WRKY transcription factors and OBERON histone-binding proteins form complexes to balance plant growth and stress tolerance.

WRKY transcription factors in plants are known to be able to mediate either transcriptional activation or repression, but the mechanism regulating their transcriptional activity is largely unclear. We found that group IId WRKY transcription factors interact with OBERON (OBE) proteins, forming redundant WRKY-OBE complexes in Arabidopsis thaliana. The coiled-coil domain of WRKY transcription factors binds to OBE proteins and is responsible for target gene selection and transcriptional repression. The PHD finger of OBE proteins binds to both histones and WRKY transcription factors. WRKY-OBE complexes repress the transcription of numerous stress-responsive genes and are required for maintaining normal plant growth. Several WRKY and OBE mutants show reduced plant size and increased drought tolerance, accompanied by increased expression of stress-responsive genes. Moreover, expression levels of most of these WRKY and OBE genes are reduced in response to drought stress, revealing a previously uncharacterized regulatory mechanism of the drought stress response. These results suggest that WRKY-OBE complexes repress transcription of stress-responsive genes, and thereby balance plant growth and stress tolerance.

Prokaryotic community assembly patterns and nitrogen metabolic potential in oxygen minimum zone of Yangtze Estuary water column.

It is predicted that oxygen minimum zones (OMZs) in the ocean will expand as a consequence of global warming and environmental pollution. This will affect the overall microbial ecology and microbial nitrogen cycle. As one of the world's largest alluvial estuaries, the Yangtze Estuary has exhibited a seasonal OMZ since the 1980s. In this study, we have uncovered the microbial composition, the patterns of community assembly and the potential for microbial nitrogen cycling within the water column of the Yangtze Estuary, with a particular focus on OMZ. Based on the 16 S rRNA gene sequencing, a specific spatial variation in the composition of prokaryotic communities was observed for each water layer, with the Proteobacteria (46.1%), Bacteroidetes (20.3%), and Cyanobacteria (10.3%) dominant. Stochastic and deterministic processes together shaped the community assembly in the water column. Further, pH was the most important environmental factor influencing prokaryotic composition in the surface water, followed by silicate, PO43-, and distance offshore (p < 0.05). Water depth, NH4+, and PO43- were the main factors in the bottom water (p < 0.05). At last, species analysis and marker gene annotation revealed candidate nitrogen cycling performers, and a rich array of nitrogen cycling potential in the bottom water of the Yangtze Estuary. The determined physiochemical parameters and potential for nitrogen respiration suggested that organic nitrogen and NO3- (or NO2-) are the preferred nitrogen sources for microorganisms in the Yangtze Estuary OMZ. These findings are expected to advance research on the ecological responses of estuarine oxygen minimum zones (OMZs) to future global climate perturbations.

Penalty mitigation for OSC-induced XPM in long-haul WDM coherent systems by digital up-conversion coding.

Due to the cross phase modulation (XPM) effect, in long-haul high-speed dense wavelength division multiplexing (DWDM) coherent systems, using a low-speed on-off-keying (OOK) format optical supervisory channel (OSC) will introduce extra nonlinear phase noise, which restricts the transmission distance. In this paper, we propose a simple OSC coding method to mitigate the OSC-induced nonlinear phase noise. According to the split-step solution of the Manakov equation, we up-convert the baseband of the OSC signal out of the pass-band of the walk-off term to reduce the spectrum density of XPM phase noise. Experimental results show that the optical signal to noise ratio (OSNR) budget on the 400 G channel of 1280-km transmission is improved by 0.96 dB, which achieves almost the same performance with the no OSC case.

214.7 Tbit/s S, C, and L-band transmission over 50†km SSMF based on silicon photonic integrated transceivers.

We experimentally demonstrate a 214.7 Tbit/s generalized mutual information (GMI) estimated throughput by ultra-wideband wavelength division multiplexing (WDM) transmission in standard single-mode fiber (SSMF). With 50-GHz grid, 396 transmission channels are used to deliver 49 GBaud probabilistically constellation-shaped (PCS) 256 quadrature amplitude modulation (QAM) and PCS-64QAM signals. Silicon photonic integrated transceiver is employed to complete electro-optic and optic-electro conversion of the modulated signals. S, C, and L-band rare-earth-doped amplifiers enable the 19.8 THz bandwidth WDM transmission without the assistance of distributed Raman amplification. The measured data rate shows great potential for Silicon photonic devices deployed in ultra-wideband WDM transmission.

Unveiling glutamic acid-functionalized LDHs: understanding the Cr(VI) removal mechanism from microscopic and macroscopic view points.

Interlayer functionalization modulation is essential for modifying LDHs and improving their selectivity and adsorption capacity for target pollutants. In this work, Glu@NiFe-LDH was synthesized using a simple one-step hydrothermal method and tested for its ability to remove CrO42- from wastewater. The modification significantly increased the composite material's removal ability by 2-3 times, up to 98.36 mg g-1. The behavior of CrO42- adsorption on Glu@NiFe-LDH was further studied by adjusting the affecting factors (i.e., temperature, pH, contact time, initial concentration, and interfering substance), and the adsorption behavior was confirmed as a spontaneous and chemisorption process. And the result was that Glu@NiFe-LDH demonstrated high capacity, efficiency, stability, and selectivity for the adsorption of CrO42- in a single electrolyte and natural water containing competing anions. Furthermore, molecular dynamics simulations (NVT ensemble) were employed to further reveal the mechanism of glutamic acid modification on LDH at the microscopic scale. Additionally, the IRI analysis method revealed the mechanism of weak interaction between glutamic acid molecules and CrO42-. This study provides a detailed understanding of the intercalation mechanism involved in the amino acid modification of LDHs. It explains the adsorption mechanism of metal oxo-acid radicals by amino acid-modified LDHs from a theoretical perspective. The findings offer experiments and a theoretical basis for designing targeted adsorbents in the future.

Fear of childbirth and sleep quality among pregnant women: a generalized additive model and moderated mediation analysis.

OBJECTIVES: This study aims to examine the associations among fear of childbirth, psychological distress, resilience, and sleep quality among Chinese pregnant women. METHODS: A cross-sectional survey was carried out between January 2022 to March 2022 among pregnant women who met the inclusion criteria and sought healthcare services at The First Affiliated Hospital of Guangzhou University of Chinese Medicine in Guangdong Province, Southern China. Data was collected using a structured questionnaire that included sociodemographic characteristics, childbirth attitudes questionnaires (CAQ), hospital anxiety and depression scale (HADS), Connor-Davidson resilience scale (CD-RISC), and Pittsburgh sleep quality index (PSQI). A generalized additive model and moderated mediation analysis were employed for data analysis. RESULTS: A non-linear and negative association between fear of childbirth and sleep quality was found in the second trimester and antenatal period. Psychological distress significantly mediated the relationship between fear of childbirth and sleep quality (first trimester: ß = 0.044, 95%CI:0.022-0.071; second trimester: ß = 0.029, 95%CI:0.009-0.056; third trimester: ß = 0.064, 95%CI:0.046-0.088; antenatal period: ß = 0.050, 95%CI:0.037-0.063). The moderating role of resilience between fear of childbirth and sleep quality was significant (second trimester: ß=-0.006, 95%CI:-0.012-0.001, P = 0.025; antenatal period: ß=-0.004, 95%CI:-0.007--0.001, P = 0.014), as well as between fear of childbirth and psychological distress (first trimester: ß=-0.016, 95%CI:-0.026--0.005, P = 0.004; antenatal period: ß=-0.005, 95%CI:-0.009--0.001, P = 0.014). CONCLUSIONS: Fear of childbirth, psychological distress, and resilience are three important factors affecting sleep quality in Chinese pregnant women.

A Study on the Effect of Precise Rehabilitation Therapy Guided by Three-dimensional-computed Tomography Reconstruction Technology in Hip Fracture Surgery Patients.

OBJECTIVE: To evaluate the effectiveness of precise rehabilitation therapy guided by three-dimensional computed tomography (3D-CT) reconstruction technology in hip fracture patients through a retrospective cohort study. METHOD: Data were retrospectively collected from 60 patients aged over 60 who had undergone hip fracture surgery. They were divided into two groups based on their chosen rehabilitation method: a control group and a test group. The study collected demographic data, fracture characteristics, and quality of life indicators to assess the impact of rehabilitation on economic indicators and daily living activities (ADL). Additionally, it included assessments of muscle strength, joint mobility, hip function, postoperative complications, and records of hospitalization information and costs. Cognitive function was also assessed postoperatively. RESULTS: There were no significant differences in demographic data, fracture characteristics, ADL, or Fugl-Meyer assessment (FMA) between the two groups. However, the test group exhibited significantly higher post-surgery muscle strength recovery and hip mobility compared to the control group (P<0.05). Additionally, the test group had significantly fewer hospitalization days and lower hospitalization costs than the control group (P<0.05). CONCLUSION: Precise rehabilitation therapy guided by 3D-CT reconstruction technology for hip fracture surgery patients can enhance early muscle strength recovery, improve mobility of the affected limb, reduce hospitalization duration and costs, and enhance overall patient recovery outcomes.

Effects of recorded maternal voice on anthropometric parameters and heart rate in premature infants: A pilot randomised controlled trial.

PURPOSE: To explore the benefits of a recorded maternal voice intervention on weight, recumbent length, head circumference, and heart rate of preterm infants in the neonatal intensive care unit. METHODS: A pilot randomised controlled trial was conducted in this study. Preterm infants in the neonatal intensive care unit (N = 109) were recruited and randomly assigned to an intervention or control group. Both groups received routine nursing care, while preterm infants in the intervention group received a recorded maternal voice program of 20 min, twice daily for 21 days. Preterm infants' daily weight, recumbent length, head circumference, and heart rate were collected during the 21-day intervention. Participants' heart rate in the intervention group was also recorded once a day pre-during-after the recorded maternal voice program. RESULTS: Preterm infants in the intervention group showed a significant increase in weight (-75.94, 95% CI -108.04, -43.85, P < 0.001), recumbent length (-0.54, 95% CI -0.76, -0.32, P < 0.001), and head circumference (-0.37, 95%CI -0.56, -0.18, P < 0.001) compared with the control group. Preterm infants in the intervention group also showed significant changes in heart rate pre-during-after the recorded maternal voice program. However, no significant differences were found in the heart rate scores between the two groups. DISCUSSION: The changes in heart rate pre-during-after the intervention may help explain participants' more significant increase in weight, recumbent length, and head circumference. PRACTICE IMPLICATIONS: The recorded maternal voice intervention could be incorporated into clinical practice to promote growth and development in preterm infants in the neonatal intensive care unit. STUDY REGISTRATION: Australian New Zealand Clinical Trials Register, https://www.anzctr.org.au/; (registration number: ACTRN12622000019707).

Effects of sirtuin 1 deficiency on trophoblasts and its implications in the pathogenesis of pre-eclampsia.

BACKGROUND: Sirtuin 1 (SIRT1) is mainly localised in syncytiotrophoblasts and cytotrophoblasts, and is involved in pregnancy regulation. However, data on the association between SIRT1 and pre-eclampsia (PE) remains limited. This study aimed to investigate the role of SIRT1 in PE pathophysiology. METHODS: Placental SIRT1 expression, as well as serum SIRT1, placental growth factor (PlGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) levels, were measured using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assays in 40 healthy pregnant women (NP group) and 40 women with severe PE (PE group). Additionally, the effects of SIRT1 on the migration, invasion, PlGF, and sFlt-1 secretion of HTR-8/SVneo cells were analysed. RESULTS: SIRT1 expression was significantly reduced in the placenta of patients with severe PE compared with that in healthy pregnant women. Compared with the NP group, serum SIRT1 and PlGF expression was significantly lower in the PE group; however, the expression of serum sFlt-1 was significantly higher in the PE group. Correlation analysis showed that in the PE group, placental SIRT1 protein levels positively correlated with serum PlGF levels (r = 0.468, P = .002) and negatively correlated with serum sFlt-1 levels (r = -0.542, P < .001). Cells with downregulated SIRT1 had a significantly shorter migration distance and a prominently reduced number of invasive cells compared with the corresponding negative control group, suggesting that SIRT1 deficiency may inhibit the migration and invasive ability of HTR-8/SVneo cells. The opposite results were observed after transfection with lentivirus overexpressing SIRT1. Compared with the corresponding controls, cells with downregulated SIRT1 had significantly reduced PlGF levels and significantly increased sFlt-1 levels in the cell culture supernatants, whereas SIRT1 overexpression produced the opposite results. CONCLUSIONS: SIRT1 deficiency may contribute to the pathogenesis of pre-eclampsia by reducing trophoblastic migration, invasion, and PlGF secretion and increasing sFlt-1 secretion.

Pre-eclampsia is a serious obstetric disorder that begins in the placenta and can occur midway through pregnancy. However, its exact disease process remains unknown. During early pregnancy, trophoblasts (cells that differentiate from fertilised eggs) evolve into new blood vessels that supply oxygen and nutrients to the placenta and maintain placental formation. In people with pre-eclampsia, problematic trophoblasts lead to abnormal placental formation and release of sFlt-1 and PlGF into the mother's blood, damaging blood vessels. Experts reported that the intracellular enzyme SIRT1 might be associated with developing pre-eclampsia. SIRT1 expression in the placenta of pregnant women with pre-eclampsia was lower than normal, and the decrease in SIRT1 levels in HTR-8/Svneo trophoblasts prevented their ability to form blood vessels and altered sFlt-1 and PlGF secretion. Hence, our findings suggest that reduced SIRT1 in trophoblasts may lead to pre-eclampsia by affecting their ability to form placental blood vessels and altering enzyme secretion.

FVE promotes RNA-directed DNA methylation by facilitating the association of RNA polymerase V with chromatin.

Association of RNA polymerase V (Pol V) with chromatin is a critical step for RNA- directed DNA methylation (RdDM) in plants. Although the methylated DNA-binding proteins SUVH2 and SUVH9 and the chromatin remodeler-containing complex DRD1-DMS3-RDM1 are known to be required for the association of Pol V with chromatin, the molecular mechanisms underlying the association of Pol V with different chromatin environments remain largely unknown. Here we found that SUVH9 interacts with FVE, a homolog of the mammalian retinoblastoma-associated protein, which has been previously identified as a shared subunit of the histone deacetylase complex and the polycomb-type histone H3K27 trimethyltransferase complex. We demonstrated that FVE facilitates the association of Pol V with chromatin and thus contributes to DNA methylation at a substantial subset of RdDM target loci. Compared with FVE-independent RdDM target loci, FVE-dependent RdDM target loci are more abundant in gene-rich chromosome arms than in pericentromeric heterochromatin regions. This study contributes to our understanding of how the association of Pol V with chromatin is regulated in different chromatin environments.

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity.

Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals that causes a significant economic burden globally. Vaccination is the most effective FMD control strategy. However, FMD virus (FMDV) particles are prone to dissociate when appropriate physical or chemical conditions are unavailable, such as an incomplete cold chain. Such degraded vaccines result in compromised herd vaccination. Therefore, thermostable FMD particles are needed for use in vaccines. This study generated thermostable FMDV mutants (M3 and M10) by serial passages at high temperature, subsequent amplification, and purification. Both mutants contained an alanine-to-threonine mutation at position 13 in VP1 (A1013T), although M3 contained 3 additional mutations. The selected mutants showed improved stability and immunogenicity in neutralizing antibody titers, compared with the wild-type (wt) virus. The sequencing analysis and cryo-electron microscopy showed that the mutation of alanine to threonine at the 13th amino acid in the VP1 protein (A1013T) is critical for the capsid stability of FMDV. Virus-like particles containing A1013T (VLPA1013T) also showed significantly improved stability to heat treatment. This study demonstrated that Thr at the 13th amino acid of VP1 could stabilize the capsid of FMDV. Our findings will facilitate the development of a stable vaccine against FMDV serotype O. IMPORTANCE Foot-and-mouth disease (FMD) serotype O is one of the global epidemic serotypes and causes significant economic loss. Vaccination plays a key role in the prevention and control of FMD. However, the success of vaccination mainly depends on the quality of the vaccine. Here, the thermostable FMD virus (FMDV) mutants (M3 and M10) were selected through thermal screening at high temperatures with improved stability and immunogenicity compared with the wild-type virus. The results of multisequence alignment and cryo-electron microscopy (cryo-EM) analysis showed that the Thr substitution at the 13th amino acid in the VP1 protein is critical for the capsid stability of FMDV. For thermolabile type O FMDV, this major discovery will aid the development of its thermostable vaccine.

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics.

MRTX849 is a novel, highly selective, targeted inhibitor of KRAS (G12C), which significantly improves the objective response rate in patients with advanced solid tumors. However, neither an analytical HPLC-MS/MS assay nor pharmacokinetics has been reported for MRTX849 in plasma. In the present study, chromatography was accomplished on a reversed phase C18 column (50 × 2.1 mm, 3.5 µm). The limit of detection of MRTX849 was 0.02 ng mL-1 at S/N ≥ 3. Only 20 µL of plasma was utilized for accurate quantitation. The optimized analytical assay was fully validated and verified in accordance with guidelines. The calibration curve for MRTX849 was linear with a correlation coefficient >0.99 in the range of 0.05-200 ng mL-1. The intra- and inter-day accuracy and precision were all within ±10%. The matrix effect and recovery were consistent and acceptable under several quality control concentrations. This HPLC-MS/MS method was successfully applied for a pharmacokinetic study of MRTX849 at a dose of 15 mg kg-1.

Effects of direct-acting antiviral treatment on reducing mortality among Medicare beneficiaries with HIV and HCV coinfection.

Hepatitis C virus (HCV) infection is common among people living with HIV. HIV and HCV coinfected patients have higher overall mortality rates compared with HIV mono-infected patients. With its high cure rate of HCV infection, direct-acting antiviral (DAA) treatment provides an opportunity to improve the survival of the HIV/HCV coinfected population. The objective of this study is to investigate the association between DAA treatment and all-cause mortality among HIV/HCV coinfected people. The study included 7103 Medicare beneficiaries in the United States who were infected with both HIV and HCV between 2014 and 2017. Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) of death for patients with and without DAA treatment while controlling for patient characteristics. During the study period, 1675 patients initiated DAA treatment (23.6%). The adjusted hazard ratio (aHR) of all-cause mortality between patients with and without DAA treatment was 0.37 (95% CI, 0.29-0.48), regardless of cirrhosis status. DAA treatment was associated with a smaller reduction in all-cause mortality for females (aHR, 0.50 [95% CI, 0.30-0.85]) compared with males (aHR, 0.34 [95% CI, 0.25-0.46]). DAA treatment was associated with improved survival among all HIV/HCV coinfected patients regardless of sex or HCV disease progression.

High prevalence of pre-treatment HIV drug resistance in Papua New Guinea: findings from the first nationally representative pre-treatment HIV drug resistance study.

BACKGROUND: Determining the prevalence of pre-treatment HIV drug resistance (PDR) is important to assess the effectiveness of first-line therapies. To determine PDR prevalence in Papua New Guinea (PNG), we conducted a nationally representative survey. METHODS: We used a two-stage cluster sampling method to recruit HIV treatment initiators with and without prior exposure to antiretroviral therapies (ART) in selected clinics. Dried blood spots were collected and tested for PDR. RESULTS: A total of 315 sequences were available for analysis. The overall PDR prevalence rate was 18.4% (95% CI 13.8-24.3%). The prevalence of PDR to non-nucleoside analog reverse-transcriptase inhibitors (NNRTIs) was 17.8% (95% CI 13.6-23.0%) and of PDR to nucleoside reverse transcriptase inhibitors (NRTIs) was 6.3% (95% CI 1.6-17.1%). The PDR prevalence rate among people reinitiating ART was 42.4% (95% CI 29.1-56.4%). CONCLUSIONS: PNG has a high PDR prevalence rate, especially to NNRTI-based first-line therapies. Our findings suggest that removing NNRTIs as part of first-line treatment is warranted and will lead to improving viral suppression rates in PNG.

Transcriptome sequencing reveals core regulation modules and gene signatures of Zusanli acupoints in response to different moxibustion warm stimulation in adjuvant arthritis rat.

BACKGROUND: The efficacy of moxibustion in treating rheumatoid arthritis is recognized, but its molecular mechanism is still unclear. This study aimed to characterize the molecular map and potential key genes in the process of different moxibustion warm at Zusanli acupoint treatment of adjuvant arthritis (AA) model. METHODS: AA rat model was induced by complete Freund's adjuvant (CFA) and then accessed by foot swelling and thermal hyperalgesia test. Transcriptome sequencing, series test of cluster (STC) and weighted gene co-expression network analysis (WGCNA) were used in this study. RESULTS: CFA-induced inflammation, foot swelling, and pain in AA rats were significantly improved by moxibustion warm. Differentially expressed genes (DEGs) were screened in nine different comparison groups and a total of 4535 DEGs were identified, and these DEGs were preferentially clustered in inflammatory and immune-related pathways, such as MAPK signaling pathway. Only 1 DEG of heat shock protein 90, alpha (cytosolic), class A member 1 (Hsp90aa1) was shared in comparison groups of model with moxibustion treatment. STC analysis also revealed that Hsp90aa1 was increased in AA model, but decreased after 37 °C moxibustion intervention, and constantly decreased after 42 °C moxibustion treatment. GO and KEGG pathway analysis revealed that these genes enriched in inflammatory and immune-related pathways. Moreover, WGCNA identified that violet module was positively correlated with model temperature while negatively correlated with control, and the paleturquoise module was positively correlated with model. The violet and paleturquoise module gene were significantly enriched in MAPK signaling pathway. Importantly, Hsp90aa1 also played a central role in the violet module by interacting with multiple proteins. CONCLUSIONS: Moxibustion warm improved AA in rat, and we obtained the transcriptome profile and excavate a critical gene of Hsp90aa1, and provided insight into gene signatures for moxibustion warm at Zusanli acupoint in AA rat.

Soil contamination with cadmium and potential risk around various mines in China during 2000-2020.

Cadmium (Cd) pollution in mining areas is the most important challenge for soil environment management in China. Assessing the actual Cd pollution risk in various mining areas and identifying the core areas requiring supervision can provide a basis for government departments and industries to carry out detailed further investigations in key areas. In this study, we collated published data on metal mine circumjacent soil contaminated by Cd in China from 2002 to 2020 to conduct a comprehensive study on soil cadmium pollution and ecological and health risks in mining areas. The temporal and spatial variations of Cd concentrations and the pollution source were investigated. Results indicated that the Cd concentration in soil was strongly associated with the types of mining area. The Cd pollution in the circumjacent soil of lead-zinc and tungsten mines with high heavy metal pollution discharging coefficient was more serious than the soil around other mines. Identification of temporal and spatial variations for soil Cd in China indicated that the high Cd concentrations were found in the central, southern, and southwestern regions of China, and the distribution of mining activities in these regions are relatively concentrated. Meanwhile, a temporal turning point in the mean soil Cd concentration occurred in these regions in 2012, which indicated that the heavy metal control management policy implemented by the government was effective. The ecological risk of soil Cd pollution around mining areas was moderate to high. Health risk assessment showed that some regions adjacent mining areas had a high non-carcinogenic risk, notably, lead-zinc and tungsten mining areas were more serious. Supervision should focus on reducing ecological risks and protecting the safety of agricultural products rather than concentrating on health risks. The research results provide a reference for the priority management of contaminated soil in mining areas.

Low Utilization of Direct-Acting Antiviral Agents in a Large National Cohort of HIV and HCV Coinfected Medicare Patients in the United States: Implications for HCV Elimination.

Hepatitis C virus (HCV) infection is common in people living with HIV/AIDS (PLWHA). The advent of direct-acting antiviral agents (DAAs) has made HCV elimination a realistic goal. We conducted a retrospective cohort study using the US Medicare Fee-For-Service claims data and outpatient prescription drug data to assess the HCV DAA initiation and completion among newly diagnosed HIV-HCV-coinfected Medicare patients enrolled in 2014-2016. DAA initiation was defined as filling at least 1 prescription of DAAs during 2014-2016. DAA completion was defined as taking an 8-week or longer DAA treatment course for patients without cirrhosis and a 12-week or longer treatment duration for those with cirrhosis. Among 12 152 HIV-HCV-coinfected Medicare patients, 20.9% received the DAA treatment in 2014-2016. The average time from HCV diagnosis to DAA initiation was 277 days. The overall DAA completion rate was 92% among 2537 patients who used DAAs. Interventions are needed to improve DAA uptake in PLWHA.

Desilylation Induced by Metal Fluoride Nanocrystals Enables Cleavage Chemistry In Vivo.

Metal fluoride nanocrystals are widely used in biomedical studies owing to their unique physicochemical properties. The release of metal ions and fluorides from nanocrystals is intrinsic due to the solubility equilibrium. It used to be considered as a drawback because it is related to the decomposition and defunction of metal fluoride nanocrystals. Many strategies have been developed to stabilize the nanocrystals, and the equilibrium concentrations of fluoride are often <1 mM. Here we make good use of this minimum amount of fluoride and unveil that metal fluoride nanocrystals could effectively induce desilylation cleavage chemistry, enabling controlled release of fluorophores and drug molecules in test tubes, living cells, and tumor-bearing mice. Biocompatible PEG (polyethylene glycol)-coated CaF2 nanocrystals have been prepared to assay the efficiency of desilylation-induced controlled release of functional molecules. We apply the strategy to a prodrug activation of monomethyl auristatin E (MMAE), showing a remarkable anticancer effect, while side effects are almost negligible. In conclusion, this desilylation-induced cleavage chemistry avails the drawback on empowering metal fluoride nanocrystals with a new function of perturbing or activating for further biological applications.

The rescue and selection of thermally stable type O vaccine candidate strains of foot-and-mouth disease virus.

Inactivated foot-and-mouth disease virus (FMDV) vaccines have been used widely to control foot-and-mouth disease (FMD). However, the virions (146S) of this virus are easily dissociated into pentamer subunits (12S), which limits the immune protective efficacy of inactivated vaccines when the temperature is higher than 30 °C. A cold-chain system can maintain the quality of the vaccines, but such systems are usually not reliable in limited-resource settings. Thus, it is imperative to improve the thermostability of vaccine strains to guarantee the quality of the vaccines. In this study, four recombinant FMDV strains containing single or multiple amino acid substitutions in the structural proteins were rescued using a previously constructed FMDV type O full-length infectious clone (pO/DY-VP1). We found that single or multiple amino acid substitutions in the structural proteins affected viral replication to different degrees. Furthermore, the heat and acid stability of the recombinant viruses was significantly increased when compared with the parental virus. Three thermally stable recombinant viruses (rHN/DY-VP1Y2098F, rHN/DY-VP1V2090A-S2093H, and rHN/DY-VP1V2090A-S2093H-Y2098F) were prepared as inactivated vaccines to immunize pigs. Blood samples were collected every week to prepare sera, and a virus neutralization test showed that the substitutions S2093H and Y2098F, separately or in combination, did not affect the immunogenicity of the virus, but the Y2098F mutation increased the thermostability significantly (p < 0.05). Therefore, the rHN/DY-VP1Y2098F mutant should be considered for use in future vaccines.

Quantitative HPLC-MS/MS determination of Nuc, the active metabolite of remdesivir, and its pharmacokinetics in rat.

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.