Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

Occurrence and Prioritization of Human Androgen Receptor Disruptors in Sewage Sludges Across China.

The global practice of reusing sewage sludge in agriculture and its landfill disposal reintroduces environmental contaminants, posing risks to human and ecological health. This study screened sewage sludge from 30 Chinese cities for androgen receptor (AR) disruptors, utilizing a disruptor list from the Toxicology in the 21st Century program (Tox21), and identified 25 agonists and 33 antagonists across diverse use categories. Predominantly, natural products 5α-dihydrotestosterone and thymidine emerged as agonists, whereas the industrial intermediate caprolactam was the principal antagonist. In-house bioassays for identified disruptors displayed good alignment with Tox21 potency data, validating employing Tox21 toxicity data for theoretical toxicity estimations. Potency calculations revealed 5α-dihydrotestosterone and two pharmaceuticals (17ß-trenbolone and testosterone isocaproate) as the most potent AR agonists and three dyes (rhodamine 6G, Victoria blue BO, and gentian violet) as antagonists. Theoretical effect contribution evaluations prioritized 5α-dihydrotestosterone and testosterone isocaproate as high-risk AR agonists and caprolactam, rhodamine 6G, and 8-hydroxyquinoline (as a biocide and a preservative) as key antagonists. Notably, 16 agonists and 20 antagonists were newly reported in the sludge, many exhibiting significant detection frequencies, concentrations, and/or toxicities, demanding future scrutiny. Our study presents an efficient strategy for estimating environmental sample toxicity and identifying key toxicants, thereby supporting the development of appropriate sludge management strategies.

Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma: A Randomized Clinical Trial.

Importance: Adjuvant therapy is an important and effective treatment for retinoblastoma. However, there is a lack of head-to-head clinical trials comparing 3 vs 6 cycles of CEV chemotherapy (carboplatin, etoposide, and vincristine) for enucleated unilateral retinoblastoma with high-risk pathological features. Objective: To assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features. Design, Setting, and Participants: This double-center, randomized, open-label, noninferiority trial was conducted at 2 premier eye centers in China and included 187 patients who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration) between August 2013 and March 2024. The final date of follow-up was March 21, 2024. Interventions: Patients were randomly assigned to receive either 3 (n = 94) or 6 (n = 93) cycles of CEV chemotherapy regimen after enucleation. Main Outcomes and Measures: The primary end point was disease-free survival, with a noninferiority margin of 12%. Secondary end points encompassed overall survival, safety, economic burden, and the quality of life of children. Results: All 187 patients (median [IQR] age, 25.0 [20.0-37.0] months; 83 [44.4%] female) completed the trial. Median (IQR) follow-up was 79.0 (65.5-102.5) months. Five-year disease-free survival was 90.4% for the 3-cycle group vs 89.2% for the 6-cycle group (difference, 1.2% [95% CI, -7.5% to 9.8%]), which met the noninferiority criterion (P = .003 for noninferiority). The 6-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life scores, and increased costs compared with the 3-cycle group. Conclusions and Relevance: Among patients with unilateral pathologic high-risk retinoblastoma, 3 cycles of CEV chemotherapy resulted in 5-year disease-free survival that was noninferior to 6 cycles of CEV chemotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01906814.

Genome-wide association study of ear tip barrenness in waxy maize.

Ear tip-barrenness (ETB), which results from aborted kernels or infertile florets at the ear tip, is an undesirable factor affecting the yield and quality of waxy maize. To uncover the genetic basis of ETB, a genome-wide association study (GWAS) was conducted using the genotype with 27,354 SNPs and phenotype with three environments. Five SNPs that distributed on chromosomes 1, 3 and 6, were identified to be significantly associated with ETB based on the threshold of false discovery rate (FDR) at 0.05. Among these significant loci, three SNPs were clustered together and colocalized with genomic regions previously reported. The average length of ETB decreased almost linearly from the inbred lines containing no favorable alleles across the three loci (1.75 cm) to those with one (1.18 cm), two (0.94 cm) and three (0.65 cm) favorable alleles. Moreover, three important genes, Zm00001d030028, Zm00001d041510 and Zm00001d038676 were predicted for three significant QTLs, respectively. These results promote the understanding genetic basis for ETB and will be useful for breeding waxy maize varieties with high-quality and high-yield.

A simple and efficient technique for suturing and knotting during endoscopic dacryocystorhinostomy.

PURPOSE: This study evaluated the long-term outcomes of endoscopic suturing and knotting-dacryocystorhinostomy (eSK-DCR) without the use of a stent or mitomycin C. METHODS: A prospective interventional case series was performed on patients with nasolacrimal duct obstruction (NLDO) who underwent eSK-DCR at Zhongshan Ophthalmic Center from October 2019 to December 2019. The surgeon sutured the lacrimal sac mucosa with the nasal mucosa by tying knots under endoscopic DCR. Subject demographics, preoperative data and postoperative data were collected, including clinical presentation, Munk score for epiphora, surgical indications, operation time, duration of knotting, number of knots, endoscopic ostium size, complications, and anatomical and functional success. Anatomic success was defined as patent ostium on lacrimal irrigation, and functional success was defined as subjective improvement in symptoms. Statistical analysis was performed by IBM SPSS software (Version 20.0; SPSS Inc., Chicago, IL, USA). RESULTS: A total of 60 patients (71 eyes) underwent pure eSK-DCR. Of these, 95.0% (57/60) were females. The mean age of the patients was 54.7 years. The mean surgical time was 37.60 min, and the average time for each knotting was 2.86 min. Endoscopic evidence found that all patients showed patent ostium and normal healing of the flaps after 4 weeks. The Munk scores dropped significantly at 6 months postoperatively compared to preoperative scores (P < 0.0001). Although 4 patients (7 eyes) were lost to follow-up at the end of the 2-year period, the anatomical and functional success remained stable during the 2-year follow-up period (anatomical, 100%; functional, 87.5%). No serious complications were detected during the follow-up period. CONCLUSION: Pure eSK-DCR is a simple and reliable therapeutic method for the management of NLDO. The surgical outcomes were good and remained stable beyond 6 months postoperatively.

Influence of dissolved organic matter on methylmercury transformation during aerobic composting of municipal sewage sludge under different C/N ratios.

Current knowledge about the transformation of total mercury and methylmercury (MeHg) in aerobic composting process is limited. In this study, the composition and transformation of mercury and dissovled organic matter (DOM) in aerobic composting process of municipal sewage sludge were were comprehensively characterized, and the differences among the three C/N ratio (20, 26 and 30) were investigated. The main form of mercury in C/N 20 and 26 was organo-chelated Hg (F3, 46%-60%); while the main form of mercury in C/N 30 was mercuric sulfide (F5, 64%-70%). The main component of DOM in C/N 20 and 26 were tyrosine-like substance (C1, 53%-76%) while the main fractions in C/N 30 were tyrosine-like substance (C1, 28%-37%) and fulvic-like substance (C2, 17%-39%). The mercury and DOM varied significantly during the 9 days composting process. Compared to C/N 20 and 26, C/N 30 produced the less MeHg after aerobic composting process, with values of 658% (C/N 20), 1400% (C/N 26) and 139% (C/N 30) of the initial, respectively. Meanwhile, C/N 30 produced the best compost showed greater degree of DOM molecular condensation and humification. Hg fraction had been altered by DOM, as indicated by a significant correlation between mercury species and DOM components. Notably, C/N 30 should be used as an appropriate C/N ratio to control the methylation processes of mercury and degration of DOM.

Water and heat stresses during grain formation affect the physicochemical properties of waxy maize starch.

BACKGROUND: Maize is frequently subjected to simultaneous water (drought or waterlogging) and heat (HS) stresses during grain formation in southern China. This work examined the effect of high temperature combined with drought (HD) or waterlogging (HW) during grain formation on the starch physicochemical properties of two waxy maize hybrids, namely Suyunnuo5 (SYN5) and Yunuo7 (YN7). RESULTS: Heat stress enlarged the starch granule size, and water stresses aggravated this effect. Heat stress reduced the ratio of small molecular weight fractions for both hybrids, and HD aggravated this reduction only in SYN5. Relative crystallinity in SYN5 was increased by stresses but in YN7 it was unaffected by HD, reduced by HS, and increased by HW. Fourier-transform infrared (FTIR) spectrometry results showed that the 1045/1022 cm-1 ratio in SYN5 was not influenced by HW but was increased by other stresses, and that in YN7 it was increased by all stresses, with the highest value induced by HW. Peak viscosity was decreased, whereas gelatinization temperatures and retrogradation percentage were increased by all of these stresses. These effects were exacerbated by combined heat and water stresses. The maximum decomposition rate was severely increased by HW. CONCLUSION: Drought or waterlogging at grain formation stage aggravated the detrimental effects of HS on the starch physicochemical properties of waxy maize. © 2020 Society of Chemical Industry.

Identification of stemness in primary retinoblastoma cells by analysis of stem-cell phenotypes and tumorigenicity with culture and xenograft models.

Retinoblastoma (RB) is a primary intraocular malignancy in childhood, and may develop relapse and metastatic disease. This study was to identify the stem-cell properties of primary retinoblastoma cells critical to tumorigenesis and metastasis. Primary cells were isolated from fresh human RB tissues after enucleation, and cultured in serum-free or serum-enriched conditions, with two RB cell-lines Weri-RB1 and Y79 for comparison. Proliferation of primary RB cells were well-maintained in serum-free condition of DMEM/F12 medium, and formed stem-cell like spheroids. The immaturity of cultured primary RB cells was demonstrated by tendency of highly expressed stem-cell markers (CD133, Nestin and OCT4) and suppressed mature retinal-cell markers (GFAP, MAP2 and Recoverin). CD133, a neural stem-cell marker being exclusively studied in RB, was found positive in small patches of cells in archival human RB by immunohistochemistry. Meanwhile, at initial isolation, insignificant CD133+ cells were detected by flow-cytometry, and substantial increase of positivity was observed after several days cultivated in serum-free condition. Cultured primary RB cells were engrafted in subretinal region of BALB/c nude mice for assessment of tumorigenicity. Strong tumorigenic activity and extensive progression of the xenograft retinoblastoma was induced by primary cells as compared with the two cell-lines. Again, immunohistochemistry confirmed that the stem-cell markers were emphasized in the xenograft tumor in mice. Our findings demonstrated that in comparison to the well-established RB cell-lines, cultured primary RB cells possess stem-cell like properties with highly expressed stem-cell markers, self-regenerative growth in culture, and strong in vivo oncogenic potentiality.

Occurrence and leaching of silver in municipal sewage sludge in China.

Sewage treatment plants effectively remove silver (Ag) from sewage. Sewage sludge can therefore be important Ag sinks, polluting the environment with this element. In this work, we report a nation-wide survey on the Ag content of sewage sludge in China (0.23-19.02 mg kg-1, average 2.72 mg kg-1). Furthermore, we identify that sludge disposal represents an important Ag pollution source (84.48 tons in 2016) for the environment by estimating the national and provincial inventories of sludge-borne Ag in China. Also the positive correlations between the per capita gross domestic product (GDP)/provincial GDP and the content/mass loadings of Ag highlighted the impact of human activities on Ag pollution. In different samples, strong complexation of thiosulfate contributed to the highest leaching concentration (95.00-438.15 µg kg-1) and ratio (1.9-8.8%) of Ag, emphasizing the necessity of a long-term risk assessment for landfill and land application of sludge.

Occurrence, speciation and fate of mercury in the sewage sludge of China.

Municipal sewage has been identified to be an important source of mercury (Hg) to the environment. However, as the major sink of sewage-borne Hg, sewage sludge (SS) remains unresolved in terms of the occurrence status of Hg species. We presented here, a nation-wide survey on the speciation of Hg in SS of China. Total Hg (THg) and methylmercury (MeHg) were detected in all SS samples, within ranges of 0.4-12.4 mg/kg and 0.1-27.0 µg/kg, respectively. Sludge-borne Hg mainly occurred in the mercury sulfide and organo-chelated phases, with only tiny portions occurring as soluble Hg. The mass loadings of sludge-borne THg and MeHg in China for year 2016 were estimated to be 12.2 metric tons and 19.9 kg, respectively. Landfill was the most important sink of sludge-borne Hg, followed by incineration, land application, and building materials.

Mercury in Municipal Sewage and Sewage Sludge.

Wide occurrence of mercury species, including the highly toxic and readily bioaccumulative methylmercury (MeHg), in municipal sewage (MS) and sewage sludge (SS) has been evidenced in recent studies. Considering that vast amounts of MS and SS are produced globally each year and the majority of MS is discharged into aqueous environments, i.e., the main sites for MeHg bioaccumulation, special attention should be paid on the source and environmental behaviors of sewage-borne and sludge-borne mercury species. This review aims to summarize the findings on the occurrence of mercury species in MS and SS, their transport and transformation in MS treatment plants, as well as their fate and environmental implications.

Tracing aquatic bioavailable Hg in three different regions of China using fish Hg isotopes.

To trace the most concerned bioavailable mercury (Hg) in aquatic environment, fish samples were collected from three typical regions in China, including 3 rivers and 1 lake in the Tibetan Plateau (TP, a high altitude background region with strong solar radiation), the Three Gorges Reservoir (TGR, the largest artificial freshwater reservoir in China), and the Chinese Bohai Sea (CBS, a heavily human-impacted semi-enclosed sea). The Hg isotopic compositions in fish muscles were analyzed. The results showed that anthropogenic emissions were the main sources of Hg in fish from TGR and CBS because of the observed negative δ202Hg and positive Δ199Hg in these two regions (TGR, δ202Hg: - 0.72 to - 0.29‰, Δ199Hg: 0.15 - 0.52‰; CBS, δ202Hg: - 2.09 to - 0.86‰, Δ199Hg: 0.07 - 0.52‰). The relatively higher δ202Hg and Δ199Hg (δ202Hg: - 0.37 - 0.08‰, Δ199Hg: 0.50 - 1.89‰) in fish from TP suggested the insignificant disturbance from local anthropogenic activities. The larger slopes of Δ199Hg/Δ201Hg in fish from TGR (1.29 ± 0.14, 1SD) and TP (1.25 ± 0.06, 1SD) indicated methylmercury (MeHg) was produced and photo-reduced in the water column before incorporation into the fish. In contrast, the photoreduction of Hg2+ was the main process in CBS (slope of Δ199Hg/Δ201Hg: 1.06 ± 0.06, 1SD). According to the fingerprint data of Hg isotopes, the most important source for aquatic bioavailable Hg in TP should be the long-range transported Hg, contrasting to the anthropogenic originated MeHg from surface sediments and runoffs in TGR and inorganic Hg from continental inputs in CBS. Therefore, the isotopic signatures of Hg in fish can provide novel clues in tracing sources and behaviors of bioavailable Hg in aquatic systems, which are critical for further understanding the biogeochemical cycling of Hg.

Genome-wide association study of kernel moisture content at harvest stage in maize.

Kernel moisture content at harvest stage (KMC) is an important factor affecting maize production, especially for mechanical harvesting. We investigated the genetic basis of KMC using an association panel comprising of 144 maize inbred lines that were phenotypically evaluated at two field trial locations. Significant positive or negative correlations were identified between KMC and a series of other agronomic traits, indicating that KMC is associated with other such traits. Combining phenotypic values and the Maize SNP3K Beadchip to perform a genome-wide association study revealed eight single nucleotide polymorphisms (SNPs) associated with KMC at P ≤ 0.001 using a mixed linear model (PCA+K). These significant SNPs could be converted into five quantitative trait loci (QTLs) distributed on chromosomes 1, 5, 8, and 9. Of these QTLs, three were colocalized with genomic regions previously reported. Based on the phenotypic values of the alleles corresponding to significant SNPs, the favorable alleles were mined. Eight maize inbred lines with low KMC and harboring favorable alleles were identified. These QTLs and elite maize inbred lines with low KMC will be useful in maize breeding.

A real-world analysis of FDA Adverse Event Reporting System (FAERS) events for liposomal and conventional doxorubicins.

The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.

Towards a better understanding of ethylmercury in the environment: Addressing propylation derivatization artifact and verifying its occurrence in Chinese wetlands.

Ethylmercury (EtHg), similar to methylmercury (MeHg), is highly neurotoxic and bioaccumulative. Although recent studies suggested its occurrence in natural soils and sediments, the common propylation derivatization for EtHg analysis might generate EtHg artifacts, potentially leading to its overestimation in environmental samples. Furthermore, the extensive environmental prevalence of EtHg remains unverified, keeping its importance largely uncertain. This study investigated the formation of EtHg artifacts during propylation derivatization, evaluating artifacts formation and recoveries under different extraction methods with real samples, and confirmed the widespread occurrence of EtHg in Chinese wetlands. EtHg artifacts were obviously present during the propylation derivatization and strongly dependent on the levels of Hg2+ (0.1-10 ng) in the derivatization solution (R² = 0.99), accounting for 1.38-2.14% of Hg2+. CuSO4-HNO3CH2Cl2 extraction (effectively removing Hg2+) combined with propylation derivatization offers excellent recovery (81-86%) and low artifacts (< LOD: 1.98 × 10-4 ng/g) for EtHg measurement in soils/sediments, with results aligning with those from online solid phase extraction-high performance liquid chromatography-inductively coupled plasma mass spectrometry (R2 = 0.99). Additionally, we observed the occurrence of EtHg in soil and sediment samples across 14 Chinese wetlands, with concentrations varying from 6.08 to 171 pg/g, similar to MeHg concentrations at some sites. EtHg positively correlates with MeHg, total Hg, and total organic carbon across all samples, indicating a possible biological formation. These findings help better understand and predict the prevalence of EtHg in wetlands and its key role in environmental Hg cycle.

Comparative transcriptome analysis between rhesus macaques ( Macaca mulatta) and crab-eating macaques ( M. fascicularis).

Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques ( Macaca mulatta, MMU) and crab-eating macaques ( M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from 84 samples (41 MFA samples and 43 MMU samples) encompassing 14 common tissues. Our findings revealed a small fraction of genes (3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover, 19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary, this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.

Effect-directed analysis of androgenic compounds from sewage sludges in China.

The safety of municipal sewage sludge has raised great concerns because of the accumulation of large-scale endocrine disrupting chemicals in the sludge during wastewater treatment. The presence of contaminants in sludge can cause secondary pollution owing to inappropriate disposal mechanisms, posing potential risks to the environment and human health. Effect-directed analysis (EDA), involving an androgen receptor (AR) reporter gene bioassay, fractionation, and suspect and nontarget chemical analysis, were applied to identify causal AR agonists in sludge; 20 of the 30 sludge extracts exhibited significant androgenic activity. Among these, the extracts from Yinchuan, Kunming, and Shijiazhuang, which held the most polluted AR agonistic activities were prepared for extensive EDA, with the dihydrotestosterone (DHT)-equivalency of 2.5 - 4.5 ng DHT/g of sludge. Seven androgens, namely boldione, androstenedione, testosterone, megestrol, progesterone, and testosterone isocaproate, were identified in these strongest sludges together, along with testosterone cypionate, first reported in sludge media. These identified androgens together accounted for 55 %, 87 %, and 52 % of the effects on the sludge from Yinchuan, Shijiazhuang, and Kunming, respectively. This study elucidates the causative androgenic compounds in sewage sludge and provides a valuable reference for monitoring and managing androgens in wastewater treatment.

Targeting ALDOA to modulate tumorigenesis and energy metabolism in retinoblastoma.

This study aims to elucidate the pivotal role of aldolase A (ALDOA) in retinoblastoma (RB) and evaluate the potential of the ALDOA inhibitor itaconate in impeding RB progression. Utilizing single-cell RNA sequencing, ALDOA consistently exhibits overexpression across diverse cell types, particularly in cone precursor cells, retinoma-like cells, and retinoblastoma-like cells. This heightened expression is validated in RB tissues and cell lines. ALDOA knockdown significantly diminishes RB cell viability, impedes colony formation, and induces notable metabolic alterations. RNA-seq analysis identifies SUSD2, ARHGAP27, and CLK2 as downstream genes associated with ALDOA. The application of itaconate demonstrates efficacy in inhibiting RB cell proliferation, validated through in vitro and in vivo models. This study emphasizes ALDOA as a promising target for innovative RB therapies, with potential implications for altering tumor energy metabolism.