The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability.

Replication fork reversal is a global response to replication stress in mammalian cells, but precisely how it occurs remains poorly understood. Here, we show that, upon replication stress, DNA topoisomerase IIalpha (TOP2A) is recruited to stalled forks in a manner dependent on the SNF2-family DNA translocases HLTF, ZRANB3, and SMARCAL1. This is accompanied by an increase in TOP2A SUMOylation mediated by the SUMO E3 ligase ZATT and followed by recruitment of a SUMO-targeted DNA translocase, PICH. Disruption of the ZATT-TOP2A-PICH axis results in accumulation of partially reversed forks and enhanced genome instability. These results suggest that fork reversal occurs via a sequential two-step process. First, HLTF, ZRANB3, and SMARCAL1 initiate limited fork reversal, creating superhelical strain in the newly replicated sister chromatids. Second, TOP2A drives extensive fork reversal by resolving the resulting topological barriers and via its role in recruiting PICH to stalled forks.

RNF4 controls the extent of replication fork reversal to preserve genome stability.

Replication fork reversal occurs via a two-step process that entails reversal initiation and reversal extension. DNA topoisomerase IIalpha (TOP2A) facilitates extensive fork reversal, on one hand through resolving the topological stress generated by the initial reversal, on the other hand via its role in recruiting the SUMO-targeted DNA translocase PICH to stalled forks in a manner that is dependent on its SUMOylation by the SUMO E3 ligase ZATT. However, how TOP2A activities at stalled forks are precisely regulated remains poorly understood. Here we show that, upon replication stress, the SUMO-targeted ubiquitin E3 ligase RNF4 accumulates at stalled forks and targets SUMOylated TOP2A for ubiquitination and degradation. Downregulation of RNF4 resulted in aberrant activation of the ZATT-TOP2A-PICH complex at stalled forks, which in turn led to excessive reversal and elevated frequencies of fork collapse. These results uncover a previously unidentified regulatory mechanism that regulates TOP2A activities at stalled forks and thus the extent of fork reversal.

The genomes of Vischeria oleaginous microalgae shed light on the molecular basis of hyper-accumulation of lipids.

BACKGROUND: With the urgent need to reduce carbon emissions, and the dwindling reserves of easily exploitable fossil fuel, microalgae-based biofuels that can be used for transport systems and CO2 abatement have attracted great attention worldwide in recent years. One useful characteristic of microalgae is their ability to accumulate high levels of lipid content, in particular under conditions of nitrogen deprivation, with numerous species identified so far. However, a trade-off between levels of lipid accumulation and biomass productivity hinders the commercial applicability of lipids from microalgae. Here, we sequenced the genomes of Vischeria sp. CAUP H4302 and Vischeria stellata SAG 33.83, which can accumulate high content of lipids rich in nutraceutical fatty acids and with excellent biomass yield in nitrogen-limiting culture. RESULTS: A whole-genome duplication (WGD) event was revealed in V. sp. CAUP H4302, which is a rare event in unicellular microalgae. Comparative genomic analyses showed that a battery of genes encoding pivotal enzymes involved in fatty acids and triacylglycerol biosynthesis, storage polysaccharide hydrolysis, and nitrogen and amino acid-related metabolisms are expanded in the genus Vischeria or only in V. sp. CAUP H4302. The most highlighted is the expansion of cyanate lyase genes in the genus Vischeria, which may enhance their detoxification ability against the toxic cyanate by decomposing cyanate to NH3 and CO2, especially under nitrogen-limiting conditions, resulting in better growth performance and sustained accumulation of biomass under the aforementioned stress conditions. CONCLUSIONS: This study presents a WGD event in microalgae, providing new insights into the genetic and regulatory mechanism underpinning hyper-accumulation of lipids and offering potentially valuable targets for future improvements in oleaginous microalgae by metabolic engineering.

The seahorse genome and the evolution of its specialized morphology.

Seahorses have a specialized morphology that includes a toothless tubular mouth, a body covered with bony plates, a male brood pouch, and the absence of caudal and pelvic fins. Here we report the sequencing and de novo assembly of the genome of the tiger tail seahorse, Hippocampus comes. Comparative genomic analysis identifies higher protein and nucleotide evolutionary rates in H. comes compared with other teleost fish genomes. We identified an astacin metalloprotease gene family that has undergone expansion and is highly expressed in the male brood pouch. We also find that the H. comes genome lacks enamel matrix protein-coding proline/glutamine-rich secretory calcium-binding phosphoprotein genes, which might have led to the loss of mineralized teeth. tbx4, a regulator of hindlimb development, is also not found in H. comes genome. Knockout of tbx4 in zebrafish showed a 'pelvic fin-loss' phenotype similar to that of seahorses.

Genome sequence of the Asian Tiger mosquito, Aedes albopictus, reveals insights into its biology, genetics, and evolution.

The Asian tiger mosquito, Aedes albopictus, is a highly successful invasive species that transmits a number of human viral diseases, including dengue and Chikungunya fevers. This species has a large genome with significant population-based size variation. The complete genome sequence was determined for the Foshan strain, an established laboratory colony derived from wild mosquitoes from southeastern China, a region within the historical range of the origin of the species. The genome comprises 1,967 Mb, the largest mosquito genome sequenced to date, and its size results principally from an abundance of repetitive DNA classes. In addition, expansions of the numbers of members in gene families involved in insecticide-resistance mechanisms, diapause, sex determination, immunity, and olfaction also contribute to the larger size. Portions of integrated flavivirus-like genomes support a shared evolutionary history of association of these viruses with their vector. The large genome repertory may contribute to the adaptability and success of Ae. albopictus as an invasive species.

[Clinical efficacy of nasal high-frequency ventilation in treatment of neonatal respiratory distress syndrome: a Meta analysis].

OBJECTIVE: To systematically evaluate the clinical efficacy of nasal high-frequency ventilation (nHFV) in the treatment of neonatal respiratory distress syndrome (NRDS). METHODS: A literature search was performed in PubMed, Cochrane Library, EMBase (Ovid), Chinese Biomedical Literature Database, Chinese Journal Full-text Database, Wanfang Data, and Weipu Data to collect the randomized controlled trials (RCTs) that compared the clinical efficacy of nHFV and nasal continuous positive airway pressure (nCPAP) in the treatment of NRDS. A Meta analysis was performed on the included RCTs using Rev Man 5.3 software after data extraction and quality evaluation by Cochrane 5.1.0. RESULTS: A total of 4 RCTs involving 218 patients were included. The Meta analysis showed that compared with the nCPAP group, the nHFV group had a significantly better treatment outcome (RR=1.73, 95%CI: 1.39-2.15, P<0.00001). There were no significant differences in the incidence rates of intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis, pneumothorax and retinopathy of prematurity. CONCLUSIONS: Compared with nCPAP, nHFV has better clinical efficacy in the treatment of NRDS, without increasing the risk of related complications.

Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization.

As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded ∼0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of ∼81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs.

Treatment effect of a flavonoid prescription on duck virus hepatitis by its hepatoprotective and antioxidative ability.

CONTEXT: Duck virus hepatitis (DVH) caused by duck hepatitis A virus type 1 (DHAV-1) is an acute and lethal disease of young ducklings. However, there is still no effective drug to treat DVH. OBJECTIVE: This study assessed the curative effect on DVH of a flavonoid prescription baicalin-linarin-icariin-notoginsenoside R1 (BLIN) as well as the hepatoprotective and antioxidative effects of BLIN. MATERIALS AND METHODS: MTT method was used to test the anti-DHAV-1 ability of BLIN in vitro. We then treated ducklings by BLIN (3 mg per duckling, once a day for 5 days) to evaluate the in vivo efficacy. To study the hepatoprotective and antioxidative roles of BLIN in its curative effect on DVH, we investigated the hepatic injury evaluation biomarkers and the oxidative stress evaluation indices of the ducklings. RESULTS: On duck embryonic hepatocytes, DHAV-1 inhibitory rate of BLIN at 20 µg/mL was 69.3%. The survival rate of ducklings treated by BLIN was about 35.5%, which was significantly higher than that of virus control (0.0%). After the treatment of BLIN, both the hepatic injury and the oxidative stress of infected ducklings alleviated. At the same time, a significant positive correlation (p < 0.05) existed between the hepatic injury indices and the oxidative stress indices. CONCLUSIONS: BLIN showed a significant curative effect on DVH. The antioxidative and hepatoprotective effects of BLIN made great contributions to the treatment of DVH. Furthermore, BLIN is expected to be exploited as a new drug for the clinical treatment of DVH.

TFIP11 promotes replication fork reversal to preserve genome stability.

Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in this process, yet its precise regulation and role remain poorly understood. In this study, we demonstrate that the GCFC domain-containing protein TFIP11 forms a complex with the BLM helicase. TFIP11 exhibits a preference for binding to DNA substrates that mimic the structure generated at stalled replication forks. Loss of either TFIP11 or BLM leads to the accumulation of the other protein at stalled forks. This abnormal accumulation, in turn, impairs RAD51-mediated fork reversal and slowing, sensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks, thereby impacting genome integrity.

Minipig and beagle animal model genomes aid species selection in pharmaceutical discovery and development.

Improving drug attrition remains a challenge in pharmaceutical discovery and development. A major cause of early attrition is the demonstration of safety signals which can negate any therapeutic index previously established. Safety attrition needs to be put in context of clinical translation (i.e. human relevance) and is negatively impacted by differences between animal models and human. In order to minimize such an impact, an earlier assessment of pharmacological target homology across animal model species will enhance understanding of the context of animal safety signals and aid species selection during later regulatory toxicology studies. Here we sequenced the genomes of the Sus scrofa Göttingen minipig and the Canis familiaris beagle, two widely used animal species in regulatory safety studies. Comparative analyses of these new genomes with other key model organisms, namely mouse, rat, cynomolgus macaque, rhesus macaque, two related breeds (S. scrofa Duroc and C. familiaris boxer) and human reveal considerable variation in gene content. Key genes in toxicology and metabolism studies, such as the UGT2 family, CYP2D6, and SLCO1A2, displayed unique duplication patterns. Comparisons of 317 known human drug targets revealed surprising variation such as species-specific positive selection, duplication and higher occurrences of pseudogenized targets in beagle (41 genes) relative to minipig (19 genes). These data will facilitate the more effective use of animals in biomedical research.

Bone marrow mesenchymal stem cell-derived exosomal microRNA-382 promotes osteogenesis in osteoblast via regulation of SLIT2.

BACKGROUND: Osteoporosis (OP) is a systemic skeletal disorder with increased bone fragility. Human bone marrow mesenchymal stem cells (hBMSCs) have multi-lineage differentiation ability, which may play important roles in osteoporosis. In this study, we aim to investigate the role of hBMSC-derived miR-382 in osteogenic differentiation. METHODS: The miRNA and mRNA expressions in peripheral blood monocytes between persons with high or low bone mineral density (BMD) were compared. Then we collected the hBMSC-secreted sEV and examined the dominant components. The over-expression of the miR-382 in MG63 cell and its progression of osteogenic differentiation were investigated by qRT-PCR, western blot and alizarin red staining. The interaction between miR-382 and SLIT2 was confirmed by dual-luciferase assay. The role of SLIT2 was also confirmed through up-regulation in MG63 cell, and the osteogenic differentiation-associated gene and protein were tested. RESULTS: According to bioinformatic analysis, a series of differential expressed genes between persons with high or low BMD were compared. After internalization of hBMSC-sEV in MG63 cells, we observed that the ability of osteogenic differentiation was significantly enhanced. Similarly, after up-regulation of miR-382 in MG63 cells, osteogenic differentiation was also promoted. According to the dual-luciferase assay, the targeting function of miR-382 in SLIT2 was demonstrated. Moreover, the benefits of hBMSC-sEV in osteogenesis were abrogated through up-regulation of SLIT2. CONCLUSION: Our study provided evidence that miR-382-contained hBMSC-sEV held great promise in osteogenic differentiation in MG63 cells after internalization by targeting SLIT2, which can be served as molecular targets to develop effective therapy.

Analysis of the application effect of continuous care for patients with viral keratitis.

BACKGROUND: In recent years, the incidence of viral keratitis has been on the rise. OBJECTIVE: This study explored the application effect of continuous care for patients with viral keratitis. METHODS: A total of 148 patients with viral keratitis admitted to the ophthalmology department of the authors' hospital from January 2019 to December 2020 were selected and divided into the observation group and the control group via the random number table method, with 74 cases in each group. Continuous care was conducted following routine discharge guidance for patients in the observation group, while routine discharge guidance only was provided for the control group. The patients in both groups were continuously observed for one year. The medication compliance, return visit rate, recurrence rate, nursing satisfaction, and quality of life between the two groups were compared and analyzed after one year. RESULTS: The medication compliance was higher in the observation than in the control group and the difference was statistically significant (P< 0.05). The rate of return visits at 1 week, 1 month, 3 months, 6 months, and 1 year in the observation group were higher than those in the control group and the differences were statistically significant (P< 0.05). The difference in the recurrence rate between the two groups at 1 week was not statistically significant (P> 0.05), while the recurrence rate at 1, 3, and 6 months, and 1 year in the observation group were higher than those in the control group, and the difference was statistically significant (P< 0.05). The total score of the quality of life in the observation group was higher than in the control group and the difference was statistically significant (P< 0.05). CONCLUSION: Continuous care had a good application effect on patients with viral keratitis, which could potentially effectively improve medication compliance and the rate of return visits, reduce recurrence rate, and improve patient satisfaction and their quality of life. Accordingly, the results of this study present high clinical value.

Isolation, identification and molecular docking of anti-inflammatory peptides from walnut (Juglans regia L.) meal hydrolysates.

The oil extraction residue of walnuts is rich in proteins and has been employed in the formulation of various functional food products. In this study, alcalase and neutrase were used to hydrolyze defatted walnut meal protein to obtain anti-inflammatory peptides. After separation by ultrafiltration and by using Sephadex G-25, the fraction with the highest anti-inflammatory activity was identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and 579 peptides were obtained. Then, four of the most stable binding tripeptides with the sequences Trp-Pro-Leu (WPL, MW: 414.2 Da), Trp-Ser-Leu (WSL, MW: 404.2 Da), Phe-Pro-Leu (FPL, MW: 375.2 Da) and Phe-Pro-Tyr (FPY, MW: 425.2 Da) were successfully identified by virtual screening. The anti-inflammatory activity determination of the synthetic peptide assay indicated that FPL (200 µM) exhibited excellent anti-inflammatory activity with inhibitory rates of 63.65 ± 2.64%, 68.25 ± 2.19%, 42.52 ± 2.01% and 59.39 ± 2.21% in terms of four inflammatory mediators (NO, TNF-α, IL-6 and IL-1ß), respectively. It was speculated that the anti-inflammatory activity of walnut peptides might be related to hydrophobic amino acids and aromatic amino acids. By molecular docking, further insight into the theoretical interaction mechanism of binding revealed that hydrophobic interactions and hydrogen bonds turned out to be the main interaction forces between the four peptides and iNOS. These results indicated that FPL screened in this study could be expected to be used as a natural anti-inflammatory active substance in the functional food and pharmaceutical industries.

Detection of RNA-dependent RNA polymerase of porcine epidemic diarrhea virus.

The RNA synthesis of porcine epidemic diarrhea virus (PEDV) is a sophisticated process performed by a multilingual viral replication complex, together with cellular factors. A key enzyme of this replication complex is RNA-dependent RNA polymerase (RdRp). However, there is limited knowledge about PEDV RdRp. In our present study, a polyclonal antibody against RdRp was prepared by using a prokaryotic expression vector pET-28a-RdRp to study the function of PEDV RdRp and provide a tool to investigate PEDV pathogenesis. In addition, the enzyme activity and half-life of PEDV RdRp were investigated. The result showed that the polyclonal antibody against PEDV RdRp was successfully prepared and was able to be used to detect PEDV RdRp by immunofluorescence and western blotting. Additionally, enzyme activity of PEDV RdRp reached nearly 2 pmol/µg/h and the half-life of PEDV RdRp was 5.47 h.

A chromosomal level genome sequence for Quasipaa spinosa (Dicroglossidae) reveals chromosomal evolution and population diversity.

Quasipaa spinosa is an Asian commercial Dicroglossidae species noted for its spiny chest found in adult males. Here, we report the first chromosomal level Q. spinosa genome employing PacBio long read sequencing and high-resolution chromosome conformation capture (Hi-C) technology. The total length of the final assembled genome was 2,839,292,578 bp, with contig N50 of 3.79 Mb and scaffold N50 of 327.44 Mb. Approximately 99.30% of the length of the assembled genome sequences were anchored to 13 chromosomes with the assistance of Hi-C reads. A total of 26,173 protein-coding genes were predicted, and 95.98% of the genes were functionally annotated. The annotated genes covered a total of 92.10% of the complete vertebrate core gene set according to the BUSCO pipeline evaluation. Approximately 41 million years ago, Q. spinosa began to diverge from its dicroglossid sister taxon Nanorana parkeri. The Q. spinosa genome revealed obvious chromosomal fissions compared with Xenopus tropicalis, which probably represented a specific chromosome evolutionary history within frogs. Population analysis showed that Chinese Q. spinosa could be divided into eastern and western genetic clusters, with the western population showing higher diversity than the eastern population. The effective population size of Q. spinosa showed a continuously decreasing trend from one million years ago to 10,000 years ago. In summary, this study sheds light on Q. spinosa evolution and population differentiation, providing a valuable genomic resource for further biological and genetic studies on this species, and other closely related frog taxa.

Comparative genome anatomy reveals evolutionary insights into a unique amphitriploid fish.

Triploids are rare in nature because of difficulties in meiotic and gametogenic processes, especially in vertebrates. The Carassius complex of cyprinid teleosts contains sexual tetraploid crucian carp/goldfish (C. auratus) and unisexual hexaploid gibel carp/Prussian carp (C. gibelio) lineages, providing a valuable model for studying the evolution and maintenance mechanism of unisexual polyploids in vertebrates. Here we sequence the genomes of the two species and assemble their haplotypes, which contain two subgenomes (A and B), to the chromosome level. Sequencing coverage analysis reveals that C. gibelio is an amphitriploid (AAABBB) with two triploid sets of chromosomes; each set is derived from a different ancestor. Resequencing data from different strains of C. gibelio show that unisexual reproduction has been maintained for over 0.82 million years. Comparative genomics show intensive expansion and alterations of meiotic cell cycle-related genes and an oocyte-specific histone variant. Cytological assays indicate that C. gibelio produces unreduced oocytes by an alternative ameiotic pathway; however, sporadic homologous recombination and a high rate of gene conversion also exist in C. gibelio. These genomic changes might have facilitated purging deleterious mutations and maintaining genome stability in this unisexual amphitriploid fish. Overall, the current results provide novel insights into the evolutionary mechanisms of the reproductive success in unisexual polyploid vertebrates.

Acupoint Injection for Alleviating Side Effects of Chemotherapy in People with Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aimed to investigate the efficacy of acupoint injection for alleviating side effects of chemotherapy in people with cancer. METHODS: PubMed, EMBASE, Cochrane library databases, CNKI, VIP, WanFang Date, and CBM were searched for randomized controlled trials (RCTs) from inception through December 28, 2020. This meta-analysis was performed using Review Manager 5.3. RESULTS: A total of 8 RCTs including 557 participants were eligible and included in the meta-analysis. The selected RCTs studied acupoint injection for alleviating side effects of chemotherapy in people with cancer. Statistically significant improvements were observed for the incidence of nausea and vomiting (RR = 0.39; 95% CI 0.26, 0.58; P < 0.00001), the number of leukocyte (MD = 1.89; 95%CI 0.74, 3.03; P = 0.001), and the number of platelet (MD = 28.82; 95%CI 19.33, 38.30; P < 0.00001). Two of these studies suggested that acupoint injection can also reduce some other adverse reactions, which showed a statistical difference (RR = 0.29; 95% CI 0.11, 0.75; P = 0.01). CONCLUSION: The analysis indicated that acupoint injection can alleviate side effects of chemotherapy in people with cancer. However, due to the high risk of bias and small sample size in the included studies, the results need to be further confirmed by further large, rigorously designed trials.

Two different clones of Candida pelliculosa bloodstream infection in a tertiary neonatal intensive care unit.

INTRODUCTION: Fungemia in preterm infants results in high mortality and morbidity. The genotypes, drug susceptibilities of Candida pelliculosa strains, and clinical features of two outbreaks of neonatal candidemia caused by C. pelliculosa were analyzed, in order to provide evidence for the outbreaks and characteristics of C. pelliculosa neonatal candidemia. METHODOLOGY: The strains were genotyped by pulsed-field gel electrophoresis to investigate their genetic relatedness. The broth microdilution method was used to determine in vitro susceptibility of the isolates to antifungal drugs. Clinical features of the infected patients were collected to analyze the risks for C. pelliculosa infection. RESULTS: Fourteen neonates, hospitalized in the neonatal intensive care unit from November 2012 to October 2013, were infected by C. pelliculosa. All 14 patients were cured after treatment with fluconazole and discharged without any complications. The C. pelliculosa isolates from the 14 patients were clustered into two groups, indicating that the outbreaks were caused by two types of strains. Eight of nine strains isolated from the 2013 outbreak were clustered into the same group, while one isolate was grouped together with five isolates from the 2012 outbreak. In vitro experiments demonstrated high antifungal activity of fluconazole, voriconazole, amphotericin B, and 5-fluorocytosine to C. pelliculosa. The common symptoms of C. pelliculosa candidaemia were fever, cyanosis, polypnea, hypoactivity, and apnea. CONCLUSIONS: The current study revealed high in vitro susceptibility of C. pelliculosa to antifungals. As C. pelliculosa candidaemia cannot be characterized by clinical symptoms and routine blood testing alone, monitoring unusual strains isolated from immunodeficient hosts is very important to prevent possible outbreaks.

The Effects of Auricular Therapy for Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to systematically assess the efficacy and safety of auricular therapy for cancer pain. METHODS: A systematic search was conducted using PubMed, EMBASE, Cochrane library databases, CNKI, VIP, WanFang Data, and CBM for randomized controlled trials (RCTs). Review Manager 5.3 was used for meta-analysis. RESULTS: Of the 275 screened studies, nine RCTs involving 783 patients with cancer pain were systematically reviewed. Compared with drug therapy, auricular therapy plus drug therapy has significant advantages both in the effective rate for pain relief (RR = 1.40; 95% CI 1.22, 1.60; P < 0.00001) and adverse effects rate (RR = 0.46; 95% CI 0.37, 0.58; P < 0.00001). And the result revealed that auricular acupuncture had superior pain-relieving effects as compared with sham auricular acupuncture (SMD = -1.45; 95% CI -2.80, -0.09; P=0.04). However, the analysis indicated no difference on the effective rate for pain relief between auricular therapy and drug therapy (RR = 1.24; 95% CI 0.71, 2.16; P=0.46). CONCLUSION: Our meta-analysis indicated that auricular therapy is effective and safe for the treatment of cancer pain, and auricular therapy plus drug therapy is more effective than drug therapy alone, whether in terms of pain relief or adverse reactions. However, the included RCTs had some methodological limitations; future large, rigor, and high-quality RCTs are still needed to confirm the benefits of auricular therapy on cancer pain.

Whole-genome sequencing provides insights into the genetic diversity and domestication of bitter gourd (Momordica spp.).

Bitter gourd (Momordica charantia) is a popular cultivated vegetable in Asian and African countries. To reveal the characteristics of the genomic structure, evolutionary trajectory, and genetic basis underlying the domestication of bitter gourd, we performed whole-genome sequencing of the cultivar Dali-11 and the wild small-fruited line TR and resequencing of 187 bitter gourd germplasms from 16 countries. The major gene clusters (Bi clusters) for the biosynthesis of cucurbitane triterpenoids, which confer a bitter taste, are highly conserved in cucumber, melon, and watermelon. Comparative analysis among cucurbit genomes revealed that the Bi cluster involved in cucurbitane triterpenoid biosynthesis is absent in bitter gourd. Phylogenetic analysis revealed that the TR group, including 21 bitter gourd germplasms, may belong to a new species or subspecies independent from M. charantia. Furthermore, we found that the remaining 166 M. charantia germplasms are geographically differentiated, and we identified 710, 412, and 290 candidate domestication genes in the South Asia, Southeast Asia, and China populations, respectively. This study provides new insights into bitter gourd genetic diversity and domestication and will facilitate the future genomics-enabled improvement of bitter gourd.