Improving Catalytic Activity, Acid-Tolerance, and Thermal Stability of Glutathione Peroxidase by Systematic Site-Directed Selenocysteine Incorporation.

Glutathione peroxidase (GPx) is an important antioxidant enzyme. Selenocysteine (Sec)-containing GPxs (Sec-GPxs) are usually superior to their conventional cysteine-containing counterparts (Cys-GPxs), which make up the majority of the natural GPxs but display unsuitable activity and stability for industrial applications. This study first heterologously expressed and characterized a Cys-GPx from Lactococcus lactis (LlGPx), systematically exchanged all the three Cys to Sec and introduced an extra Sec. The results showed that the insertion of Sec at the active site could effectively increase the enzyme activity and confer a lower optimal pH value on the mutants. The double mutant C36U/L157U increased by 2.65 times (5.12 U/mg). The thermal stability of the C81U mutant was significantly improved. These results suggest that site-directed Sec incorporation can effectively improve the enzymatic properties of LlGPx, which may be also used for the protein engineering of other industrial enzymes containing catalytic or other functional cysteine residues.

The regulation loop of MARVELD1 interacting with PARP1 in DNA damage response maintains genome stability and promotes therapy resistance of cancer cells.

The DNA damage response (DDR) plays crucial roles in cancer prevention and therapy. Poly(ADP-ribose) polymerase 1 (PARP1) mediates multiple signal transduction in the DDR as a master regulator. Uncovering the regulatory factors of PARP1 contributes to a more comprehensive view of tumorigenesis and treatment strategies. Here, we reveal that MARVELD1 acts as a mediator of DDR to perform early events and maintain genome stability. Mechanistically, PARP1 PARylates MARVELD1 at D102, D118 and D130, and in turn, MARVELD1 stabilizes PARP1 by enhancing NAA50-mediated acetylation, thus forming a positive feedback loop. MARVELD1 knockout mice and their embryo fibroblasts exhibit genomic instability and shorter half-life of PARP1. Moreover, MARVELD1 partnering with PARP1 facilitates resistance to genotoxic drugs and disrupts PARP inhibitor (PARPi) effect in PDX model of colorectal cancer (CRC). Overall, our results underline the link between MARVELD1 and PARP1 in therapeutic resistance based on DDR and provide new insights for clinical tumor therapy of PARPi.

Utilization of feather keratin waste to antioxidant and migration-enhancer peptides by Bacillus licheniformis 8-4.

AIMS: Feathers are keratin-rich byproducts of poultry processing, but those are often frequently abandoned as garbage and thus polluting the environment. Therefore, the study focused on the efficient biodegradation, bioactivity, and high-value application of feather keratin. METHODS AND RESULTS: Feather-degrading bacteria were identified, and the degradation properties were characterized. DPPH (1,1-Diphenyl-2-picrylhydrazyl radical) and ABTS (2,2'-Azino-bis (3-ethylbenzthiazoline-6-sulfonic acid))radical scavenging assays, cytotoxicity assays, intracellular reactive oxygen scavenging assays, and cell migration assays were used to examine the biological activities of the feather keratin hydrolysis peptides (FKHPs). The results showed that we screened a feather-degrading strain of Bacillus licheniformis 8-4, which achieved complete degradation of 2% (w/v) feathers within 48 h. Notably, the feather fermentation broth was particularly high in FKHPs, which exhibited good DPPH and ABTS radical scavenging ability. Further studies revealed that FKHPs had both the ability to scavenge H2O2-induced ROS from HaCat cells and the ability to promote HaCat cell migration, while remaining non-toxic. CONCLUSIONS: The effective feather-degrading ability of B. licheniformis 8-4 allowed for the fermentation of feather medium to yield active peptides that were both antioxidants and cell-migration enhancers.

Biosynthesis of Melanin Nanoparticles for Photoacoustic Imaging Guided Photothermal Therapy.

Photothermal therapy (PTT) has attracted considerable attention in recent years due to their unique advantages in minimal invasiveness and spatiotemporal selectivity. However, the fabrication procedures of PTT agents frequently require complex chemical and/or physical methods that involves harsh and environmentally hazardous conditions. Here, a genetically engineered bacterium is developed to synthesize melanin nanoparticles under mild and environmentally friendly conditions. The biosynthetic melanin nanoparticles exhibit excellent biocompatibility, good stability, and negligible toxicity. In addition, the biosynthetic melanin nanoparticles have strong absorption at near-infrared (NIR) region and higher photothermal conversion efficiency (48.9%) than chemically synthesized melanin-like polydopamine nanoparticles under an 808 nm laser irradiation. Moreover, the results show that the biosynthetic melanin nanoparticles have excellent photoacoustic imaging (PAI) performance and can be used for PAI guided PTT in vivo. In conclusion, the study provides an alternative approach to synthesize PTT agents with broad application potential in the diagnosis and treatment of cancer.

Dual-Modality Molecular Imaging of Tumor via Quantum Dots-Liposome-Microbubble Complexes.

Molecular imaging has demonstrated promise for evaluating the expression levels of biomarkers for the early prediction of tumor progression and metastasis. However, most of the commonly used molecular imaging modalities are relatively single and have difficulties imaging complex biological processes. Here, we fabricated αvß3-integrin-targeted quantum-dots-loaded liposome-microbubble (iRGD-QDLM) complexes that combined ultrasound imaging with optical imaging. The resulting iRGD-QDLM has excellent binding capability to 4T1 breast cancer cells. Ultrasound molecular imaging of 4T1 tumors demonstrated that significantly enhanced ultrasound molecular signals could be observed in comparison with non-targeted QDLM. Importantly, our study also suggested that iRGD-QDL on the surface of microbubbles could be delivered into a tumor by ultrasound-mediated microbubble destruction and adhered to αvß3 integrin on breast cancer cells, achieving transvascular fluorescent imaging. Our study provides a novel approach to dual-modality molecular imaging of αvß3 integrin in the tumor tissue.

Does the Metabolome of Wild-like Dendrobium officinale of Different Origins Have Regional Differences?

Dendrobium officinale, as a traditional Chinese medicine, has considerable commercial value and pharmacological activity. Environmental factors of different origins have a great influence on Dendrobium officinale metabolites, which affect its pharmacological activity. This study sought to identify the differential metabolites of wild-imitating cultivated D. officinale stems of different origins. Using the widely-targeted metabolomics approach, 442 metabolites were detected and characterized, including flavonoids, lipids, amino acids and derivatives, and alkaloids. We found that although the chemical constitution of D. officinale cultured in the three habitats was parallel, the contents were significantly different. Meanwhile, the KEGG pathway enrichment analysis revealed that the distinctive metabolites among the three groups were mainly involved in flavone and flavonol biosynthesis. To further explore the different contents of flavonoids, HPLC was performed on four main flavonoid contents, which can be used as one of the references to distinguish D. officinale from different growing origins. In conclusion, a comprehensive profile of the metabolic differences of D. officinale grown in different origins was provided, which contributed a scientific basis for further research on the quality evaluation of D. officinale.

Computer-assisted in vitro reconstitution of purine degradation pathway to lower the purine content in food.

BACKGROUND: With the increasing prevalence of gout and its etiological hyperuricemia, dietary control of gout based on low-purine food according to patients' eating habits is becoming a better choice compared to the existing drug treatment such as allopurinol with notorious side effects. Reconstructing the purine metabolic pathway in vitro to degrade purine substances in food into natural functional allantoin appears to be an innovative method for preparing nutritious and healthy food of low purine content. The present study reports a computer-assisted in vitro reconstruction of four purinolytic enzymes metabolizing adenosine into allantoin to reduce purine content in food for personalized dietary control of hyperuricemia and gout. RESULTS: Under the optimum reaction conditions of 40 °C and pH 7, 0.1 U of enzymes and 0.5 mmol L-1 adenosine determined by an orthogonal test design, 16 different enzyme complexes were experimentally tested. The tested enzyme composition and allantoin production values were used as input and output to build a three-layer back propagation artificial neural network (BP-ANN) model, which was further optimized by a genetic algorithm (GA). The optimum enzyme complex predicted by the GA-BP-ANN model produced 248.08±7.832 µmol L-1 allantoin, which was 19.9% higher than equimolar mixture of enzymes, and also more efficiently lowered purine contents in beer, as well as beef and yeast extracts. CONCLUSION: This is the first in vitro reconstitution of complete purine metabolic pathway by combining ANN and GA technologies, with successful application with respect to lowering the purine content in food, indicating a promising application of computer-assisted in vitro reconstitution of purinolytic pathway in low-purine food to prevent hyperuricemia and gout. © 2022 Society of Chemical Industry.

Prevalence and characterization of Salmonella from meat in slaughterhouses in Hangzhou, China.

Salmonella is an essential food-borne pathogenic microorganism. Humans could get infected by consuming of Salmonella-contaminated foods, especially contaminated meat. In this study, a total of 580 retail meat samples (280 pork, 240 chicken, and 60 goose) were collected from slaughterhouses in Hangzhou to determine the prevalence and antimicrobial susceptibility patterns of Salmonella. Isolates were characterized by serotyping, PFGE (Pulsed-field gel electrophoresis), Polymerase chain reaction (PCR), and antibiotic susceptibility testing. The rates of Salmonella-positive pork, chicken, and goose samples were 21.1% (n = 59), 10.4% (n = 25) and 10.0% (n = 6), respectively. The prevalence of Salmonella was 15.5% in slaughterhouses. Thirteen different Salmonella serovars were identified, and 6 isolates could not be identified. The most commonly prevalent serovars are Salmonella Rissen (S. Rissen) (n = 20, 22.2%), S. Derby (n = 16, 17.8%) and S. Typhimurium (n = 12, 13.3%). The detection rate of the remaining serovars ranged from 1.1%-11.11%. All Derby, Corvallis, and Kentucky strains were from pork. Seventy-two isolates (80.0%) showed drug resistance (DR) to at least one antibiotics, 19 (21.1%) were multi-drug resistant strains, 2 (2.2%) showed seven or more. The detection rate of Trimethoprim/Sulfamethoxazole-resistance (70.0%) was highest, followed by Ampicillin (55.6%). Salmonella resistance was found related to serovar and origin. The positive rates of DR gene sul1, sul2, sul3, class I integrons and blaTEM were 92.2%, 95.6%, 86.7%, 83.3% and 62.2%, respectively. Fifty-seven different PFGE patterns and 7 main clusters were obtained. This study revealed the high positive rates of Salmonella resistance and related DR genes, especially for Sulfamethoxazole-resistance and its related gene.

Heritability Analysis in Twins Indicates a Genetic Basis for Velopharyngeal Morphology.

The velopharyngeal mechanism is comprised of several muscular components that act in a coordinated manner to control airflow through the nose and mouth. Proper velopharyngeal function is essential for normal speech, swallowing, and breathing. The genetic basis of normal-range velopharyngeal morphology is poorly understood. The purpose of this study was to estimate the heritability of velopharyngeal dimensions.We measured five velopharyngeal variables (velar length, velar thickness, effective velar length, levator muscle length and pharyngeal depth) from MRIs of 155 monozygotic and 208 dizygotic twin pairs and then calculated heritability for these traits using a structural equation modeling approach.The heritability estimates were statistically significant (95% confidence intervals excluded zero) and ranged from 0.19 to 0.46. There was also evidence of significant genetic correlations between pairs of traits, pointing to the influence of common genetic effects.These results indicate that genetic factors influence variation in clinically relevant velopharyngeal structures.

Improved Stabilization and In Vitro Digestibility of Mulberry Anthocyanins by Double Emulsion with Pea Protein Isolate and Xanthan Gum.

There is significant evidence that double emulsion has great potential for successfully encapsulating anthocyanins. However, few research studies are currently using a protein-polysaccharide mixture as a stable emulsifier for double emulsion. This study aimed to improve the stability and in vitro digestibility of mulberry anthocyanins (MAs) by employing a double emulsion composed of pea protein isolate (PPI) and xanthan gum (XG). The influence of various XG concentrations (0%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%) and different temperatures (5 °C, 25 °C, 45 °C, 65 °C) on the physical stability and the thermal degradation of MAs from double emulsions were investigated. In addition, the physicochemical properties of double emulsions and the release performance of MAs during in vitro simulated digestion were evaluated. It was determined that the double emulsion possessed the most stable physical characteristics with the 1% XG addition. The PPI-1% XG double emulsion, when compared to the PPI-only double emulsion, expressed higher thermal stability with a retention rate of 83.19 ± 0.67% and a half-life of 78.07 ± 4.72 days. Furthermore, the results of in vitro simulated digestion demonstrated that the MAs in the PPI-1% XG double emulsion were well-protected at oral and gastric with ample release found in the intestine, which was dissimilar to findings for the PPI-only double emulsion. Ultimately, it was concluded that the double emulsion constructed by the protein-polysaccharide system is a quality alternative for improving stability and absorption with applicability to a variety of food and beverage systems.

Effects of Different Molecular Weight Polysaccharides From Dendrobium officinale Kimura & Migo on Human Colorectal Cancer and Transcriptome Analysis of Differentially Expressed Genes.

We investigated the antitumor effects of four fractions of Dendrobium officinale Kimura & Migo (D. officinale) polysaccharides with different molecular weights (Mw), Astragalus membranaceus polysaccharides (APS) and Lentinus edodes polysaccharides (LNT) on colorectal cancer (CRC) using a zebrafish xenograft model. Transcriptome sequencing was performed to further explore the possible antitumor mechanisms of D. officinale polysaccharides. Fractions of D. officinale polysaccharides, LNT, and APS could significantly inhibit the growth of HT-29 cells in a zebrafish xenograft model. One fraction of D. officinale polysaccharides called DOPW-1 (Mw of 389.98 kDa) exhibited the strongest tumor inhibition. Compared with the control group, RNA-seq revealed that the DOPW-1-treated experimental group had 119 differentially expressed genes (DEGs), of which 45 had upregulated expression and 74 had downregulated expression. Analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes suggested that the pathway "apoptosis-multiple species" was the most significantly enriched. Our data indicated that 1) fractions of D. officinale polysaccharides of Mw 389.98 kDa were most suitable against CRC; 2) DOPW-1 could be developed into a clinical agent against CRC; and 3) an apoptosis pathway is important for DOPW-1 to inhibit the proliferation of HT-29 cells.

Discovery of new genetic loci for male sexual orientation in Han population.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10-8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10-8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10-8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10-9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10-9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations.

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10-8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10-10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.

A Study on the Improvement of Nursing Interruption Risk by a Closed-Loop Management Model.

OBJECTIVE: This study aimed to evaluate the effect of closed-loop management on nursing disruption risk. METHODS: Using a quasi-experimental research method, convenient sampling was used to extract 20 nurses working at our hospital as the research objects. The control group members were selected from January to March 2018 via the traditional method, and the experimental group members were selected from April to June 2018 via the closed-loop management method. At three months before and after the implementation of the management model, a self-designed quantitative test form and satisfaction questionnaire were used to analyze the frequency of nursing disruption events, the accuracy rate of doctors' advice, the average drug delivery time of the static distribution center, the implementation rate of personal digital assistant (PDA) code scanning, and the report rate of risk-outcome nursing disruption events. RESULTS: After the implementation of the management model, the frequency of nursing disruptions and average drug delivery time of the static distribution center were significantly lower than before, and the differences were statistically significant (p < 0.05). Moreover, the accuracy rate of doctors' advice, the implementation rate of PDA code scanning, and the reporting rate of risk-outcome nursing disruption events were significantly higher than before, and these differences were statistically significant as well (p < 0.05). CONCLUSION: The application of a closed-loop management model could significantly reduce the occurrence and optimize the outcomes of nursing disruption events and improve the work processes of medical care.

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation.

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10-3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10-8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10-10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.

Gigantol inhibits proliferation and enhances DDP-induced apoptosis in breast-cancer cells by downregulating the PI3K/Akt/mTOR signaling pathway.

AIMS: Gigantol is a bibenzyl compound isolated from orchids of the genus Dendrobium. Gigantol has been demonstrated to possess various pharmacologic (including anticancer) effects. Cisplatin (DDP) has been used and studied as the first-line agent for breast cancer (BC) treatment. Often, its efficacy is jeopardized due to intolerance and organ toxicity. We investigated if gigantol could enhance the anticancer effects of DDP in BC cells and its underlying mechanism of action. MAIN METHODS: The potential pathway of gigantol in BC cells was detected by network-pharmacology and molecular-docking studies. The proliferation and apoptosis of BC cell lines were measured by the MTT assay, colony formation, Hoechst-33342 staining, and flow cytometry. Protein expression was measured by western blotting. KEY FINDINGS: Gigantol could inhibit proliferation of BC cells and enhance DDP-induced apoptosis. According to the results of western blotting, gigantol reinforced DDP-induced anticancer effects through downregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in BC cells. The effects were consistent with those of the pathway inhibitor LY294002. SIGNIFICANCE: Our data might provide new insights into the underlying antitumor effect of gigantol in BC cells. This enhancement effect in the combination of gigantol and DDP may provide many therapeutic benefits in clinical treatment regimens against BC.

Network Analysis of Transcriptome and LC-MS Reveals a Possible Biosynthesis Pathway of Anthocyanins in Dendrobium officinale.

Anthocyanins, a group of flavonoids, are widely present in plants and determine the colors of the peels of stems, fruits, and flowers. In this study, we used UHPLC-ESI-MS to identify anthocyanins in the herbal plant Dendrobium officinale, which has been used for centuries in China. The results indicated that the total anthocyanin content in samples from Guangxi was the highest. Seven anthocyanins were identified, and the fragmentation pathways were proposed from D. officinale. Most of the identified anthocyanins were composed of cyanidin and sinapoyl groups. We also carried out that the sinapoyl group had active sites on breast cancer receptors by using Schrödinger. The relative levels of the 7 anthocyanins in the samples from the three locations were determined. Transcriptomic analysis was used to analyze the sinapoyl anthocyanin synthesis-related genes in plants, such as genes encoding UGTs and serine carboxypeptidase. We speculated that sinapoyl anthocyanin biosynthesis was associated with the activities of certain enzymes, including chalcone flavonone isomerase-like, hydroxycinnamoyltransferase 1, UGT-83A1, UGT-88B1 isoform X1, serine carboxypeptidase-like 18 isoform X3, and serine carboxypeptidase-like 18.

The schizophrenia genetics knowledgebase: a comprehensive update of findings from candidate gene studies.

Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies' findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci (MTHFR, DAOA, ARVCF) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.

Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles.

Schizophrenia is a psychiatric disorder with a worldwide prevalence of ∼1%. The high heritability and reduced fertility among schizophrenia patients have raised an evolutionary paradox: why has negative selection not eliminated schizophrenia associated alleles during evolution? To address this question, we examined evolutionary markers, known as modern-human-specific (MD) sites and archaic-human-specific sites, using existing genome-wide association study (GWAS) data from 34,241 individuals with schizophrenia and 45,604 healthy controls included in the Psychiatric Genomics Consortium (PGC). By testing the distribution of schizophrenia single nucleotide polymorphisms (SNPs) with risk and protective effects in the human-specific sites, we observed a negative selection of risk alleles for schizophrenia in modern humans relative to archaic humans (e.g., Neanderthal and Denisovans). Such findings indicate that risk alleles of schizophrenia have been gradually removed from the modern human genome due to negative selection pressure. This novel evidence contributes to our understanding of the genetic origins of schizophrenia.