Long-term exposure to ambient particulate matter is associated with prognosis in people living with HIV/AIDS: Evidence from a longitudinal study.

BACKGROUND: Evidence on the association between particulate matter (PM) exposure and prognosis in people living with HIV/AIDS (PWHA) is scarce. We aim to investigate the associations of long-term exposure to PM with AIDS-related deaths and complications. METHODS: We collected follow-up information on 7444 PWHAs from 2000 to 2021 from the HIV/AIDS Comprehensive Response Information Management System of the Wuhan Center for Disease Control and Prevention. The AIDS-related deaths and complications were assessed by physicians every 3 to 6 months, and the monthly average PM concentrations for each PWHA were extracted from the China High Air Pollutants dataset. We employed time-varying Cox regression models to evaluate the associations of the average cumulative PM exposure concentrations with AIDS-related deaths and complications, as well as the mediating effects of AIDS-related complications in PM-induced AIDS-related deaths. RESULTS: For each 1 µg/m3 increase in PM1, PM2.5, and PM10, the adjusted hazard ratios (HRs) for AIDS-related deaths were 1.021 (1.009, 1.033), 1.012 (1.005, 1.020), and 1.010 (1.005, 1.015), respectively; and the HRs for AIDS-related complications were 1.049 (1.034, 1.064), 1.029 (1.020, 1.038), and 1.031 (1.024, 1.037), respectively. AIDS-related complications mediated 18.38 % and 18.68 % of the association of exposure to PM1 and PM2.5 with AIDS-related deaths, respectively. The association of PM exposure with AIDS-related deaths was more significant in older PWHA. Meanwhile, the association between PM exposure and AIDS-related complications was stronger in PWHA with a BMI ≥ 24 kg/m2. CONCLUSION: Long-term exposure to PM is positively associated with AIDS-related deaths and complications, and AIDS-related complications have mediating effects in PM-induced AIDS-related deaths. Our evidence emphasizes that enhanced protection against PM exposure for PWHAs is an additional mitigation strategy to reduce AIDS-related deaths and complications.

Genomics comparisons of three chromosome-level mudskipper genome assemblies reveal molecular clues for water-to-land evolution and adaptation.

INTRODUCTION: Mudskippers are a large group of amphibious fishes that have developed many morphological and physiological capacities to live on land. Genomics comparisons of chromosome-level genome assemblies of three representative mudskippers, Boleophthalmus pectinirostris (BP), Periophthalmus magnuspinnatus (PM) and P. modestus (PMO), may be able to provide novel insights into the water-to-land evolution and adaptation. METHODS: Two chromosome-level genome assemblies for BP and PM were respectively sequenced by an integration of PacBio, Nanopore and Hi-C sequencing. A series of standard assembly and annotation pipelines were subsequently performed for both mudskippers. We also re-annotated the PMO genome, downloaded from NCBI, to obtain a redundancy-reduced annotation. Three-way comparative analyses of the three mudskipper genomes in a large scale were carried out to discover detailed genomic differences, such as different gene sizes, and potential chromosomal fission and fusion events. Comparisons of several representative gene families among the three amphibious mudskippers and some other teleosts were also performed to find some molecular clues for terrestrial adaptation. RESULTS: We obtained two high-quality haplotype genome assemblies with 23 and 25 chromosomes for BP and PM respectively. We also found two specific chromosome fission events in PM. Ancestor chromosome analysis has discovered a common fusion event in mudskipper ancestor. This fusion was then retained in all the three mudskipper species. A loss of some SCPP (secretory calcium-binding phosphoprotein) genes were identified in the three mudskipper genomes, which could lead to reduction of scales for a part-time terrestrial residence. The loss of aanat1a gene, encoding an important enzyme (arylalkylamine N-acetyltransferase 1a, AANAT1a) for dopamine metabolism and melatonin biosynthesis, was confirmed in PM but not in PMO (as previously reported existence in BP), suggesting a better air vision of PM than both PMO and BP. Such a tiny variation within the genus Periophthalmus exemplifies to prove a step-by-step evolution for the mudskippers' water-to-land adaptation. CONCLUSION: These high-quality mudskipper genome assemblies will become valuable genetic resources for in-depth discovery of genomic evolution for the terrestrial adaptation of amphibious fishes.

Saltwater-Induced Rapid Gelation of Photoredox-Responsive Mucomimetic Hydrogels.

Shear-thinning hydrogels represent an important class of injectable soft materials that are often used in a wide range of biomedical applications. Creation of new shear-thinning materials often requires that factors such as viscosity, injection rate/force, and needle gauge be evaluated to achieve efficient delivery, while simultaneously protecting potentially sensitive cargo. Here, a new approach to establishing shear-thinning hydrogels is reported where a host-guest cross-linked network initially remains soluble in deionized water but is kinetically trapped as a viscous hydrogel once exposed to saltwater. The shear-thinning properties of the hydrogel is then "switched on" in response to heating or exposure to visible light. These hydrogels consist of polynorbornene-based bottlebrush copolymers with porphyrin- and oligoviologen-containing side chains that are cross-linked through the reversible formation of ß-cyclodextrin-adamantane inclusion complexes. The resultant viscous hydrogels display broad adhesive properties across polar and nonpolar substrates, mimicking that of natural mucous and thus making it easier to distribute onto a wide range of surfaces. Additional control over the hydrogel's mechanical properties (storage/loss moduli) and performance (adhesion) is achieved post-injection using a low-energy (blue light) photoinduced electron-transfer process. This work envisions these injectable copolymers and multimodal hydrogels can serve as versatile next-generation biomaterials capable of light-based mechanical manipulation post-injection.

Relationship between vitamin D deficiency and neonatal hypocalcemia: a meta-analysis.

We aimed to explore the associations of neonatal hypocalcemia with neonatal vitamin D deficiency and maternal vitamin D deficiency. A comprehensive systematic literature search using PubMed and web of science was performed for relevant articles from inception to February 17th, 2023. We used odds ratio (OR) and 95 % confidence interval (CI) as effect sizes for our meta-analysis. Publication bias was evaluated using funnel plot, Begg's test, and Egger regression test. All the statistical analyses were performed using Stata 14.0. A total of 11 studies were included and analyzed, including 452 newborns with hypocalcemia and 2,599 newborns with normal serum calcium level. Our research results revealed that vitamin D deficiency in newborns may be related to the higher prevalence of hypocalcemia (OR: 2.87, 95 % CI: 1.17-7.04). In addition, maternal vitamin D deficiency might also be a risk factor for neonatal hypocalcemia (OR: 7.83, 95 % CI: 3.62-16.92). There was a significant correlation between vitamin D deficiency and neonatal hypocalcemia.This meta-analysis indicates that newborns with vitamin D deficiency have a higher risk of hypocalcemia, and maternal vitamin D level play a crucial role in this association. Vitamin D supplementation may have a positive effect in reducing the prevalence of neonatal hypocalcemia.

Huobahuagen tablet improves renal function in diabetic kidney disease: a real-world retrospective cohort study.

Objective: We aimed to explore the value of Huobahuagen tablet (HBT) in improving decreased renal function for patients with diabetic kidney disease (DKD) over time. Methods: This was a single-center, retrospective, real-world study on eligible 122 DKD patients who continued to use HBT + Huangkui capsule (HKC) therapy or HKC therapy without interruption or alteration in Jiangsu Province Hospital of Chinese Medicine from July 2016 to March 2022. The primary observation outcomes included estimated glomerular filtration rate (eGFR) at baseline and 1-, 3-, 6-, 9-, and 12-month follow-up visits and changes in eGFR from baseline (ΔeGFR). Propensity score (PS) and inverse probability treatment weighting (IPTW) were used to control for confounders. Results: eGFR was significantly higher in the HBT + HKC group than in the HKC alone group at the 6-, 9-, and 12-month follow-up visits (p = 0.0448, 0.0002, and 0.0037, respectively), indicating the superiority of HBT + HKC over HBT alone. Furthermore, the ΔeGFR of the HBT + HKC group was significantly higher than that of the HKC alone group at the 6- and 12-month follow-up visits (p = 0.0369 and 0.0267, respectively). In the DKD G4 patients, eGFR was higher in the HBT + HKC group at the 1-, 3-, 6-, 9-, and 12-month follow-up visits compared with baseline, with statistically significant differences at the 1-, 3-, and 6- month follow-up visits (p = 0.0256, 0.0069, and 0.0252, respectively). The fluctuations in ΔeGFR ranged from 2.54 ± 4.34 to 5.01 ± 5.55 ml/min/1.73 m2. Change in the urinary albumin/creatinine ratio from baseline did not exhibit a significant difference between the two groups at any of the follow-up visits (p > 0.05 for all). Adverse event incidence was low in both groups. Conclusion: The findings of this study based on real-world clinical practice indicate that HBT + HKC therapy exhibited better efficacy in improving and protecting renal function with a favorable safety profile than HKC therapy alone. However, further large-scale prospective randomized controlled trials are warranted to confirm these results.

Albumin-Based Cyanine Crizotinib Conjugate Nanoparticles for NIR-II Imaging-Guided Synergistic Chemophototherapy.

Colorectal cancer (CRC) is presently the third deadliest cancer in the world. This malignant cancer usually precedes the progression of precancerous lesions, and it is challenging to distinguish its nuanced morphological changes. Molecular-based near-infrared-II (NIR-II) fluorescence imaging can effectively recognize lesion targets to improve image contrast and increase early tumor detection compared with traditional wide-light screening endoscopy. c-Met has been determined to be overexpressed in advanced stages of CRC and is considered to be a potent tumor biomarker. Herein, based on the well-targeted inhibitory effect of Crizotinib on c-Met positive tumor cells, the dye IR808 was covalently combined with the drug molecule Crizotinib, resulting in the synthesis of a NIR fluorescent probe Crizotinib-IR808 targeting c-Met positive tumor cells. Then, water-insoluble Crizotinib-IR808 was fabricated by using bovine serum albumin (BSA) nanoparticles (NPs) with excellent biocompatibility and biosafety. The prepared Crizotinib-IR808@BSA NPs showed tumor targeting capability as well as use for noninvasive biomedical vascular NIR-II imaging with intraoperative real-time NIR-II imaging to guide tumor resection. Under 808 nm laser irradiation, Crizotinib-IR808@BSA NPs exhibited synergistic chemophototherapy effects on tumors. In conclusion, this innovative imaging-mediated multifunctional combination therapy strategy with good c-Met targeting ability may provide a new approach for colorectal cancer treatment.

A chromosome-level reference genome assembly of the Reeve's moray eel (Gymnothorax reevesii).

Due to potentially hostile behaviors and elusive habitats, moray eels (Muraenidae) as one group of apex predators in coral reefs all across the globe have not been well investigated. Here, we constructed a chromosome-level genome assembly for the representative Reeve's moray eel (Gymnothorax reevesii). This haplotype genome assembly is 2.17 Gb in length, and 97.87% of the sequences are anchored into 21 chromosomes. It contains 56.34% repetitive sequences and 23,812 protein-coding genes, of which 96.77% are functionally annotated. This sequenced marine species in Anguilliformes makes a good complement to the genetic resource of eel genomes. It not only provides a genetic resource for in-depth studies of the Reeve's moray eel, but also enables deep-going genomic comparisons among various eels.

Metformin Alleviates Sepsis-Associated Myocardial Injury by Enhancing AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Signaling Pathway-Mediated Autophagy.

ABSTRACT: Sepsis-associated myocardial injury is one of the main causes of death in intensive care units, and current clinical treatments have not been satisfactory. Therefore, finding an effective intervention is an urgent requirement. Metformin, an anti-type 2 diabetes drug, has been reported to be an autophagic activator agent that confers protection in some diseases. However, it is unclear whether it can provide defense against sepsis-associated myocardial injury. In this study, we investigated the cardioprotective effects of metformin pretreatment against lipopolysaccharide (LPS)-induced myocardial injury in C57BL/6J mice or H9c2 cells and the possible underlying mechanisms. Metformin was administered at a dose of 100 mg/kg for a week before LPS intraperitoneal injection. Twenty-four hours after LPS intervention, echocardiographic evaluation, reactive oxygen species measurement, Hoechst staining, western blotting, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay were performed. Inhibitors of autophagy and AMP-activated protein kinase (AMPK) were used to further clarify the mechanisms involved. Metformin pretreatment effectively attenuated cardiac dysfunction, reduced the levels of myocardial enzymes, and alleviated cardiac hydroncus in LPS-treated mice. In addition, metformin restored the LPS-disrupted antioxidant defense and activated LPS-reduced autophagy by modulating the AMPK/mammalian target of rapamycin (AMPK/mTOR) pathway both in vivo and in vitro. The antioxidant effects of metformin on cardiomyocytes were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Treatment with compound C, an AMPK inhibitor, reversed the metformin-induced autophagy in LPS-treated H9c2 cells. In conclusion, metformin pretreatment alleviates LPS-induced myocardial injury by activating AMPK/mTOR pathway-mediated autophagy.

Low-Fouling Zwitterionic Polymeric Colloids as Resuscitation Fluids for Hemorrhagic Shock.

Colloids, known as volume expanders, have been used as resuscitation fluids for hypovolemic shock for decades, as they increase plasma oncotic pressure and expand intravascular volume. However, recent studies show that commonly used synthetic colloids have adverse interactions with human biological systems. In this work, a low-fouling amine(N)-oxide-based zwitterionic polymer as an alternative volume expander with improved biocompatibility and efficacy is designed. It is demonstrated that the polymer possesses antifouling ability, resisting cell interaction and deposition in major organs, and is rapidly cleared via renal filtration and hepatic circulation, reducing the risk of long-term side effects. Furthermore, in vitro and in vivo studies show an absence of adverse effects on hemostasis or any acute safety risks. Finally, it is shown that, in a head-to-head comparison with existing colloids and plasma, the zwitterionic polymer serves as a more potent oncotic agent for restoring intravascular volume in a hemorrhagic shock model. The design of N-oxide-based zwitterionic polymers may lead to the development of alternative fluid therapies to treat hypovolemic shock and to improve fluid management in general.

Identification of candidate sex-specific genomic regions in male and female Asian arowana genomes.

BACKGROUND: Asian arowana, Scleropages formosus, is one of the most expensive aquarium fish species worldwide. Its sex, however, cannot be distinguished clearly at any development stage, which impedes captive breeding and species protection for this endangered aquarium fish. RESULTS: To discover molecular clues to the sex of Asian arowana, we sequenced 26.5 Gb of PacBio HiFi reads and 179.2 Gb of Hi-C reads for 1 male fish and also sequenced 106.5 Gb of Illumina reads, 36.0 Gb of PacBio Sequel reads, and 80.7 Gb of Hi-C reads for 1 female individual. The final male and female genome assemblies were approximately 756.8 Mb and 781.5 Mb in length and contained 25,262 and 25,328 protein-coding genes, respectively. We also resequenced the genomes of 15 male and 15 female individuals with approximately 722.1 Gb of Illumina reads. A genome-wide association study identified several potentially divergent regions between male and female individuals. In these regions, cd48 and cfap52 could be candidate genes for sex determination of Asian arowana. We also found some structural variations in few chromosomes between male and female individuals. CONCLUSION: We provided an improved reference genome assembly of female arowana and generated the first sequenced genome of 1 male individual. These valuable genetic resources and resequencing data may improve global aquarium fish research.

Discrete Missing Data Imputation Using Multilayer Perceptron and Momentum Gradient Descent.

Data are a strategic resource for industrial production, and an efficient data-mining process will increase productivity. However, there exist many missing values in data collected in real life due to various problems. Because the missing data may reduce productivity, missing value imputation is an important research topic in data mining. At present, most studies mainly focus on imputation methods for continuous missing data, while a few concentrate on discrete missing data. In this paper, a discrete missing value imputation method based on a multilayer perceptron (MLP) is proposed, which employs a momentum gradient descent algorithm, and some prefilling strategies are utilized to improve the convergence speed of the MLP. To verify the effectiveness of the method, experiments are conducted to compare the classification accuracy with eight common imputation methods, such as the mode, random, hot-deck, KNN, autoencoder, and MLP, under different missing mechanisms and missing proportions. Experimental results verify that the improved MLP model (IMLP) can effectively impute discrete missing values in most situations under three missing patterns.

A chromosome-level genome assembly of the jade perch (Scortum barcoo).

Endemic to Australia, jade perch (Scortum barcoo) is a highly profitable freshwater bass species. It has extraordinarily high levels of omega-3 polyunsaturated fatty acids (PUFAs), which detailed genes involved in are largely unclear. Meanwhile, there were four chromosome-level bass species have been previous sequenced, while the bass ancestor genome karyotypes have not been estimated. Therefore, we sequenced, assembled and annotated a genome of jade perch to characterize the detailed genes for biosynthesis of omega-3 PUFAs and to deduce the bass ancestor genome karyotypes. We constructed a chromosome-level genome assembly with 24 pairs of chromosomes, 657.7 Mb in total length, and the contig and the scaffold N50 of 4.8 Mb and 28.6 Mb respectively. We also identified repetitive elements (accounting for 19.7% of the genome assembly) and predicted 26,905 protein-coding genes. Meanwhile, we performed genome-wide localization and characterization of several important genes encoding some key enzymes in the biosynthesis pathway of PUFAs. These genes may contribute to the high concentration of omega-3 in jade perch. Moreover, we conducted a series of comparative genomic analyses among four representative bass species at a chromosome level, resulting in a series of sequences of a deductive bass ancestor genome.

Evolutionary Genomics Reveals Multiple Functions of Arylalkylamine N-Acetyltransferase in Fish.

As an important hormone, melatonin participates in endocrine regulation of diverse functions in vertebrates. Its biosynthesis is catalyzed by four cascaded enzymes, among them, arylalkylamine N-acetyltransferase (AANAT) is the most critical one. Although only single aanat gene has been identified in most groups of vertebrates, researchers including us have determined that fish have the most diverse of aanat genes (aanat1a, aanat1b, and aanat2), playing various potential roles such as seasonal migration, amphibious aerial vision, and cave or deep-sea adaptation. With the rapid development of genome and transcriptome sequencing, more and more putative sequences of fish aanat genes are going to be available. Related phylogeny and functional investigations will enrich our understanding of AANAT functions in various fish species.

Strongest Angle-of-Arrival Estimation for Hybrid Millimeter Wave Architecture with 1-Bit A/D Equipped at Transceivers.

This paper proposes an effective strongest angles of arrival (AoAs) estimation algorithm for a hybrid millimeter wave (mmWave) communication system with 1-bit analog-to-digital/digital-to-analog converters (A/Ds) equipped at transceivers. The proposed algorithm aims to reduce the required number of estimation overheads, while maintaining the root mean square error (RMSE) of strongest AoA estimates at the base station. We obtain the quantization thresholds of A/Ds for different signal-to-noise ratios (SNRs) and numbers of antennas via numerical simulations, based on which, the strongest AoAs can be estimated with a small amount of overheads. The proposed algorithm is compared with conventional schemes including 1-bit FFT and 1-bit exhaustive search, as well as 1-bit Cramér-Rao lower bound. Simulation results verify the effectiveness of our proposed algorithm in terms of reducing estimation overheads while maintaining reasonable estimation performance in low SNRs.

Topologically Controlled Syntheses of Unimolecular Oligo[n]catenanes.

Catenanes are a well-known class of mechanically interlocked molecules that possess chain-like architectures and have been investigated for decades as molecular machines and switches. However, the synthesis of higher-order catenanes with multiple, linearly interlocked molecular rings has been greatly impeded by the generation of unwanted oligomeric byproducts and figure-of-eight topologies that compete with productive ring closings. Here, we report two general strategies for the synthesis of oligo[n]catenanes that rely on a molecular "zip-tie" strategy, where the "zip-tie" is a central core macrocycle precursor bearing two phenanthroline (phen) ligands to make odd-numbered oligo[n]catenanes, or a preformed asymmetric iron(II) complex consisting of two macrocycle precursors bearing phen and terpyridine ligands to make even-numbered oligo[n]catenanes. In either case, preformed macrocycles or [2]catenanes are threaded onto the central "zip-tie" core using metal templation prior to ring-closing metathesis (RCM) reactions that generate several mechanical bonds in one pot. Using these synthetic strategies, a family of well-defined linear oligo[n]catenanes were synthesized, where n = 2, 3, 4, 5, or 6 interlocked molecular rings, and n = 6 represents the highest number of linearly interlocked rings reported to date for any isolated unimolecular oligo[n]catenane.

General recommendation for assessment and management on the risk of glucocorticoid-induced osteonecrosis in patients with COVID-19.

BACKGROUND/OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a disaster in human medical history and glucocorticoids remain the most promising therapy. Osteonecrosis is a disease caused by reduced intraosseous blood flow to bones in the joints, which will rapidly induce joint destruction. Approximately one-third patients with severe acute respiratory syndrome (SARS) who received high cumulative doses and long treatment durations of glucocorticoids occurred osteonecrosis. Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics, and therapeutic strategies, it is particularly desirable to investigate whether osteonecrosis will become a common sequela among convalescent COVID-19 patients. METHODS: This multi-strategy study was designed by integrating different research methods, such as meta-analysis, systematic review, and cross-sectional investigations to address above study objectives. At first, two meta-analyses were performed on the osteonecrosis incidence among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in Wuhan city of China were also conducted. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis patients with COVID-19 infection were further presented and discussed. RESULTS: Our meta-analysis showed that 32% of SARS patients had developed osteonecrosis after receiving glucocorticoid treatment with high dose, and our system review supported that low level glucocorticoid exposure might also lead to the occurrence of osteonecrosis. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in Wuhan city of China found that the average of cumulative glucocorticoid exposure level was 504 â€‹mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case was identified from 1406 patients with COVID-19 during our cross-sectional investigation, implying that preventive management of osteonecrosis should be better started with regular clinical follow-up observation. CONCLUSION: Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to establish risk-classification-based early screening and to introduce early prevention protocol of its associated osteonecrosis that will be of clinical significance in favor of improved prognosis of this disease. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: To establish risk-classification-based early screening and to introduce early prevention protocol of glucocorticoid-induced osteonecrosis will be of clinical significance in favor of improved prognosis of COVID-19.

Whole-Genome Sequencing of Sinocyclocheilus maitianheensis Reveals Phylogenetic Evolution and Immunological Variances in Various Sinocyclocheilus Fishes.

An adult Sinocyclocheilus maitianheensis, a surface-dwelling golden-line barbel fish, was collected from Maitian river (Kunming City, Yunnan Province, China) for whole-genome sequencing, assembly, and annotation. We obtained a genome assembly of 1.7 Gb with a scaffold N50 of 1.4 Mb and a contig N50 of 24.7 kb. A total of 39,977 protein-coding genes were annotated. Based on a comparative phylogenetic analysis of five Sinocyclocheilus species and other five representative vertebrates with published genome sequences, we found that S. maitianheensis is close to Sinocyclocheilus anophthalmus (a cave-restricted species with similar locality). Moreover, the assembled genomes of S. maitianheensis and other four Sinocyclocheilus counterparts were used for a fourfold degenerative third-codon transversion (4dTv) analysis. The recent whole-genome duplication (WGD) event was therefore estimated to occur about 18.1 million years ago. Our results also revealed a decreased tendency of copy number in many important genes related to immunity and apoptosis in cave-restricted Sinocyclocheilus species. In summary, we report the first genome assembly of S. maitianheensis, which provides a valuable genetic resource for comparative studies on cavefish biology, species protection, and practical aquaculture of this potentially economical fish.

Phylogenetic Analysis of Core Melanin Synthesis Genes Provides Novel Insights Into the Molecular Basis of Albinism in Fish.

Melanin is the most prevalent pigment in animals. Its synthesis involves a series of functional genes. Particularly, teleosts have more copies of these genes related to the melanin synthesis than tetrapods. Despite the increasing number of available vertebrate genomes, a few systematically genomic studies were reported to identify and compare these core genes for the melanin synthesis. Here, we performed a comparative genomic analysis on several core genes, including tyrosinase genes (tyr, tyrp1, and tyrp2), premelanosome protein (pmel), microphthalmia-associated transcription factor (mitf), and solute carrier family 24 member 5 (slc24a5), based on 90 representative vertebrate genomes. Gene number and mutation identification suggest that loss-of-function mutations in these core genes may interact to generate an albinism phenotype. We found nonsense mutations in tyrp1a and pmelb of an albino golden-line barbel fish, in pmelb of an albino deep-sea snailfish (Pseudoliparis swirei), in slc24a5 of cave-restricted Mexican tetra (Astyanax mexicanus, cavefish population), and in mitf of a transparent icefish (Protosalanx hyalocranius). Convergent evolution may explain this phenomenon since nonsense mutations in these core genes for melanin synthesis have been identified across diverse albino fishes. These newly identified nonsense mutations and gene loss will provide molecular guidance for ornamental fish breeding, further enhancing our in-depth understanding of human skin coloration.

Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway.

Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.