Causal association between type 2 diabetes mellitus and acute suppurative otitis media: insights from a univariate and multivariate Mendelian randomization study.

Background: Type 2 diabetes mellitus (T2DM) and hearing loss (HL) constitute significant public health challenges worldwide. Recently, the association between T2DM and HL has aroused attention. However, possible residual confounding factors and other biases inherent to observational study designs make this association undetermined. In this study, we performed univariate and multivariable Mendelian Randomization (MR) analysis to elucidate the causal association between T2DM and common hearing disorders that lead to HL. Methods: Our study employed univariate and multivariable MR analyses, with the Inverse Variance Weighted method as the primary approach to assessing the potential causal association between T2DM and hearing disorders. We selected 164 and 9 genetic variants representing T2DM from the NHGRI-EBI and DIAGRAM consortium, respectively. Summary-level data for 10 hearing disorders were obtained from over 500,000 participants in the FinnGen consortium and MRC-IEU. Sensitivity analysis revealed no significant heterogeneity of instrumental variables or pleiotropy was detected. Results: In univariate MR analysis, genetically predicted T2DM from both sources was associated with an increased risk of acute suppurative otitis media (ASOM) (In NHGRI-EBI: OR = 1.07, 95% CI: 1.02-1.13, P = 0.012; In DIAGRAM: OR = 1.14, 95% CI: 1.02-1.26, P = 0.016). Multivariable MR analysis, adjusting for genetically predicted sleep duration, alcohol consumption, body mass index, and smoking, either individually or collectively, maintained these associations. Sensitivity analyses confirmed the robustness of the results. Conclusion: T2DM was associated with an increased risk of ASOM. Strict glycemic control is essential for the minimization of the effects of T2DM on ASOM.

A chemical probe to modulate human GID4 Pro/N-degron interactions.

The C-terminal to LisH (CTLH) complex is a ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via its substrate receptor Glucose-Induced Degradation 4 (GID4), but its function and substrates in humans remain unclear. Here, we report PFI-7, a potent, selective and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation and quantitative proteomics enabled the identification of GID4 interactors and GID4-regulated proteins. GID4 interactors are enriched for nucleolar proteins, including the Pro/N-degron-containing RNA helicases DDX21 and DDX50. We also identified a distinct subset of proteins whose cellular levels are regulated by GID4 including HMGCS1, a Pro/N-degron-containing metabolic enzyme. These data reveal human GID4 Pro/N-degron targets regulated through a combination of degradative and nondegradative functions. Going forward, PFI-7 will be a valuable research tool for investigating CTLH complex biology and facilitating development of targeted protein degradation strategies that highjack CTLH E3 ligase activity.

An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer.

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin-proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo, without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

A review of smart electrochemical devices for pesticide detection in agricultural food and runoff contaminants.

In the evolving field of food and agriculture, pesticide utilization is inevitable for food production and poses an increasing threat to the ecosystem and human health. This review systematically investigates and provides a comprehensive overview of recent developments in smart electrochemical devices for detecting pesticides in agricultural food and runoff contaminants. The focus encompasses recent progress in lab-scale and portable electrochemical sensors, highlighting their significance in agricultural pesticide monitoring. This review compares these sensors comprehensively and provides a scientific guide for future sensor development for infield agricultural pesticide monitoring and food safety. Smart devices address challenges related to power consumption, low cost, wearability, and portability, contributing to the advancement of agricultural sustainability. By elucidating the intricate details of these smart devices, this review offers a comprehensive discussion and roadmap for future research aimed at cost-effective, flexible, and smart handy devices, including novel electrocatalysts, to foster the development of next-generation agricultural sensor technology, opportunity and future direction for food security.

Boosting acetaminophen degradation in water by peracetic acid activation: A novel approach using chestnut shell-derived biochar at varied pyrolysis temperatures.

In this study, biochar derived from chestnut shells was synthesized through pyrolysis at varying temperatures from 300 °C to 900 °C. The study unveiled that the pyrolysis temperature is pivotal in defining the physical and chemical attributes of biochar, notably its adsorption capabilities and its role in activating peracetic acid (PAA) for the efficient removal of acetaminophen (APAP) from aquatic environments. Notably, the biochar processed at 900 °C, referred to as CN900, demonstrated an exceptional adsorption efficiency of 55.8 mg g-1, significantly outperforming its counterparts produced at lower temperatures (CN300, CN500, and CN700). This enhanced performance of CN900 is attributed to its increased surface area, improved micro-porosity, and a greater abundance of oxygen-containing functional groups, which are a consequence of the elevated pyrolysis temperature. These oxygen-rich functional groups, such as carbonyls, play a crucial role in facilitating the decomposition of the O-O bond in PAA, leading to the generation of reactive oxygen species (ROS) through electron transfer mechanisms. This investigation contributes to the development of sustainable and cost-effective materials for water purification, underscoring the potential of chestnut shell-derived biochar as an efficient adsorbent and catalyst for PAA activation, thereby offering a viable solution for environmental cleanup efforts.

Clinical evaluation of a novel digital microfluidic based point-of-care test platform for detection of SARS-Cov-2 and influenza A/B.

Respiratory pathogens, such as SARS-CoV-2 and influenza A/B, can cause severe illnesses in susceptible individuals. This research evaluated a novel digital microfluidic point-of-care testing platform designed to detect 23 pathogens, comparing its performance to conventional laboratory-based nucleic acid tests. The platform integrates nucleic acid extraction and amplification processes for rapid detection with only 2 min of hands-on time. Performance assays demonstrated that the platform has high sensitivity (87 %-100 %) and specificity (99 %-100 %) for the detection of the evaluated 3 viruses. Additionally, the platform can be adapted for the detection of other respiratory pathogens, aiding in the early diagnosis of respiratory diseases, identifying the source of an outbreak or epidemic, and curbing the spread of the disease.

Preparation of Activated Carbon Nanostructured Al@CuO with Low Static Sensitivity and High Reactivity.

The porous skeleton structure of oxidizers can effectively enlarge the contact area with fuels and boost the reactivity of thermites, but the overly complex preparation processes tend to limit their use to some extent. To overcome this issue, water-soluble starch and copper nitrate were used as a template to form a carbon skeleton copper oxide (C-CuO) after spray drying and calcination. By adding nanoaluminum into the spray drying process, the n-Al@C-CuO was prepared and compared with the physically mixed n-Al/C-CuO in the context. Scanning electron microscopy and differential scanning calorimetry were used to observe the morphology and analyze the thermal process. The pressure-time test and the electrostatic sensitivity test were used to measure the energy release properties and the safety of the thermites. Results indicated that the n-Al@C-CuO had 60.97 °C earlier initial exothermic temperature and 1.74 times higher peak pressure than that of the physically mixed sample. The n-Al@C-CuO was not ignited under 25 kV in the electrostatic sensitivity test, showing the great electrostatic safety of the sample. These findings are expected to facilitate the development of spray drying and promote energy release of traditional thermites.

Synergistic microwave and acidic deep eutectic solvent-based pretreatment of Theobroma cacao pod husk biomass for xylooligosaccharides production.

The bioconversion of lignocellulosic biomass into novel bioproducts is crucial for sustainable biorefineries, providing an integrated solution for circular economy objectives. The current study investigated a novel microwave-assisted acidic deep eutectic solvent (DES) pretreatment of waste cocoa pod husk (CPH) biomass to extract xylooligosaccharides (XOS). The sequential DES (choline chloride/citric acid, molar ratio 1:1) and microwave (450W) pretreatment of CPH biomass was effective in 67.3% xylan removal with a 52% XOS yield from total xylan. Among different XOS of varying degrees of polymerization, a higher xylobiose content corresponding to 69.3% of the total XOS (68.22 mg/g CPH) from liquid fraction was observed. Enzymatic hydrolysis of residual xylan from pretreated CPH biomass with low commercial xylanase (10 IU/g) concentration yielded 24.2% XOS. The MW-ChCl/citric acid synergistic pretreatment approach holds great promise for developing a cost-effective and environmentally friendly method contributing to the sustainable production of XOS from agricultural waste streams.

Advancements in Nano-Enhanced microalgae bioprocessing.

Microalgae are promising sources of valuable compounds: carotenoids, polyunsaturated fatty acids, lipids, etc. To overcome the feasibility challenge due to low yield and attain commercial potential, researchers merge technologies to enhance algal bioprocess. In this context, nanomaterials are attractive for enhancing microalgal bioprocessing, from cultivation to downstream extraction. Nanomaterials enhance biomass and product yields (mainly lipid and carotenoids) through improved nutrient uptake and stress tolerance during cultivation. They also provide mechanistic insights from recent studies. They also revolutionize harvesting via nano-induced sedimentation, flocculation, and flotation. Downstream processing benefits from nanomaterials, improving extraction and purification. Special attention is given to cost-effective extraction, showcasing nanomaterial integration, and providing a comparative account. The review also profiles nanomaterial types, including metallic nanoparticles, magnetic nanomaterials, carbon-based nanomaterials, silica nanoparticles, polymers, and functionalized nanomaterials. Challenges and future trends are discussed, emphasizing nanomaterials' role in advancing sustainable and efficient microalgal bioprocessing, unlocking their potential for bio-based industries.

Kumquat peel-derived biochar to support zeolitic imidazole framework-67 (ZIF-67) for enhancing peracetic acid activation to remove acetaminophen from aqueous solution.

This study presents the synthesis of a novel composite catalyst, ZIF-67, doped on sodium bicarbonate-modified biochar derived from kumquat peels (ZIF-67@KSB3), for the enhanced activation of peracetic acid (PAA) in the degradation of acetaminophen (APAP) in aqueous solutions. The composite demonstrated a high degradation efficiency, achieving 94.3% elimination of APAP at an optimal condition of 200 mg L-1 catalyst dosage and 0.4 mM PAA concentration at pH 7. The degradation mechanism was elucidated, revealing that superoxide anion (O2•-) played a dominant role, while singlet oxygen (1O2) and alkoxyl radicals (R-O•) also contributed significantly. The degradation pathways of APAP were proposed based on LC-MS analyses and molecular electrostatic potential calculations, identifying three primary routes of transformation. Stability tests confirmed that the ZIF-67@KSB3 catalyst retained an 86% efficiency in APAP removal after five successive cycles, underscoring its durability and potential for application in pharmaceutical wastewater treatment.

Accelerated biological aging as a potential risk factor for rheumatoid arthritis.

OBJECTS: Previous studies have suggested a potential correlation between rheumatoid arthritis (RA) and biological aging, but the intricate connections and mechanisms remain elusive. METHODS: In our study, we focused on two specific measures of biological age (PhenoAge and BioAge), which are derived from clinical biomarkers. The residuals of these measures, when compared to chronological age, are defined as biological age accelerations (BAAs). Utilizing the extensive UK Biobank dataset along with various genetic datasets, we conducted a thorough assessment of the relationship between BAAs and RA at both the individual and aggregate levels. RESULTS: Our observational studies revealed positive correlations between the two BAAs and the risk of developing both RA and seropositive RA. Furthermore, the genetic risk score (GRS) for PhenoAgeAccel was associated with an increased risk of RA and seropositive RA. Linkage disequilibrium score regression (LDSC) analysis further supported these findings, revealing a positive genetic correlation between PhenoAgeAccel and RA. PLACO analysis identified 38 lead pleiotropic single nucleotide polymorphisms linked to 301 genes, providing valuable insights into the potential mechanisms connecting PhenoAgeAccel and RA. CONCLUSION: In summary, our study has successfully revealed a positive correlation between accelerated biological aging, as measured by BAAs, and the susceptibility to RA.

PdmIRD: missense variants pathogenicity prediction for inherited retinal diseases in a disease-specific manner.

Accurate discrimination of pathogenic and nonpathogenic variation remains an enormous challenge in clinical genetic testing of inherited retinal diseases (IRDs) patients. Computational methods for predicting variant pathogenicity are the main solutions for this dilemma. The majority of the state-of-the-art variant pathogenicity prediction tools disregard the differences in characteristics among different genes and treat all types of mutations equally. Since missense variants are the most common type of variation in the coding region of the human genome, we developed a novel missense mutation pathogenicity prediction tool, named Prediction of Deleterious Missense Mutation for IRDs (PdmIRD) in this study. PdmIRD was tailored for IRDs-related genes and constructed with the conditional random forest model. Population frequencies and a newly available prediction tool were incorporated into PdmIRD to improve the performance of the model. The evaluation of PdmIRD demonstrated its superior performance over nonspecific tools (areas under the curves, 0.984 and 0.910) and an existing eye abnormalities-specific tool (areas under the curves, 0.975 and 0.891). We also demonstrated the submodel that used a smaller gene panel further slightly improved performance. Our study provides evidence that a disease-specific model can enhance the prediction of missense mutation pathogenicity, especially when new and important features are considered. Additionally, this study provides guidance for exploring the characteristics and functions of the mutated proteins in a greater number of Mendelian disorders.

Bioaccumulation and Trophodynamics of Novel Brominated Flame Retardants (NBFRs) in Marine Food Webs from the Arctic and Antarctic Regions.

The pervasive contamination of novel brominated flame retardants (NBFRs) in remote polar ecosystems has attracted great attention in recent research. However, understanding regarding the trophic transfer behavior of NBFRs in the Arctic and Antarctic marine food webs is limited. In this study, we examined the occurrence and trophodynamics of NBFRs in polar benthic marine sediment and food webs collected from areas around the Chinese Arctic Yellow River Station (n = 57) and Antarctic Great Wall Station (n = 94). ∑7NBFR concentrations were in the range of 1.27-7.47 ng/g lipid weight (lw) and 0.09-1.56 ng/g lw in the Arctic and Antarctic marine biota, respectively, among which decabromodiphenyl ethane (DBDPE) was the predominant compound in all sample types. The biota-sediment bioaccumulation factors (g total organic carbon/g lipid) of NBFRs in the Arctic (0.85-3.40) were 4-fold higher than those in the Antarctica (0.13-0.61). Trophic magnification factors (TMFs) and their 95% confidence interval (95% CI) of individual NBFRs ranged from 0.43 (95% CI: 0.32, 0.60) to 1.32 (0.92, 1.89) and from 0.34 (0.24, 0.49) to 0.92 (0.56, 1.51) in the Arctic and Antarctic marine food webs, respectively. The TMFs of most congeners were significantly lower than 1, indicating a trophic dilution potential. This is one of the very few investigations on the trophic transfer of NBFRs in remote Arctic and Antarctic marine ecosystems, which provides a basis for exploring the ecological risks of NBFRs in polar regions.

Controlling effects of terrestrial organic matter on metal contamination and toxicity risks in port sediments.

The contents of metals, total carbon, total nitrogen (TN), total organic carbon (TOC), and stable isotope composition (δ13Corg and δ15N) of sediment organic matter (SOM) were investigated to explore the sources and spatial distribution of metals and SOM in the surface sediments (Kaohsiung Port, Taiwan). Results showed that TOC and metals in estuarine sediments are high, gradually decreasing toward the port entrances. The δ13Corg, δ15N, and TOC/TN ratios indicate that SOM comes mainly from terrestrial sources. This study proposes a befitting model between metal pollution and toxicity risk index and SOM sources in port sediments by combining stable isotope composition, correlation matrix, and multiple linear regression analysis. The model indicates that the degree of metal pollution and toxicity risk in sediments are mainly affected by TOCterr content and SOM source. The results help to understand the influence of organic matter sources in port sediments on metal concentration distribution.

Sustainable production of cellulose and hemicellulose-derived oligosaccharides from pineapple leaves: Impact of hydrothermal pretreatment and controlled enzymatic hydrolysis.

Globally, the demands for sustainably sourced functional foods like prebiotic oligosaccharides have been constantly increasing. This study assessed the potential of pineapple leaves (PL) as lignocellulosic feedstock for sustainable production of cellulose and hemicellulose-derived oligosaccharides through its hydrothermal pretreatment (HT) followed by controlled enzymatic hydrolysis. PL was subjected to HT at 160, 175, and 190 °C for 20, 30, 60, and 90 min without any catalyst for xylooligosaccharide (XOS) production, whereas, the resulting solid content after HT was subjected to controlled enzymatic hydrolysis by commercial cellulase using conduritol B epoxide (0.5-5 mM) for glucooligosaccharides (GOS) production. HT at 160 °C for 60 min resulted in maximum yield of XOS and GOS at 23.7 and 18.3 %, respectively, in the liquid phase. Controlled enzymatic hydrolysis of HT treated (160 °C) PL solids for 20 and 30 min yielded âˆ¼ 174 mg cellobiose/g dry biomass within 24 h, indicating overall high oligosaccharide production.

Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex.

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

Crystal Structure Assignment for Unknown Compounds from X-ray Diffraction Patterns with Deep Learning.

Determining the structures of previously unseen compounds from experimental characterizations is a crucial part of materials science. It requires a step of searching for the structure type that conforms to the lattice of the unknown compound, which enables the pattern matching process for characterization data, such as X-ray diffraction (XRD) patterns. However, this procedure typically places a high demand on domain expertise, thus creating an obstacle for computer-driven automation. Here, we address this challenge by leveraging a deep-learning model composed of a union of convolutional residual neural networks. The accuracy of the model is demonstrated on a dataset of over 60,000 different compounds for 100 structure types, and additional categories can be integrated without the need to retrain the existing networks. We also unravel the operation of the deep-learning black box and highlight the way in which the resemblance between the unknown compound and a structure type is quantified based on both local and global characteristics in XRD patterns. This computational tool opens new avenues for automating structure analysis on materials unearthed in high-throughput experimentation.

Advanced sustainable processes via functionalized Fe-N co-doped fishbone biochar for the remediation of plasticizer di-(2-ethylhexyl) phthalate-contaminated marine sediment.

Sediments are important sinks for di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, and thus, maintaining the sediment quality is essential for eliminating plasticizers in aqueous environments and recovering the sediment ecological functions. To mitigate the potential risks of endocrine-disrupting compounds, identifying an effective and eco-friendly degradation process of organic pollutants from sediments is important. However, sustainable and efficient utilization of slow pyrolysis for converting shark fishbone to generate shark fishbone biochar (SFBC) has rarely been explored. Herein, SFBC biomass was firstly produced by externally incorporating heteroatoms or iron oxide onto its surface in conjunction with peroxymonosulfate (PMS) to promote DEHP degradation and explore the associated benthic bacterial community composition from the sediment in the water column using the Fe-N-SFBC/PMS system. SFBC was pyrolyzed at 300-900 °C in aqueous sediment using a carbon-advanced oxidation process (CAOP) system based on PMS. SFBC was rationally modified via N or Fe-N doping as a radical precursor in the presence of PMS (1 × 10-5 M) for DEHP removal. The innovative SFBC/PMS, N-SFBC/PMS, and Fe-N-SFBC/PMS systems could remove 82%, 65%, and 90% of the DEHP at pH 3 in 60 min, respectively. The functionalized Fe3O4 and heteroatom (N) co-doped SFBC composite catalysts within a hydroxyapatite-based structure demonstrated the efficient action of PMS compared to pristine SFBC, which was attributed to its synergistic behavior, generating reactive radicals (SO4•-, HO•, and O2•-) and non-radicals (1O2) involved in DEHP decontamination. DEHP was significantly removed using the combined Fe-N-SFBC/PMS system, revealing that indigenous benthic microorganisms enhance their performance in DEHP-containing sediments. Further, DEHP-induced perturbation was particularly related to the Proteobacteria phylum, whereas Sulfurovum genus and Sulfurovum lithotrophicum species were observed. This study presents a sustainable method for practical, green marine sediment remediation via PMS-CAOP-induced processes using a novel Fe-N-SFBC composite material and biodegradation synergy.

Development in health-promoting essential polyunsaturated fatty acids production by microalgae: a review.

Polyunsaturated fatty acids (PUFAs) found in microalgae, primarily omega-3 (ω-3) and omega-6 (ω-6) are essential nutrients with positive effects on diseases such as hyperlipidemia, atherosclerosis, and coronary risk. Researchers still seek improvement in PUFA yield at a large scale for better commercial prospects. This review summarizes advancements in microalgae PUFA research for their cost-effective production and potential applications. Moreover, it discusses the most promising cultivation modes using organic and inorganic sources. It also discusses biomass hydrolysates to increase PUFA production as an alternative and sustainable organic source. For cost-effective PUFA production, heterotrophic, mixotrophic, and photoheterotrophic cultivation modes are assessed with traditional photoautotrophic production modes. Also, mixotrophic cultivation has fascinating sustainable attributes over other trophic modes. Furthermore, it provides insight into growth phase (stage I) improvement strategies to accumulate biomass and the complementing effects of other stress-inducing strategies during the production phase (stage II) on PUFA enhancement under these cultivation modes. The role of an excessive or limiting range of salinity, nutrients, carbon source, and light intensity were the most effective parameter in stage II for accumulating higher PUFAs such as ω-3 and ω-6. This article outlines the commercial potential of microalgae for omega PUFA production. They reduce the risk of diabetes, cardiovascular diseases (CVDs), cancer, and hypertension and play an important role in their emerging role in healthy lifestyle management.