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Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has escalated into a global tragedy afflicting human health, life, and social governance. Through the increasing depth of research and a better understanding of this disease, it has been ascertained that, in addition to the lungs, SARS-CoV-2 can also induce injuries to other organs including the liver. Liver injury is a common clinical manifestation of COVID-19, particularly in severe cases, and is often associated with a poorer prognosis and higher severity of COVID-19. This review focuses on the general existing information on liver injury caused by COVID-19, including risk factors and subpopulations of liver injury in COVID-19, the association between preexisting liver diseases and the severity of COVID-19, and the potential mechanisms by which SARS-CoV-2 affects the liver. This review may provide some useful information for the development of therapeutic and preventive strategies for COVID-19-associated liver injury.

The novel coronavirus disease (COVID-19) outbreak that emerged at the end of 2019 has now swept the world for more than 2 years, causing immeasurable damage to the lives and economies of the world. It has drawn so much attention to discovering how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated and entered the human body. The current argument revolves around two contradictory theories: a scenario of laboratory spillover events and human contact with zoonotic diseases. Here, we reviewed the transmission, pathogenesis, possible hosts, as well as the genome and protein structure of SARS-CoV-2, which play key roles in the COVID-19 pandemic. We believe the coronavirus was originally transmitted to human by animals rather than by a laboratory leak. However, there still needs more investigations to determine the source of the pandemic. Understanding how COVID-19 emerged is vital to developing global strategies for mitigating future outbreaks.

In July 2022, the World Health Organization announced monkeypox as a public health emergency of international concern (PHEIC), over 85,000 global cases have been reported currently. However, preventive and therapeutic treatments are very limited. The monkeypox virus (MPXV) E12, an mRNA capping enzyme small subunit, is essential for the methyltransferase activity of RNA capping enzymes of MPXV. Here, we solved a 2.16 Å crystal structure of E12. We also docked the D1 subunit c-terminal domain (D1CTD) of vaccinia virus (VACV) with E12 to analyze the critical residues of interface between them. These residues are used for drug screening. The top six compounds are Rutin, Quercitrin, Epigallocatechin, Rosuvastatin, 5-hydroxy-L-Tryptophan, and Deferasirox. These findings may provide insights into the development of anti-MPXV drugs.

Lysine crotonylation (Kcr) is a newly identified protein translational modification and is involved in major biological processes including glycolysis, but its role in colorectal cancer (CRC) is unknown. Here, we found that the Kcr of α enolase (ENO1) was significantly elevated in human CRC tissues compared with the paratumoral tissues. CREB-binding protein (CBP) functioned as a crotonyltranferase of ENO1, and SIRT2 was involved in the decrotonylation of ENO1. Using quantitative mass spectrometry for crotonylomics analysis, we further found that K420 was the main Kcr site of ENO1 and ENO1 K420 Kcr promoted the growth, migration, and invasion of CRC cells in vitro by enhancing the activity of ENO1 and regulating the expression of tumor-associated genes. Our study reveals an important mechanism by which ENO1 regulates CRC through crotonylation.

Background The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated. Methods Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy. Results Within 30 min, both SiNPs (10-8-10-6 g/mL) did not affect the resting potential and IK1 channels. SiNP-100 increased the action potential amplitude (APA) and the INa current density, but SiNP-20 decreased APA and INa density. SiNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SiNPs (10-6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4-10 mg/kg) and SiNP-20 (4-30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice. Conclusion SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the INa and Ito channels and Ca2+ homeostasis but not IK1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.

It is widely considered that sport and physical activities contribute to the development of human wellbeing. It is a fact that sport brings positive energy, discipline, and human wellbeing. Sports have an enormous effect on human health. Therefore, we assess the effects of the sports industry on the human health of China by using the autoregressive distributed lag (ARDL) approach from 1998 to 2020. Findings show that sports activities significantly improve human health and wellbeing. Tourism has found a positive influence on health and helped to contribute to human wellbeing. Empirical results prove that health expenditure and financial development significantly increase the population health in China. China's government should focus on the sports and tourism industry to play an important role in human health and wellbeing.

BackgroundThe Ilheus virus (ILHV) is an encephalitis associated arthropod-borne flavivirus. It was first identified in Ilheus City in the northeast Brazil before spreading to a wider geographic range. No specific vaccines or drugs are currently available for the treatment of ILHV infections. The ILHV helicase, like other flavivirus helicases, possesses 5ʹ-triphosphatase activity. This allows it to perform ATP hydrolysis to generate energy as well as sustain double-stranded RNA’s unwinding during ILHV genome replication. Thus, ILHV helicase is an ideal target for inhibitor design.ResultsWe determined the crystal structure of the ILHV helicase at 1.75-Å resolution. We then conducted molecular docking of ATP-Mn2+to the ILHV helicase. Comparisons with related flavivirus helicases indicated that both the NTP and the RNA-ILHV helicase binding sites were conserved across intra-genus species. This suggested that ILHV helicase adopts an identical mode in recognizing ATP/Mn2+. However, the P-loop in the active site showed a distinctive conformation; reflecting a different local structural rearrangement. ILHV helicase enzymatic activity was also characterized. This was found to be relatively lower than that of the DENV, ZIKV, MVE, and ALSV helicases. Our structure-guided mutagenesis revealed that R26A, E110A, and Q280A greatly reduced the ATPase activities. Moreover, we docked two small molecule inhibitors of DENV helicase (ST-610 and suramin) to the ILHV helicase and found that these two molecules had the potential to inhibit the activity of ILHV helicase as well.ConclusionHigh-resolution ILHV helicase structural analysis demonstrates the key amino acids of ATPase activities and could be useful for the design of inhibitors targeting the helicase of ILHV.

Lysine malonylation, a novel identified protein posttranslational modification (PTM), is conservative and present in both eukaryotic and prokaryotic cells. Previous studies have reported that malonylation plays an important role in inflammation, angiogenesis, and diabetes. However, its potential role in cardiac remodeling remains unknown. Here, we observed a reduced lysine malonylation in hypertrophic mice hearts created by transverse aortic constriction (TAC) for 8 weeks. We also detected a decreased lysine malonylation in hypertrophic H9C2 cardiomyocytes induced by angiotensin II for 48 h. Using a proteomic method based on affinity purification and LC-MS/MS, we identified total 679 malonylated sites in 330 proteins in the hearts of sham mice and TAC mice. Bioinformatic analysis of the proteomic data revealed enrichment of malonylated proteins involved in cardiac structure and contraction, cGMP-PKG pathway, and metabolism. Specifically, we detected a decreased lysine malonylation in myocardial isocitrate dehydrogenase 2 (IDH2) by immunoprecipitation coupled with Western blotting both in vivo and in vitro. Together, our work suggests an important role and implication of protein lysine malonylation in cardiac hypertrophy, especially the IDH2. SIGNIFICANCE: Heart failure is the terminal stage of cardiac hypertrophy, which imposes an enormous clinical and economic burden worldwide. Despite our knowledge on the pathophysiology of the disease, current therapeutic approaches are still largely limited. Cardiac hypertrophy can be regulated at post-translational modifications (PTMs), and several PTMs have been reported in cardiac hypertrrophy and heart failure. In our study, we first reported a novel PTMs, lysine malonylation, in cardiac hypertophy. we found a reduced lysine malonylation in hypertrophic mice hearts in vivo and H9C2 cardiomyocytes after stimulating with angiotensinII for 48 h in vitro. Using affinity purification and LC-MS/MS, we identified 679 malonylated sites in 330 proteins in the hearts of sham and TAC mice. Compared to the sham group, 5 sites in 2 proteins were quantified as downregulated targets using a 2-fold threshold (downregulation0.5-fold, P 0.05). Functional analysis showed a significant enrichment in cardiac structure and contraction, cGMP-PKG pathway and metabolism. Notably, we identified a decreased Kmal level in isocitrate dehydrogenase 2 (IDH2), but the protein level of IDH2 has no changed in cardiac hypertrophy, These results highlight that lysine malonylation is associated with cardiac hypertrophy, and may be a new therapeutic target of the disease.

Flaviviruses are still a hidden threat to global human safety, as we are reminded by recent reports of dengue virus infections in Singapore and African-lineage-like Zika virus infections in Brazil. Therapeutic drugs or vaccines for flavivirus infections are in urgent need but are not well developed. The Flaviviridae family comprises a large group of enveloped viruses with a single-strand RNA genome of positive polarity. The genome of flavivirus encodes ten proteins, and each of them plays a different and important role in viral infection. In this review, we briefly summarized the major information of flavivirus and further introduced some strategies for the design and development of vaccines and anti-flavivirus compound drugs based on the structure of the viral proteins. There is no doubt that in the past few years, studies of antiviral drugs have achieved solid progress based on better understanding of the flavivirus biology. However, currently, there are no fully effective antiviral drugs or vaccines for most flaviviruses. We hope that this review may provide useful information for future development of anti-flavivirus drugs and vaccines.

Crotonylation of proteins is a newly found type of post-translational modifications (PTMs) which occurs leadingly on the lysine residue, namely, lysine crotonylation (Kcr). Kcr is conserved and is regulated by a series of enzymes and co-enzymes including lysine crotonyltransferase (writer), lysine decrotonylase (eraser), certain YEATS proteins (reader), and crotonyl-coenzyme A (donor). Histone Kcr has been substantially studied since 2011, but the Kcr of non-histone proteins is just an emerging field since its finding in 2017. Recent advances in the identification and quantification of non-histone protein Kcr by mass spectrometry have increased our understanding of Kcr. In this review, we summarized the main proteomic characteristics of non-histone protein Kcr and discussed its biological functions, including gene transcription, DNA damage response, enzymes regulation, metabolic pathways, cell cycle, and localization of heterochromatin in cells. We further proposed the performance of non-histone protein Kcr in diseases and the prospect of Kcr manipulators as potential therapeutic candidates in the diseases.

Precision medicine for gastric cancer (GC) is still an unsolved issue, because most available target drugs are not specifically designed for GC. Exploring novel signaling molecules with target value for GC is in urgent need. This study aimed to reveal that interleukin-2 receptor subunit gamma (IL2RG) is such a key molecule in human GC progression. GC tissues and paracancerous gastric tissues were collected from 7 patients (5 males and 2 females) during tumor radical excision surgery. These tissues were used to identify the differentially expressed genes (DEGs) with RNA-seq and serial bioinformatics analyses including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, gene expression profiling interactive analysis (GEPIA), and survival analysis. RT-qPCR and western blotting were performed to compare the mRNA and protein expression levels of IL2RG between GC tissues and adjacent normal gastric tissues as well as between GC cell line SGC-7901 and normal gastric epithelial cell line GES-1. Results showed striking elevations of IL2RG both in the mRNA and protein levels in GC tissues and human gastric cancer SGC-7901 cell line compared, respectively, with the adjacent normal gastric tissues and normal GES-1 cells, and higher IL2RG expression was associated with lower survival. Analyses on the GSE29272 and GSE15459 datasets from Gene Expression Omnibus verified that IL2RG was highly expressed in GC patients and was associated with poor overall survival. In addition, molecular docking showed that a small molecule, resatorvid (TAK 242), might be an inhibitor of IL2RG. We conclude that IL2RG is overexpressed in advanced GC and is associated with low survival. IL2RG may serve as a biomarker of GC progression and poor prognosis.

The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.

In-depth analysis on the rambling genes of psoriasis may help to identify the pathologic mechanism of this disease. However, this has seldom been performed. Using bioinformatic approaches, we analyzed four gene expression profiles in gene expression omnibus (GEO) database, identified the differentially expressed genes (DEGs), and found out the overlapping DEGs (common DEGs, CDEGs) in the above four profiles. The CDEGs were further subjected to Gene Ontology (GO) enrichment analysis, Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network analysis, and hub genes were ranked. We identified 139 CDEGs associated with a variety of GO processes including keratinization, immune and inflammatory responses, and type 1 interferon signaling pathway. These CDEGs were enriched in a variety of KEGG processes, including cytokine-cytokine receptor interaction and chemokine signaling. PPI analysis showed that seven genes (HERC6, ISG15, MX1, RSAD2, OAS2, OASL, and OAS3) were likely the novel hub genes of psoriasis. RT-qPCR identified that five (ISG15, MX1, OAS2, OASL, and OAS3) of the seven predicted hub genes were overexpressed in TNF-α stimulated HaCaT cell lines, a result quite consistent with the predictions. The study provides new information in exploring the mechanisms and therapeutic targets of psoriasis.

Growth hormone secretagogues (GHS) have been proved to exert protective effects on the cardiovascular system, while their potential beneficial effects on macrophages in atherosclerosis (AS) are rarely been clarified. This study aimed to demonstrate whether hexarelin, a synthetic peptidyl GHS, can suppress AS progression via regulating the function of macrophages. AS was induced by chronic (3 months) feeding with high lipid diet in ApoE-/- mice. Mice were treated either with hexarelin (100 μg/kg s.c., q.d. for 3 months) (AS + Hex group) or saline (AS group). Age-matched C57BL/6 J mice were used as normal controls. AS and related signaling molecules in aortic tissues and RAW264.7 macrophages were identified with variant methods including histological staining, ELISA, western blotting, confocal microscopy and flow cytometry. AS significantly developed in ApoE−/− mice fed with high lipids diet. Hexarelin decreased serum TC, TG and LDL-c, increased serum HDL-c and attenuated the formation of atherosclerotic plaques and neointima compared with the AS group. Hexarelin decreased the aortic expressions of CD68 and LOX-1 which were elevated in the AS group. Hexarelin increased GHSR expression, suppressed ox-LDL uptake and LOX-1 expression and inhibited nuclear factor-kappa B (NF-κB) activation both in the aorta of ApoE−/− mice and in RAW264.7 macrophages. We conclude that hexarelin effectively attenuates AS progression in ApoE−/− mice by modulating circulatory lipids profile and inhibiting macrophage ox-LDL uptake via suppressing the LOX-1-NF-κB signaling pathway. The study supports the perspective of hexarelin as an anti-AS drug.

Mono-modified β-cyclodextrins ligands, L1 (6-mono-(N-aminoethyl) amino-β-cyclodextrin) and L2 (6-mono-(N-(pyridin-2-yl) ethylamino)-β-cyclodextrin), and their platinum (II) complexes, 1 ([Pt (L1)Cl2]·8H2O) and 2 ([Pt (L2)Cl2]·4H2O), were successfully synthesized. As revealed by UV-Vis and CD spectroscopic studies, both complexes mainly adopt a non-intercalative mode with DNA. The interaction between platinum complex 1 and DNA was obviously observed in agarose Gel Electrophoresis. Meanwhile, two ligands L1, L2 and platinum complex 2 have no obvious interaction with DNA. The difference interaction between complexes 1, 2 and DNA should be ascribed to their different structures.

Strontium Hydroxyapatite (SrxCa10-x(PO4)(6)(OH)(2), x=0, 3, 5, 10) powder with fluorescence property was successfully synthesized by a facile hydrothermal process. X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectra, field emission scanning electron microscope and photoluminescence excitation and emission spectra were employed to analyze phase change, characteristics and fluorescence property of samples. The experimental results indicate that the morphology of samples is spherical particle(D=1 similar to 2 mu m), and with the amount of strontium changed from 0 to 100mol%, the morphology of spherical particle changes from short nanorods to nanosheets and then long nanorods. The samples show an intense and bright blue emission from 375 nm to 500 nm centered at 432 nm under long-wavelength UV light excitation (351 nm). The PL emission intensity firstly increases and then decreases with increasing the strontium content. When strontium content is 30%, the PL emission intensity reaches the maximum.

As a naturally-occurring trace element, boron involves many life processes including embryogenesis, bone growth and maintenance, immune function and psychomotor skills. Thus, the low chemical durable glass based on 3-fold coordination boron network former shows potential in delivering boron for bone health. However, its high dissolution rate may result in cytotoxicity. The addition of strontium seems to be an effective approach not only inhibits its rapid degradation, but delivers strontium as a ‘drug’ to enhance the ability of bone formation. Thus, strontium-incorporated borosilicate shows special role in bone regeneration, in particular in women past menopause.

A simple method to prepare hollow hydroxyapatite (HAP) microspheres with mespores on the surfaces is performed using a precipitation method assisted with Li2O-CaO-B2O3(LCB) glass fabrication process. This research is concerned with the effect of sintering temperature on the microstructure evolution, phase purity, surface morphology, specific surface area, and porosity after sintering process. The microspheres were sintered in air atmosphere at temperatures ranging from 500 to 900 °C. The starting hollow HAP microspheres and the sintered specimens were characterized by scanning electron microscope, X-ray diffractometer, specific surface area analyzer, and Hg porosimetry, respectively. The as-prepared microspheres consisted of calcium deficient hydroxyapatite. The results showed that the as-prepared hollow HAP microspheres had the highest specific surface areas, and the biggest total pore volume. The pore size distribution of the as-prepared hollow HAP microspheres were mainly the mesopores in the range of 2～40 nm. The specific surface area and total pore volume of hollow HAP microspheres decreased with increasing sintering temperature. Whereas the mean pore size increased with increasing sintering temperature. It showed that at 700°C, Ca-dHAP decomposes into a biphasic mixture of HAP and β-calcium phosphate(TCP).

Unlike alpha-amino acids, peptides formed from beta-amino acids (beta-peptides) display stability toward enzymatic degradation and may form turns and helices with as few as four residues. Because both the C alpha and C beta of the beta-amino acid may bear substituents, a large number of beta-amino acids can be synthesized. Beta-peptides form various well-defined secondary structures, including 14-helix, 12-helix, 10/12-helix, 10-helix, 8-helix, turn structures, sheets, and hairpins. For all of these reasons, beta-amino acids have been increasingly used as building blocks for molecular design and pharmaceutical applications. To explain the conformational features of beta-peptides, several quantum mechanics and molecular dynamics studies that rationalize the observed conformational features have been reported. However, a systematic account that unifies various factors critical to the conformational features is still lacking. In this Account, we present a detailed analysis of the conformational features of various beta-peptides. We start by studying the basic local conformational features of beta-peptides using di- and tripeptide models. Then, various secondary structures of unsubstituted beta-peptides with differing numbers of residues are investigated using a repeating unit approach to derive the intrinsic backbone conformational features. We find that the 10/12-helix is intrinsically most stable for the beta-peptide backbone. The 14-helix, 12-helix, and 10-helix structures have similar stabilities for beta-peptide backbones of four to six residues. The substituent effects on the stabilities of beta-peptide secondary structures are then analyzed. Combined with the substituent effect and the intrinsic backbone preferences, all experimental observations of secondary structure formation can be understood. For example, the 10/12-helix is favored for like-beta(2)/beta(3)-peptides, unlike-beta(3)/beta(3)-peptides, and beta(3)/beta-hGly-peptides because these substitution patterns do not cause steric problems for the 10/12-helix. Beta(3)-peptides, beta(2)-peptides, and beta (2,3)-peptides favor the 14-helix because the substituents in these peptides benefit the 14-helix the most but significantly destabilize the 10/12-helix. Because the 10/12-helix is intrinsically favored and has two favorable positions in each residue for substituents, many more hybrid beta-peptides are predicted to exist in this secondary structure, which suggests the need for further experiments. These results are valuable for determining the best use of these building blocks in the design of well-structured molecules with desirable chemical functions.

PEG-modified ZnGd0.1Fe1.9O4 ferrite nanoparticles were synthesized by a coprecipitation process combined with a microemulsion technique. The effect of modification on the structure, magnetic properties of ZnGd0.1Fe1.9O4 nanoparticles was also investigated by XRD, FTIR, TEM and VSM. The results showed immobilizing PEG on the surfaces of magnetic nanoparticles effectively improved their dispersibility. Magnetic measurements indicated that the as-prepared PEG-modified nanoparticles exhibited relatively high magnetic properties, although a slight reduction in saturation and remanent magnetization were observed compared with unmodified samples. Therefore, with promising high magnetic behavior and potentially good biocompatibility, PEG-modified ZnGd0.1Fe1.9O4 ferrite nanoparticles would be feasible as thermoseeds for interstitial hyperthermia to tumor.

The combination of Pd(OAc) 2 and DABCO (triethylenediamine) was observed as an efficient catalytic system for the Heck cross-coupling reaction. In the presence of Pd(OAc) 2 and DABCO, a number of ArX (X = I, Br, and Cl) were coupled with olefins efficiently and selectively to afford the corresponding unsymmetric internal olefins in good to excellent yields. Furthermore, the Pd(OAc) 2 /DABCO-catalyzed Heck cross-coupling reaction provided high TONs up to 1,000,000.

Our previous work revealed that two adjacent D-alpha-aminoxy acids could form two homochiral N-O turns, with the backbone folding into an extended helical structure (1.8(8)-helix). Here, we report the conformational studies of linear peptides 3-6, which contain a D,L-alpha-aminoxy acid dimer segment. The NMR and X-ray analysis of 3 showed that it folded into a loop conformation with two heterochiral N-O turns. This loop segment can be used to constrain tetrapeptides 4 and 6 to form a reverse turn structure. (1)H NMR dilution studies, DMSO-d6 addition studies, and 2D-NOESY data indicated that tetrapeptides 4 and 6 folded into reverse turn conformations featured by a head-to-tail 16-membered-ring intramolecular hydrogen bond. In contrast, tetrapeptide 5 with L-Ala instead of Gly or D-Ala as the N-terminal amino acid could not form the desired reverse turn structure for steric reasons. Quantum mechanics calculations showed that model pentamide 7, with the same substitution pattern of 4, adopted a novel reverse turn conformation featuring two heterochiral N-O turns (each of an 8-membered ring hydrogen bond), a cross-strand 16-membered ring hydrogen bond, and a 7-membered ring gamma-turn.

Results of Monte Carlo (MC) simulations for more than 200 nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) representing eight diverse chemotypes have been correlated with their anti-HIV activities in an effort to establish simulation protocols and methods that can be used in the development of more effective drugs. Each inhibitor was modeled in a complex with the protein and by itself in water, and potentially useful descriptors of binding affinity were collected during the MC simulations. A viable regression equation was obtained for each data set using an extended linear response approach, which yielded r(2) values between 0.54 and 0.85 and an average unsigned error of only 0.50 kcal/mol. The most common descriptors confirm that a good geometrical match between the inhibitor and the protein is important and that the net loss of hydrogen bonds with the inhibitor upon binding is unfavorable. Other physically reasonable descriptors of binding are needed on a chemotype case-by-case basis. By including descriptors in common from the individual fits, combination regressions that include multiple data sets were also developed. This procedure led to a refined "master" regression for 210 NNRTIs with an r(2) of 0.60 and a cross-validated q(2) of 0.55. The computed activities show an rms error of 0.86 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. Encouraging results were obtained for the predictions of 27 NNRTIs, representing a new chemotype not included in the development of the regression model. Predictions for this test set using the master regression yielded a q(2) value of 0.51 and an average unsigned error of 0.67 kcal/mol. Finally, additional regression analysis reveals that use of ligand-only descriptors leads to models with much diminished predictive ability.

Apolipoprotein F (ApoF) inhibits cholesteryl ester transfer protein (CETP) activity and plays an important role in lipid metabolism. In the present study, the full-length human ApoF promoter was cloned, and the molecular mechanism of the regulation of ApoF was investigated. The ApoF promoter displayed higher activities in hepatoma cell lines, and the −198 nt to +79 nt promoter region contained the maximum promoter activity. In the promoter region of −198 nt to −2 nt there were four putative binding sites for transcription factors ETS-1/ETS-2 (named EBS-1 to EBS-4) and one for C/EBP. Mutation of EBS-2, EBS4 and the C/EBP binding site abolished the promoter activity, and ETS-1/ETS-2 and C/EBPα could interact with corresponding binding sites. In addition, overexpression of ETS-1/2 or C/EBPα enhanced, while dominant-negative mutants of ETS-1/2 and knockdown of C/EBPα decreased, ApoF promoter activities. ETS-1 and C/EBPα associated physically, and acted synergistically to activate ApoF transcription. These results demonstrated combined activation of the ApoF promoter by liver-enriched and ubiquitous transcription factors. Direct interactions between C/EBPα and ETS-1 were important for high liver-specific expression of ApoF.

Monte Carlo/free energy perturbation (MC/FEP) calculations were used to evaluate the binding free energy change for HIV-RT/inhibitor complexes upon L100I mutation. Inhibitor size and flexibility adjacent to hydrogen-bonding sites are evident as important considerations for antiviral drug design.

Conformational features of α,β-disubstituted β2,3-dipeptide models have been studied with quantum mechanics method. Geometries were optimized with the HF/6-31G** method, and energies were evaluated with the B3LYP/6-31G** method. Solvent effect was evaluated with the SCIPCM method. For (2S,3S)-β2,3-dipeptide model 1, a six-membered-ring hydrogen bonded structure is most stable. However, the conformation corresponding to the formation of the 14-helix is only about 1.7 kcal/mol less stable in methanol solution, indicating that the 14-helix is favored if a (2S,3S)-β2,3-polypeptide contains more than 5 residues. On the other hand, the conformation corresponding to the formation of β-sheet is most stable for (2R,3S)-β2,3-dipeptide model 2, suggesting that this type of β-peptides is intrinsically favored for the formation of β-sheet secondary structure.

Quantum mechanics methods have been applied to study the conformational features of peptides formed by aminoxy acids. Geometry and vibration frequencies were calculated by the HF/6-31G** method. Energy was further evaluated using the MP2/6-31G** or B3LYP/6-31G* calculation. Solvent effect was modeled by the self-consistent isosurface polarization continuum model with the HF/6-31G** method. There is a significant preference for the formation of an eight-membered-ring hydrogen bond between adjacent amino acid residues, which resembles a γ-turn. The rotation direction of the C8 structure is determined by the chirality of the Cα center and is independent upon the size of the alkyl side chain. There is a cooperative effect for the formation of adjacent C8 structures, which promotes the formation of helix. Thus, a homo (S)-oxa-polypeptide forms a right-handed 1.88-helix, with each turn of the helix containing about 1.8 units of aminoxy acids.

The conformational features of a series of β-peptide models 1−11 have been studied by the molecular mechanics MM2* force-field and quantum mechanics methods. The geometries were optimized by the HF...

In this review, the author summarized the current status, challenges, and strategies in China in the development of transgenic plants and its commercialization. Based on sets of successful examples and data achieved from execution of the National Special Project for Transgenic Plant Research and Commercialization in the last five years, the priorities and key directions were put forward for the future development of transgenic plants in China.