Integrating Traditional Machine Learning and Deep Learning for Precision Screening of Anticancer Peptides: A Novel Approach for Efficient Drug Discovery.

The rapid and effective identification of anticancer peptides (ACPs) by computer technology provides a new perspective for cancer treatment. In the identification process of ACPs, accurate sequence encoding and effective classification models are crucial for predicting their biological activity. Traditional machine learning methods have been widely applied in sequence analysis, but deep learning provides a new approach to capture sequence complexity. In this study, a two-stage ACPs classification model was innovatively proposed. Three novel coding strategies were explored; two mainstream Natural Language Processing (NLP) models and 11 machine learning models were fused to identify ACPs, which significantly improved the prediction accuracy of ACPs. We analyzed the correlation between peptide chain amino acids and evaluated the relevant performance of the model by the ROC curve and t-SNE dimensionality reduction technique. The results indicated that the deep learning and machine learning fusion models of M3E-base and KNeighborsDist models, especially when considering the semantic information on amino acid sequences, achieved the highest average accuracy (AvgAcc) of 0.939, with an AUC value as high as 0.97. Then, in vitro cell experiments were used to verify that the two ACPs predicted by the model had antitumor efficacy. This study provides a convenient and effective method for screening ACPs. With further optimization and testing, these strategies have the potential to play an important role in drug discovery and design.

The burden of epilepsy in the People's Republic of China from 1990 to 2019: epidemiological trends and comparison with the global burden of epilepsy.

Background: Epilepsy is associated with a significant global burden of disease, affecting over 50 million people worldwide. The specific aim of this study is to compare the burden of epilepsy in the People's Republic of China (PRC) with the global burden, and to analyze the epidemiological trends of epilepsy, the relationship between the burden of epilepsy and social demographic index (SDI), and the relative contributions of epidemiological factors. Methods: This is a retrospective population-based study, data were obtained from the Global Burden of Disease (GBD) study in 2019. We employed Joinpoint software and the age-period-cohort (APC) model to analyze epilepsy's epidemiological trends. Health inequality analysis was conducted to investigate the impact of SDI on epilepsy burden. Decomposition analysis was performed to examine the relative contributions of age, population, and epidemiological changes to epilepsy. Results: Between 1990 and 2019, the incidence rate in the PRC increased by 45%, significantly surpassing the global incidence of epilepsy. However, Disability-Adjusted Life Years (DALY) decreased notably, and the proportion of Years of Life Lost (YLL) decreased from 62.73 to 39.03%. Concerning incidence, the period Rate Ratio (RR) in the PRC initially increased and then decreased, while the cohort RR in the PRC and globally exhibited a consistent upward trend. In terms of mortality, period RR and cohort RR in the PRC displayed a gradual decrease, with mortality starting higher but eventually falling below the global mortality. The net drifts of incidence were greater than 0, whereas the net drifts of mortality were less than 0, both were lower in the PRC than at the global level. Decomposition analysis indicated that the changes of incidence and mortality in the PRC were mainly attributed to epidemiological changes. Additionally, global disparities in epilepsy decreased, with the burden concentrating in low SDI countries. Conclusion: The incidence of epilepsy in the PRC rose during the 30-year study period, while epilepsy mortality decreased. The improved survival rate in the PRC is predominantly attributable to epidemiological changes. The burden of epilepsy in the PRC predominantly affects males, children, and the elderly, Chinese government should focus on specific populations.

Temperature dependence of stimulated Raman scattering from a VYO4 crystal.

The microstructural, electrical, and optical properties of crystals are critical to laser device performance, and the temperature-dependence effect of crystals has gained a great deal of attention in research. The linewidth, stimulated Raman scattering (SRS) shift, and intensity of the characteristic peak at 890 cm-1 of YVO4 crystal have been investigated between 148 and 448 K. As the crystal temperature increases, the bond length increases and the crystal force constant decreases, and the phonon softening process arises in the crystal at high temperature. The temperature effect on Raman shift and full width at half maximum is explained in detail in terms of the phonon anharmonic effect. The temperature dependence of SRS can be well demonstrated by an empirical equation. This work can provide new insights into the further understanding of lattice anharmonicity and contribute to the discovery of new optoelectronic materials.

Hydrogen bond network dynamics of heavy water resolved by alcohol hydration under an intense laser.

Despite a great deal of effort spanning for decades, it remains yet puzzling concerning how alcohol molecules functionalize the hydrogen bond (H-bond) networks of water. We employed an isotopic substitution method (using alcohol-heavy water system) to avoid spectral overlap between the alcohol hydroxyl groups and water hydrogen bonds. We showed spectrometrically that under the strong pulse laser, the low mixing ratio (VA < 20%) of alcohol can strengthen the H-bond network structure of D2O through :ÖC2H6↔ D2Ö: compression. But when VA > 20%, H-bond network of D2O will deform via the self-association between alcohol molecules. Our experiments not only reveal the H-bond kinetics of heavy water-alcohol interactions but also provide important reference for understanding the distinctive properties of H-bond in water-organic system.

A novel EDAR variant identified in non-syndromic tooth agenesis: Insights from molecular dynamics.

OBJECTIVE: This study aims to investigate a novel pathogenic variant in a Chinese family of non-syndromic tooth agenesis (NSTA) and study the impact of the variant on related protein and pathway. DESIGN: One NSTA family was collected. Whole exome sequencing and Sanger sequencing were performed on the proband with NSTA and his 5 family members. The pathogenic influence of the mutant is evaluated by bioinformatics analyses including evolutionary conservation analysis and secondary structure prediction. Molecular dynamics (MD) simulations and binding free energy calculations were then performed to explore changes in the tertiary structure and binding ability of the protein. RESULTS: We found a novel missense ectodysplasin A receptor (EDAR) variant (c .1292 T > G; p.Ile431Arg) in all affected family members. The results of bioinformatics analyses revealed that the EDAR had harmful changes after mutation. MD simulations and the binding free energy calculations results showed that the mutant EDAR protein and EDAR/ectodysplasin-A receptor-associated adapter (EDARADD) complex displayed tertiary structural change, and EDAR possessed a lower affinity to EDARADD after mutation. CONCLUSIONS: We found a novel EDAR variant (c.1292 T > G; p.Ile431Arg) in one NSTA family, which affects the binding of EDAR and EDARADD.

Coherent Raman comb generation in H2O2aqueous solutions by crossing-pump stimulated Raman scattering.

The cascaded stimulated Raman scattering (SRS) of 30% H2O2 aqueous solutions was investigated using a pulsed Nd: YAG laser with a wavelength of 532 nm. The transfer of excess electrons between H2O2 and H2O molecules enhanced the SRS. Together, the decomposition of H2O2 and the intense SRS Stokes led to the generation of the crossing-pump effect of H2O2 aqueous solutions and the appearance of a new peak at 4229 cm-1 that is excited by Stokes as the pump source. Crossing-pump not only reduced the threshold but also generated the broadband-coherent Raman comb, defined as a coherent radiation wavelength ranging from 434 to 831 nm (i.e., a Raman shift ranging from -4225 to 6756 cm-1). The anti-Stokes SRS was attributed to the four-wave mixing (FWM) process.

Effects of Acupuncture on Endometrium and Pregnancy Outcomes in Patients with Polycystic Ovarian Syndrome Undergoing in vitro Fertilization-Embryo Transfer: A Randomized Clinical Trial.

OBJECTIVE: To observe the effect of acupuncture on endometrium and pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) infertility undergoing in vitro fertilization-embryo transfer (IVF-ET). METHODS: Eighty-three patients were randomly assigned to observation group (40 cases) and control group (43 cases) according to the random numbers generated by SPSS software. The patients of the two groups received GnRH agonist long protocol as a routine treatment. In the observation group, acupuncture was given at two acupoint groups for 30 min once every other day. Group 1 included Guanyuan (CV 4), Qihai (CV 6), Zhongji (CV 3), bilateral acupoints Zigong (EX-CA1). Group 2 included Mingmen (GV 4), Yaoyangguan (GV 3), bilateral Shenshu (BL 23) and Ciliao (BL 32). The two groups of acupoints were used alternately. The whole needling process was performed at the time of ovulation induction until the transplantation day and consisted of 3 courses, while the control group did not receive acupuncture interventions. The Gn dosage and Gn stimulation time, endometrial thickness and type (A, B, and C), serum oestradiol (E2) and progesterone (P) levels on the day of injection of human chorionic gonadotropin (hCG), clinical pregnancy rate, as well as live birth rate were observed. Adverse reactions were also be recorded. All patients were followed up for the pregnant rate 14 days after IVF-ET and live birth rate after pregnancy. All adverse reactions (AEs) of acupuncture were recorded during the trial. RESULTS: The Gn dosage and Gn stimulation time in the observation group were lower in the observation group than in the control group (P<0.01). The proportion of type A endometrium in the observation group were higher than that in the control group (P<0.05). The serum E2 and P levels on the day of hCG injection was lower and the clinical pregnancy rate was higher in the observation group compared to those in the control group (P<0.05). There was no serious AEs during this trial. CONCLUSION: Acupuncture can improve the proportion of type A endometrium, regulate the levels of serum E2 and P on the day of hCG injection, and improve the pregnancy rate in patients with PCOS infertility undergoing IVF-ET.

In Vivo Visualized Tracking of Tumor-Derived Extracellular Vesicles Using CRISPR-Cas9 System.

Introduction: Tumor extracellular vesicles (EVs) and their relevance to various processes of tumor growth have been vigorously investigated over the past decade. However, obtaining direct evidence of spontaneous EV transfer in vivo remains challenging. In our previous study, a single-guide RNA (sgRNA): Cas9 ribonucleoprotein complex, which can efficiently delete target genes, was delivered into recipient cells using an engineered EV. Aim: Applying this newly discovered exosomal bio-cargo to track the uptake and distribution of tumor EVs. Methods: Tumor cells of interest were engineered to express and release the sgRNA:Cas9 complex, and a reporter cell/system containing STOP-fluorescent protein (FP) elements was also generated. EV-delivered Cas9 proteins from donor cells were programmed by a pair of sgRNAs to completely delete a blockade sequence and, in turn, recuperated the expression of FP in recipient reporter cells. Thus, fluorescently illuminated cells indicate the uptake of EVs. To improve the efficiency and sensitivity of this tracking system in vivo, we optimized the sgRNA design, which could more efficiently trigger the expression of reporter proteins. Results: We demonstrated the EV-mediated crosstalk between tumor cells, and between tumor cells and normal cells in vitro. In vivo, we showed that intravenously administered EVs can be taken up by the liver. Moreover, we showed that EVs derived from melanoma xenografts in vivo preferentially target the brain and liver. This distribution resembles the manifestation of organotrophic metastasis of melanoma. Conclusion: This study provides an alternative tool to study the distribution and uptake of tumor EVs.

[Progress of classification algorithms for motor imagery electroencephalogram signals].

Motor imagery (MI), motion intention of the specific body without actual movements, has attracted wide attention in fields as neuroscience. Classification algorithms for motor imagery electroencephalogram (MI-EEG) signals are able to distinguish different MI tasks based on the physiological information contained by the EEG signals, especially the features extracted from them. In recent years, there have been some new advances in classification algorithms for MI-EEG signals in terms of classifiers versus machine learning strategies. In terms of classifiers, traditional machine learning classifiers have been improved by some researchers, deep learning and Riemannian geometry classifiers have been widely applied as well. In terms of machine learning strategies, ensemble learning, adaptive learning, and transfer learning strategies have been utilized to improve classification accuracies or reach other targets. This paper reviewed the progress of classification algorithms for MI-EEG signals, summarized and evaluated the existing classifiers and machine learning strategies, to provide new ideas for developing classification algorithms with higher performance.

In vivo self-assembled small RNAs as a new generation of RNAi therapeutics.

RNAi therapy has undergone two stages of development, direct injection of synthetic siRNAs and delivery with artificial vehicles or conjugated ligands; both have not solved the problem of efficient in vivo siRNA delivery. Here, we present a proof-of-principle strategy that reprogrammes host liver with genetic circuits to direct the synthesis and self-assembly of siRNAs into secretory exosomes and facilitate the in vivo delivery of siRNAs through circulating exosomes. By combination of different genetic circuit modules, in vivo assembled siRNAs are systematically distributed to multiple tissues or targeted to specific tissues (e.g., brain), inducing potent target gene silencing in these tissues. The therapeutic value of our strategy is demonstrated by programmed silencing of critical targets associated with various diseases, including EGFR/KRAS in lung cancer, EGFR/TNC in glioblastoma and PTP1B in obesity. Overall, our strategy represents a next generation RNAi therapeutics, which makes RNAi therapy feasible.

Pancreatic ß cells control glucose homeostasis via the secretion of exosomal miR-29 family.

Secreted microRNAs (miRNAs) are novel endocrine factors that play essential pathological and physiological roles. Here, we report that pancreatic ß cell-released exosomal miR-29 family members (miR-29s) regulate hepatic insulin sensitivity and control glucose homeostasis. Cultured pancreatic islets were shown to secrete miR-29s in response to high levels of free fatty acids (FFAs) in vitro. In vivo, high levels of FFAs, promoted by either high-fat diet (HFD) feeding (physiopathological) or fasting (physiological), increased the secretion of miR-29s into plasma. Intravenous administration of exosomal miR-29s attenuated insulin sensitivity. The overexpression of miR-29s in the ß cells of transgenic (TG) mice promoted the secretion of miR-29s and inhibited the insulin-mediated suppression of glucose output in the liver. We used selective overexpression of traceable heterogenous mutant miR-29s in ß cells to confirm that islet-derived exosomal miR-29s target insulin signalling in the liver and blunt hepatic insulin sensitivity. Moreover, in vivo disruption of miR-29s expression in ß cells reversed HFD-induced insulin resistance. In vitro experiments demonstrated that isolated exosomes enriched in miR-29s inhibited insulin signalling in the liver and increased hepatic glucose production. These results unveil a novel ß cell-derived secretory signal-exosomal miR-29s-and provide insight into the roles of miR-29s in manipulating glucose homeostasis.

An engineered exosome for delivering sgRNA:Cas9 ribonucleoprotein complex and genome editing in recipient cells.

CRISPR-Cas9 is a versatile genome-editing technology that is a promising gene therapy tactic. However, the delivery of CRISPR-Cas9 is still a major obstacle to its broader clinical application. Here, we confirm that the components of CRISPR-Cas9-sgRNA and Cas9 protein-can be packaged into exosomes, where sgRNA and Cas9 protein exist as a sgRNA:Cas9 ribonucleoprotein complex. Although exosomal CRISPR-Cas9 components can be delivered into recipient cells, they are not adequate to abrogate the target gene in recipient cells. To solve this, we engineered a functionalized exosome (M-CRISPR-Cas9 exosome) that could encapsulate CRISPR-Cas9 components more efficiently. To improve the loading efficiency of Cas9 proteins into exosomes, we artificially engineered exosomes by fusing GFP and GFP nanobody with exosomal membrane protein CD63 and Cas9 protein, respectively. Therefore, Cas9 proteins could be captured selectively and efficiently loaded into exosomes due to the affinity of GFP-GFP nanobody rather than random loading. sgRNA and Cas9 protein exist as a complex in functionalized exosomes and can be delivered into recipient cells. To show the function of modified exosomes-delivered CRISPR-Cas9 components in recipient cells visually, we generated a reporter cell line (A549stop-DsRed) that produced a red fluorescent signal when the stop element was deleted by the sgRNA-guided endonuclease. Using A549stop-DsRed reporter cells, we showed that modified exosomes loaded with CRISPR-Cas9 components abrogated the target gene more efficiently in recipient cells. Our study reports an alternative tactic for CRISPR-Cas9 delivery.

High extinction ratio electromagnetically induced transparency analogue based on the radiation suppression of dark modes.

A high extinction ratio (ER) electromagnetically induced transparency (EIT) analogue based on single-layer metamaterial is designed and experimentally demonstrated in this paper. This design involves four mirror-like symmetrically coupled split ring resonators (SRRs) that exhibit a bright-dark-dark-bright mode configuration. The EIT-like effect is realized by coupling between the bright resonators and dark resonators. The high ER feature is achieved from the suppression of radiative losses, due to opposite directions of electric and magnetic dipoles of two dark modes in the unit cell. Classical coupled resonator model is used to theoretically analyze the device transmission performances and to characterize parameter influence of the ER. Both numerical simulation and experiment results demonstrate that the ER of this device can reach more than 21 dB, which is 11 dB higher than that of conventional bright-dark coupling SRR arrangement. Finally, the potential multi-channel sensing utility of this device is demonstrated to show the importance of high ER feature.

Cloning and functional identification of the AcLFY gene in Allium cepa.

Onion (Allium cepa L.) is one of the important vegetable crops in the world, usually with a two-year life cycle. The bulbs form in the first year after sowing, then bolting and flowering are induced by low temperature in the following year. Previous studies have shown that LEAFY gene is an inflorescence tissue specific gene, and that it is also the ultimate collection channel of all flowering pathway. In this study, using homologous gene cloning and reverse transcription-PCR (RT-PCR), we isolated an inflorescence meristem specific LEAFY cDNA, AcLFY (JX275962), from onion. AcLFY contains a 1119 bp open reading frame, which encodes a putative protein of 372 amino acids, with ∼70% homology to the daffodils LEAFY and >50% homology to LEAFY proteins from other higher plants. Fluorescence quantitative results showed that AcLFY gene has the highest expression level in inflorescence meristem during early bolting, and is still expressed in leaves after the formation of flower organs. Overexpression of AcLFY gene in Arabidopsis thaliana induced early bolting and flowering, whereas knockdown of the endogenous LEAFY gene by RNAi caused a significant delay in bolting. In addition, transgenic plants also exhibited significant morphological changes in rosette leaves, branches, and plant height.