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•Dynamic changes in neutrophil NETosis in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) are assessed.•Similar to DNase I, recombinant ADAMTS13 or caplacizumab prevents the accumulation of neutrophil extracellular traps under flow in iTTP.

Cardiovascular diseases are caused by hypercholesterolemia. Astaxanthin (AST) has been reported to exhibit antioxidant and anti-inflammatory properties. However, its bioavailability is poor because of low solubility and instability. In order to improve the bioavailability of AST, we developed an intestinal-responsive composite carrier termed as “liposomes in micropheres” incorporating N-succinyl-chitosan (NSC)-poly(ethylene glycol) (PEG) liposomes that functionalized by neonatal Fc receptors (FcRn) into hydrogels of sodium alginate (SA) and carboxymethyl chitosan (CMCS). In the AST NSC/HSA-PEG liposomes@SA/CMCS microspheres, the AST’s encapsulation efficiency (EE) was 96.26% (w/w) and its loading capacity (LC) was 6.47% (w/w). AST NSC/HSA-PEG liposomes had stability in the gastric conditions and achieved long-term release of AST in intestinal conditions. Then, AST NSC/HSA-PEG liposomes@SA/CMCS bind to intestinal epithelial cell targets by the neonatal Fc receptor. In vitropermeation studies show that there was a 4-fold increase of AST NSC/HSA-PEG liposomes@SA/CMCS in AST permeation across the intestinal epithelium. Subsequent in vivoexperiments demonstrated that the composite carrier exhibited a remarkable mucoadhesive capacity, allowing for extended intestinal retention of up to 12 h, and it displayed deep penetration through the mucus layer, efficiently entering the intestinal villi epithelial cells, and enhancing the absorption of AST and its bioavailability in vivo. And oral administration of AST NSC/HSA-PEG liposomes@SA/CMCS could effectively prevent hypercholesterolemia caused by a high-fat, high-cholesterol diet (HFHCD). These advancements highlight the potential of NSC/HSA-PEG liposomes@SA/CMCS composite carriers for targeted and oral uptake of hydrophobic bioactives.

Diabetic retinopathy (DR), caused by hyperglycemia, has been becoming the tremendous public health threaten globally. Recently, there has been a growing interest in using natural bioactive products for dietary intervention to manage the progression of DR. In this study, we utilized the streptozotocin (STZ)-induced retinopathy model in C57BL/6 J mice to investigate the impact of blueberry anthocyanin extract (BAEs) on the retinal cells of diabetic mice and assess the antioxidant activity of BAEs. Our results indicate that BAEs intervention significantly improved oxidative stress and inflammation levels in the retina of STZ-induced diabetic mice by downregulating the expression of regulated in development and DNA damage 1 (REDD1) in the choroid-retinal pigment epithelium (choroid-RPE). Cyanidin-3-O-glucoside (C3G), a primary component of BAEs, was further examined to explore potential molecular mechanisms. Our findings suggest that upregulation of REDD1 led to increase the vascular endothelial growth factor A (VEGFA) expression in ARPE-19 cells exposed to high glucose (HG); however, intervention with C3G mediated REDD1-driven VEGFA transcription and mitigated HG-induced changes in cell injury by regulating intracellular redox balance. The knockout of REDD1 effectively reversed HG-induced alterations in VEGFA levels, confirming the crucial role of REDD1 in the regulating of retinal vascular permeability factors. Overall, BAEs demonstrate potential in alleviating HG-induced DR, with the key component C3G exerting significant effects by inhibiting REDD1 activity and its downstream signaling pathways. These findings underscore the potential of REDD1 as a target for mitigating hyperglycemia-induced retinopathy and emphasize the value of BAEs as a dietary intervention strategy.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical–stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P< .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P< .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P< .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Cynoglossus semilaevis(half-smooth tongue sole) is an important aquaculture species that has a ZW/ZZ sex-determination system (females, ZW; males, ZZ). Some genotypic females may develop phenotypic males, and are known as pseudomales (ZW). These pseudomales can develop mature testes and produce sperm. However, previous studies have shown that pseudomales cannot produce sperms bearing W chromosome (W sperm). In this study, transcriptomic, proteomic, and ubiquitinated proteomic analyses were employed simultaneously to investigate the differences in gonads between pseudomales and normal males. Functional enrichment analysis of the differentially expressed genes/proteins showed that non-coding RNA metabolic processes and RNA degradation were more active in the gonads of pseudomales, and they showed higher levels of ubiquitination compared to males. In addition, most genes/proteins related to sperm morphogenesis expressed downwards in pseudomales. These genes included genes located exclusively on the Z chromosome, such as sperm flagellar protein 2 (spef2), doublesex and mab-3 related transcription factor 1 (dmrt1), doublesex and mab-3 related transcription factor 3 (dmrt3), and cilia- and flagella-associated protein 157 (cfap157). These findings characterized the transcriptional and proteomic profiles of the gonads of pseudomales and males, and suggested that W sperm were absent in pseudomales, possibly due to the disruption of sperm morphogenesis, resulting from W chromosome lacking spermatogenesis-related genes.

The retinal pigment epithelium (RPE) serves dual roles: it acts as a selective barrier and also as a regulator for the photoreceptor layer situated above it. The RPE is considered a crucial target for halting the development and progression of diabetic retinopathy (DR). This study focuses on understanding the protective role of blueberry anthocyanin extracts (BAEs), particularly its anti-oxidant constituent, cyanidin-3-O-glucoside (C3G), against damage to RPE cells induced by high glucose (HG) levels. The findings revealed that the BAEs mitigated damage to HG-induced ARPE-19 cells by decreasing the intracellular reactive oxygen species (ROS) levels, which improved cell morphology and cell viability (p < 0.01). Importantly, these cytoprotective effects were linked to the C3G rich in BAEs. The underlying mechanism may involve C3G interrupting the ROS generation feedback loop by downregulating REDD1 expression, which in turn enhanced the retinal Nrf2 antioxidant response to HG through the promotion of the GSK3β phosphorylation at Ser-9. Moreover, C3G suppressed VEGFA expression by inhibiting REDD1 levels in HG-induced ARPE-19 cells, subsequently preventing an increase in vascular permeability. In conclusion, this study suggested that the C3G relieved HG-induced oxidative stress damage in ARPE-19 cells via REDD1/GSK3β pathway and inhibited an increase in vascular permeability by downregulating VEGFA expression. These insights could shed light on how this natural bioactive compound can help manage HG-associated eye disorders like DR.

Cancer cells are generally immersed in an oxidative stress environment with a high intracellular reduction level. Thus, nanocarriers with sequential responsiveness to oxidative and reductive species, matching the traits of high oxidation in the tumor tissue microenvironment and high reduction potential inside cancer cells, are highly desired for specific cancer therapy. Herein, we report a supramolecular nanomedicine comprised of a reduction-responsive nanoparticle (NP) core whose surface was modified by an oxidation-responsive polyethylene glycol (PEG) derivative viastrong host–guest interactions. In this delicate design, the PEGylation of NPs not only reduced their immunogenicity and extended systemic circulation, but also enabled oxidation-responsive de-PEGylation in the tumor tissues and subsequent intracellular payload release in response to glutathione (GSH) inside tumor cells. As a proof of concept, this supramolecular nanomedicine exhibited specific chemotherapeutic effects against cancer in vitroand in vivowith a decent safety profile.

IMPORTANCE: Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant. OBJECTIVE: To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo. DESIGN, SETTING, AND PARTICIPANTS: This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance. INTERVENTIONS: Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks. MAIN OUTCOMES AND MEASURES: Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins. RESULTS: In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was −16.0% with bempedoic acid vs 1.8% with placebo (difference, −17.8%; 95% CI, −19.5% to −16.0%; P &lt; .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were −23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, −24.5%; 95% CI, −27.8% to −21.1%; P &lt; .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of −12.7% at week 52; patients with statin intolerance, difference of −22.2% at week 24). Decreases in non–high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs &lt;0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%). CONCLUSIONS AND RELEVANCE: Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115

Host genetic variation may be a contributing factor to variability in Staphylococcus aureusbacteremia duration. We assessed whether 28 single nucleotide polymorphisms (SNPs) in seven genes (TLR2, TLR4, TIRAP, IRAK4, TRAF6, NOD2, and CISH) that mediate host immune response were associated with S. aureusbacteremia duration. Subjects included 158 patients with short-term (≤4 days) and 44 with persistent (>4 days) S. aureusbacteremia from an academic medical center. In single SNP analyses, the minor allele frequencies of three TIRAPSNPs (rs655540, rs563011, and rs8177376) were higher in persistent bacteremia (P< 0.05). A haplotype with all three minor alleles was also associated with persistent bacteremia (P= 0.037). The minor allele frequencies of four other TIRAPSNPs (rs8177342, rs4937114, rs3802813, and rs4937115) were higher in short-term bacteremia (P< 0.05), and a haplotype containing the four minor alleles was associated with short-term bacteremia (P= 0.045). All seven SNPs are located in binding sites for proteins or noncoding RNAs that regulate transcription. None of the associations remained statistically significant after adjustment for multiple comparisons. Further investigation is needed to understand how genetic variation in TIRAPand other host immune genes may influence the duration of S. aureusbacteremia.

In recent years, RNA-sequencing (RNA-seq) has emerged as a powerful technology for transcriptome profiling. For a given gene, the number of mapped reads is not only dependent on its expression level and gene length, but also the sequencing depth. To normalize these dependencies, RPKM (reads per kilobase of transcript per million reads mapped) and TPM (transcripts per million) are used to measure gene or transcript expression levels. A common misconception is that RPKM and TPM values are already normalized, and thus should be comparable across samples or RNA-seq projects. However, RPKM and TPM represent the relative abundance of a transcript among a population of sequenced transcripts, and therefore depend on the composition of the RNA population in a sample. Quite often, it is reasonable to assume that total RNA concentration and distributions are very close across compared samples. Nevertheless, the sequenced RNA repertoires may differ significantly under different experimental conditions and/or across sequencing protocols; thus, the proportion of gene expression is not directly comparable in such cases. In this review, we illustrate typical scenarios in which RPKM and TPM are misused, unintentionally, and hope to raise scientists’ awareness of this issue when comparing them across samples or different sequencing protocols.

We aimed to estimate the carrier frequency of Zellweger spectrum disorder (ZSD), a rare autosomal recessive disease, and the associated disease incidence based on data from the Exome Aggregation Consortium (ExAC) of approximately 60,000 individuals.

Metal–organic framework-templated g-C3N4–NiCoP2–porous carbon (PC) ternary hybrid nanomaterials were designed by taking full advantage of the metal–organic framework (MOF) derivative in the photocatalytic reaction for the first time. The MOF-templated porous structure could prevent the stacking of the carbon nitride nanosheet, and the carefully designed NiCoP2, possessing low electrocatalytic hydrogen evolution reaction (HER) overpotential and flat-band potential, could improve the separation as well as the utilization efficiency of photogenerated electron–hole pairs. Moreover, the ligand-templated porous carbon, acting as an interface mediator between g-C3N4and the NiCoP2cocatalyst, could boost the charge carrier transport. Consequently, the optimal ternary g-C3N4–NiCoP2–PC heterostructure exhibited enhanced photocatalytic HER performance and considerable H2evolution performance of 5.8 μmol/h/g under UV–visible light with stoichiometric H2O2production even in pure water. This work took full advantage of the MOF derivative for improving the photocatalytic reaction activity and provided a method that can hopefully help in designing a novel high-performance catalyst for solar conversion.

Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor–encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor–encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Rationally designing a photocatalytic system is of significance for effectively converting infinite solar energy into clean hydrogen energy. This study revealed that bulk modification of ZnCdS–CdS heterojunction viaphosphorus doping and surface modulation by adopting the novel VS2as the cocatalyst exhibited synergistic effects for improving the photocatalytic activity of the heterojunction. Notably, the photocatalytic hydrogen evolution rate of the pristine ZnCdS–CdS heterostructure raised from 25.46 to 72.82 and 52.82 μmol h−1using only 5 mg photocatalyst with the bulk and surface modification alone, respectively, while the hydrogen evolution rate increased to 192.28 μmol h−1with both bulk phosphorus doping and surface adoption of VS2, opening a new method for the improving the photocatalytic activity by both bulk and surface modulation.

Three typical edible oils (palm oil, PO; leaf lard oil, LO; rapeseed oil, RO) and triacylglycerols (TAGs) (glycerol tripalmitate, GTP; glycerol tristearate, GTS; glycerol trioleate, GTO) were selected to conduct digestion experiments using fully designed in vitro digestion model. The evolutions in mean particle diameter, ζ-potential, and microstructural changes during different digestion stages were investigated. Free fatty acid (FFA) release extent and kinetics were monitored by pH-Stat method. The particle characterization of different lipids during passage through the GIT depended on lipid type and the microenvironment they encountered. Absorbed surface protein can hardly be the obstacle for pancreas lipase to catalyze lipid hydrolysis after gastric digestion. The maximum FFA release level and apparent rate constant in small intestine digestion stage of the three oils and TAGs were: PO > RO > LO, GTP > GTS > GTO, respectively. PO showed the highest FFA release level and rate mainly due to the short chain length saturated palmitic acid (C16:0) specifically located in the Sn-1, 3 positions of TAG molecules in palm oil, while the Sn-1, 3 positions of TAG molecules in RO and LO were mainly mono- or polyunsaturated fatty acids (C18:1 or C18:2), restricting the continuous hydrolysis reaction. These findings can provide some basic understanding of the digestion differences of different lipids, which may be useful for their nutritional and functional evaluation and the applicability in the food area.

The study objective was to evaluate the workflow of dental providers who use the existing electronic dental record (EDR) system at a large regional health care system to establish a diagnostic-centric culture as part of their dental practice. A further goal focused on identifying when improvements to the workflow and design of the EDR may be indicated.

The authors conducted this study to identify the most relevant patient dental information in a medical-dental integrated electronic health record (iEHR) necessary for medical care providers to inform holistic treatment.

Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

Supplemental Digital Content is Available in the Text.Genetic variants within the BUD13–APOA5gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin–fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13–APOA5region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P= 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P= 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P= 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13–APOA5region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13–APOA5can affect TG and LDL-C response to statin therapy in a North American population.

The use of electronic health records (EHRs) in dental care and their effect on dental care provider-patient interaction have not been studied sufficiently. The authors conducted a study to explore dental care providers' interactions with EHRs during patient visits, how these interactions influence dental care provider-patient communication, and the providers' and patients' perception of EHR use in the dental clinic setting during patient visits.

The use of electronic health records (EHRs) in dental care and their effect on dental care provider-patient interaction have not been studied sufficiently. The authors conducted a study to explore dental care providers' interactions with EHRs during patient visits, how these interactions influence dental care provider-patient communication, and the providers' and patients' perception of EHR use in the dental clinic setting during patient visits.