLUSION: Age is the major factor that affects the occurrence of hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation for beta-thalassemia.


Subject(s)
Cystitis/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , beta-Thalassemia/therapy , Age Factors , Child , China/epidemiology , Cystitis/epidemiology , Humans , Incidence , Risk Factors , Transplantation, Homologous
10.
Bioorg Med Chem ; 18(7): 2370-4, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20307984

ABSTRACT

A series of novel diarylpyrimidine analogues featuring a hydroxyiminomethyl group between the pyrimidine scaffold and the aryl wing I have been synthesized and tested in MT-4 cells culture as non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus (HIV). Most of these new congeners exhibited moderate to excellent activity against wild-type virus with an EC(50) value ranging from 0.569microM to 0.005microM. 4-(4-((Hydroxyimino) (3-methoxyphenyl)methyl)pyrimidin-2-ylamino)benzonitrile (12n) was identified as the most active compound of this new series (EC(50)=0.025microM, SI >1223) associated with moderate activity against HIV-1 double mutant strains (K103N+Y181C) (EC(50)=8.72microM) in addition to its anti-HIV-2 activity with an EC(50) value of 8.31microM. Preliminary structure-activity relationship (SAR) among the newly synthesized DAPYs was also investigated.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Cell Line/drug effects , Cell Survival/drug effects , HIV-2/drug effects , Humans , Indicators and Reagents , Stereoisomerism , Structure-Activity Relationship
12.
Carcinogenesis ; 31(5): 858-63, 2010 May.
Article in English | MEDLINE | ID: mdl-20223788

ABSTRACT

The base excision repair (BER) pathway is important in repairing DNA damage incurred from occupational exposure to 1,3-butadiene (BD). This study examines the relationship between inherited polymorphisms of the BER pathway (x-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg280His, Arg399Gln, T-77C, ADPRT Val762Ala, MGMT Leu84Phe and APE1 Asp148Glu) and chromosomal damage in BD-exposed workers, using the cytokinesis-blocked (CB) micronucleus (MN) assay in peripheral lymphocytes of 166 workers occupationally exposed to BD and 41 non-exposed healthy individuals. The MN frequency of exposed workers (3.39 +/- 2.42) per thousand was higher than that of the non-exposed groups (1.48 +/- 1.26) per thousand (P < 0.01). Workers receiving greater than median annual BD exposures had higher MN values than lower exposed workers: frequency ratio (FR) of 1.30, 95% confidence interval (CI) 1.14-1.53; P < 0.05. Workers who carried the following genotypes were associated with greater frequency of MN (P < 0.05 for each comparison, unless specified): XRCC1 -77 C/T genotype (FR = 1.28, 95% CI: 1.04-1.57; reference C/C), ADPRT 762 Ala/Ala (FR = 1.54, 95% CI: 1.17-2.03; P < 0.01), XRCC1 194 Arg/Trp (FR = 1.13, 95% CI: 0.87-1.27; reference, Arg/Arg), XRCC1 280 Arg/His (FR = 1.67, 95% CI: 1.10-2.42; reference, Arg/Arg), XRCC1 399 Arg/Gln and Gln/Gln genotypes (FR = 1.26, 95% CI: 1.03-1.53 and FR = 1.24, 95% CI 1.03-1.49; reference Arg/Arg, respectively). As XRCC1 polymorphisms were linked, workers carrying the XRCC1 (-77)-(194)-(280)-(399) diplotype, TCGA/TCGA, had a higher MN frequency compared with individuals carrying the wild-type CCGG/CCGG (FR = 1.57, 95% CI: 1.02-2.41; P < 0.05). In conclusion, CB-MN is a sensitive index of early damage among BD-exposed workers. In workers exposed to BD, multiple BER polymorphisms and a XRCC1 haplotype were associated with differential levels of chromosome damage.


Subject(s)
Butadienes/toxicity , DNA Repair/genetics , Micronuclei, Chromosome-Defective , Occupational Exposure , Polymorphism, Genetic , Adult , DNA-Binding Proteins/genetics , Female , Genotype , Haplotypes , Humans , Male , Middle Aged , Poisson Distribution , Risk Assessment , X-ray Repair Cross Complementing Protein 1
13.
ChemMedChem ; 4(9): 1537-45, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19591191

ABSTRACT

A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC50 value of 0.002 microM and against the double mutant strain with an EC50 value of 0.24 microM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure-activity relationship (SAR) of the newly synthesized DAPYs is presented herein.


Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrimidines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/toxicity , Binding Sites , Cell Line , Computer Simulation , Drug Design , HIV Reverse Transcriptase/metabolism , Humans , Pyrimidines/chemistry , Pyrimidines/toxicity , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/toxicity , Structure-Activity Relationship
14.
ChemMedChem ; 4(2): 219-24, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19090525

ABSTRACT

A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild-type HIV-1.A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were synthesized and evaluated for their in vitro activity against HIV in MT-4 cells. All compounds exhibited strong activity against wild-type HIV-1. The most active compound showed activity against wild-type HIV-1 with an EC(50) value of 2.35 nM and against the double mutant strain (K103N+Y181C) with an EC(50) value of 6.6 microM, with a selectivity index greater than 60 000 against wild-type HIV-1. Additionally, some compounds also showed activity against HIV-2 (EC(50)=5.82 microM).


Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Cell Line , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Spectrometry, Mass, Electrospray Ionization
15.
Chem Pharm Bull (Tokyo) ; 54(9): 1248-53, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16946529

ABSTRACT

A series of novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues bearing a 6-(1-naphthoyl) group of non-nucleoside human immunodeficiency virus (HIV) reverse transcriptase inhibitors were synthesized and evaluated for their activity against HIV-1 and HIV-2. It was found that most of these compounds showed good activity against HIV-1. Among them, compound 5-isopropyl-6-(1-naphthoyl)-1-[(2E)-3-phenylallyl]-2,4-pyrimidinedione (23) displayed the greatest inhibitory potency (IC(50)=0.14 muM), which is about 35-fold more active than HEPT and DDI. To rationalize the relationships between structure and activity of these novel compounds, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also generated. The results provided a tool for guiding the further design of more potent antiviral agents and for predicting the affinity of related compounds.


Subject(s)
Anti-HIV Agents , HIV Reverse Transcriptase/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Reverse Transcriptase Inhibitors , Thymine/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Line , Cell Proliferation/drug effects , Chemical Phenomena , Chemistry, Physical , Drug Design , HIV Reverse Transcriptase/chemistry , Humans , Hydrogen Bonding , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Stereoisomerism , Thymine/chemical synthesis , Thymine/chemistry , Thymine/pharmacology
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