Exploring the chemical diversity of sesquiterpenes from the rarely studied South China Sea soft coral Sinularia tumulosa assisted by molecular networking strategy.

Molecular networking strategy-based prioritization of the isolation of the rarely studied soft coral Sinularia tumulosa yielded 14 sesquiterpenes. These isolated constituents consisted of nine different types of carbon frameworks, namely asteriscane, humulane, capillosane, seco-asteriscane, guaiane, dumortane, cadinane, farnesane, and benzofarnesane. Among them, situmulosaols A-C (1, 3 and 4) were previously undescribed ones, whose structures with absolute configurations were established by the combination of extensive spectral data analyses, quantum mechanical-nuclear magnetic resonance and time-dependent density functional theory electronic circular dichroism calculations, the Snatzke's method, and the modified Mosher's method. Notably, situmulosaol C (4) was the second member of capillosane-type sesquiterpenes. The plausible biogenetic relationships of these skeletally different sesquiterpenes were proposed. All sesquiterpenoids were evaluated for their antibacterial, cytotoxic and anti-inflammatory effects. The bioassay results showed compound 14 exhibited significant antibacterial activities against a variety of fish and human pathogenic bacteria with MIC90 values ranging from 3.6 to 33.8 µg/mL. Moreover, moderate cytotoxic effects against HEL cells for components 13 and 14 and moderate inhibitory effect on lipopolysaccharide-induced inflammatory responses in RAW264.7 cells for substance 13 were also observed.

N4BP1 functions as a dimerization-dependent linear ubiquitin reader which regulates TNF signalling.

Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4-binding protein 1 (N4BP1) is a critical suppressor of proinflammatory cytokine production that acts as a regulator of innate immune signalling and inflammation. However, our current understanding about the molecular properties that enable N4BP1 to exert its suppressive potential remain limited. Here, we show that N4BP1 is a novel linear ubiquitin reader that negatively regulates NFκB signalling by its unique dimerization-dependent ubiquitin-binding module that we named LUBIN. Dimeric N4BP1 strategically positions two non-selective ubiquitin-binding domains to ensure preferential recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex, where it regulates duration of proinflammatory signalling in LUBIN-dependent manner. N4BP1 deficiency accelerates TNFα-induced cell death by increasing complex II assembly. Under proapoptotic conditions, caspase-8 mediates proteolytic processing of N4BP1, resulting in rapid degradation of N4BP1 by the 26 S proteasome, and acceleration of apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a novel type of ubiquitin reader that selectively recognises linear ubiquitin which enables the timely and coordinated regulation of TNFR1-mediated inflammation and cell death.

Speckle Variance Photoacoustic Microscopy for Microhemodynamic Imaging.

Relying on the strong optical absorption of hemoglobin to pulsed laser energy, photoacoustic microscopy provides morphological and functional information on microvasculature label-freely. Here, we propose speckle variance photoacoustic microscopy (SV-PAM), which harnesses intrinsic imaging contrast from temporal-varied photoacoustic signals of moving red blood cells in blood vessels, for recovering three-dimension hemodynamic images down to capillary-level resolution within the microcirculatory tissue beds in vivo. Calculating the speckle variance of consecutive photoacoustic B-scan frames acquired at the same lateral position enables accurate identification of blood perfusion and occlusion, which provides interpretations of dynamic blood flow in the microvasculature, in addition to the microvascular anatomic structures. We demonstrate high-resolution hemodynamic imaging of vascular occlusion and reperfusion in the microvasculature of mice ears in vivo. The results suggest that our SV-PAM is potentially invaluable for biomedical hemodynamic investigations, for example, imaging ischemic stroke and hemorrhagic stroke.

Systems engineering Escherichia coli for efficient production p-coumaric acid from glucose.

P-coumaric acid (p-CA), a pant metabolite with antioxidant and anti-inflammatory activity, is extensively utilized in biomedicine, food, and cosmetics industry. In this study, a synthetic pathway (PAL) for p-CA was designed, integrating three enzymes (AtPAL2, AtC4H, AtATR2) into a higher l-phenylalanine-producing strain Escherichia coli PHE05. However, the lower soluble expression and activity of AtC4H in the PAL pathway was a bottleneck for increasing p-CA titers. To overcome this limitation, the soluble expression of AtC4H was enhanced through N-terminal modifications. And an optimal mutant, AtC4HL373T/G211H, which exhibited a 4.3-fold higher kcat/Km value compared to the wild type, was developed. In addition, metabolic engineering strategies were employed to increase the intracellular NADPH pool. Overexpression of ppnk in engineered E. coli PHCA20 led to a 13.9-folds, 1.3-folds, and 29.1% in NADPH content, the NADPH/NADP+ ratio and p-CA titer, respectively. These optimizations significantly enhance p-CA production, in a 5-L fermenter using fed-batch fermentation, the p-CA titer, yield and productivity of engineered strain E. coli PHCA20 were 3.09 g/L, 20.01 mg/g glucose, and 49.05 mg/L/h, respectively. The results presented here provide a novel way to efficiently produce the plant metabolites using an industrial strain.

Polygonatum kingianum Polysaccharides Enhance the Preventive Efficacy of Heat-Inactivated Limosilactobacillus reuteri WX-94 against High-Fat-High-Sucrose-Induced Liver Injury and Gut Dysbacteriosis.

Limosilactobacillus reuteri (L. reuteri) is an efficacious probiotic that could reduce inflammation and prevent metabolic disorders. Here, we innovatively found that Polygonatum kingianum polysaccharides (PKP) promoted proliferation and increased stability of L. reuteri WX-94 (a probiotic strain showing anti-inflammation potentials) in simulated digestive fluids in vitro. PKP was composed of galactose, glucose, mannose, and arabinose. The cell-free supernatant extracted from L. reuteri cultured with PKP increased ABTS•+, DPPH•, and FRAP scavenging capacities compared with the supernatant of the medium without PKP and increased metabolites with health-promoting activities, e.g., 3-phenyllactic acid, indole-3-lactic acid, indole-3-carbinol, and propionic acid. Moreover, PKP enhanced alleviating effects of heat-inactivated L. reuteri on high-fat-high-sucrose-induced liver injury in rats via reducing inflammation and regulating expressions of protein and genes involved in fatty acid metabolism (such as HIF1-α, FAßO, CPT1, and AMPK) and fatty acid profiles in liver. Such benefits correlated with its prominent effects on enriching Lactobacillus and short-chain fatty acids while reducing Dubosiella, Fusicatenilacter, Helicobacter, and Oscillospira. Our work provides novel insights into the probiotic property of PKP and emphasizes the great potential of the inactivated L. reuteri cultured with PKP in contracting unhealthy diet-induced liver dysfunctions and gut dysbacteriosis.

The association between soyfoods or soybean products consumption and executive functioning among Chinese adolescents: A cross-sectional multicenter study.

BACKGROUND: The association of soyfoods or soybean products with executive functions in the brain has been less well studied. In this study, we investigated the consumption of soyfoods or soybean products and its association with executive functions in Chinese adolescents. METHODS: A three-stage stratified whole group sampling method was used to investigate the consumption of soyfoods or soybean products and executive functions among 1643 Chinese adolescents aged 13-15 years. One-way ANOVA and chi-square test were used to compare the basic conditions and executive functions of adolescents with different soyfoods or soybean products consumption. Linear regression analysis and logistic regression analysis were used to analyze the association between soyfoods or soybean products and executive functions. RESULTS: The proportions of Chinese adolescents with soyfoods or soybean products consumption ≤0 time/week, 1-3 time/week, and ≥4 time/week were 41.14 %, 46.80 %, and 12.05 %, respectively. Logistic regression analysis showed that with adolescents with soyfoods or soybean products consumption ≥4 time/week as a reference, adolescents with ≤0 time/week were less likely to have executive dysfunction in inhibiting functional (OR = 17.523, 95 % CI: 7.501, 40.938), 2back (OR = 3.384, 95 % CI: 1.729, 6.623), and switching functional (OR = 7.846, 95 % CI: 3.300, 18.657), were at higher risk of executive dysfunction (P < 0.001). CONCLUSION: Chinese adolescents' consumption of soyfoods or soybean products is inadequate and has a positive association with executive functions. The consumption of soyfoods or soybean products among Chinese adolescents should be increased in the future.

[Analysis on Hydrochemical Evolution of Shallow Groundwater East of Yongding River in Fengtai District, Beijing].

In order to enhance the support for groundwater development and utilization, as well as pollution control and prevention in Fengtai District, Beijing, a comprehensive study was conducted based on long-term monitoring data of shallow groundwater in the eastern area of Yongding River during the dry season. The mathematical statistics, Piper diagram, Gibbs diagram, and ion ratio analysis and other methods were employed to explore the pattern of groundwater hydrochemical evolution, the formation mechanism, and sources of pollution in Fengtai District. The findings were as follows:① Overall, the current groundwater quality in the study area was poor. The average concentration of each index in groundwater increased and then decreased from 1976 to the present. The pollution range of Cl-, SO42-, and TH generally expanded, whereas the pollution range of TDS and NO3- expanded before 2005 and then decreased with 2005 as the turning point. ② The hydrochemical types of groundwater samples displayed a complex regional variation each year, as well as along the groundwater direction. The dominant anion in groundwater was HCO3-, and the dominant cation was Ca2+ each year. The number of groundwater hydrochemical types in 1976 was 8, in which the predominant type was HCO3·SO4-Ca·Mg·Na, accounting for 40%. However, the number of groundwater hydrochemical types in 2021 was 17, in which the predominant type was HCO3·Cl·SO4-Ca·Na·Mg, accounting for 23.88%. The groundwater hydrochemical type showed a complex trend within the region and upstream along the flow direction each year, whereas the migration characteristics of groundwater samples, as depicted on the Piper diagram, indicated that the hydrochemical components of groundwater were significantly affected by human activities during its evolution. ③ The groundwater chemistry in the study area was influenced by both rock weathering and evaporative crystallization processes, with evaporation playing a major role. The alternation of groundwater cations was relatively weak, and the dissolution of carbonate minerals served as the primary source of Ca2+ and Mg2+. ④ The ion ratio analysis suggested that exogenous sources, mainly agricultural activities and urban sewage, contributed to the input of NO3- and Cl-. The pollution impact from agricultural activities was significant before 2005, which aligned with the historical presence of numerous seepage pits, seepage wells, and direct discharge of industrial and domestic sewage for irrigation purposes in the study area. These activities were closely associated with the high levels of pollution. However, pollution input from agricultural activities notably decreased in 2021, likely due to the effective implementation of water environmental protection programs and action plans in recent years.

Activation of the Photosensitive Potential of 2D GaSe by Interfacial Engineering.

Two-dimensional (2D) gallium selenide (GaSe) holds great promise for pioneering advancements in photodetection due to its exceptional electronic and optoelectronic properties. However, in conventional photodetectors, 2D GaSe only functions as a photosensitive layer, failing to fully exploit its inherent photosensitive potential. Herein, we propose an ultrasensitive photodetector based on out-of-plane 2D GaSe/MoSe2 heterostructure. Through interfacial engineering, 2D GaSe serves not only as the photosensitive layer but also as the photoconductive gain and passivation layer, introducing a photogating effect and extending the lifetime of photocarriers. Capitalizing on these features, the device exhibits exceptional photodetection performance, including a responsivity of 28 800 A/W, specific detectivity of 7.1 × 1014 Jones, light on/off ratio of 1.2 × 106, and rise/fall time of 112.4/426.8 µs. Moreover, high-resolution imaging under various wavelengths is successfully demonstrated using this device. Additionally, we showcase the generality of this device design by activating the photosensitive potential of 2D GaSe with other transition metal dichalcogenides (TMDCs) such as WSe2, WS2, and MoS2. This work provides inspiration for future development in high-performance photodetectors, shining a spotlight on the potential of 2D GaSe and its heterostructure.

Comparative Analysis of Sipeimine Content, Metabolome, and Chloroplast Genome in Cultivated and Wild Varieties of Fritillaria taipaiensis.

BACKGROUND: The wild variety Fritillaria taipaiensis E. B (EB) is known for its superior therapeutic effects, but its limited production cannot meet the demands. As a result, the cultivated variety F. taipaiensis P. Y. Li (PY) has been widely grown. In this study, we conducted a comprehensive analysis comparing EB and PY in terms of external features, Sipeimine content, metabolome, and chloroplast genome to differentiate these two varieties. RESULTS: Our research revealed that the petals and pods of EB are green, while those of PY have purple markings. The bulbs of EB contain significantly higher levels of Sipeimine compared to PY. Metabolomic analysis identified 56 differentially expressed metabolites (DMs), with 23 upregulated and 33 downregulated in EB bulbs. Particularly, 3-Hydroxycinnamic acid and Secoxyloganin may serve as distinctive differential metabolites. These DMs were associated with 17 KEGG pathways, including Pyrimidine metabolism, Alanine, Aspartate and Glutamate, and Galactose metabolism. Differences in the length of the chloroplast genome were primarily observed in the LSC region, with the largest variation in the trnH-GUC~psbA region. The placement of the trnH gene and the rps gene in proximity to the LSC/IRb boundary differs between EB and PY. CONCLUSION: The results of this study provide valuable insights for the introduction and comprehensive development of wild F. taipaiensis from a scientific perspective. This article is protected by copyright. All rights reserved.

The protective effect and mechanism of glycosides of cistanche deserticola on rats in middle cerebral artery occlusion (MCAO) model.

Cerebral ischemia-reperfusion injury (CIRI) occurs frequently clinically as a complication following cardiovascular resuscitation resulting in neuronal damage specifically to the hippocampal CA1 region with consequent cognitive impairment. Apoptosis and oxidative stress were proposed as major risk factors associated with CIRI development. Previously, glycosides obtained from Cistanche deserticola (CGs) were shown to play a key role in counteracting CIRI; however, the underlying mechanisms remain to be determined. This study aimed to investigate the neuroprotective effect of CGs on subsequent CIRI in rats. The model of CIRI was established for 2 hr and reperfusion for 24 hr by middle cerebral artery occlusion (MCAO) model. The MCAO rats were used to measure the antioxidant and anti-apoptotic effects of CGs on CIRI. Neurological function was evaluated by the Longa neurological function score test. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to detect the area of cerebral infarction. Nissl staining was employed to observe neuronal morphology. TUNEL staining was used to detect neuronal apoptosis, while Western blot determined protein expression levels of factors for apoptosis-related and PI3K/AKT/Nrf2 signaling pathway. Data demonstrated that CGs treatment improved behavioral performance, brain injury, and enhanced antioxidant and anti-apoptosis in CIRI rats. In addition, CGs induced activation of PI3K/AKT/Nrf2 signaling pathway accompanied by inhibition of the expression of apoptosis-related factors. Evidence indicates that CGs amelioration of CIRI involves activation of the PI3K/AKT/Nrf2 signaling pathway associated with increased cellular viability suggesting these glycosides may be considered as an alternative compound for CIRI treatment.

The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats.

Purpose: To study the potential drug-drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice. Methods: A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC50) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation. Results: The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib. Conclusion: Our study has demonstrated the presence of drug-drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Emerging racial disparities among Medicare beneficiaries and Veterans with metastatic castration-sensitive prostate cancer.

BACKGROUND: Previous studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era. METHODS: We evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015-2018) and Veterans Health Administration (VHA; 2015-2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone. RESULTS: We analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58-0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57-0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09-1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01-1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61-0.92), with no significant OS difference between races. CONCLUSIONS: Guideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes.

Integrated transcriptomics and metabolomics reveal the mechanism of intestinal damage upon acute patulin exposure in mice.

Mycotoxin contamination has become a major food safety issue and greatly threatens human and animal health. Patulin (PAT), a common mycotoxin in the environment, is exposed through the food chain and damages the gastrointestinal tract. However, its mechanism of enterotoxicity at the genetic and metabolic levels remains to be elucidated. Herein, the intestinal histopathological and biochemical indices, transcriptome, and metabolome of C57BL/6 J mice exposed to different doses of PAT were successively assessed, as well as the toxicokinetics of PAT in vivo. The results showed that acute PAT exposure induced damaged villi and crypts, reduced mucus secretion, decreased SOD and GSH-Px activities, and enhanced MPO activity in the small intestine and mild damage in the colon. At the transcriptional level, the genes affected by PAT were dose-dependently altered in the small intestine and fluctuated in the colon. PAT primarily affected inflammation-related signaling pathways and oxidative phosphorylation in the small intestine and immune responses in the colon. At the metabolic level, amino acids decreased, and extensive lipids accumulated in the small intestine and colon. Seven metabolic pathways were jointly affected by PAT in two intestinal sites. Moreover, changes in PAT products and GST activity were detected in the small intestinal tissue but not in the colonic tissue, explaining the different damage degrees of the two sites. Finally, the integrated results collectively explained the toxicological mechanism of PAT, which damaged the small intestine directly and the colon indirectly. These results paint a clear panorama of intestinal changes after PAT exposure and provide valuable information on the exposure risk and toxic mechanism of PAT.

Anti-inflammatory steroids from the South China Sea Sponge Spongia officinalis.

One new highly degraded steroid, namely 21-nor-4-ene-chaxine A (1) furnishing a 5/6/5-tricyclic, along with one known related analogue (2), were isolated from the South China Sea sponge Spongia officinalis. Their structures including absolute configurations were established by extensive spectroscopic data analysis, TDDFT-ECD calculation, and comparison with the spectral data previously reported in the literature. Compound 1 represent the new member of incisterols family with a highly degradation in ring B. In vitro bioassays revealed compound 2 exhibited significant anti-microglial inflammatory effect on lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells.

Iron deficiency at birth and risk of hidden hearing loss in infants modification by socioeconomic status: mother-newborn cohort in Shenyang, China.

OBJECTIVE: The diagnosis of hidden hearing loss (HHL) in calm state has not yet been determined, while the nutritional status is not involved in its pathogenic risk factors. In utero iron deficiency (ID) may delay auditory neural maturation in infants. We evaluated the association between ID and HHL as well as the modification effect of socioeconomic status (SES) on this association in newborns. STUDY DESIGN: We included 859 mother-newborns from the baseline of this observational northeast cohort. Data on exposure assessment included iron status [maternal hemoglobin (Hb) and neonatal heel prick serum ferritin (SF)] and SES (occupation, education and income). Auditory neural maturation was reflected by auditory brainstem response (ABR) testing and electrocochleography (ECochG). RESULTS: Iron status and SES were independently and jointly associated with the prediction of neonatal HHL by logistic and linear regression model. The mediation effects were performed by Process. ID increased absolute latency wave V, interpeak latency (IPL) III-V, and summting potentials (SP) /action potentials (AP), which were combined as HHL. Low SES showed the highest risk of HHL and the highest levels of related parameters in ID newborns. Moreover, after Corona Virus Disease 2019 (COVID-19) were positive, preschool children who experience ID in neonatal period were more likely to suffer from otitis media with effusion (OME). High SES also showed similar risk effects. CONCLUSION: Both low and high SES may strengthen the risk of ID on neonatal HHL in Northeast China.

Rational design improves both thermostability and activity of a new D-tagatose 3-epimerase from Kroppenstedtia eburnean to produce D-allulose.

D-allulose is a naturally occurring rare sugar and beneficial to human health. However, the efficient biosynthesis of D-allulose remains a challenge. Here, we mined a new D-tagatose 3-epimerase from Kroppenstedtia eburnean (KeDt3e) with high catalytic efficiency. Initially, crucial factors contributing to the low conversion of KeDt3e were identified through crystal structure analysis, density functional theory calculations (DFT), and molecular dynamics (MD) simulations. Subsequently, based on the mechanism, combining restructuring the flexible region, proline substitution based onconsensus sequence analysis, introducing disulfide bonds, and grafting properties, and reshaping the active center, the optimal mutant M5 of KeDt3e was obtained with enhanced thermostability and activity. The optimal mutant M5 exhibited an enzyme activity of 130.8 U/mg, representing a 1.2-fold increase; Tm value increased from 52.7 °C to 71.2 °C; and half-life at 55 °C extended to 273.7 min, representing a 58.2-fold improvement, and the detailed mechanism of performance improvement was analyzed. Finally, by screening the ribosome-binding site (RBS) of the optimal mutant M5 recombinant bacterium (G01), the engineered strain G08 with higher expression levels was obtained. The engineered strain G08 catalyzed 500 g/L D-fructose to produce 172.4 g/L D-allulose, with a conversion of 34.4% in 0.5 h and productivity of 344.8 g/L/h on a 1 L scale. This study presents a promising approach for industrial-scale production of D-allulose.

DDX20 is required for cell-cycle reentry of prospermatogonia and establishment of spermatogonial stem cell pool during testicular development in mice.

RNA-binding proteins (RBPs), as key regulators of mRNA fate, are abundantly expressed in the testis. However, RBPs associated with human male infertility remain largely unknown. Through bioinformatic analyses, we identified 62 such RBPs, including an evolutionarily conserved RBP, DEAD-box helicase 20 (DDX20). Male germ-cell-specific inactivation of Ddx20 at E15.5 caused T1-propsermatogonia (T1-ProSG) to fail to reenter cell cycle during the first week of testicular development in mice. Consequently, neither the foundational spermatogonial stem cell (SSC) pool nor progenitor spermatogonia were ever formed in the knockout testes. Mechanistically, DDX20 functions to control the translation of its target mRNAs, many of which encode cell-cycle-related regulators, by interacting with key components of the translational machinery in prospermatogonia. Our data demonstrate a previously unreported function of DDX20 as a translational regulator of critical cell-cycle-related genes, which is essential for cell-cycle reentry of T1-ProSG and formation of the SSC pool.

Exploiting genomic tools for genetic dissection and improving the resistance to Fusarium stalk rot in tropical maize.

KEY MESSAGE: A stable genomic region conferring FSR resistance at ~250 Mb on chromosome 1 was identified by GWAS. Genomic prediction has the potential to improve FSR resistance. Fusarium stalk rot (FSR) is a global destructive disease in maize; the efficiency of phenotypic selection for improving FSR resistance was low. Novel genomic tools of genome-wide association study (GWAS) and genomic prediction (GP) provide an opportunity for genetic dissection and improving FSR resistance. In this study, GWAS and GP analyses were performed on 562 tropical maize inbred lines consisting of two populations. In total, 15 SNPs significantly associated with FSR resistance were identified across two populations and the combinedPOP consisting of all 562 inbred lines, with the P-values ranging from 1.99 × 10-7 to 8.27 × 10-13, and the phenotypic variance explained (PVE) values ranging from 0.94 to 8.30%. The genetic effects of the 15 favorable alleles ranged from -4.29 to -14.21% of the FSR severity. One stable genomic region at ~ 250 Mb on chromosome 1 was detected across all populations, and the PVE values of the SNPs detected in this region ranged from 2.16 to 5.18%. Prediction accuracies of FSR severity estimated with the genome-wide SNPs were moderate and ranged from 0.29 to 0.51. By incorporating genotype-by-environment interaction, prediction accuracies were improved between 0.36 and 0.55 in different breeding scenarios. Considering both the genome coverage and the threshold of the P-value of SNPs to select a subset of molecular markers further improved the prediction accuracies. These findings extend the knowledge of exploiting genomic tools for genetic dissection and improving FSR resistance in tropical maize.

Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

BACKGROUND: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments. METHODS: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months. RESULTS: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78). CONCLUSIONS: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted.

Sleep deprivation boosts O2·- levels in the brains of mice as visualized by a Golgi apparatus-targeted ratiometric fluorescence nanosensor.

Sleep deprivation (SD) is highly prevalent in the modern technological world. Emerging evidence shows that sleep deprivation is associated with oxidative stress. At the organelle level, the Golgi apparatus actively participates in the stress response. In this study, to determine whether SD and Golgi apparatus stress are correlated, we rationally designed and fabricated a novel Golgi apparatus-targeted ratiometric nanoprobe called Golgi dots for O2·- detection. This probe exhibits high sensitivity and selectivity in cells and brain slices of sleep-deprived mice. Golgi dots can be readily synthesized by coprecipitation of Golgi-F127, an amphiphilic polymer F127 modified with a Golgi apparatus targeting moiety, caffeic acid (CA), the responsive unit for O2·-, and red emissive carbon nanodots (CDs), which act as the reference signal. The fluorescence emission spectrum of the developed nanoprobe showed an intense peak at 674 nm, accompanied by a shoulder peak at 485 nm. As O2·- was gradually added, the fluorescence at 485 nm continuously increased; in contrast, the emission intensity at 674 nm assigned to the CDs remained constant, resulting in the ratiometric sensing of O2·-. The present ratiometric nanoprobe showed high selectivity for O2·- monitoring due to the specific recognition of O2·- by CA. Moreover, the Golgi dots exhibited good linearity with respect to the O2·- concentration within 5 to 40 µM, and the limit of detection (LOD) was ~ 0.13 µM. Additionally, the Golgi dots showed low cytotoxicity and an ability to target the Golgi apparatus. Inspired by these excellent properties, we then applied the Golgi dots to successfully monitor exogenous and endogenous O2·- levels within the Golgi apparatus. Importantly, with the help of Golgi dots, we determined that SD substantially elevated O2·- levels in the brain.