Deciphering single-cell gene expression variability and its role in drug response.

The effectiveness of drug treatments is profoundly influenced by individual responses, which are shaped by gene expression variability, particularly within pharmacogenes. Leveraging single-cell RNA sequencing (scRNA-seq) data, our study explores the extent of expression variability among pharmacogenes in a wide array of cell types across eight different human tissues, shedding light on their impact on drug responses. Our findings broaden the established link between variability in pharmacogene expression and drug efficacy to encompass variability at the cellular level. Moreover, we unveil a promising approach to enhance drug efficacy prediction. This is achieved by leveraging a combination of cross-cell and cross-individual pharmacogene expression variation measurements. Our study opens avenues for more precise forecasting of drug performance, facilitating tailored and more effective treatments in the future.

Unveiling the micronutrient-immunity puzzle in inactivated COVID-19 vaccination: A comprehensive analysis of circulating micronutrient levels and humoral responses in healthy adults.

While micronutrients are crucial for immune function, their impact on humoral responses to inactivated COVID-19 vaccination remains unclear. We investigated the associations between seven key micronutrients and antibody responses in 44 healthy adults with two doses of an inactivated COVID-19 vaccine. Blood samples were collected pre-vaccination and 28 days post-booster. We measured circulating minerals (iron, zinc, copper, and selenium) and vitamins (A, D, and E) concentrations alongside antibody responses and assessed their associations using linear regression analyses. Our analysis revealed inverse associations between blood iron and zinc concentrations and anti-SARS-CoV-2 IgM antibody binding affinity (AUC for iron: ß = -258.21, p < 0.0001; zinc: ß = -17.25, p = 0.0004). Notably, antibody quality presented complex relationships. Blood selenium was positively associated (ß = 18.61, p = 0.0030), while copper/selenium ratio was inversely associated (ß = -1.36, p = 0.0055) with the neutralizing ability against SARS-CoV-2 virus at a 1:10 plasma dilution. There was no significant association between circulating micronutrient concentrations and anti-SARS-CoV-2 IgG binding affinity. These findings suggest that circulating iron, zinc, and selenium concentrations and copper/selenium ratio, may serve as potential biomarkers for both quantity (binding affinity) and quality (neutralization) of humoral responses after inactivated COVID-19 vaccination. Furthermore, they hint at the potential of pre-vaccination dietary interventions, such as selenium supplementation, to improve vaccine efficacy. However, larger, diverse studies are needed to validate these findings. This research advances the understanding of the impact of micronutrients on vaccine response, offering the potential for personalized vaccination strategies.

Improvement of mechanical properties of elastic materials by chemical methods.

Elastomers such as gels and rubbers play various roles in our lives. Elastomers, which guarantee the safety of airplanes and automobiles and the stability of buildings, are materials that have made the lives of people in the twentieth century extremely convenient. The existence of macromolecules, that is, giant molecules, has been clarified; the development of synthetic macromolecules has progressed; and understanding of elastomers has progressed. By introducing new ideas, it has become possible to obtain tough and hard elastomers, which was difficult under conventional ideas. In this paper, we will explain the development from the classical theory of elastomers to current efforts.

MnO2/rGO/CNTs Framework as a Sulfur Host for High-Performance Li-S Batteries.

Lithium-sulfur batteries are very promising next-generation energy storage batteries due to their high theoretical specific capacity. However, the shuttle effect of lithium-sulfur batteries is one of the important bottlenecks that limits its rapid development. Herein, physical and chemical dual adsorption of lithium polysulfides are achieved by designing a novel framework structure consisting of MnO2, reduced graphene oxide (rGO), and carbon nanotubes (CNTs). The framework-structure composite of MnO2/rGO/CNTs is prepared by a simple hydrothermal method. The framework exhibits a uniform and abundant mesoporous structure (concentrating in ~12 nm). MnO2 is an α phase structure and the α-MnO2 also has a significant effect on the adsorption of lithium polysulfides. The rGO and CNTs provide a good physical adsorption interaction and good electronic conductivity for the dissolved polysulfides. As a result, the MnO2/rGO/CNTs/S cathode delivered a high initial capacity of 1201 mAh g-1 at 0.2 C. The average capacities were 916 mAh g-1, 736 mAh g-1, and 547 mAh g-1 at the current densities of 0.5 C, 1 C, and 2 C, respectively. In addition, when tested at 0.5 C, the MnO2/rGO/CNTs/S exhibited a high initial capacity of 1010 mAh g-1 and achieved 780 mAh g-1 after 200 cycles, with a low capacity decay rate of 0.11% per cycle. This framework-structure composite provides a simple way to improve the electrochemical performance of Li-S batteries.

Bioinspired Surface Functionalization of Titanium for Enhanced Lubrication and Sustained Drug Release.

Titanium and its alloys have long been used as implantable biomaterials in orthopedics; however, to the best of our knowledge, few studies were reported to investigate surface functionalization of titanium for enhanced lubrication and sustained drug release. In the present study, titania nanotube arrays (TNTs) were prepared by anodization as effective drug nanocarriers, using titanium as the substrate. Meanwhile, motivated by articular cartilage-inspired superlubricity and mussel-inspired adhesion, a copolymer containing both dopamine methacrylamide and 2-methacryloyloxyethyl phosphorylcholine was synthesized (DMA-MPC) and spontaneously grafted onto the TNT surface, which was validated by characterization techniques such as scanning electron microscopy, water contact angle measurements, and X-ray photoelectron spectroscopy. Additionally, the lubrication test showed that copolymer-grafted TNTs have remarkably reduced friction coefficients compared with bare TNTs. Furthermore, the drug release test demonstrated that copolymer-grafted TNTs inhibited burst drug release and achieved sustained drug release in comparison with bare TNTs. In conclusion, the bioinspired surface functionalization strategy developed here, namely DMA-MPC copolymer-grafted TNTs, can be applied to modify orthopedic biomaterials (such as titanium) for enhanced lubrication and sustained drug release.

Bioinspired Surface Functionalization of Titanium Alloy for Enhanced Lubrication and Bacterial Resistance.

In clinics it is extremely important for implanted devices to achieve the property of enhanced lubrication and bacterial resistance; however, such a strategy has rarely been reported in previous literature. In the present study, a surface functionalization method, motivated by articular cartilage-inspired superlubrication and mussel-inspired adhesion, was proposed to modify titanium alloy (Ti6Al4V) using the copolymer (DMA-MPC) synthesized via free radical copolymerization. The copolymer-coated Ti6Al4V (Ti6Al4V@DMA-MPC) was evaluated by X-ray photoelectron spectroscopy, water contact angle, and Raman spectra to confirm that the DMA-MPC copolymer was successfully coated onto the Ti6Al4V substrate. In addition, the tribological test, with the polystyrene microsphere and Ti6Al4V or Ti6Al4V@DMA-MPC as the tribopair, indicated that the friction coefficient was greatly reduced for Ti6Al4V@DMA-MPC. Furthermore, the bacterial resistance test showed that bacterial attachment was significantly inhibited for Ti6Al4V@DMA-MPC for the three types of bacteria tested. The enhanced lubrication and bacterial resistance of Ti6Al4V@DMA-MPC was due to the tenacious hydration shell formed surrounding the zwitterionic charges in the phosphorylcholine group of the DMA-MPC copolymer. In summary, a bioinspired surface functionalization strategy is developed in this study, which can act as a universal and promising method to achieve enhanced lubrication and bacterial resistance for biomedical implants.

Linking capacity loss and retention of nickel hexacyanoferrate to a two-site intercalation mechanism for aqueous Mg2+ and Ca2+ ions.

Prussian blue analogues (PBAs) are promising cation intercalation materials for electrochemical desalination and energy storage applications. Here, we investigate the mechanism of capacity fade and degradation of nickel hexacyanoferrate (NiHCFe) during galvanostatic cycling in aqueous electrolytes that are rich in either Mg2+ or Ca2+. We combine experimental characterization, first principles electronic structure calculations, statistical mechanics and lattice-percolation modeling of electron transfer to elucidate the mechanisms responsible for the degradation of NiHCFe and its partial retention of capacity. Electrochemical characterization of porous NiHCFe electrodes suggests a two-site intercalation mechanism, while spectroscopy reveals the presence of Ni2+ and Fe(CN)63- ions in the electrolyte post cycling in Mg2+(aq). Using simple coprecipitation reactions, we show that Mg2+ and Ni2+ can coexist in the lattice framework, forming stable PBAs. Galvanostatic cycling of these PBAs shows that the presence of Mg2+ in the lattice framework results in the dissolution of Mg1.5FeIII(CN)6 in water during oxidation. We propose that Mg2+ can partially substitute Ni2+ ions in the lattice framework during galvanostatic cycling, displacing the substituted Ni2+ ions into interstitial sites. Based on differential capacitance analysis we show that Mg2+ intercalates into interstitial sites at ∼0.45 V vs. Ag/AgCl and it displaces Ni2+ in the lattice framework at ∼0.05 V vs. Ag/AgCl. Substitution of Ni2+ leads to Fe(CN)63- and Ni2+ ions being removed into the electrolyte during oxidation. Using first principles density functional theory (DFT) calculations combined with a statistical mechanics model, we verify the thermodynamic feasibility of the proposed reaction mechanism and predict the fraction of Ni2+ ions being substituted by Mg2+ during intercalation. Further, analysis of the electron density distribution and local density of states indicates that Mg2+ ions can act as insulating defects in the lattice framework that render certain Fe ions electrically inactive and likely contribute to capacity fade along with dissolution of Fe(CN)63-.

Neighborhood social cohesion and cognitive function in U.S. Chinese older adults-findings from the PINE study.

Objectives: The projected increase in the population of older adults in the United States entails a pressing need to examine risk and protective factors associated with cognitive function. This study aims to examine the association between neighborhood social cohesion and cognitive function among older Chinese adults in the United States. Method: Using the first epidemiological survey of older Chinese Americans and applying ordinary least squares and quantile regressions, this study examines the association between neighborhood social cohesion and various domains of cognitive function. Results: Results show that neighborhood social cohesion is independently associated with most domains of cognitive function (i.e. global cognition score, and its components such as the Chinese Mini-Mental State Examination and executive function and episodic memory measures). Conclusion: This study represents one of a few initial efforts that examined the association between neighborhood social cohesion and cognitive function for Chinese older adults in the United States. Our findings suggest that socially cohesive neighborhoods can provide enriched environments where active lifestyles can be encouraged, and cognitive skills and abilities can be stimulated, practiced, and preserved for older adults.

Bioinspired Surface Functionalization of Nanodiamonds for Enhanced Lubrication.

The addition of nanoparticles to water-based lubricants is a commonly used method to improve lubrication, but to the best of our knowledge few studies have been reported to investigate the lubrication property of surface-modified nanodiamonds (ND) with polyzwitterionic brushes. In this study, a bioinspired copolymer containing dopamine and 2-methacryloyloxyethyl phosphorylcholine (MPC) was synthesized (DMA-MPC) and then spontaneously grafted onto the ND surface (ND-MPC) through simple stirring in order to enhance lubrication. The characterization of transmission electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis indicated that the DMA-MPC was successfully modified on the ND surface. Furthermore, a series of tribological experiment were performed on a universal materials tester using glycerol, glycerol + ND, and glycerol + ND-MPC as the lubricants. It was found that the addition of ND to the lubricant (i.e., glycerol + ND and glycerol + ND-MPC) significantly reduced wear with a smaller wear scar and wear track on the tribopairs, and the coefficient of friction further decreased by about 40% when using glycerol + ND-MPC as the lubricant, which could be attributed to the hydration lubrication of the polyzwitterionic brushes modified on the ND surface and the rolling effect of nanoparticles. In conclusion, in this study a universal and versatile surface modification method was proposed on the basis of the synthesis of bioinspired copolymer DMA-MPC, which remarkably enhanced the lubrication property of ND nanoparticles when added to water-based lubricants.

Alkalinity Regulation and Optimization of Cementitious Materials Used in Ecological Porous Concrete.

Ecological porous concrete (EPC) is one of the novel formulations of concrete with unique phytogenic properties. However, achieving both low alkalinity and high strength in EPC proves challenging due to the inherently high alkalinity of the pore environment, which hinders the growth of the plant and affects its ecological benefits significantly. This research investigated the utilization of 15 types of chemical admixtures and diatomaceous earth as alkali-reducing agents to optimize the properties of silicate cementitious materials for the applications of EPC. To identify the most effective agents, the pH value and compressive strength of the cement paste were adopted as the screening criteria for the selection of the essential alkali-reducing ingredients. Subsequently, a composite approach combining chemical admixtures and DE was employed to explore the synergistic effects on the pH and strength of silicate cementitious materials. The results revealed that a combination of 8% DE, 5% oxalic acid, and 5% iron sulfate functioned effectively and resulted in desirable performance for the concrete. This synergistic blend effectively consumed a large amount of Ca(OH)2, reducing the pH of cement paste to 10.48 within 3 days. Furthermore, the hydration reaction generated C-S-H with a low Ca/Si ratio, leading to a remarkable increase in the compressive strength of the concrete, reaching 89.7 MPa after 56 days. This composite approach ensured both low alkalinity and high strength in silicate cementitious materials, providing a theoretical basis for the application and promotion of EPC in the ecological field.

The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.

NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.

Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA.

Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif-dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA-induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.

Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor.

Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

CircRNA based multivalent neuraminidase vaccine induces broad protection against influenza viruses in mice.

Developing broad-spectrum influenza vaccines is crucial for influenza control and potential pandemic preparedness. Here, we reported a novel vaccine design utilizing circular RNA (circRNA) as a delivery platform for multi-subtype neuraminidases (NA) (influenza A N1, N2, and influenza B Victoria lineage NA) immunogens. Individual NA circRNA lipid nanoparticles (LNP) elicited robust NA-specific antibody responses with neuraminidase inhibition activity (NAI), preventing the virus from egressing and infecting neighboring cells. Additionally, the administration of circRNA LNP induced cellular immunity in mice. To achieve a universal influenza vaccine, we combined all three subtypes of NA circRNA-LNPs to generate a trivalent circRNA vaccine. The trivalent vaccine elicited a balanced antibody response against all three NA subtypes and a Th1-biased immune response in mice. Moreover, it protected mice against the lethal challenge of matched and mismatched H1N1, H3N2, and influenza B viruses, encompassing circulating and ancestral influenza virus strains. This study highlights the potential of delivering multiple NA antigens through circRNA-LNPs as a promising strategy for effectively developing a universal influenza vaccine against diverse influenza viruses.

Upregulation of MAD2L1 mediated by ncRNA axis is associated with poor prognosis and tumor immune infiltration in hepatocellular carcinoma: A review.

BACKGROUND: The mortality rate and prognosis of patients with hepatocellular carcinoma (HCC) are well known. A variety of highly malignant human cancers express mitotic arrest deficient 2 like 1 (MAD2L1), a transcription factor that plays a critical role in their development and progression. However, MAD2L1's particular mechanisms and effects on HCC remain uncertain. METHODS: We performed a pan-cancer analysis for MAD2L1 prognosis and expression using The Cancer Genome Atlas and Genotype-Tissue Expression data in the present study. MAD2L1 may act as an oncogene in HCC, and a combination of in silico analyses, including expression, survival, and correlation analyses, were performed to identify non-coding ribonucleic acids (ncRNAs) that contribute to MAD2L1 overexpression. RESULTS: In conclusion, MAD2L1 is most likely regulated by HCP5/miRNA-139-5p/MAD2L1 in HCC based on its upstream ncRNA-related pathway. A significant positive association was also found between MAD2L1 levels and tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. CONCLUSION: Our findings demonstrate that ncRNA-mediated upregulation of MAD2L1 in HCC is closely related to poor prognosis and tumor infiltration.

Role of the HIF-1α/BNIP3 Signaling Pathway in Recurrent Hepatocellular Carcinoma and the Mechanism of Traditional Chinese Medicine.

Recurrence of hepatocellular carcinoma (HCC) negatively affects the quality of life of patients and leads to death. Studies have shown that recurrent hepatocellular carcinoma (RHCC) is closely related to tissue hypoxia and autophagy. It has been shown that hypoxia-inducible factor-1α (HIF-1α) and its downstream factor BCL-2 19 kDa-interacting protein 3 (BNIP3) promote cellular autophagy under hypoxic conditions, resulting in metastasis and RHCC. In this article, the molecular structures of HIF-1α and BNIP3 are described, and the significance of the HIF-1α/BNIP3 signaling pathway in RHCC is explained. Moreover, the role and mechanism of traditional Chinese medicine (TCM) in treating RHCC by modulating the HIF-1α/BNIP3 signaling pathway is discussed. Studies have shown that the HIF-1α/BNIP3 signaling pathway is a potential target of TCM in the treatment of RHCC. The mechanism of the HIF-1α/BNIP3 signaling pathway in RHCC and the progress achieved in TCM research on targeting and regulating this pathway are also reviewed in this article. The objective was to provide a theoretical basis for the prevention and treatment of RHCC, as well as further drug development.

The Association between Intergenerational Support and Self-Rated Health among Chinese Older Adults: Do Resilience and Gender Matter?

This study aims to examine the association between intergenerational support and self-rated health (SRH) levels using data collected from Chinese older adults residing in Honolulu, United States (N = 329). We also investigated the mediating role of resilience and the moderating role of gender in the association. We found that receiving emotional support was significantly and positively associated with better SRH for the whole sample. The positive effect of receiving emotional support on health was significant among older women only. In contrast, the beneficial effect of providing economic support on health was significant among older men only. We found that resilience significantly mediated the positive effect of received emotional support on SRH, and this effect was found for the whole sample and among older women. However, resilience did not mediate the positive effect of the economic support provided on SRH among older men.

RBD class 1 and 2 antibody epitopes elicit around 70% neutralizing capacity against SARS-CoV-2 virus following boosting with inactivated virus vaccine.

A third dose of inactivated virus vaccine (IVV) boosts neutralizing antibodies, reducing SARS-CoV-2 transmission rate and COVID-19 severity. However, the impact of RBD-elicited antibodies and their neutralizing activity by the boost of IVV is unknown. We investigated the impact of IVV's boost shot on RBD-elicited antibodies and their neutralizing activity in 18 subjects receiving the second and third IVV doses. Using an RBD antibodies depletion assay, we assessed the neutralizing activity of RBD-elicited antibodies. After the second dose, RBD-antigen elicitation accounted for ∼60% of neutralizing activity, which increased to 82% after the IVV boost against ancestral SARS-CoV-2. Depleting class 3 and class 4-specific antibodies with the Beta-RBD protein revealed that NAbs targeting RBD class 1 and class 2 subdomains increased from 57% to 75% post-boost. These findings highlight the significant enhancement of RBD-specific antibodies, especially against RBD class 1 and class 2, with IVV booster doses. Our study offers valuable insights for optimizing COVID-19 vaccine strategies.

Benchmarking various types of partial atomic charges for classical all-atom simulations of metal-organic frameworks.

The density derived electrostatic and chemical (DDEC) approach for calculating the charges of atoms in a metal-organic framework (MOF) is considered to be the most accurate (yet computationally costly) one among many charge-assignment methods. Here, we conducted a comparative study on five different types of atomic partial charges (namely CM5, Mulliken, Qeq, EQeq and PACMOF) prepared for a subset of MOFs with affordable computational costs and benchmarked them with respect to the DDEC charges, which is particularly relevant because currently most databases lack MOFs with pre-calculated DDEC charges. To find a suitable charge type alternative to the DDEC approach, we statistically ranked the five charge types based on two metrics, the relative standard deviation of charges and relative dipole moment difference, based on which we provide general guidance as well as suggestions for specific MOFs according to bond polarity analyses. Finally, we recommend a possible and more accurate parametrization scheme for future studies.

Engineered living materials (ELMs) design: From function allocation to dynamic behavior modulation.

Natural materials possess many distinctive "living" attributes, such as self-growth, self-healing, environmental responsiveness, and evolvability, that are beyond the reach of many existing synthetic materials. The emerging field of engineered living materials (ELMs) takes inspiration from nature and harnesses engineered living systems to produce dynamic and responsive materials with genetically programmable functionalities. Here, we identify and review two main directions for the rational design of ELMs: first, engineering of living materials with enhanced performances by incorporating functional material modules, including engineered biological building blocks (proteins, polysaccharides, and nucleic acids) or well-defined artificial materials; second, engineering of smart ELMs that can sense and respond to their surroundings by programming dynamic cellular behaviors regulated via cell-cell or cell-environment interactions. We next discuss the strengths and challenges of current ELMs and conclude by providing a perspective of future directions in this promising area.