Tissue-specific RNA methylation prediction from gene expression data using sparse regression models.

N6-methyladenosine (m6A) is a highly prevalent and conserved post-transcriptional modification observed in mRNA and long non-coding RNA (lncRNA). Identifying potential m6A sites within RNA sequences is crucial for unraveling the potential influence of the epitranscriptome on biological processes. In this study, we introduce Exp2RM, a novel approach that formulates single-site-based tissue-specific elastic net models for predicting tissue-specific methylation levels utilizing gene expression data. The resulting ensemble model demonstrates robust predictive performance for tissue-specific methylation levels, with an average R-squared value of 0.496 and a median R-squared value of 0.482 across all 22 human tissues. Since methylation distribution varies among tissues, we trained the model to incorporate similar patterns, significantly improves accuracy with the median R-squared value increasing to 0.728. Additonally, functional analysis reveals Exp2RM's ability to capture coefficient genes in relevant biological processes. This study emphasizes the importance of tissue-specific methylation distribution in enhancing prediction accuracy and provides insights into the functional implications of methylation sites.

Practical NTRU Signcryption in the Standard Model.

Based on the NTRU trapdoor used in NIST's Falcon, a signcryption scheme following the sign-then-encrypt paradigm is constructed. The existing partitioning technique based on Waters hash over the lattice can not complete the security reduction in the standard model for the signature part due to the "partiality" of the pre-image generated with the NTRU trapdoor. To address this, a variant of Waters hash over small integers is proposed and, the probability of the successful reduction is analyzed. The resulting signcryption achieves existential unforgeability under the adaptive chosen-message attacks. By utilizing the uniqueness of the secret and the noise in an NTRU instance, the tag used in encryption is eliminated. Furthermore, a method to construct tamper-sensitive lattice public key encryption is proposed. This approach implants the ciphertext-sensitive information into the lattice public key encryption and binds it to the encrypted information. The malleability to the public key ciphertext triggers the change of the message-signature pair so that the IND-CCA2 security of the entire ciphertext can be guaranteed by the signature for the message. Thanks to the rational design and the efficiency of the NTRU trapdoor, the computational overhead of the proposed scheme is reduced significantly compared to the existing lattice-based signcryption scheme, reaching orders of magnitude improvement in efficiency. The experiment shows that the proposed scheme is efficient.

Discovery of Novel Sesquiterpene Lactone Derivatives as Potent PKM2 Activators for the Treatment of Ulcerative Colitis.

The pyruvate kinase M2 (PKM2) can significantly affect the differentiation of Th17 and Treg cells; thus, it is considered a promising target for UC therapy. Herein, five series of costunolide (Cos) derivatives are designed, synthesized, and biologically evaluated. Among them, D5 exhibits excellent immunomodulatory activity against T-cell proliferation and potent PKM2 activating activity. Meanwhile, it has been confirmed that D5 can also covalently interact with Cys424 of PKM2. The molecular docking and molecular dynamic (MD) studies indicate that difluorocyclopropyl derivative of D5 improves the protein-ligand interaction by interacting with Arg399 electrostatically. Furthermore, D5 significantly dampens the differentiation of Th17 but not Treg cells to recover the Th17/Treg balance, which is attributed to the suppression of PKM2-mediated glycolysis. Oral administration of D5 ameliorates the symptoms of dextran sulfate sodium (DSS)- and 2,4,6-trinitro-benzenesulfonic acid (TNBS)-induced colitis in mouse model. Collectively, D5 has the potential to be developed as a novel anti-UC candidate.

4acCPred: Weakly supervised prediction of N 4-acetyldeoxycytosine DNA modification from sequences.

DNA methylation is one of the earliest epigenetic regulation mechanisms studied extensively, and it is critical for normal development, diseases, and gene expression. As a recently identified chemical modification of DNA, N4-acetyldeoxycytosine (4acC) was shown to be abundant in Arabidopsis and highly associated with gene expression and actively transcribed genes. Precise identification of 4acC is essential for studying its biological function. We proposed the 4acCPred, the first computational framework for predicting 4acC-carrying regions from Arabidopsis genomic DNA sequences. Since the existing 4acC data are not precise for a specific base but only report regions that are hundreds of bases long, we formulated the task as a weakly supervised learning problem and built 4acCPred using a multi-instance-based deep neural network. Both cross-validation and independent testing on the four datasets under different conditions show promising performance, with mean areas under the receiver operating characteristic curve (AUCs) of 0.9877 and 0.9899, respectively. 4acCPred also provides motif mining through model interpretation. The motifs found by 4acCPred are consistent with existing knowledge, indicating that the model successfully captured real biological signals. In addition, a user-friendly web server was built to facilitate 4acC prediction, motif visualization, and data access. Our framework and web server should serve as useful tools for 4acC research.

Nasal Mucosa Exploited by SARS-CoV-2 for Replicating and Shedding during Reinfection.

Reinfection risk is a great concern with regard to the COVID-19 pandemic because a large proportion of the population has recovered from an initial infection, and previous reports found that primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques without viral presence and pathological injury; however, a high possibility for reinfection at the current stage of the pandemic has been proven. We found the reinfection of SARS-CoV-2 in Syrian hamsters with continuous viral shedding in the upper respiratory tracts and few injuries in the lung, and nasal mucosa was exploited by SARS-CoV-2 for replication and shedding during reinfection; meanwhile, no viral replication or enhanced damage was observed in the lower respiratory tracts. Consistent with the mild phenotype in the reinfection, increases in mRNA levels in cytokines and chemokines in the nasal mucosa but only slight increases in the lung were found. Notably, the high levels of neutralizing antibodies in serum could not prevent reinfection in hamsters but may play roles in benefitting the lung recovery and symptom relief of COVID-19. In summary, Syrian hamsters could be reinfected by SARS-CoV-2 with mild symptoms but with obvious viral shedding and replication, and both convalescent and vaccinated patients should be wary of the transmission and reinfection of SARS-CoV-2.

Comparison of nonhuman primates identified the suitable model for COVID-19.

Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.

Isolation and identification of two new strains of mammalian orthoreovirus from Chinese tree shrews.

Chinese tree shrews have been used extensively in studies of different types of cancer and for the modeling of viral infections. In the present study, we report the isolation and characterization of two strains of mammalian orthoreovirus (MRV), MRV1/TS/2011 and MRV3/TS/2012, which were isolated from the feces of tree shrews in Yunnan, China. These two strains of MRV were isolated and cultured in both primary tree shrew intestinal epithelial cells (pTIECs) and primary tree shrew alveolar epithelial cells (pTAECs). A neutralization test using immunofluorescence was employed to determine the subtype of each isolate. Viral RNA was extracted and analyzed by polyacrylamide gel electrophoresis (PAGE), and the sequence was determined by next-generation sequencing for construction of a phylogenetic tree and analysis of gene polymorphism. Electron microscopy examination revealed the presence of virus particles with the typical morphological characteristics of MRV. Serotype analysis showed that strain MRV1/TS/2011 was of type I and strain MRV3/TS/2012 was of type III. A sequence comparison showed that the isolates were 25.4% identical in the S1 gene.

Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening.

Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.

Development of novel nanoantibiotics using an outer membrane vesicle-based drug efflux mechanism.

Conventionally used antibiotics are present in low concentrations at the infection site and require multiple administrations to sustain a continuous bactericidal effect, which not only increases their systemic toxicity but also results in bacterial drug resistance. In this study, we first identified an interesting drug resistance mechanism mediated by bacterial outer membrane vesicles (OMVs) and then designed novel antibiotic-loaded OMVs using this mechanism. We show that these antibiotic-loaded OMVs can effectively enter and kill pathogenic bacteria in vitro. In a mouse model of intestinal bacterial infection, one low-dose oral administration of antibiotic-loaded OMVs showed that the drug was retained in the intestine for 36 h, and no systemic spread was detected 12 h after drug administration. The antibiotic-loaded OMVs significantly reduced the bacterial load in the small intestine and feces of infected mice. Safety experiments confirmed that the antibiotic-loaded OMVs had excellent biocompatibility. This study extends the application range of OMVs and provides new ideas for the development of antibacterial drugs.

Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening.

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.

Anti-outer Membrane Vesicle Antibodies Increase Antibiotic Sensitivity of Pan-Drug-Resistant Acinetobacter baumannii.

Acinetobacter baumannii often causes serious nosocomial infections. Because of its serious drug resistance problems, complex drug resistance mechanism, and rapid adaptation to antibiotics, it often shows pan-drug resistance and high fatality rates, which represent great challenges for clinical treatment. Therefore, identifying new ways to overcome antibiotic resistance is particularly important. In this study, mice immunized with A. baumannii outer membrane vesicles (AbOMVs) produced high IgG levels for a long time, and this antiserum significantly increased the small molecule intracellular aggregation rate and concentrations. In vitro experiments demonstrated that the combined used of anti-AbOMV serum and quinolone antibiotics significantly increased the sensitivity of the bacteria to these antibiotics. Mouse sepsis model experiments demonstrated that delivery of these antibodies using both active and passive immunization strategies significantly improved the susceptibility to quinolone antibiotics, improved the survival rate of mice infected with A. baumannii, and reduced the bacterial load in the organs. In a pneumonia model, the combination of serum anti-AbOMVs and levofloxacin improved levofloxacin sensitivity, which significantly reduced the bacterial loads in the lung and spleen compared with those of the antibiotic or antibody alone. This combination also significantly reduced lung inflammatory cell infiltration and inflammatory cytokine aggregation. In this study, the main protein targets that bound to these antibodies were identified. Structural modeling showed that seven of the proteins were porins. Therefore, we speculated that the anti-AbOMV antibodies mainly improved the intracellular aggregation of antibiotics by affecting porins, thus improving susceptibility to quinolone antibiotics. This study provides a method to improve susceptibility to existing antibiotics and a novel idea for the prevention and treatment of pan-drug-resistant A. baumannii.

PPCD: Privacy-preserving clinical decision with cloud support.

With the prosperity of machine learning and cloud computing, meaningful information can be mined from mass electronic medical data which help physicians make proper disease diagnosis for patients. However, using medical data and disease information of patients frequently raise privacy concerns. In this paper, based on single-layer perceptron, we propose a scheme of privacy-preserving clinical decision with cloud support (PPCD), which securely conducts disease model training and prediction for the patient. Each party learns nothing about the other's private information. In PPCD, a lightweight secure multiplication is presented and introduced to improve the model training. Security analysis and experimental results on real data confirm the high accuracy of disease prediction achieved by the proposed PPCD without the risk of privacy disclosure.

The association of adiponectin gene promoter variations with non-small cell lung cancer in a Han Chinese population.

Recently, in vitro studies have demonstrated that adiponectin has antiangiogenic and tumor growth-limiting properties. Additionally, serum adiponectin levels have been associated with the risk of several cancers; specifically, serum adiponectin was significantly lower in lung cancer patients with advanced-stage disease. In this study, we examined the association of adiponectin gene promoter variations associated with adiponectin gene expression and plasma levels in non-small cell lung cancer (NSCLC) in a Han Chinese population. A total of 319 patients with NSCLC and 489 healthy individuals were recruited to evaluate the association of four adiponectin gene promoter single-nucleotide polymorphisms (SNPs) (SNP-12140G>A, SNP-11426A>G, SNP-11391G>A and SNP-11377C>G) with NSCLS risk. Additionally, we constructed haplotypes of these four SNPs and evaluated the association of these haplotypes with NSCLS risk. Our results showed that among these four SNPs, only SNP-12140G>A was associated with NSCLC risk (P<0.05). The haplotype analysis showed that no haplotype was associated with NSCLC after performing a Bonferroni correction (P>0.05). Additionally, an association analysis of the four SNPs stratified into pathologic stages I+II and III+IV showed that these SNPs did not exhibit significant differences between pathologic stages I+II and III+IV. Moreover, we did not observe any differences in allele and genotype frequency for these SNPs between adenocarcinoma and squamous cell carcinoma. Our results indicated that the G allele of SNP-12140 may be a risk factor for NSCLC (OR = 1.516; 95% CI: 1.098-2.094) in this Han Chinese population.

Distribution of HLA-A, -B, and -C alleles and HLA/KIR combinations in Han population in China.

We investigated polymorphisms of the human leukocyte antigen (HLA) class I (A, B, and C) loci of a Han population (n, 239) from the Yunnan province, Southwest China, using high-resolution polymerase chain reaction-Luminex (PCR-Luminex) typing. We combined the HLA data from this study with the KIR genotypes from a previous study of this Han population to analyze the combination of KIR/HLA ligands. A total of 27 HLA-A, 54 HLA-B, and 31 HLA-C alleles were found in this population. The frequencies of A*11:01, A*24:02, B*40:01, B*46:01, C*01:02, C*03:04, and C*07:02 were all > 10%. The following haplotypes were common, with frequencies > 5%: 1 A-B (A*02:07-B*46:01), 2 A-C (A*02:07-C*01:02, and A*11:01-C*07:02), 4 C-B (B*13:01-C*03:04, B*40:01-C*07:02, B*46:01-C*01:02 and B*58:01-C*03:02), and 1 A-C-B (A*02:07-C*01:02-B*46:01). Analysis of KIR3D and their ligands HLA-A3/A11 and HLA-Bw4 showed that the frequencies of 3DL2(+)-A3/A11(+) and 3DL2(+)-A3/A11(-) were 0.527 and 0.473, and the frequencies of 3DL1(+)-Bw4(+), 3DL1(+)-Bw4(-), 3DL1(-)-Bw4(+), and 3DL1(-)-Bw4(-) were 0.552, 0.397, 0.038, and 0.013, respectively. The results of KIR/HLA-C combination analysis showed that all individuals had at least one inhibitory or activating KIR/HLA-C pair, and one KIR/HLA-C pair was the most frequent (157/239), followed by two pairs (46/239), three pairs (33/239), and no pairs (3/239). Comparison of KIR gene and HLA gene and their pair frequency between Yunnan Han and the isolated Han (FYDH) who also lived in Yunnan province showed no significant difference (P > 0.05) in KIR frequencies, but significant differences (P < 0.05) for some HLA allele frequencies. In addition, there was no significant difference (P > 0.05) between the two populations for KIR/HLA pairs.

Association and differentiation of MHC class I and II polymorphic Alu insertions and HLA-A, -B, -C and -DRB1 alleles in the Chinese Han population.

In order to investigate the polymorphism of Alu insertions (POALINs) in the HLA region, we genotyped ten Alu loci (AluMICB, AluTF, AluHJ, AluHG, AluHF in the HLA class I region and AluDPB2, AluDQA2, AluDQA1, AluDRB1, AluORF10 in the HLA class II region) to determine their allele frequencies and associations with the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes in the Chinese Han population. Our results showed the ten-loci POALINs varied in frequency between 0.003 and 0.425. By comparing the data of the ten-loci POALIN in Chinese Han with Japanese and Caucasian data, marked differences were observed between the three ethnic groups at the allelic or haplotypic levels. Each POALIN was in significant linkage disequilibrium with a variety of HLA-A, -B, -C and -DRB1 alleles, and was associated with a variety of HLA-A, -B, -C and -DRB1 allele in Chinese Han. This comparative study of multilocus POALINs in the HLA class I and II regions of the Chinese Han population shows that POALINs alone or as haplotypes together with the HLA class I and II alleles are informative genetic markers for the identification of HLA class I and II allele and variations, such as crossing over events within the same and/or different populations.

[A study on the relationship between endoplasmic reticulum aminopeptidase2 genetic polymorphisms and non-small cell lung cancer in Yunnan Han population].

OBJECTIVE: To evaluate the association between the genetic polymorphisms of endoplasmic reticulum aminopeptidase 2 (ERAP2) and the susceptibility of non-small cell lung cancer (NSCLC) in Yunnan Han population. METHODS: A total of 223 patients with NSCLC and 205 healthy controls in Yunnan Han population were included in the present study. The SNP of rs2248374 and rs2549782 in ERAP2 gene were genotyped using TaqMan fluorescence probe technique, and their haplotypes were constructed. Then, the association between the two SNPs with NSCLC was assessed. RESULTS: The allele A and allele G frequencies for rs2248374 in NSCLC patients and the control groups were 45.5% (203/446), 54.5% (243/446) and 37.8% (155/410), 62.2% (255/410), respectively (χ² = 5.220, P < 0.05). The genotypic GG, GT, TT for rs2549782 in NSCLC patients and the control groups were 21.5% (48/223), 48.9% (109/223), 29.6% (66/223) and 11.7% (24/205), 49.8% (102/205), 38.5% (79/205), respectively(χ² = 8.656, P < 0.05). And the allele G and allele T frequencies for rs2549782 in NSCLC patients and the control groups were 46.0% (205/446), 54.0% (241/446) and 36.6% (150/410), 63.4% (260/410), respectively (χ² = 7.741, P < 0.05). The frequencies of haplotype rs2248374/rs2549782-AG were 44.6% (199/446), 36.1% (148/410) and rs2248374/rs2549782-GT were 53.1% (237/446), 61.7% (253/410), which also showed difference between NSCLC patients and the control groups (χ² = 6.567, P < 0.01;χ² = 6.567, P < 0.01). The allele A and allele G frequencies for rs2248374 were 52.9% (72/136), 47.1% (64/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively (χ² = 4.498, P < 0.05), while the allele G and allele T frequencies for rs2549782 were 54.4% (74/136), 45.6% (62/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively(χ² = 5.831, P < 0.05). The genotypic AA,AG,GG for rs2248374 were 17.3% (24/139), 56.1% (78/139), 26.6% (37/139) and 27.8% (22/79), 38.0% (30/79), 34.2% (27/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 6.999, P < 0.05), while the genotypic GG, GT, TT for rs2549782 were 18.7% (26/139), 55.4% (77/139), 25.9% (36/139) and 27.8% (22/79), 36.7% (29/79), 35.4% (28/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 7.093, P < 0.05). CONCLUSION: ERAP2 rs2248374 and rs2549782 had a strong association with NSCLC and the pathological pattern. The rs2248374/rs2549782-AG haplotype was associated with increased NSCLC risk (OR = 1.435, 95%CI: 1.088-1.893), whereas the rs2248374/rs2549782-GT haplotype individuals may have a reduced NSCLC risk (OR = 0.697, 95%CI: 0.528-0.919).

Analysis of the prevalence and risk factors of hypertension in the She population in Fujian, China.

OBJECTIVES: The aim of this study was to investigate the prevalence and epidemiological characteristics of hypertension in the Chinese She ethnic minority in Fujian province of China. After analyzing relevant risk factors of hypertension, we wanted to provide information for prevention and control of hypertension in this ethnic minority. METHODS: Using the stratified and cluster methods, we randomly selected 5,350 She subjects for a questionnaire survey. Their weight, height and blood pressure were measured. Hypertension was defined as a mean systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg, or use of antihypertensive medication. SPSS 13.0 software was used for database building and the χ(2) test for statistical analysis. RESULTS: The number of patients with hypertension was 1,931 (prevalence 36.09%) and 71.15% of them (1,374 patients) were undiagnosed. The prevalence of hypertension increased with age and was associated with education levels, occupation, body mass index, smoking, salt intake levels and a lack of health concepts. CONCLUSIONS: The prevalence of hypertension in the She has grown rapidly, which is closely correlated with lifestyle and lack of health education of hypertension. The prevention and control of hypertension in the She is imperative, and the promotion of health education on hypertension can be improved to enhance awareness, prevention, and control of hypertension.