Deciphering the enigmas of non-nucleoside reverse transcriptase inhibitors (NNRTIs): A medicinal chemistry expedition towards combating HIV drug resistance.

The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016-2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide-ranging anti-HIV medications is anticipated.

Photoinduced Palladium-Catalyzed Radical Germylative Arylation of Alkenes with Chlorogermanes.

We describe a visible light-induced palladium-catalyzed radical germylative arylation of alkenes with easily accessible chlorogermanes. This protocol provides expedient access to germanium-substituted indolin-2-ones in good to excellent yields under mild reaction conditions. The key step for this strategy lies in the reductive activation of germanium-chloride bonds with an excited palladium complex under visible light irradiation. The involvement of germanium radicals was evidenced by electron paramagnetic resonance spectroscopy experiments.

Direct C-H Arylation Derived Ternary D-A Conjugated Polymers: Effects of Monomer Geometries, D/A Ratios, and Alkyl Side Chains on Photocatalytic Hydrogen Production and Pollutant Degradation.

Donor-acceptor (D-A) conjugated polymer (CP) featuring high charge mobility and widely tunable energy bands have shown promising prospects in photocatalysis. In this work, a library of ternary D-A CPs (22 polymers) based on benzothiadiazole, bithiophene, and fluorene derivatives (i.e., fluorene [Fl], 9,9-dihexylfluorene [HF], and 9,9'-spirobifluorene [SF]) with and without alkyl side chains, and with 3D geometry are designed and synthesized via atom-economical direct C-H arylation polymerization to explore the synergetic effects of stereochemistry, D/A ratio, and alkyl chains on the properties and photocatalytic performances, which reveal that 1) the cross-shaped 3D spirobifluorene (SF) building block shows the highest hydrogen evolution rates (HER) owing to the sufficient photocatalytic active sites exposed, 2) the alkyl-free linear polymer (FlBtBT0.05 ) exhibit the highest photocatalytic pollutant degradation performance owing to its superior charge separation, and 3) the alkyl side chains are redundances that will exert detrimental effects on the aqueous photocatalysis owing to their insulating and hydrophobic property. The structure-property-performance correlation results obtained will provide a desirable guideline for the rational design of CP-based photocatalysts.

The association between non­high­density lipoprotein cholesterol to high­density lipoprotein cholesterol ratio (NHHR) and low muscle mass in adults aged 20-59: a population-based study in the United States.

BACKGROUND: The ratio between non-high-density lipoprotein cholesterol and high-density lipoprotein cholesterol (NHHR) is a reliable marker for assessing the risk linked to lipid metabolism disorders. Sarcopenia, characterized by age-related loss of muscle mass and strength/function, includes the assessment of muscle mass, muscle strength, and muscle-specific strength. However, research into NHHR's relationship with low muscle mass risk remains unexplored. METHODS: Our study utilized a cross-sectional approach, examining data derived from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Through multivariable linear and logistic regression, we investigated the relationships of the NHHR with muscle mass and low muscle mass. We visualized the results using smoothing curves and assessed threshold effects. We also performed various subgroup and sensitivity analyses. RESULTS: This research encompassed 9,012 participants and demonstrated significant nonlinear associations between NHHR and ALMBMI or low muscle mass risk in a generalized additive model (GAM), pinpointing critical NHHR values (3.328 and 3.367) where changes in NHHR significantly impacted ALMBMI and low muscle mass risk. CONCLUSIONS: The NHHR demonstrates a significant association with an increased risk of low muscle mass among middle-aged Americans. This ratio has potential as a predictive marker for low muscle mass. Further exploration of NHHR is expected to aid in advancing preventive and therapeutic measures for this condition.

Two new Nb-oxide indole alkaloids with ß-hematin inhibitory activity from the stems and leaves of Rauvolfia dichotoma.

Rauvolfia dichotoma, a shrub of Apocynaceae, was collected from the Islands of SAO Tome and Principe and cultivated locally for medicinal purpose. Phytochemical investigation of 95% ethanol extract from the stems and leaves of R. dichotoma led to the isolation of two new Nb-oxide indole alkaloids, namely Nb-oxide-mitoridine (1) and Nb-oxide-raucaffricine (2), together with two known alkaloids (3-4) and eleven known lignans (5-15). Their chemical structures were elucidated by extensive NMR and HR-ESI-MS data analysis. All compounds (except 13) were tested for their ß-hematin inhibitory activity. Compounds 2, 4, 14, and 15 showed certain inhibitory activity, indicating that they may have an antimalarial effect.

Cigarette smoke extract-induced inflammatory response via inhibition of the TFEB-mediated autophagy in NR8383 cells.

Objective: Chronic pulmonary inflammation caused by long-term smoking is the core pathology of COPD. Alveolar macrophages (AMs) are involved in the pulmonary inflammation of COPD. The accumulation of damaged materials caused by impaired autophagy triggers inflammatory response in macrophages. As a key transcription regulator, transcription factor EB (TFEB) activates the transcription of target genes related autophagy and lysosome by binding to promoters, whereas it is unclarified for the relationship between inflammatory response induced by cigarette smoke extract (CSE) and TFEB-mediated autophagy. Thus, we investigated the role of TFEB-mediated autophagy in inflammatory response induced by CSE in NR8383 cells, and to explore its potential mechanism. Methods: Based on cell viability and autophagy, cells treated with 20% concentration of CSE for 24 h were selected for further studies. Cells were divided into control group, chloroquine (CQ, the autophagy inhibitor) group, CSE group, CSE + rapamycin (the autophagy inducer) group and CSE + fisetin (the TFEB inducer) group. The levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in supernatant were detected by ELISA kits. The protein expressions were tested by western blot. The intensity of fluorescence of Lysosome-associated membrane protein 1 (LAMP1) and TFEB was detected by immunofluorescence. Lyso-Tracker Red staining was applied to detect the lysosome environment. Results: CSE inhibited the cell viability, increased the contents of TNF-α, IL-1ß, IL-6, the ratio of LC3II/I, and the level of P62 protein. Besides, CSE decreased the fluorescence intensity of LAMP1 protein and Lyso-Tracker Red staining, as well as the ratio of nucleus/cytosol of TFEB protein. Activating autophagy with rapamycin alleviated CSE-induced inflammatory response. The activation of TFEB via fisetin alleviated CSE-induced autophagy impairment and lysosomal dysfunction, thus alleviated inflammatory response in NR8383 cells. Conclusion: CSE-induced inflammatory response in NR8383 cells, which may be related to the inhibition of TFEB-mediated autophagy.

Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study.

BACKGROUND: Genetic variation increases the risk of lung cancer, but the extent to which smoking amplifies this effect remains unknown. Therefore, we aimed to investigate the risk of lung cancer in people with different genetic risks and smoking habits. METHODS: This prospective cohort study included 345,794 European ancestry participants from the UK Biobank and followed up for 7.2 [6.5-7.8] years. RESULTS: Overall, 26.2% of the participants were former smokers, and 9.8% were current smokers. During follow-up, 1687 (0.49%) participants developed lung cancer. High genetic risk and smoking were independently associated with an increased risk of incident lung cancer. Compared with never-smokers, HR per standard deviation of the PRS increase was 1.16 (95% CI, 1.11-1.22), and HR of heavy smokers (≥40 pack-years) was 17.89 (95% CI, 15.31-20.91). There were no significant interactions between the PRS and the smoking status or pack-years. Population-attributable fraction analysis showed that smoking cessation might prevent 76.4% of new lung cancers. CONCLUSIONS: Both high genetic risk and smoking were independently associated with higher lung cancer risk, but the increased risk of smoking was much more significant than heredity. The combination of traditional risk factors and additional PRS provides realistic application prospects for precise prevention.

Associations of genetic risk and smoking with incident COPD.

BACKGROUND: Genetic factors and smoking contribute to chronic obstructive pulmonary disease (COPD), but whether a combined polygenic risk score (PRS) is associated with incident COPD and whether it has a synergistic effect on smoking remains unclear. We aimed to investigate the association of the PRS with COPD and explore whether smoking behaviours could modify such association. METHODS: Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals for the association of the PRS and smoking with COPD. RESULTS: The study included 439 255 participants (mean age 56.5 years; 53.9% female), with a median follow-up of 9.0 years. PRSlasso containing 2.5 million variants showed better discrimination and a stronger association for incident COPD than PRS279 containing 279 genome-wide significance variants. Compared with low genetic risk, the HRs of medium and high genetic risk were 1.39 (95% CI 1.31-1.48) and 2.40 (95% CI 2.24-2.56), respectively. The HR of high genetic risk and current smoking was 11.62 (95% CI 10.31-13.10) times that of low genetic risk and never smoking. There were significant interactions between PRSlasso and smoking status for incident COPD (pinteraction<0.001). From low genetic risk to high genetic risk, the HRs of current smoking increased from 4.32 (95% CI 3.69-5.06) to 6.89 (95% CI 6.21-7.64) and the population-attributable risks of smoking increased from 42.7% to 61.1%. CONCLUSIONS: The PRS constructed from millions of variants below genome-wide significance showed significant associations with incident COPD. Participants with a high genetic risk may be more susceptible to developing COPD when exposed to smoking.

Combination treatment with 30% salicylic acid and fractional CO2 laser for acne scars: A 20-week prospective, randomized, split-face study.

Multiple approaches are used to treat acne scars, but some are expensive, ineffective, and cause complications. We aimed to evaluate the efficacy and safety of ultra-pulsed CO2 fractional laser combined with 30% supramolecular salicylic acid in the treatment of acne scars in a prospective split-face control study. Twenty patients with facial symmetrical acne scars were enrolled. One side of face was randomly treated with 30% supramolecular salicylic acid, and two sides were treated with ultra-pulsed CO2 fractional laser. The Echelle d'evaluation clinique des cicatrices d'acne (ECCA) scale was used to evaluate the clinical efficacy before and 3 months after treatment, and a quartile scale was used to self-evaluate the improvement of patients. A visual analog scale was used to record pain scores after each treatment, and side effects and other adverse reactions on the face were recorded. All the patients completed treatment and follow-up. There was statistical difference in ECCA scores of bilateral facial acne scars after three treatments (p < 0.001). ECCA scores on the combined side were lower after three treatments than those on the laser side (p = 0.003). The patient satisfaction quartile scale on the combined side was higher than that on the laser side alone (p = 0.015). Ultra-pulsed CO2 fractional laser combined with 30% supramolecular salicylic acid has better efficacy in the treatment of acne scars than laser alone, and patient self-assessment of combined treatment has a greater degree of improvement in acne scars, and does not increase patient pain scores and related adverse reactions.

Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression.

Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9-/-) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil-/-) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.

Association of physical activity and air pollution exposure with the risk of type 2 diabetes: a large population-based prospective cohort study.

BACKGROUND: The interplay between physical activity (PA) and air pollution in relation to type 2 diabetes (T2D) remains largely unknown. Based on a large population-based cohort study, this study aimed to examine whether the benefits of PA with respect to the risk of T2D are moderated by exposure to air pollution. METHODS: UK Biobank participants (n = 359,153) without diabetes at baseline were included. Information on PA was obtained using the International Physical Activity Questionnaire short form. Exposure to air pollution, including PM2.5, PMcoarse (PM2.5-10), PM10, and NO2, was estimated from land use regression models. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: During a median of 8.9 years of follow-up, 13,706 T2D events were recorded. Compared with a low PA level, the HRs for the risk of T2D among individuals with moderate and high PA were 0.82 (95% CI, 0.79-0.86) and 0.73 (95% CI, 0.70-0.77), respectively. Compared with low levels of air pollution, the HRs for risk of T2D for high levels of air pollution (PM2.5, PMcoarse, PM10, and NO2) were 1.19 (1.14-1.24), 1.06 (1.02-1.11), 1.13 (1.08-1.18), and 1.19 (1.14-1.24), respectively. There was no effect modification of the associations between PA and T2D by air pollution (all P-interactions > 0.05). The inverse associations between PA and T2D in each air pollution stratum were generally consistent (all P for trend < 0.05). CONCLUSION: A higher PA and lower air pollution level were independently associated with a lower risk of T2D. The beneficial effects of PA on T2D generally remained stable among participants exposed to different levels of air pollution. Further studies are needed to replicate our findings in moderately and severely polluted areas.

Association between single nucleotide polymorphism of rs1937 in TFAM gene and longevity among the elderly Chinese population: based on the CLHLS study.

BACKGROUND: To investigate whether the mitochondrial transcription factor A (TFAM) rs1937 single nucleotide polymorphism (SNP) is associated with longevity. METHODS: We conducted a case-control study among Chinese long-lived individuals (≥90 years). Data were obtained on 3294 participants who were able to voluntarily provided a saliva sample during 2008-2009 from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). In this study, 1387 young elderly (65-74 years) were allocated to the control group, and 1907 long-lived individuals were recruited as the case group. SNP rs1937 on TFAM were genotyped. Logistic regression models were applied to evaluate the association between rs1937 SNP and longevity. RESULTS: The genotype frequency of the SNP of rs1937 in the two groups had a significant difference (p = 0.003). Binary logistic regression analysis showed that compared to younger elderly, the long-lived individuals with "CC genotype" of rs1937 were more closely related to increased longevity than those with "GG genotype" (OR: 1.989, 95% CI: 1.160-3.411). The positive association between rs1937 SNP and longevity was robust in stratified analyses and sensitivity analyses. CONCLUSIONS: We found the SNP of rs1937 may be a potential biomarker for longer human life span. Further studies are necessary to elucidate the biological mechanism of rs1937 on TFAM with promoting longevity.

Characterizing the Complete Mitochondrial Genome of Arma custos and Picromerus lewisi (Hemiptera: Pentatomidae: Asopinae) and Conducting Phylogenetic Analysis.

We characterized the mitochondrial genome (mitogenome) and conducted phylogenetic analyses of 48 Hemiptera species by sequencing and analyzing the mitogenome of Arma custos (Fabricius) and Picromerus lewisi (Scott). The complete mitogenomes of the two predators were 16,024 bp and 19,587 bp in length, respectively, and it contained 37 classical genes, including 13 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), and 22 transfer RNA genes (tRNAs), and a control region. Most PCGs in these predators use ATN as the start codon. This research revealed that the genes of the two natural enemy species have an A + T content of 75.40% and all tRNAs have a typical cloverleaf structure, with the exception of trnS1, which lacks a dihydrouridine arm. This is the first study to compare the mitochondrial genetic structure of two predatory insects; the mitochondrial genetic structure of individual predatory insects has been sequenced in previous studies. Here, phylogenetic analysis on the basis of amino acid and nucleotide sequences of 13 mitochondrial PCGs using Bayesian inference and maximum likelihood methods were conducted to generate similar tree topologies, which suggested that the two predators with close genetic relationships belong to Asopinae subfamily. Furthermore, the monophyly of the Pentatomoidea superfamily is well accepted despite limited taxon and species sampling. Finally, their complete mitogenome provided data to establish a predator-prey food web, which is the foundation of effective pest management. Our results also enhanced the database of natural enemy insects.

[Influence of coexisting components in Coptidis Rhizoma on excretion of magnoflorine in rat bile, urine, and feces].

Magnoflorine is an important aporphine alkaloid in Coptidis Rhizoma. As reported previously, coexisting components in Coptidis Rhizoma can change the pharmacokinetic characteristics of magnoflorine. To illustrate the interactional links of magnoflorine with its coexisting components in Coptidis Rhizoma, the present study investigated the influence of coexisting components in Coptidis Rhizoma on the excretion of magnoflorine in rat bile, urine, and feces. The rats were dosed with magnoflorine(30 mg·kg~(-1)) and water decoction of Coptidis Rhizoma(equivalent to 30 mg·kg~(-1) magnoflorine) via intragastric administration, and magnoflorine(10 mg·kg~(-1)) by intravenous administration, respectively, and the excretion of magnoflorine in rat bile, urine, and feces in 24 h was observed. The excretion rates of magnoflorine in bile and urine in 24 h were 0.90% and 37.11% respectively after intravenous administration of magnoflorine, which suggested that urination was the main excretive way of magnoflorine. The excretion rates of magnoflorine in feces were 8.77% and 6.18% respectively after intragastric administration of magnoflorine and water decoction of Coptidis Rhizoma, which indicated that defecation was the main excretion route of magnoflorine. The cumulative excretion rates of magnoflorine in the bile, urine, and feces in the Coptidis Rhizoma water decoction group were 77.78%, 79.44%, and 70.47% of those in the magnoflorine group. The results showed that the cumulative excretion rates of magnoflorine in rat bile, urine, and feces were not high, suggesting that magnoflorine was metabolized significantly in rats. The coexisting components of Coptidis Rhizoma could inhibit the excretion of magnoflorine in rat bile, urine, and feces, which was consistent with the decrease in the elimination rate of magnoflorine in the pharmacokinetics of Coptidis Rhizoma water decoction. It indicated interactions between drugs. This study is expected to provide references for the development of magnoflorine-containing new drugs and rational clinical medication of Coptidis Rhizoma.

[Toxicokinetics of emodin-8-O-ß-D-glucoside in rats in vivo].

This study aims to establish an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) method for the determination of emodin-8-O-ß-D-glucoside(EG) and its metabolites in plasma, and to investigate the toxicokinetics(TK) behavior of them in rats. To be specific, the TK of EG and its metabolites from the first to the last administration in the repeated dose toxicity study was determined, and the kinetic parameters were calculated. The exposure of EG prototype and metabolites in rat plasma after oral administration of different doses of EG was evaluated. The result showed that the prototype of EG and its metabolites aloe-emodin-8-O-ß-D-glucoside, emodin, aloe-emodin, and hydroxyemodin could be detected in rats after oral administration of high-, medium-, and low-dose EG. The area under the curve(AUC) of the prototype and metabolites after the first and last administration was in positive correlation with the dose. The time to the maximum concentration(T_(max)) of EG and metabolites in the three administration groups was <6 h, and the longest in vivo residence time was 12 h. The T_(max) and in vivo residence time of EG were prolonged with the increase in the dose. The metabolites emodin, aloe-emodin, and hydroxyemodin all had two peaks. Both hydroxyemodin and aloe-emodin exhibited increased plasma exposure, slow metabolism, and accumulation in vivo. In addition, aloe-emodin-8-O-ß-D-glucoside and emodin disappeared with the increase in dose, suggesting the change of the metabolic pathway of EG in vivo in the case of high-dose administration. The mechanism of high-dose EG in vivo needs to be further explored. This study preliminarily elucidates the TK behavior of EG in rats, which is expected to support clinical drug use.

[Effect of Suanzaoren Decoction on molecular levels of bile acids in serum, liver, and ileum of insomnia mice].

To explore the mechanism of Suanzaoren Decoction in the treatment of insomnia from endogenous bile acid regulation, the present study investigated the hepatoprotective effect of Suanzaoren Decoction and the molecular changes of bile acids in the serum, liver, and ileum of insomnia model mice and Suanzaoren Decoction treated mice. The insomnia model in mice was established by the sleep deprivation method. After Suanzaoren Decoction(48.96 mg·kg~(-1)·d~(-1)) intervention by gavage for 7 days, the related indicators, such as water consumption, food intake, body weight, aspartate aminotransferase(AST), alanine transaminase(ALT), and total bile acid(TBA) were detected, and the pathological changes of the liver and ileum were observed. The molecular levels and distribution of 23 bile acids in the serum, liver, and ileum were analyzed by UPLC-MS/MS combined with principal component analysis(PCA) and partial least squares discriminant analysis(PLS-DA). The results showed that Suanzaoren Decoction could improve the decreased water consumption and food intake, weight loss, and increased AST and ALT in the model group, and effectively reverse the injury and inflammation in the liver and ileum. The bile acids in the liver of the insomnia model mice were in the stage of decompensation, and the bile acids in the serum, liver, and ileum of the mice decreased or increased. Suanzaoren Decoction could regulate the anomaly of some bile acids back to normal. Seven bile acids including glycoursodeoxycholic acid(GUDCA), glycodesoxycholic acid(GDCA), tauro-α-MCA(T-α-MCA), α-MCA, taurodeoxycholate(TDCA), T-ß-MCA, and LCA were screened out as the main discriminant components by PLS-DA. It is concluded that Suanzaoren Decoction possesses the hepatoprotective effect and bile acids could serve as the biochemical indicators to evaluate the drug efficacy in the treatment of abnormal liver functions caused by insomnia. The mechanism of Suanzao-ren Decoction in soothing the liver, resolving depression, tranquilizing the mind, and improving sleep may be related to the molecular regulation of bile acid signals.

Integrating Pt16 Te Nanotroughs and Nanopillars into a 3D "Self-Supported" Hierarchical Nanostructure for Boosting Methanol Electrooxidation.

To develop durable and low-price catalysts of methanol oxidation to commercialize direct methanol fuel cell, many attempts have been made at fabricating Pt-based hybrids by designing component-, morphology-, facet-, integration-pattern-varied nanostructures, and have achieved considerable successes. However, most of present catalysts still lack robust catalytic durability especially owing to the corrosion of mixed carbon and the poor mechanical stability of catalyst layer. Herein, Te nanowire array is transformed at an air/water interface into a 3D Pt16 Te hierarchical nanostructure via an interface-confined galvanic replacement reaction. As-formed Pt16 Te nanostructure has an asymmetrical architecture composed of nanotroughs and nanopillars, and nanopillars are perpendicular to nanotroughs with a loose arrangement. Pt16 Te hierarchical nanostructure has a "self-supported" feature and, when directly used as the catalyst of methanol electrooxidation, exhibits superior catalytic activity (>four times larger in mass activity than state-of-the-art Pt/C in either acidic or basic solution) and long-term durability (after 500 cycles of cyclic voltammetric measurement, more than 55% of the initial specific activity remains whereas Pt/C only remains 22.2% in acidic solution and almost loses all activity in basic solution). This study fully demonstrates that designing "self-supported" catalyst film may be the next promising step for improving the catalytic performance of Pt-based hybrids.

Integrating regulatory features data for prediction of functional disease-associated SNPs.

Genome-wide association studies (GWASs) are an effective strategy to identify susceptibility loci for human complex diseases. However, missing heritability is still a big problem. Most GWASs single-nucleotide polymorphisms (SNPs) are located in noncoding regions, which has been considered to be the unexplored territory of the genome. Recently, data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomics projects have shown that many GWASs SNPs in the noncoding regions fall within regulatory elements. In this study, we developed a pipeline named functional disease-associated SNPs prediction (FDSP), to identify novel susceptibility loci for complex diseases based on the interpretation of the functional features for known disease-associated variants with machine learning. We applied our pipeline to predict novel susceptibility SNPs for type 2 diabetes (T2D) and hypertension. The predicted SNPs could explain heritability beyond that explained by GWAS-associated SNPs. Functional annotation by expression quantitative trait loci analyses showed that the target genes of the predicted SNPs were significantly enriched in T2D or hypertension-related pathways in multiple tissues. Our results suggest that combining GWASs and regulatory features data could identify additional functional susceptibility SNPs for complex diseases. We hope FDSP could help to identify novel susceptibility loci for complex diseases and solve the missing heritability problem.

Modeling circRNA expression pattern with integrated sequence and epigenetic features demonstrates the potential involvement of H3K79me2 in circRNA expression.

MOTIVATION: CircRNAs are an abundant class of non-coding RNAs with widespread, cell-/tissue-specific patterns. Previous work suggested that epigenetic features might be related to circRNA expression. However, the contribution of epigenetic changes to circRNA expression has not been investigated systematically. Here, we built a machine learning framework named CIRCScan, to predict circRNA expression in various cell lines based on the sequence and epigenetic features. RESULTS: The predicted accuracy of the expression status models was high with area under the curve of receiver operating characteristic (ROC) values of 0.89-0.92 and the false-positive rates of 0.17-0.25. Predicted expressed circRNAs were further validated by RNA-seq data. The performance of expression-level prediction models was also good with normalized root-mean-square errors of 0.28-0.30 and Pearson's correlation coefficient r over 0.4 in all cell lines, along with Spearman's correlation coefficient ρ of 0.33-0.46. Noteworthy, H3K79me2 was highly ranked in modeling both circRNA expression status and levels across different cells. Further analysis in additional nine cell lines demonstrated a significant enrichment of H3K79me2 in circRNA flanking intron regions, supporting the potential involvement of H3K79me2 in circRNA expression regulation. AVAILABILITY AND IMPLEMENTATION: The CIRCScan assembler is freely available online for academic use at https://github.com/johnlcd/CIRCScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Characterization and Phylogenetic Analysis of the Mitochondrial Genome Sequence of Nisia fuliginosa (Hemiptera: Fulgoroidea: Meenoplidae).

We explored characterization of the mitochondrial genome (mitogenome or mtGenome) and phylogenetic analysis between 32 Fulgoroid species by sequencing and analyzing the mitogenome of Nisia fuliginosa Yang and Hu, 1985 (Hemiptera: Fulgoroidea: Meenoplidae), thereby making it the first determined mitogenome from the family Meenoplidae. The mitogenome was found to be 15,754 bp in length and contained 13 protein-coding genes (PCGs), 22 tRNA genes, two ribosomal RNA genes (rRNAs), and a control region. All PCGs started with typical ATN codons, except for nad1, which used GTG as the start codon. Canonical TAA termination codons were found in 10 PCGs and the remaining three genes (cox2, nad6, and nad1) had incomplete stop codons T. All tRNAs could fold into typical cloverleaf secondary structures, with the exception of trnC, trnV, and trnS1. Additionally, we compared the AT and GC skews of 13 PCGs of 32 Fulgoroidea mitogenomes, on the L-strand, the AT and GC skews were negative and positive, respectively. However, on the H-strand, the AT skew could be positive or negative and the GC skew was always negative. Phylogenetic results showed that the eight families of Fulgoroidea were divided into two large groups. Delphacidae formed a monophyletic group sister to a clade comprising Meenoplidae and other six families (Fulgoridae, Ricaniidae, Flatidae, Issidae, Caliscelidae, and Achilidae). Meenoplidae was located near the clade of Delphacidae, and Fulgoridae was located near the clade of Meenoplidae. Furthermore, Caliscelidae, Issidae, Ricaniidae, and Flatidae are closely related and they collectively formed a sister group to Achilidae.