SANS reveals lipid-dependent oligomerization of an intramembrane aspartyl protease from H. volcanii.

Reactions that occur within the lipid membrane involve, at minimum, ternary complexes among the enzyme, substrate, and lipid. For many systems, the impact of the lipid in regulating activity or oligomerization state is poorly understood. Here, we used small-angle neutron scattering (SANS) to structurally characterize an intramembrane aspartyl protease (IAP), a class of membrane-bound enzymes that use membrane-embedded aspartate residues to hydrolyze transmembrane segments of biologically relevant substrates. We focused on an IAP ortholog from the halophilic archaeon Haloferax volcanii (HvoIAP). HvoIAP purified in n-dodecyl-ß-D-maltoside (DDM) fractionates on size-exclusion chromatography (SEC) as two fractions. We show that, in DDM, the smaller SEC fraction is consistent with a compact HvoIAP monomer. Molecular dynamics flexible fitting conducted on an AlphaFold2-generated monomer produces a model in which loops are compact alongside the membrane-embedded helices. In contrast, SANS data collected on the second SEC fraction indicate an oligomer consistent with an elongated assembly of discrete HvoIAP monomers. Analysis of in-line SEC-SANS data of the HvoIAP oligomer, the first such experiment to be conducted on a membrane protein at Oak Ridge National Lab (ORNL), shows a diversity of elongated and spherical species, including one consistent with the tetrameric assembly reported for the Methanoculleus marisnigri JR1 IAP crystal structure not observed previously in solution. Reconstitution of monomeric HvoIAP into bicelles increases enzyme activity and results in the assembly of HvoIAP into a species with similar dimensions as the ensemble of oligomers isolated from DDM. Our study reveals lipid-mediated HvoIAP self-assembly and demonstrates the utility of in-line SEC-SANS in elucidating oligomerization states of small membrane proteins.

Lipid environment modulates processivity and kinetics of a presenilin homolog acting on multiple substrates in vitro.

Intramembrane proteases (IPs) hydrolyze peptides in the lipid membrane. IPs participate in a number of cellular pathways including immune response and surveillance, and cholesterol biosynthesis, and they are exploited by viruses for replication. Despite their broad importance across biology, how activity is regulated in the cell to control protein maturation and release of specific bioactive peptides at the right place and right time remains largely unanswered, particularly for the intramembrane aspartyl protease (IAP) subtype. At a molecular biochemical level, different IAP homologs can cleave non-biological substrates, and there is no sequence recognition motif among the nearly 150 substrates identified for just one IAP, presenilin-1, the catalytic component of γ-secretase known for its involvement in the production of amyloid-ß plaques associated with Alzheimer disease. Here we used gel-based assays combined with quantitative mass spectrometry and FRET-based kinetics assays to probe the cleavage profile of the presenilin homolog from the methanogen Methanoculleus marisnigri JR1 as a function of the surrounding lipid-mimicking environment, either detergent micelles or bicelles. We selected four biological IAP substrates that have not undergone extensive cleavage profiling previously, namely, the viral core protein of Hepatitis C virus, the viral core protein of Classical Swine Fever virus, the transmembrane segment of Notch-1, and the tyrosine receptor kinase ErbB4. Our study demonstrates a proclivity toward cleavage of substrates at positions of low average hydrophobicity and a consistent role for the lipid environment in modulating kinetic properties.

DNA Origami Plasmonic Nanoantenna for Programmable Biosensing of Multiple Cytokines in Cancer Immunotherapy.

Herein, we report a DNA origami plasmonic nanoantenna for the programmable surface-enhanced Raman scattering (SERS) detection of cytokine release syndrome (CRS)-associated cytokines (e.g., tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)) in cancer immunotherapy. Typically, the nanoantenna was made of self-assembled DNA origami nanotubes (diameter: ∼19 nm; length: ∼90 nm) attached to a silver nanoparticle-modified silicon wafer (AgNP/Si). Each DNA origami nanotube contains one miniature gold nanorod (AuNR) inside (e.g., length: ∼35 nm; width: ∼7 nm). Intriguingly, TNF-α and IFN-γ logically regulate the opening of the nanotubes and the dissociation of the AuNRs from the origami structure upon binding to their corresponding aptamers. On this basis, we constructed a complete set of Boolean logic gates that read cytokine molecules as inputs and return changes in Raman signals as outputs. Significantly, we demonstrated that the presented system enables the quantification of TNF-α and IFN-γ in the serum of tumor-bearing mice receiving different types of immunotherapies (e.g., PD1/PD-L1 complex inhibitors and STING agonists). The sensing results are consistent with those of the ELISA. This strategy fills a gap in the use of DNA origami for the detection of multiple cytokines in real systems.

Fruit but not vegetable consumption is beneficial for low prevalence of colorectal polyps in a high-risk population: findings from a Chinese Lanxi Pre-colorectal Cancer Cohort study.

PURPOSE: The available evidence regarding the role of fruit and vegetable consumption in the development of colorectal polyps remains inconclusive, and there is a lack of data on different histopathologic features of polyps. We aimed to evaluate the associations of fruit and vegetable consumption with the prevalence of colorectal polyps and its subtypes in a high-risk population in China. METHODS: We included 6783 Chinese participants aged 40-80 years who were at high risk of colorectal cancer (CRC) in the Lanxi Pre-colorectal Cancer Cohort (LP3C). Dietary information was obtained through a validated food-frequency questionnaire (FFQ), and colonoscopy screening was used to detect colorectal polyps. Dose-response associations of fruit and vegetable intake with the prevalence of polyps were calculated using multivariate-adjusted regression models, which was reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: 2064 cases of colorectal polyps were ascertained in the LP3C during 2018-2019. Upon multivariable adjustments, including the diet quality, fruit consumption was inversely associated with the prevalence of polyps (P trend = 0.02). Participants in the highest tertile of fruit intake had a 25% lower risk (OR: 0.75; 95% CI 0.62‒0.92) compared to non-consumers, while vegetable consumption had no significant association with polyp prevalence (P trend = 0.86). In terms of colorectal histopathology and multiplicity, higher fruit intake was correlated with 24, 23, and 33% lower prevalence of small polyps (OR: 0.76; 95% CI 0.62‒0.94; P trend = 0.05), single polyp (OR: 0.77; 95% CI 0.62‒0.96; P trend = 0.04), and distal colon polyps (OR: 0.67; 95% CI 0.51‒0.87; P trend = 0.003), respectively. CONCLUSIONS: Fresh fruit is suggested as a protective factor to prevent colorectal polyps in individuals at high risk of CRC, and should be underscored in dietary recommendations, particularly for high-risk populations.

Tetracycline-induced gut community dysbiosis and Israeli Acute Paralysis Virus infection synergistically negatively affect honeybees.

Antibiotics are frequently employed to control bacterial diseases in honeybees, but their broad-spectrum action can disrupt the delicate balance of the gut microbiome, leading to dysbiosis. This imbalance in the gut microbiota of honeybees adversely affects their physiological health and weakens their resistance to pathogens, including viruses that significantly threaten honeybee health. In this study, we investigated whether tetracycline-induced gut microbiome dysbiosis promotes the replication of Israeli acute paralysis virus (IAPV), a key virus associated with colony losses and whether IAPV infection exacerbates gut microbiome dysbiosis. Our results demonstrated that tetracycline-induced gut microbiome dysbiosis increases the susceptibility of honeybees to IAPV infection. The viral titer in worker bees with antibiotic-induced gut microbiome dysbiosis prior to IAPV inoculation was significantly higher than in those merely inoculated with IAPV. Furthermore, we observed a synergistic effect between tetracycline and IAPV on the disruption of the honeybee gut microbiome balance. The progression of IAPV replication could, in turn, exacerbate antibiotic-induced gut microbiome dysbiosis in honeybees. Our research provides novel insights into the role of the gut microbiota in host-virus interactions, emphasizing the complex interplay between antibiotic use, gut microbiome health, and viral susceptibility in honeybees. We highlight the crucial role of a balanced gut microbiota in honey bees for their immune response against pathogens and emphasize the importance of careful, safe antibiotic use in beekeeping to protect these beneficial microbes.

Synergistic effects of peracetic acid and free ammonia pretreatment on anaerobic fermentation of waste activated sludge to promote short-chain fatty acid production for polyhydroxyalkanoate biosynthesis: Mechanisms and optimization.

Peracetic acid (PAA) combined with free ammonia (FA) pretreatment can be utilized to promote anaerobic fermentation (AF) of waste activated sludge (WAS) to produce short-chain fatty acids (SCFAs), and the resulting SCFAs are desirable carbon sources (C-sources) for polyhydroxyalkanoate (PHA) biosynthesis. This work aimed to determine the optimum conditions for PAA + FA pretreatment of sludge AF and the feasibility of using anaerobic fermentation liquor (AFL) for PHA production. To reveal the mechanisms of integrated pretreatment, the impacts of PAA + FA pretreatment on different stages of sludge AF and changes in the microbial community structure were explored. The experimental results showed that the maximum SCFA yield reached 491.35 ± 6.02 mg COD/g VSS on day 5 after pretreatment with 0.1 g PAA/g VSS +70 mg FA/L, which was significantly greater than that resulting from PAA or FA pretreatment alone. The mechanism analysis showed that PAA + FA pretreatment promoted sludge solubilization but strongly inhibited methanogenesis. According to the analysis of the microbial community, PAA + FA pretreatment changed the microbial community structure and promoted the enrichment of bacteria related to hydrolysis and acidification, and Proteiniclasticum, Macellibacteroides and Petrimonas became the dominant hydrolytic and acidifying bacteria. Finally, after alkali treatment, the AFL was utilized for batch-mode PHA production, and a maximum PHA yield of 55.05 wt% was achieved after five operation periods.

Microbial community changes and metabolic pathways analysis during waste activated sludge and meat processing waste anaerobic co-digestion.

Waste activated sludge (WAS) and meat processing waste (MPW) were acted as co-substrates in anaerobic co-digestion (AcD), and biochemical methane potential (BMP) test was carried out to investigate the methane production performances. Microbial community structure and metabolic pathways analyses were conducted by 16S rRNA high-throughput sequencing and functional prediction analysis. BMP test results indicated that AcD of 70% WAS+30% MPW and 50% WAS+50% MPW (VS/VS) could significantly improve methane yield to 371.05 mL/g VS and 599.61 mL/g VS, respectively, compared with WAS acting as sole substrate (191.87 mL/g VS). The results of microbial community analysis showed that Syntrophomonas and Petrimonas became the dominant bacteria genera, and Methanomassiliicoccus and Methanobacterium became the dominant archaea genera after MPW addition. 16S functional prediction analysis results indicated that genes expression of key enzymes involved in syntrophic acetate oxidation (SAO), hydrogenotrophic and methylotrophic methanogenesis were up-regulated, and acetoclastic methanogenesis was inhibited after MPW addition. Based on these analyses, it could be inferred that SAO combined with hydrogenotrophic and methylotrophic methanogenesis was the dominant pathway for organics degradation and methane production during AcD. These findings provided systematic insights into the microbial community changes and metabolic pathways during AcD of WAS and MPW.

Parental Autonomy Granting, Peer Attachment and Problematic Internet Use Among Chinese Adolescents: The Moderating Effect of School Climate.

While the correlation between parental autonomy granting and adolescents' problematic Internet use (PIU) has been confirmed, the processes underlying this connection have not been thoroughly investigated. Drawing on the ecological systems theory, this study sought to investigate the mediating mechanism of peer attachment and the moderating mechanism of school climate that link parental autonomy granting to PIU. A two-wave longitudinal design was employed with a time interval of six months. The participants were 852 adolescents who attended three middle schools located in Guangdong Province, China. Self-report questionnaires were used to obtain data on demographics, parental autonomy granting, peer attachment, school climate, and PIU. The findings indicated that peer attachment significantly mediated the link between parental autonomy granting and adolescent PIU. A positive school climate significantly moderated the influence of parental autonomy granting on peer attachment and the influence of peer attachment on PIU. Specifically, the association between parental autonomy granting and peer attachment and the association between peer attachment and PIU were more pronounced when the school climate was perceived to be positive. This research underscores the possible significance of peer attachment in the association between parental autonomy granting and PIU and offers valuable insights for mitigating the negative outcomes of PIU.

[Systematic review and Meta-analysis of efficacy and safety of Bidouyan Oral Liquid in treatment of rhinosinusitis].

This study aimed to systematically review the efficacy and safety of Bidouyan Oral Liquid in the treatment of rhinosinu-sitis(RS). CNKI, Wanfang, SinoMed, VIP, Cochrane Library, PubMed, EMbase, Web of Science, and Ovid were searched for the randomized controlled trial(RCT) of Bidouyan Oral Liquid for the treatment of RS patients. Moreover, the reference lists and the grey literature were searched manually. Two researchers independently screened the literature and extracted data. The Cochrane collaboration's tool for assessing risk of bias(RoB 2.0) in randomized trial was used to assess the methodological quality of the included stu-dies. Meta-analysis was performed in RevMan 5.3 and Stata 12.0, and the grades of recommendation, assessment, development and evaluation(GRADE) was employed to evaluate the quality of evidence. A total of 54 RCTs(35 with drug combinations and 19 with single drugs) comprising 7 511 patients(3 973 in the observation group and 3 538 in the control group) were included. Meta-analysis showed that Bidouyan Oral Liquid + conventional treatment was superior to conventional treatment alone in increasing the total response rate(RR=1.19, 95%CI[1.15, 1.24], P<0.000 01) and decreasing the Lund-Kennedy scores(MD=-1.94, 95%CI[-2.61,-1.26], P<0.000 01), Lund-Mackay scores(MD=-2.14, 95%CI[-2.98,-1.31], P<0.000 01), and visual analogue scale(VAS) scores(MD_(total VAS scores)=-1.28, 95%CI[-1.56,-1.01], P<0.000 01; MD_(nasal congestion VAS scores)=-0.58, 95%CI[-0.89,-0.27], P=0.000 2; MD_(runny nose VAS scores)=-0.61, 95%CI[-0.93,-0.29], P=0.000 2; MD_(olfactory dysfunction VAS scores)=-0.43, 95%CI[-0.52,-0.34], P<0.000 01; MD_(head and facial pain VAS scores)=-0.41, 95%CI[-0.57,-0.26], P<0.000 01). Furthermore, the combined treatment outperformed conventional treatment alone in improving the mucociliary transport rate(MTR)(MD=1.64, 95%CI[1.08, 2.20], P<0.000 01) and lowering the levels of inflammatory cytokines{tumor necrosis factor-α(TNF-α)(SMD=-1.95, 95%CI[-2.57,-1.33], P<0.000 01), interleukin-6(IL-6)(SMD=-2.64, 95%CI[-4.08,-1.21], P=0.000 3)} in RS patients. In addition, the combined treatment did not increase the incidence of adverse reactions(RR=0.83, 95%CI[0.44, 1.57], P=0.57). Bidouyan Oral Liquid was superior to conventional treatment in increasing total response rate(RR=1.25, 95%CI[1.18, 1.32], P<0.000 01), decreasing the Lund-Kennedy(P<0.01) and Lund-Mackay scores(P<0.05), alleviating major symptoms(P_(total VAS scores)<0.01; P_(nasal congestion VAS scores)<0.01; P_(runny nose VAS scores)<0.01; P_(olfactory dysfunction VAS scores)<0.05; P_(head and facial pain VAS scores)<0.01), and decreasing adverse reactions(P=0.03). The results showed that either Bidouyan Oral Liquid or Bidouyan Oral Liquid + conventional treatment can increase the total response rate, decrease the Lund-Kennedy and Lund-Mackay scores, and mitigate major symptoms. In addition, Bidouyan Oral Liquid + conventional treatment improved MTR and reduced the expression of TNF-α and IL-6 without causing serious adverse events. However, due to the limited methodological quality of the included studies, large-sample and high-quality RCTs are needed to provide evidence support.

Racial Disparities in Utilization of Emergency Medical Services and Related Impact on Poststroke Disability.

BACKGROUND: Prompt seeking of emergency medical services (EMS) assistance at stroke onset is critical to minimize poststroke disability. OBJECTIVE: The aim was to study how racial differences in EMS decision-relevant factors and EMS use impact stroke care and disability outcomes. DESIGN: A prospective observational study. PARTICIPANTS: A total of 1168 acute ischemic stroke patients discharged from April 2016 to October 2017 at a safety net hospital were included; 108 patients were surveyed before discharge. MEASURES: (1) Prehospital delay: EMS use, timely hospital arrival; (2) Stroke care: alteplase receipt and inpatient rehab; (3) Outcomes: Functional improvement at discharge (admission minus discharge scores on National Institutes of Health Stroke Scale), 90-day modified Rankin Scale; (4) EMS decision-relevant factors: Stroke symptom knowledge, source of knowledge, unfavorable past EMS/care experiences, and financial barriers to EMS use. RESULTS: Despite more Black patients using EMS than Whites/Asians (56% vs. 48%, P =0.003), their timely hospital arrival was 30% less likely. Adjusted for stroke severity, receipt of alteplase, and inpatient rehab were similar, but Black patients fared worse on functional improvement at discharge (among severe strokes, 2.4 National Institutes of Health Stroke Scale points less improvement, P <0.01), and on functional normalcy at 90 days (modified Rankin Scale score 0-1 being 60% less likely across severity categories) ( P <0.01). Fewer Black patients knew any stroke symptoms before the stroke (72% vs. 87%, P =0.03), and fewer learned about stroke from providers ( P =0.01). Financial barriers and provider mistrust were similar. CONCLUSIONS: Black patients had less knowledge of stroke symptoms, more care-seeking delay, and poorer outcomes. Including stroke education as a standard of chronic disease care may mitigate stroke outcome disparities.

Cellular retinol-binding protein 1: a therapeutic and diagnostic tumor marker.

Cellular Retinol Binding Protein 1 (CRBP1) gene is a protein coding gene located on human chromosome 3q21, which codifies a protein named CRBP1. CRBP1 is widely expressed in many tissues as a chaperone protein to regulate the uptake, subsequent esterification and bioavailability of retinol. CRBP1 combines retinol and retinaldehyde with high affinity to protect retinoids from non-specific oxidation, and transports retinoids to specific enzymes to promote the biosynthesis of retinoic acid. The vital role of CRBP1 in retinoids metabolism has been gradually discovered, which has been implicated in tumorigenesis. However, the precise functions of CRBP1 in different diseases are still poorly understood. The purpose of this review is to provide an overview of the role of CRBP1 in various diseases, especially in both the promotion and inhibition of cancers, which may also offer a novel biomarker and potential therapeutic target for human diseases.

Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice.

PURPOSE: Previous evidence indicated anti-ageing potential of docosahexaenoic acid (DHA), but the underlying mechanism remains unclear. We investigated protective effect of DHA on telomere attrition and lipid disturbance in male mice with premature ageing caused by telomerase deficiency. METHODS: Wild-type (WT) and fourth-generation telomerase-deficient (G4 Terc-/-, Terc knockout, KO) male mice (C57BL/6, 2 months old) were fed control diet (WT-C and KO-C groups) or DHA-enriched diet containing 0.80% DHA by weight (WT-DHA and KO-DHA groups) for 10 months. The ageing phenotypes and metabolic level [carbon dioxide emission, oxygen consumption, and respiratory exchange ratio (RER)] were assessed at the end of the experiment. Telomere length in various tissues and the hepatic gene and protein expression for regulating lipid synthesis and lipolysis were measured. Data were tested using one- or two-factor ANOVA. RESULTS: In KO male mice, DHA prevented weight loss, corrected high RER, and reduced fat loss. Telomere shortening was reduced by 22.3%, 25.5%, and 13.5% in heart, liver, and testes of the KO-DHA group compared with those in the KO-C group. The KO-DHA group exhibited higher gene transcription involved in glycerol-3-phosphate pathway [glycerol-3-phosphate acyltransferase (Gpat)], lower gene expression of ß-oxidation [carnitine palmitoyltransferase 1a (Cpt1a)], and upregulation of proteins in lipid synthesis [mammalian target of rapamycin complex 1 (mTORC1) and sterol responsive element binding protein 1 (SREBP1)] in liver than the KO-C group. CONCLUSION: Long-term DHA intervention attenuates telomere attrition and promotes lipid synthesis via the tuberous sclerosis complex 2 (TSC2)-mTORC1-SREBP1 pathway in KO male mice.

Determination of Vitamin K1, MK-4, MK-7, and D Levels in Human Serum of Postmenopausal Osteoporosis Women Based on High Stability LC-MS/MS: MK-7 May Be a New Marker of Bone Metabolism.

INTRODUCTION: Vitamin K (VK) as well as vitamin D (VD) plays an important role in osteoporosis. Vitamin K1 (VK1), vitamin K2 (VK2, menaquinone-4 (MK-4), and menaquinone-7 (MK-7)) are significant for the metabolism of skeletal muscle. 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 (25(OH)D2 and 25(OH)D3) reflect circulating VD levels. More sensitive measurements remain to be developed. In the present study, a new high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of VK1, VK2 (MK-4 and MK-7), as well as 25(OH)D2 and 25(OH)D3 levels in human serum. METHODS: We developed a simple LC-MS/MS method for the determination of VK1, MK-4, MK-7, 25(OH)D2, and 25(OH)D3 levels in human serum and validated the method in a study cohort of 200 patients divided into the premenopausal women group and postmenopausal osteoporosis patient group. RESULTS: The overall precision (coefficient of variation) ranged from 2.66 to 10.11% in the specified working range (0.05-5 ng/mL) for VK1, MK-4, and MK-7. Serum VK1, MK-4, and MK-7 levels in postmenopausal women with osteoporosis were 1.187 ± 0.094 ng/mL, 0.058 ± 0.009 ng/mL, and 0.885 ± 0.064 ng/mL, respectively (mean ± standard deviation). Serum VK1, MK-4, and MK-7 levels in premenopausal women were 1.143 ± 0.103 ng/mL, 0.028 ± 0.003 ng/mL, and 1.553 ± 0.226 ng/mL, respectively. Serum 25(OH)D2 and 25(OH)D3 levels in postmenopausal women with osteoporosis were 0.757 ± 0.056 ng/mL and 11.72 ± 0.632 ng/mL, respectively. Serum 25(OH)D2 and 25(OH)D3 levels in premenopausal were 1.793 ± 0.575 ng/mL and 12.42 ± 1.069 ng/mL, respectively. CONCLUSION: A new LC-MS/MS method for determination of serum VK and VD levels was evaluated and validated. MK-7 in plasma decreased earlier than VD in postmenopausal osteoporosis patients. MK-7 status is significantly associated with osteoporosis and could be considered a predictable biomarker in the diagnosis of osteoporosis in postmenopausal women.

Layered double hydroxides for phosphorus recovery from lipid-rich waste anaerobic fermentation liquor.

This study aimed to extract orthophosphate (ortho-P) from lipid-rich waste AF liquor (AFL) by Mg/Al layered double hydroxides (Mg/Al LDHs) adsorption, evaluate the influence of carbonate and investigate adsorption mechanisms. The carbonate influence experiment using synthetic P-rich wastewater indicated that low carbonate level was favorable for P extraction by LDHs. And then, real AFL rich in volatile fatty acids (VFAs), carbonate and ortho-P was applied as adsorbate to explore the Mg/Al LDHs adsorption performance. Experimental results indicated that 4 g/L Mg/Al LDHs could extract 88.3% of ortho-P from the AFL with low carbonate level (4829.83 mg CaCO3/L), and the adsorption quantity was 62.99 mg P/g LDHs, however, negligible VFAs were extracted. Kinetics and mechanisms analysis indicated that adsorption of P onto Mg/Al LDHs was a rapid physiochemical process, including ion exchange and surface adsorption. Finally, the nutrients release test confirmed the slow-release property of intercalated P.

Aptamer-LYTACs for Targeted Degradation of Extracellular and Membrane Proteins.

Recently, lysosome targeting chimeras (LYTACs) have emerged as a promising technology that expands the scope of targeted protein degradation to extracellular targets. However, the preparation of chimeras by conjugation of the antibody and trivalent N-acetylgalactosamine (tri-GalNAc) is a complex and time-consuming process. The large uncertainty in number and position and the large molecular weights of the chimeras result in low internalization efficiency. To circumvent these problems, we developed the first aptamer-based LYTAC (Apt-LYTAC) to realize liver-cell-specific degradation of extracellular and membrane proteins by conjugating aptamers to tri-GalNAc. Taking advantage of the facile synthesis and low molecular weight of the aptamer, the Apt-LYTACs can efficiently and quickly degrade the extracellular protein PDGF and the membrane protein PTK7 through a lysosomal degradation pathway. We anticipate that the novel Apt-LYTACs will expand the usage of aptamers and provide a new dimension for targeted protein degradation.

EVALUATING THE OUTCOMES OF MINIMALLY INVASIVE THERAPY VS SURGERY FOR ORAL MUCOCELES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVES: Oral mucoceles could be managed with minimally invasive therapy (MIT) or conventional surgery, and both modalities reportedly possess advantages and demerits. This review aims to investigate and compare the postoperative disease recurrence and complications of these interventions with each other. METHODS: Relevant studies were searched in 5 databases (PubMed, Embase, Scopus, Web of Science and Cochrane Library) from inception to December 17, 2022. The pooled relative risks (RRs) with 95% confidence intervals (CIs) of disease recurrence, overall complications, nerve injury and bleeding/hematoma in MIT vs conventional surgery were calculated in meta-analysis. Trial Sequential Analysis (TSA) was performed to confirm our conclusions and assess the need for future trials. RESULTS: Six studies (1 randomized controlled trial and 5 cohort studies) were included for systematic review and meta-analysis. The results showed no significant difference in recurrence between MIT and conventional surgery (RR=0.80; 95% CI, 0.39-1.64; P = .54; I2=17%), and the results of the subgroup analysis were consistent. The incidence of the overall complications (RR=0.15; 95% CI, 0.05-0.47; P = .001; I2=0%) and nerve injury (RR=0.22; 95% CI, 0.06-0.82; P = .02; I2=0%) was significantly lower in MIT than in conventional surgery, but the incidence of bleeding/hematoma presented no significant difference (RR=0.34; 95% CI, 0.06-2.07; P = .24; I2=0%). The results of TSA suggested that the conclusion of MIT significantly reducing the risk of overall complications was stable; and additional clinical trials were need in the future for confirming the conclusions regarding disease recurrence, nerve injury and bleeding/hematoma. CONCLUSIONS: For mucoceles in the oral cavity, MIT is less likely to induce complications (i.e., nerve injury) compared with surgical removal, and the control of disease recurrence is comparable to that of conventional surgery. Therefore, the application of MIT for mucoceles could be a promising alternative to conventional surgery when the latter is not applicable.

NIR-II Photoacoustic-Active DNA Origami Nanoantenna for Early Diagnosis and Smart Therapy of Acute Kidney Injury.

Herein, we designed and synthesized a novel microRNA (miR)-responsive nanoantenna capable of early diagnosis and smart treatment of acute kidney injury (AKI). The nanoantenna was made of two miniature gold nanorods (AuNRs) (e.g., length: ∼48 nm; width: ∼9 nm) linked together by a rectangular DNA origami nanostructure (rDONs) scaffold (e.g., length: ∼90 nm; width: ∼60 nm) (rDONs@AuNR dimer). The surface plasmon resonance peak of the constructed nanoantenna is located within the NIR-II window (e.g., ∼1060 nm), thus guaranteeing photoacoustic (PA) imaging of the nanoantenna in deep tissues. Intriguingly, the nanoantenna displayed exclusive kidney retention in both healthy mice and ischemia reperfusion-induced AKI mice by leveraging the kidney-targeting ability of rDONs. Distinguished from the stable signals in the healthy mice, the PA signals of the nanoantenna would turn down in the AKI mice due to the AuNR detached from rDONs upon interaction with miR-21, which were up-expressed in AKI mice. The limit of detection toward miR-21 was down to 2.8 nM, enabling diagnosis of AKI as early as 10 min post-treatment with ischemia reperfusion, around 2 orders of magnitude earlier than most established probes. Moreover, the naked rDON scaffold generated by AKI could capture more reactive oxygen species (e.g., 1.5-fold more than rDONs@AuNR dimer), alleviating ischemic AKI. This strategy provided a new avenue for early diagnosis and smart treatment of AKI.

Gut microbiota induces DNA methylation via SCFAs predisposing obesity-prone individuals to diabetes.

Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1, which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes.

The relationship between n-3 polyunsaturated fatty acids and telomere: A review on proposed nutritional treatment against metabolic syndrome and potential signaling pathways.

Metabolic syndrome (MetS), a cluster of metabolic abnormalities composed of central obesity, elevated blood pressure, glucose disturbances, hypercholesterolemia and dyslipidaemia, has increasingly become a public health problem in the 21st century worldwide. The dysfunction of telomeres, the repetitive DNA with highly conserved sequences (5'-TTAGGG-3'), is remarkably correlated with organismal aging, even suggesting a causal relationship with metabolic disorders. The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple disorders are associated with telomere length in evidence, which have recently drawn wide attention. However, functional targets and pathways for the associations of n-3 PUFAs and telomere with MetS remain scare. Few studies have summarized the role of n-3 PUFAs in DNA damage repair pathways, anti-inflammatory pathways, and redox balance, linking with telomere biology, and other potential telomere-related signaling pathways. This review aims to (i) elucidate how n-3 PUFAs ameliorate telomere attrition in the context of anti-oxidation and anti-inflammation; (ii) unravel the role of n-3 PUFAs in modulating telomere-related neuron dysfunction and regulating the neuro-endocrine-immunological network in MetS; (iii) epidemiologically implicate the associations of metabolic disorders and n-3 PUFAs with telomere length; and (iv) suggest promising biochemical approaches and advancing methodologies to overcome the inter-variation problem helpful for future research.

Environmental and economic cost-benefit comparison of sponge city construction in different urban functional regions.

This study conducts a life cycle environmental and economic quantification comparison of urban runoff source control facilities (URSCFs) through construction and operation stages in two urban functional regions (i.e., residential area and campus). From the environmental perspective, URSCFs construction in residential area has both higher environmental impacts and benefits than that in campus. The operation stage of URSCFs can observe significant benefit for both residential area and campus. We then develop a set of monetized method to make a comprehensive benefit evaluation (i.e., environmental, economic, and social benefit) of URSCFs. Overall, the two areas have payback time less than thirteen years for their investment which is acceptable when compared with the assumed total service period (30 years). Specifically, the payback time of campus is 5.62 years and residential area is 12.44 years. This implies that the campus has great potential to achieve high cost-benefit ratio and thus the Sponge City construction in campus can implement URSCFs with less engineering and material consumption due to its more spacious site than residential area with high building density. For both residential area and campus, permeable pavement has the highest environmental impact and economic cost because of the concrete consumption. Thus, we recommend that it should be cautious of the construction of concrete permeable pavement and find environmentally and economically alternatives in future URSCFs projects.