Common Alterations in Parallel Metabolomic Profiling of Serum and Spinal Cord and Mechanistic Studies on Neuropathic Pain following PPARα Administration.

Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.

Long-baseline quantum sensor network as dark matter haloscope.

Ultralight dark photons constitute a well-motivated candidate for dark matter. A coherent electromagnetic wave is expected to be induced by dark photons when coupled with Standard-Model photons through kinetic mixing mechanism, and should be spatially correlated within the de Broglie wavelength of dark photons. Here we report the first search for correlated dark-photon signals using a long-baseline network of 15 atomic magnetometers, which are situated in two separated meter-scale shield rooms with a distance of about 1700 km. Both the network's multiple sensors and the shields large size significantly enhance the expected dark-photon electromagnetic signals, and long-baseline measurements confidently reduce many local noise sources. Using this network, we constrain the kinetic mixing coefficient of dark photon dark matter over the mass range 4.1 feV-2.1 peV, which represents the most stringent constraints derived from any terrestrial experiments operating over the aforementioned mass range. Our prospect indicates that future data releases may go beyond the astrophysical constraints from the cosmic microwave background and the plasma heating.

Methyl 3,4-dihydroxybenzoate alleviates oxidative damage in granulosa cells by activating Nrf2 antioxidant pathway.

Oxidative damage induced granulosa cells (GCs) apoptosis was considered as a significant cause of compromised follicle quality, antioxidants therapy has emerged as a potential method for improving endometriosis pregnancy outcomes. Here, we found that GCs from endometriosis patients show increased oxidative stress level. Methyl 3,4-dihydroxybenzoate (MDHB), a small molecule compound that is extracted from natural plants, reversed tert-butyl hydroperoxide (TBHP) induced GCs oxidative damage. Therefore, the aim of this study was to assess the protective effect of MDHB for GCs and its potential mechanisms. TUNEL staining and immunoblotting of cleaved caspase-3/7/9 showed MDHB attenuated TBHP induced GCs apoptosis. Mechanistically, MDHB treatment decreased cellular and mitochondria ROS production, improved the mitochondrial function by rescuing the mitochondrial membrane potential (MMP) and ATP production. Meanwhile, MDHB protein upregulated the expression of vital antioxidant transcriptional factor Nrf2 and antioxidant enzymes SOD1, NQO1 and GCLC to inhibited oxidative stress state, further beneficial to oocytes and embryos quality. Therefore, MDHB may represent a potential drug candidate in protecting granulosa cells in endometriosis, which can improve pregnancy outcomes for endometriosis-associated infertility.

Combining fecal 16 S rRNA sequencing and spinal cord metabolomics analysis to explain the modulatory effect of PPARα on neuropathic pain.

BACKGROUND: Existing evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury. METHODS: We analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16 S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia. RESULTS: PPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16 S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels. CONCLUSION: Our study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.

Effect of different shapes of steel fibers and palygorskite-nanofibers on performance of ultra-high-performance concrete.

Herein, a practical ultra-high-performance concrete (UHPC) was created by adding two different shapes of steel fibers and curing them at ambient temperature using palygorskite-nanofiber (PN) as the modifier. The compressive strength, flexural strength, water absorption capacity, and porosity were analyzed to determine the effects of the steel fibers and PNs on the UHPC mechanical and physical properties. The steel fibers and PNs were found to improve these properties. The UHPC mechanical properties were outstanding at 1.5% fiber dosage, while physical properties were excellent at 1.0% fiber dosage. The mechanical and physical characteristics of UHPC were preferably at a PN dosage of 0.2% and the fiber dosage of 1.0%. The compressive and flexural strengths of straight-steel-fiber UHPC were 145.57 and 19.67 MPa, respectively, i.e., 42.0 and 109.4% higher than those of the reference specimens (i.e., those without fibers or PNs); the water absorption capacity and porosity decreased by 50.1 and 60.7%, respectively. The compressive and flexural strengths of hooked-end-steel-fiber UHPC were 18.3 and 96.0% higher than those of the reference specimens, respectively, and the water absorption capacity and porosity decreased by 43.2 and 29.8%, respectively. These results could provide vital information for the promotion and practical application of UHPC.

Review on mechanism and remediation strategies of dissolved oxygen abnormal in surface water.

Dissolved oxygen (DO) is an important index to evaluate the quality of surface water environments. In recent years, anomalies in DO level have emerged as a major contributor to the decline of surface water quality. These anomalies have triggered several ecological and environmental challenges such as biodiversity loss, the degradation of water environmental quality, intensification of eutrophication, and an exacerbation of the greenhouse effect. Understanding the mechanisms underlying DO anomalies and devising targeted remediation strategies holds paramount importance in the scientific pursuit of water pollution control and aquatic ecosystem restoration. We explored and summarized the fluctuations and abnormal mechanism of DO concentration in surface water, focusing on factors like oxygen solubility, reoxygenation rates, and oxygen consumption by water bodies. We compiled a range of approaches for addressing DO anomalies, including pollution source management, artificial oxygenation, and the reconfiguration of aquatic ecosystems. Ultimately, we underscored the emerging significance of monitoring and regulating DO level in surface waters. Future research in this realm should encompass the establishment of distinct quality standards for surface water, the development of a comprehensive real-time spatial monitoring system for DO levels across watersheds, and the formulation of standardized procedures and technical norms.

Dietary and other lifestyle factors and their influence on non-communicable diseases in the Western Pacific region.

The Western Pacific region is a diverse region experiencing fast economic growth and nutrition transition. We systematically examined 94 cohort studies on the associations of dietary and other lifestyle factors on non-communicable diseases (NCDs) in the region. These studies were mainly from China, Japan, the Republic of Korea, and Singapore. Patterns and changes in lifestyle risk factors for NCDs based on national surveys were examined. They showed some dietary intake improvements over the past three decades, featured as increased consumption of unsaturated oils, fruits, and vegetables, and decreased consumption of sodium and unhealthy fat. Despite a decrease in smoking rate and salt intake, the values remained higher than the global levels in 2019. The ultra-processed food intake in the region increased at a higher rate than the global estimate. National guidelines relevant to NCDs in five selected countries were highlighted. Strong future actions and policies are needed to tackle NCDs.

SARS-CoV-2 infection in pregnant patients on TNFα inhibitor: Real-life data with a review of literature.

Tumor necrosis factor alpha (TNFα) is involved in the occurrence of negative pregnancy outcomes. The study aimed to evaluate the safety and efficacy of the immunosuppressive TNFα inhibitors (TNFαi) in the treatment of patients with a history of recurrent reproductive failure in the context of COVID-19 pandemics. We reviewed 85 patients who received TNFαi (certolizumab pegol) during Mainland China's first wave of COVID-19 pandemic, from 21st Nov 2022-11 th Jan 2023. We also collected corresponding data from 130 pregnant patients who never used TNFαi for comparison. There were no significant differences in the history of previous pregnancy loss, miscarriage, embryo implantation failure, comorbidities and doses of COVID-19 vaccination. 82.2% and 87.7% pregnant patients contracted primary COVID-19 with symptoms in TNFαi group and no-TNFαi group. Duration of symptoms was significantly longer in TNFαi group and the incidences of cough and lethargy was significantly higher in TNFαi group. Both groups reported similar severity to same-aged close contacts, similar rates of other symptoms and hospitalization. No deaths were reported. In the in vitro fertilization (IVF) subgroup, we achieved a biochemical pregnancy loss rate of 17.4%, miscarriage rate of 21.7%, ongoing pregnancy rate and live birth rate of 34.2%. COVID-19 did not influence the live birth rate. We concluded that TNFαi administration in pregnancy was not associated with increased susceptivity to and severity of COVID-19. However, TNFαi users showed more prominent symptoms and longer recovery time. The pregnancy outcomes with TNFαi in such high-risk group for pregnancy loss was satisfactory.

Preparation of anisotropic polyimide aerogels for thermal protection with outstanding flexible resilience using the freeze-drying method.

Polyimide aerogels (PIAs) not only possess excellent thermodynamic properties but also have a high porosity structure, making them an exceptional protective and thermal insulation material, and further broadening their application scope in aerospace and other cutting-edge fields. In this work, a series of anisotropic polyimide aerogels (3,3',4,4'-biphenyltetracarboxylic dianhydride (S-BPDA), p-phenylenediamine (PDA), 4,4'-diaminodiphenyl ether (ODA)) with excellent properties were prepared. These PIAs were obtained by unidirectional freeze-drying and thermal amination of two different precursor solutions mixed in proportion. These PIAs possess an irregularly oval tubular structure, exhibiting pronounced anisotropy. (PIA-2 exhibits outstanding flexible resilience in the radial direction. It can still regain its original form after half an hour of compression by a universal testing machine, yet it cannot do so in the axial direction. The thermal diffusivity of PIA-5 in the radial direction at room temperature is as low as 0.067 mm2 s-1, and even at 200 °C, the thermal diffusivity is as low as 0.057 mm2 s-1. Meanwhile, the thermal diffusivity in the axial direction at room temperature is 0.11 mm2 s-1, surpassing the value of 0.106 mm2 s-1 of aerogels prepared from monomeric raw materials and dried under supercritical conditions). PIAs exhibit outstanding thermal stability (the axial strength and modulus retention of PIA-8 at 200 °C are as high as 52.63% and 44.82%), and its weight loss temperature of 5% is as high as 603 °C and it has a glass softening temperature of 387 °C. PIAs also demonstrate exceptional flame retardancy in imitation flame retardant experiments and exhibit outstanding thermal insulation performance when heated on a 150 °C heating plate for 10 minutes (the radial surface temperature of PIA-5 was only 49.9 °C). These anisotropic PIAs materials exhibit outstanding flexible resilience, and thermal protection performance, holding significant importance for their widespread adoption as thermal insulation materials in aerospace, high-precision electronic components, and other domains.

The miR6445-NAC029 module regulates drought tolerance by regulating the expression of glutathione S-transferase U23 and reactive oxygen species scavenging in Populus.

MicroRNAs are essential in plant development and stress resistance, but their specific roles in drought stress require further investigation. Here, we have uncovered that a Populus-specific microRNAs (miRNA), miR6445, targeting NAC (NAM, ATAF, and CUC) family genes, is involved in regulating drought tolerance of poplar. The expression level of miR6445 was significantly upregulated under drought stress; concomitantly, seven targeted NAC genes showed significant downregulation. Silencing the expression of miR6445 by short tandem target mimic technology significantly decreased the drought tolerance in poplar. Furthermore, 5' RACE experiments confirmed that miR6445 directly targeted NAC029. The overexpression lines of PtrNAC029 (OE-NAC029) showed increased sensitivity to drought compared with knockout lines (Crispr-NAC029), consistent with the drought-sensitive phenotype observed in miR6445-silenced strains. PtrNAC029 was further verified to directly bind to the promoters of glutathione S-transferase U23 (GSTU23) and inhibit its expression. Both Crispr-NAC029 and PtrGSTU23 overexpressing plants showed higher levels of PtrGSTU23 transcript and GST activity while accumulating less reactive oxygen species (ROS). Moreover, poplars overexpressing GSTU23 demonstrated enhanced drought tolerance. Taken together, our research reveals the crucial role of the miR6445-NAC029-GSTU23 module in enhancing poplar drought tolerance by regulating ROS homeostasis. This finding provides new molecular targets for improving the drought resistance of trees.

Role of TRAK1 variants in epilepsy: genotype-phenotype analysis in a pediatric case of epilepsy with developmental disorder.

Purpose: The TRAK1 gene is mapped to chromosome 3p22.1 and encodes trafficking protein kinesin binding 1. The aim of this study was to investigate the genotype-phenotype of TRAK1-associated epilepsy. Methods: Trio-based whole-exome sequencing was performed on a cohort of 98 patients with epilepsy of unknown etiologies. Protein modeling and the VarCards database were used to predict the damaging effects of the variants. Detailed neurological phenotypes of all patients with epilepsy having TRAK1 variants were analyzed to assess the genotype-phenotype correlations. Results: A novel TRAK1 compound heterozygous variant comprising variant c.835C > T, p.Arg279Cys and variant c.2560A > C, p.Lys854Gln was identified in one pediatric patient. Protein modeling and VarCards database analyses revealed that the variants were damaging. The patient received a diagnosis of early infantile epileptic spasms with a developmental disorder; he became seizure-free through valproate and adrenocorticotropic hormone treatment. Further results for six variants in 12 patients with epilepsy indicated that biallelic TRAK1 variants (including homozygous or compound heterozygous variants) were associated with epilepsy with developmental disorders. Among these patients, eight (67%) had epileptic spasms and seven (58%) were intractable to anti-seizure medicines. Moreover, eight patients experienced refractory status epilepticus, of which seven (88%) died in early life. To our knowledge, this is the first reported case of epilepsy caused by TRAK1 compound heterozygous variants. Conclusion: Biallelic TRAK1 variants can cause epilepsy and developmental disorders. In these patients, seizures progress to status epilepticus, suggesting a high risk for poor outcomes and the requirement of early treatment.

Novel MEI1 mutations cause chromosomal and DNA methylation abnormalities leading to embryonic arrest and implantation failure.

This study presents a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. The primary objective was to assess the copy number variations (CNVs) and DNA methylation of her embryos. Genetic diagnosis was conducted by whole-exome sequencing and validated through Sanger sequencing. CNV evaluation of two cleavage stage embryos was performed using whole-genome sequencing, while DNA methylation and CNV assessment of two blastocysts were carried out using whole-genome bisulfite sequencing. We identified two novel pathogenic frameshift variants in the MEI1 gene (NM_152513.3, c.3002delC, c.2264_2268 + 11delGTGAGGTATGGACCAC) in the proband. These two variants were inherited from her heterozygous parents, consistent with autosomal recessive genetic transmission. Notably, two Day 3 embryos and two Day 6 blastocysts were all aneuploid, with numerous monosomy and trisomy events. Moreover, global methylation levels greatly deviated from the optimized window of 0.25-0.27, measuring 0.344 and 0.168 for the respective blastocysts. This study expands the mutational spectrum of MEI1 and is the first to document both aneuploidy and abnormal methylation levels in embryos from a MEI1-affected female patient presenting with embryonic arrest. Given that females affected by MEI1 mutations might experience either embryonic arrest or monospermic androgenetic hydatidiform moles due to the extrusion of all maternal chromosomes, the genetic makeup of the arrested embryos of MEI1 patients provides important clues for understanding the different disease mechanisms of the two phenotypes.

Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review.

CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.

Dexamethasone-Loaded Lipid Calcium Phosphate Nanoparticles Treat Experimental Colitis by Regulating Macrophage Polarization in Inflammatory Sites.

Background: The M1/M2 polarization of intestinal macrophages exerts an essential function in the pathogenesis of ulcerative colitis (UC), which can be adjusted to alleviate the UC symptoms. Purpose: A kind of pH-sensitive lipid calcium phosphate core-shell nanoparticles (NPs), co-loading with dexamethasone (Dex) and its water-soluble salts, dexamethasone sodium phosphate (Dsp), was constructed to comprehensively regulate macrophages in different states towards the M2 phenotype to promote anti-inflammatory effects. Methods: Dex and Dsp were loaded in the outer lipid shell and inner lipid calcium phosphate (Cap) core of the LdCaPd NPs, respectively. Then, the morphology of NPs and methods for determining drug concentration were investigated, followed by in vitro protein adsorption, stability, and release tests. Cell experiments evaluated the cytotoxicity, cellular uptake, and macrophage polarization induction ability of NPs. The in vivo distribution and anti-inflammatory effect of NPs were evaluated through a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced BALB/c mice ulcerative colitis model. Results: The LdCaPd NPs showed a particle size of about 200 nm and achieved considerable loading amounts of Dex and Dsp. The in vitro and in vivo studies revealed that in the acidic UC microenvironment, the cationic lipid shell of LdCaPd underwent protonated dissociation to release Dex first for creating a microenvironment conducive to M2 polarization. Then, the exposed CaP core was further engulfed by M1 macrophages to release Dsp to restrict the pro-inflammatory cytokines production by inhibiting the activation and function of the nuclear factor kappa-B (NF-κB) through activating the GC receptor and the NF kappa B inhibitor α (I-κBα), respectively, ultimately reversing the M1 polarization to promote the anti-inflammatory therapy. Conclusion: The LdCaPd NPs accomplished the sequential release of Dex and Dsp to the UC site and the inflammatory M1 macrophages at this site, promoting the regulation of macrophage polarization to accelerate the remission of UC symptoms.

Antiviral Mechanisms of Anisomycin Produced by Streptomyces albulus SN40 on Potato Virus Y.

Microbial secondary metabolites produced by Streptomyces have diverse application prospects in the control of plant diseases. Herein, the fermentation filtrate of Streptomyces SN40 effectively inhibited the infection of tobacco mosaic virus (TMV) in Nicotiana glutinosa and systemic infection of potato virus Y (PVY) in Nicotiana benthamiana. Additionally, metabolomic analysis indicated that anisomycin (C14H19NO4) and trans-3-indoleacrylic acid (C11H9NO2) were highly abundant in the crude extract and that anisomycin effectively suppressed the infection of TMV as well as PVY. Subsequently, transcriptomic analysis was conducted to elucidate its mechanisms on the induction of host defense responses. Furthermore, the results of molecular docking suggested that anisomycin can potentially bind with the helicase domain (Hel) of TMV replicase, TMV coat protein (CP), and PVY helper component proteinase (HC-Pro). This study demonstrates new functions of anisomycin in virus inhibition and provides important theoretical significance for the development of new biological pesticides to control diverse plant viruses.

Maternal anaemia during early pregnancy and the risk of neonatal outcomes: a prospective cohort study in Central China.

BACKGROUND: The purpose of this study was to explore the association between anaemia during early pregnancy and the risk of neonatal outcomes. METHODS: We collected clinical data from pregnant women (≥18 years) who received their first antenatal care between 8 and 14 weeks of gestation in Hunan Provincial Maternal and Child Health Care Hospital. Multiple logistic regression models and restricted cubic spline regression models were used to analyse the association between anaemia during early pregnancy and the risk of neonatal outcomes. In addition, sensitivity analysis was further performed to assess the robustness of the results. RESULTS: The prospective cohort study ultimately included 34 087 singleton pregnancies. In this study, the rate of anaemia during early pregnancy was 16.3%. Our data showed that there was a positive relationship between the rate of preterm birth, low birth weight as well as small for gestational age (SGA) and the severity of maternal anaemia (Ptrend<0.05). After adjustment, the association of early pregnancy anaemia and haemoglobin (Hb) levels with the risk of preterm birth (mild anaemia adjusted OR (aOR) 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 4.03 (95% CI 2.67 to 6.08), respectively), low birth weight (mild anaemia aOR 1.61 (95% CI 1.44 to 1.79), moderate anaemia aOR 2.01 (95% CI 1.75 to 2.30) and severe anaemia aOR 6.11 (95% CI 3.99 to 9.36), respectively) and SGA (mild anaemia aOR 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 2.61 (95% CI 1.74 to 4.50), respectively; Pnon-linear<0.05) was observed. However, no association was found between early pregnancy anaemia or Hb levels and the risk of congenital malformations. Sensitivity analysis verified the stability of the results. CONCLUSIONS: Maternal anaemia during early pregnancy was associated with an increased risk of preterm birth, low birth weight and SGA and their rates may increase with the severity of maternal anaemia. TRIAL REGISTRATION NUMBER: ChiCTR1800016635.

Prenatal diagnosis and appearance of nasal chondromesenchymal hamartoma in a fetus: A case report.

We report a case of fetal nasal chondromesenchymal hamartoma (NCMH) first noted on prenatal ultrasound at 34 weeks. A solid-cystic mass which predominantly hyperechoicgenic and relatively clear margin, was located on the left nasal cavity and pharynx, with anterior extension and moderate blood flow. Further follow-up ultrasound examination depicted an enlargement of the tumor. Fetal magnetic resonance imaging (MRI) showed an inhomogeneous signal lesion involving the ethmoid sinuses, nasal cavity, and pharynx. The infant, delivered via cesarean section at 37 + 5 weeks, required urgent neonatology intervention due to respiratory difficulties. Neonatal MRI and computer tomography were subsequently performed at 1 day after birth. Surgical excision occurred at 7 days, confirming NCMH via histological examination. Awareness of this entity, is essential to avoid potentially harmful therapies, especially in prenatal period. Considered NCMH in diagnosis when fetal nasal masses presenting with predominantly high-level echo, well-defined margins and moderate vascularity.

DNA looping mediates cooperative transcription activation.

Transcription factors respond to multilevel stimuli and co-occupy promoter regions of target genes to activate RNA polymerase (RNAP) in a cooperative manner. To decipher the molecular mechanism, here we report two cryo-electron microscopy structures of Anabaena transcription activation complexes (TACs): NtcA-TAC composed of RNAP holoenzyme, promoter and a global activator NtcA, and NtcA-NtcB-TAC comprising an extra context-specific regulator, NtcB. Structural analysis showed that NtcA binding makes the promoter DNA bend by ∼50°, which facilitates RNAP to contact NtcB at the distal upstream NtcB box. The sequential binding of NtcA and NtcB induces looping back of promoter DNA towards RNAP, enabling the assembly of a fully activated TAC bound with two activators. Together with biochemical assays, we propose a 'DNA looping' mechanism of cooperative transcription activation in bacteria.

Two new 2-(2-phenylethyl)chromone derivatives and two sesquiterpenes from agarwood of Aquilaria sinensis with anti-inflammatory activity.

Two new 2-(2-phenylethyl)chromones (1-2), two new sesquiterpenes (12-13), and twelve known compounds (3-11, 14-16) were isolated from agarwood of Aquilaria sinensis. These structures were confirmed by HRESIMS, 1D and 2D NMR spectra. The absolute configurations of two new sesquiterpenes were determined by comparing the experimental and calculated ECD spectra. Among them, 7,8-dihydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (2) was the first time found that the hydroxyl groups at both C-7/C-8 in agarwood. And Aseudesm B (13), the aldehyded methyl group at C-5 of eucalyptane sesquiterpenes was first discovered in natural products. In the bioassays, all compounds were evaluated for their inhibitory activity against lipopolysaccharide-activated nitric oxide (NO) production in RAW264.7 cells. Compounds 2-5, 7, 9-10, and 13-14 revealed notable inhibitory effects against NO production with IC50 values ranging from 4.0 to 13.0 µM.

Oteseconazole versus fluconazole for the treatment of severe vulvovaginal candidiasis: a multicenter, randomized, double-blinded, phase 3 trial.

Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.