A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

DNA methylation regulates biosynthesis of tanshinones and phenolic acids during growth of Salvia miltiorrhiza.

DNA methylation plays a crucial role in the regulation of plant growth and the biosynthesis of secondary metabolites. Danshen (Salvia miltiorrhiza) is a valuable Chinese herbal medicine commonly used to treat cardiovascular diseases; its active ingredients are tanshinones and phenolic acids, which primarily accumulate in roots. Here, we conducted a targeted metabolic analysis of S. miltiorrhiza roots at 3 distinct growth stages: 40 d old (r40), 60 d old (r60), and 90 d old (r90). The contents of tanshinones (cryptotanshinone, tanshinone I, tanshinone IIA, and rosmariquinone) and phenolic acids (rosmarinic acid and salvianolic acid B) gradually increased during plant development. Whole-genome bisulfite sequencing and transcriptome sequencing of roots at the 3 growth stages revealed an increased level of DNA methylation in the CHH context (H represents A, T, or C) context at r90 compared with r40 and r60. Increased DNA methylation levels were associated with elevated expression of various genes linked to epigenetic regulations, including CHROMOMETHYLASE2 (SmCMT2), Decrease in DNA Methylation 1 (SmDDM1), Argonaute 4 (SmAGO4), and DOMAINS REARRANGED METHYLTRANSFERASE 1 (SmDRM1). Moreover, expression levels of many genes involved in tanshinone and salvianolic acid biosynthesis, such as copalyldiphosphate synthase 5 (SmCPS5), cytochrome P450-related enzyme (SmCYP71D464), geranylgeranyl diphosphate synthase (SmGGPPS1), geranyl diphosphate synthase (SmGPPS), hydroxyphenylpyruvate reductase (SmHPPR), and hydroxyphenylpyruvate dioxygenase (SmHPPD), were altered owing to hyper-methylation, indicating that DNA methylation plays an important role in regulating tanshinone and phenolic acid accumulation. Our data shed light on the epigenetic regulation of root growth and the biosynthesis of active ingredients in S. miltiorrhiza, providing crucial clues for further improvement of active compound production via molecular breeding in S. miltiorrhiza.

Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion.

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell­derived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels. Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.

Free fatty acids stabilize integrin ß1via S-nitrosylation to promote monocyte-endothelial adhesion.

Hyperlipidemia characterized by high blood levels of free fatty acids (FFAs) is important for the progression of inflammatory cardiovascular diseases. Integrin ß1 is a transmembrane receptor that drives various cellular functions, including differentiation, migration, and phagocytosis. However, the underlying mechanisms modifying integrin ß1 protein and activity in mediating monocyte/macrophage adhesion to endothelium remain poorly understood. In this study, we demonstrated that integrin ß1 protein underwent S-nitrosylation in response to nitrosative stress in macrophages. To examine the effect of elevated levels of FFA on the modulation of integrin ß1 expression, we treated the macrophages with a combination of oleic acid and palmitic acid (2:1) and found that FFA activated inducible nitric oxide synthase/nitric oxide and increased the integrin ß1 protein level without altering the mRNA level. FFA promoted integrin ß1 S-nitrosylation via inducible nitric oxide synthase/nitric oxide and prevented its degradation by decreasing binding to E3 ubiquitin ligase c-Cbl. Furthermore, we found that increased integrin α4ß1 heterodimerization resulted in monocyte/macrophage adhesion to endothelium. In conclusion, these results provided novel evidence that FFA-stimulated N--O stabilizes integrin ß1via S-nitrosylation, favoring integrin α4ß1 ligation to promote vascular inflammation.

Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Phloroglucinol Meroterpenoids.

Natural products perennially serve as prolific sources of drug leads and chemical probes, fueling the development of numerous therapeutics. Despite their scarcity, natural products that modulate protein function through covalent interactions with lysine residues hold immense potential to unlock new therapeutic interventions and advance our understanding of the biological processes governed by these modifications. Phloroglucinol meroterpenoids constitute one of the most expansive classes of natural products, displaying a plethora of biological activities. However, their mechanism of action and cellular targets have, until now, remained elusive. In this study, we detail the concise biomimetic synthesis, computational mechanistic insights, physicochemical attributes, kinetic parameters, molecular mechanism of action, and functional cellular targets of several phloroglucinol meroterpenoids. We harness synthetic clickable analogues of natural products to probe their disparate proteome-wide reactivity and subcellular localization through in-gel fluorescence scanning and cell imaging. By implementing sample multiplexing and a redesigned lysine-targeting probe, we streamline a quantitative activity-based protein profiling, enabling the direct mapping of global reactivity and ligandability of proteinaceous lysines in human cells. Leveraging this framework, we identify numerous lysine-meroterpenoid interactions in breast cancer cells at tractable protein sites across diverse structural and functional classes, including those historically deemed undruggable. We validate that phloroglucinol meroterpenoids perturb biochemical functions through stereoselective and site-specific modification of lysines in proteins vital for breast cancer metabolism, including lipid signaling, mitochondrial respiration, and glycolysis. These findings underscore the broad potential of phloroglucinol meroterpenoids for targeting functional lysines in the human proteome.

A critical role of the endothelial S-phase kinase-associated protein 2/phosphatase and tensin homologue axis in angiogenesis and psoriasis.

BACKGROUND: Psoriasis is a common chronic skin disorder. Pathologically, it features abnormal epidermal proliferation, infiltrating inflammatory cells and increased angiogenesis in the dermis. Aberrant expression of E3 ubiquitin ligase and a dysregulated protein ubiquitination system are implicated in the pathogenesis of psoriasis. OBJECTIVES: To examine the potential role of S-phase kinase-associated protein 2 (Skp2), an E3 ligase and oncogene, in psoriasis. METHODS: Gene expression and protein levels were evaluated with quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence staining of skin samples from patients with psoriasis vulgaris and an imiquimod (IMQ)-induced mouse model, as well as from cultured endothelial cells (ECs). Protein interaction, substrate ubiquitination and degradation were examined using co-immunoprecipitation, Western blotting and a cycloheximide chase assay in human umbilical vein ECs. Angiogenesis was measured in vitro using human dermal microvascular ECs (HDMECs) for BrdU incorporation, migration and tube formation. In vivo angiogenesis assays included chick embryonic chorioallantoic membrane, the Matrigel plug assay and quantification of vasculature in the mouse lesions. Skp2 gene global knockout (KO) mice and endothelial-specific conditional KO mice were used. RESULTS: Skp2 was increased in skin samples from patients with psoriasis and IMQ-induced mouse lesions. Immunofluorescent double staining indicated a close association of Skp2 expression with excessive vascularity in the lesional dermal papillae. In HDMECs, Skp2 overexpression was enhanced, whereas Skp2 knockdown inhibited EC proliferation, migration and tube-like structure formation. Mechanistically, phosphatase and tensin homologue (PTEN), which suppresses the phosphoinositide 3-kinase/Akt pathway, was identified to be a novel substrate for Skp2-mediated ubiquitination. A selective inhibitor of Skp2 (C1) or Skp2 small interfering RNA significantly reduced vascular endothelial growth factor-triggered PTEN ubiquitination and degradation. In addition, Skp2-mediated ubiquitination depended on the phosphorylation of PTEN by glycogen synthase kinase 3ß. In the mouse model, Skp2 gene deficiency alleviated IMQ-induced psoriasis. Importantly, tamoxifen-induced endothelial-specific Skp2 KO mice developed significantly ameliorated psoriasis with diminished angiogenesis of papillae. Furthermore, topical use of the Skp2 inhibitor C1 effectively prevented the experimental psoriasis. CONCLUSIONS: The Skp2/PTEN axis may play an important role in psoriasis-associated angiogenesis. Thus, targeting Skp2-driven angiogenesis may be a potential approach to treating psoriasis.

N6-methyladenosine promotes induction of ADAR1-mediated A-to-I RNA editing to suppress aberrant antiviral innate immune responses.

Among over 150 distinct RNA modifications, N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing represent 2 of the most studied modifications on mammalian mRNAs. Although both modifications occur on adenosine residues, knowledge on potential functional crosstalk between these 2 modifications is still limited. Here, we show that the m6A modification promotes expression levels of the ADAR1, which encodes an A-to-I RNA editing enzyme, in response to interferon (IFN) stimulation. We reveal that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) mediates up-regulation of ADAR1; YTHDF1 is a reader protein that can preferentially bind m6A-modified transcripts and promote translation. Knockdown of YTHDF1 reduces the overall levels of IFN-induced A-to-I RNA editing, which consequently activates dsRNA-sensing pathway and increases expression of various IFN-stimulated genes. Physiologically, YTHDF1 deficiency inhibits virus replication in cells through regulating IFN responses. The A-to-I RNA editing activity of ADAR1 plays important roles in the YTHDF1-dependent IFN responses. Therefore, we uncover that m6A and YTHDF1 affect innate immune responses through modulating the ADAR1-mediated A-to-I RNA editing.

In Situ Photodeposition of Gold Nanoparticles with Exposed High-Activity Crystal Facets under Different Sacrificial Agents.

In situ photodeposition presents a powerful approach for integrating noble metal co-catalysts onto semiconductor surfaces. However, achieving precise control over the microstructure of the deposited co-catalyst remains a major challenge. Au nanoparticles (NPs) are deposited onto H-KCNO using HAuCl4 in the presence of various sacrificial agents in this study. Notably, the choice of sacrificial agent decisively influences the exposed crystal facets, loaded content, and particle size of the deposited Au NPs. Importantly, in situ photodeposition under an ethanol solution facilitates the exposure of the highly active (111) and (220) crystal facets of Au. The introduction of Au NPs significantly enhances photocatalytic hydrogen evolution, achieving rates of 4.93, 57.88, and 15.44 µmol/h for H-KCNO/Au-(water, ethanol, and lactic acid), respectively. The observed photocatalytic activity for hydrogen evolution indicates that the exposure of the highly active planes emerges as critical for significant performance enhancement. Photoelectrochemical and photoluminescence measurements suggest that the highly active (111) and (220) crystal facets effectively segregate sites for redox reactions, thereby impeding the recombination of photogenerated electron-hole pairs.

Uterine Artery Doppler Parameters: An Excellent Tool for Assessing Adverse Pregnancy Outcomes.

Objective: ObjectiveThis study aims to assess the utility of uterine artery Doppler parameters in predicting adverse pregnancy outcomes among pregnant women, thereby enhancing the safety of pregnancy. Methods: This study utilized a prospective observational design. A total of 142 pregnant women who underwent prenatal ultrasonography at our hospital and Wuxi Maternal and Child Health Hospital (Maternity Hospital affiliated with Jiangnan University) from May 2022 to May 2023 were included. Uterine artery Doppler ultrasonography was performed between 11-22 weeks of gestation, and the pulsatility index (PI) and resistance index (RI) were determined. Patients were followed until delivery, and outcomes were categorized into safety and risk groups. Differences in resistance index and pulsatility index between the groups were analyzed, along with their impact on adverse pregnancy outcomes. Results: Among the participants, 34 experienced adverse pregnancy outcomes. The risk group exhibited a higher resistance index and pulsatility index compared to the safety group (P < .05). The receiver operating characteristic curve analysis indicated that the resistance index had a sensitivity of 64.71% and specificity of 93.52% for adverse pregnancy outcomes (P < .05), while the sensitivity and specificity of the pulsatility index were 67.65% and 78.70%, respectively (P < .05). Within the subset of women with adverse outcomes, those with hypertensive disorders of pregnancy and/or gestational diabetes mellitus displayed the highest resistance index and pulsatility index (P < .05). Logistic regression analysis identified the resistance index and pulsatility index as independent risk factors for adverse pregnancy outcomes (P < .05). Conclusions: Uterine artery Doppler parameters demonstrate excellent predictive value for adverse pregnancy outcomes in pregnant women. This underscores their potential in enhancing prenatal care and pregnancy management strategies.

Family with sequence similarity 111 member B contributes to tumor growth and metastasis by mediating cell proliferation, invasion, and EMT via transforming acidic coiled-coil protein 3/PI3K/AKT signaling pathway in hepatocellular carcinoma.

As a complex systemic disease, primary liver cancer ranks third in death rate for solid tumors worldwide. Family with sequence similarity 111 member B (FAM111B), which was found to be aberrantly mutated in multiple cancers, is a candidate oncogene. We aimed to determine the function and mechanism of FAM111B in hepatocellular carcinoma (HCC). The expression of FAM111B was evaluated in HCC tissues, adjacent tissues, HCC cell lines. The impact of FAM111B on proliferation, invasion, apoptosis and EMT of HCC cells were detected by CCK-8, Transwell, flow cytometry and Western blot assays. The relationship between FAM111B and transforming acidic coiled-coil protein 3 (TACC3) was assessed by CoIP and Immunofluorescence (IF) staining assays. The effect of FAM111B on tumor growth was detected by using xenograft model of nude mice. The expression of FAM111B was upregulated in HCC tissues and cell lines, and the prognosis of HCC patients was worse in the high FAM111B expression group, and its expression level was associated with the TNM stage of HCC. FAM111B silencing inhibited HCC cell proliferation and invasion, EMT and induced apoptosis. Besides, TACC3 served as an interactor for FAM111B, which could enhance TACC3 expression, thus activing PI3K/AKT pathway. Rescue experiments revealed that elevated of TACC3 restored the inhibitory effect of FAM111B overexpression on the cell functions via PI3K/AKT pathway. In vivo, FAM111B inhibition hampered tumor growth and metastasis of HCC. This study highlighted a key player of FAM111B in modulating the malignant biological progression of HCC via TACC3/PI3K/AKT signaling pathway, displaying a potential therapeutic target for HCC.

Coupling of Photon Emitters in Monolayer WS2 with a Photonic Waveguide Based on Bound States in the Continuum.

On-chip light sources are an essential component of scalable photonic integrated circuits (PICs), and coupling between light sources and waveguides has attracted a great deal of attention. Photonic waveguides based on bound states in the continuum (BICs) allow optical confinement in a low-refractive-index waveguide on a high-refractive-index substrate and thus can be employed for constructing PICs. In this work, we experimentally demonstrated that the photoluminescence (PL) from a monolayer of tungsten sulfide (WS2) could be coupled into a BIC waveguide on a lithium-niobate-on-insulator (LNOI) substrate. Using finite-difference time-domain simulations, we numerically obtained a coupling efficiency of ∼2.3% for an in-plane-oriented dipole and a near-zero loss at a wavelength of 620 nm. By breaking through the limits of 2D-material integration with conventional photonic architectures, our work offers a new perspective for light-matter coupling in monolithic PICs.

Identification and Expression Analysis of Putative Sugar Transporter Gene Family during Bulb Formation in Lilies.

Sugar transporters play important roles in plant growth and development, flowering and fruiting, as well as responses to adverse abiotic and biotic environmental conditions. Lilies (Lilium spp.) are some of the most representative ornamental bulbous flowers. Sugar metabolism is critical for bulb formation in lilies; therefore, clarifying the amount and expression pattern of sugar transporters is essential for further analyzing their roles in bulb formation. In this study, based on the transcriptome data of the Lilium Oriental hybrid 'Sorbonne' and Lilium × formolongi, a total of 69 and 41 sugar transporters were identified in 'Sorbonne' and Lilium × formolongi, respectively, by performing bioinformatics analysis. Through phylogenetic analysis, monosaccharide transporters (MSTs) can be divided into seven subfamilies, sucrose transporters (SUTs) can be divided into three subgroups, and sugars will eventually be exported transporters (SWEETs) can be divided into four clades. According to an analysis of conserved motifs, 20, 14, and 12 conserved motifs were predicted in MSTs, SUTs, and SWEETs, respectively. A conserved domain analysis showed that MSTs and SUTs contained a single domain, whereas most of the SWEETs harbored two MtN3/saliva domains, also known as a PQ-loop repeat. The LohINT1, which was predicted to have a smaller number of transmembrane structural domains, was cloned and analyzed for subcellular localization. It was found that the LohINT1 protein is mainly localized in the cell membrane. In addition, the expression analysis indicated that 22 LohMSTs, 1 LohSUTs, and 5 LohSWEETs were upregulated in 'Sorbonne' 1 day after scale detachment treatment, suggesting that they may regulate the initiation of the bulblet. A total of 10 LflMSTs, 1 LflSUTs, and 6 LflSWEETs were upregulated 4~6 months after sowing, which corresponds to the juvenile-to-adult transition phase of Lilium × formolongi, suggesting that they may also play a role in the accompanying bulb swelling process. Combined with quantitative real-time PCR (qRT-PCR) analysis, LohSTP8 and LohSTP12 were significantly overexpressed during the extremely early stage of bulblet initiation, and LflERD6.3 was significantly overexpressed during the growth of the underground bulblet, suggesting that they may be key sugar transporters in the formation of lily bulbs, which needs further functional verification.

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OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.

Famotidine Enhances Rifampicin Activity against Acinetobacter baumannii by Affecting OmpA.

The development of novel antibiotic adjuvants is imminent because of the frequent emergence of resistance in Gram-negative bacteria, which severely restricts the efficiency and longevity of commonly used clinical antibiotics. It is reported that famotidine, a clinical inhibitor of gastric acid secretion, enhances the antibacterial activity of rifamycin antibiotics, especially rifampicin, against Gram-negative bacteria and reverses drug resistance. Studies have shown that famotidine disrupts the cell membrane of Acinetobacter baumannii and inhibits the expression of the outer membrane protein ompA gene, while causing a dissipation of the plasma membrane potential, compensatively upregulating the pH gradient and ultimately increasing the accumulation of reactive oxygen species by leading to increased bacterial mortality. In addition, famotidine also inhibited the efflux pump activity and the biofilm formation of A. baumannii. In the Galleria mellonella and mouse infection models, the combination of famotidine and rifampicin increased the survival rate of infected animals and decreased the bacterial load in mouse organs. In conclusion, famotidine has the potential to be a novel rifampicin adjuvant, providing a new option for the treatment of clinical Gram-negative bacterial infections. IMPORTANCE In this study, famotidine was discovered for the first time to have potential as an antibiotic adjuvant, enhancing the antibacterial activity of rifamycin antibiotics against A. baumannii and overcoming the limitations of drug therapy. With the discovery of novel applications for the guanidine-containing medication famotidine, the viability of screening prospective antibiotic adjuvants from guanidine-based molecules was further explored. In addition, famotidine exerts activity by affecting the OmpA protein of the cell membrane, indicating that this protein might be used as a therapeutic drug target to treat A. baumannii infections.

Coded aperture snapshot hyperspectral light field tomography.

Multidimensional imaging has emerged as a powerful technology capable of simultaneously acquiring spatial, spectral, and depth information about a scene. However, existing approaches often rely on mechanical scanning or multi-modal sensing configurations, leading to prolonged acquisition times and increased system complexity. Coded aperture snapshot spectral imaging (CASSI) has introduced compressed sensing to recover three-dimensional (3D) spatial-spectral datacubes from single snapshot two-dimensional (2D) measurements. Despite its advantages, the reconstruction problem remains severely underdetermined due to the high compression ratio, resulting in limited spatial and spectral reconstruction quality. To overcome this challenge, we developed a novel two-stage cascaded compressed sensing scheme called coded aperture snapshot hyperspectral light field tomography (CASH-LIFT). By appropriately distributing the computation load to each stage, this method utilizes the compressibility of natural scenes in multiple domains, reducing the ill-posed nature of datacube recovery and achieving enhanced spatial resolution, suppressed aliasing artifacts, and improved spectral fidelity. Additionally, leveraging the snapshot 3D imaging capability of LIFT, our approach efficiently records a five-dimensional (5D) plenoptic function in a single snapshot.

Limited view correction in low-optical-NA photoacoustic microscopy.

Photoacoustic microscope (PAM) with a low-optical NA suffers from a limited view along the optical axis, due to the coherent cancellation of acoustic pressure waves after being excited with a smoothly focused beam. Using larger-NA (NA > 0.3) objectives can readily overcome the limited-view problem, while the consequences are the shallow working distance and time-consuming depth scanning for large-volume imaging. Instead, we report an off-axis oblique detection strategy that is compatible with a low-optical-NA PAM for turning up the optical-axis structures. Comprehensive photoacoustic modeling and ex vivo phantom and in vivo mouse brain imaging experiments are conducted to validate the efficacy of correcting the limited view. Proof-of-concept experiment results show that the visibility of optical-axis structures can be greatly enhanced by making the detection angle off the optical axis larger than 45°, strongly recommending that off-axis oblique detection is a simple and cost-effective alternative method to solve the limited-view problems in low-optical-NA PAMs.

Validity of the food frequency questionnaire for adults in nutritional epidemiological studies: A systematic review and meta-analysis.

As the most widely used tool for assessing dietary intake, the validity of food frequency questionnaires (FFQs) should be evaluated before application. A comprehensive search of the PubMed and Web of Science databases was conducted for publications from January 2000 to April 1, 2020. Pooled estimates were calculated for correlation coefficients and mean differences for energy and 61 nutrients between FFQs and standard methods. The literature search identified 130 articles that included 21,494 participants. Subgroup analyses according to the number of administrations of the reference method, sample size, administration methods, FFQ items, reference periods, quality of the studies, gender, and regions were also performed. We conducted a meta-analysis by summarizing the available evidence to comprehensively assess the validity of FFQs stratified by the reference method type (24-hour recall (24HRs) and food records (FRs). We also performed subgroup analyses to examine the impact on the final summary estimates. After a meta-analysis of the FFQs' validity correlation coefficients of the included studies, this study showed that the range (median) of the validity coefficients of the 24HRs as reference methods was 0.220-0.770 (0.416), and for the FRs, it was 0.173-0.735 (0.373), which indicated that FFQs were suitable to assess the overall dietary intake in nutritional epidemiological studies. The results of the subgroup analysis showed that the number of administrations of the reference method, administration mode, number of items, reference periods, sample size, and gender mainly affected the validity correlation of FFQs.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1966737 .

Orbital magnetic resonance imaging of giant cell arteritis with ocular manifestations: a systematic review and individual participant data meta-analysis.

OBJECTIVES: We conducted a systematic review and individual participant data meta-analysis of publications reporting the ophthalmologic presentation, clinical exam, and orbital MRI findings in patients with giant cell arteritis and ocular manifestations. METHODS: PubMed and Cochrane databases were searched up to January 16, 2022. Publications reporting patient-level data on patients with ophthalmologic symptoms, imaged with orbital MRI, and diagnosed with biopsy-proven giant cell arteritis were included. Demographics, clinical symptoms, exam, lab, imaging, and outcomes data were extracted. The methodological quality and completeness of reporting of case reports were assessed. RESULTS: Thirty-two studies were included comprising 51 patients (females = 24; median age, 76 years). Vision loss (78%) and headache (45%) were commonly reported visual and cranial symptoms. Ophthalmologic presentation was unilateral (41%) or bilateral (59%). Fundus examination most commonly showed disc edema (64%) and pallor (49%). Average visual acuity was very poor (2.28 logMAR ± 2.18). Diagnoses included anterior (61%) and posterior (16%) ischemic optic neuropathy, central retinal artery occlusion (8%), and orbital infarction syndrome (2%). On MRI, enhancement of the optic nerve sheath (53%), intraconal fat (25%), and optic nerve/chiasm (14%) was most prevalent. Among patients with monocular visual symptoms, 38% showed pathologic enhancement in the asymptomatic orbit. Six of seven cases reported imaging resolution after treatment on follow-up MRIs. CONCLUSIONS: Vision loss, pallid disc edema, and optic nerve sheath enhancement are the most common clinical, fundoscopic, and imaging findings reported in patients diagnosed with giant cell arteritis with ocular manifestations, respectively. MRI may detect subclinical inflammation and ischemia in the asymptomatic eye and may be an adjunct diagnostic tool. CLINICAL RELEVANCE STATEMENT: Brain and orbital MRIs may have diagnostic and prognostic roles in patients with suspected giant cell arteritis who present with ophthalmic symptoms.

RNA Modifications in Cancer Stem Cell Biology.

Post-transcriptional regulation of gene expression shapes the cell state both in health and disease. RNA modifications-especially N6-methyladenosine (m6A)-have recently emerged as key players in RNA processing that depends on a sophisticated interplay between proteins of the RNA modification machinery. Importantly, the RNA epitranscriptome becomes dysregulated in cancer and promotes cancer-associated gene expression programs as well as cancer cell adaptation to the tumor microenvironment. At the top of the tumor hierarchy, cancer stem cells (CSCs) are master regulators of tumorigenesis and resistance to therapeutic intervention. Therefore, defining how RNA modifications influence the CSC state is of great importance for cancer drug development. In this chapter, we summarize the current knowledge of the roles of RNA modifications in shaping the CSC state and driving gene expression programs that confer stem-like properties to CSCs, promote CSC adaptation to the local microenvironment, and endow CSCs with metastatic potential and drug resistance.

Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.