Polydopamine-Based Resveratrol-Hyaluronidase Nanomedicine Inhibited Pancreatic Cancer Cell Invasive Phenotype in Hyaluronic Acid Enrichment Tumor Sphere Model.

The dense storm microenvironment formed by an excessively cross-linked extracellular matrix, such as hyaluronic acid and collagens, serves as a major barrier that prevents drugs from reaching the deeper tumor. Current traditional two-dimensional (2D) cultures are not capable of modeling this drug delivery barrier in vitro. Thus, tumor spheroids have become increasingly important in cancer research due to their three-dimensional structure. Currently, various methods have been developed to construct tumor spheroids. However, there are still challenges, such as lengthy construction time, complex composition of added growth factors, and high cultivation costs. To address this technical bottleneck, our study combined the GelMA hydrogel system to develop a rapid and high-yield method for tumor spheroids generation. Additionally, we proposed an evaluation scheme to assess the effects of drugs on tumor spheroids. Building on the hyaluronic acid-rich pathological tumor microenvironment, we constructed a resveratrol-loaded nano-drug delivery system with tumor stroma modulation capability and used a three-dimensional (3D) tumor sphere model to simulate in vivo tumor conditions. This process was utilized to completely evaluate the ability of the nano-drug delivery system to enhance the deep penetration of resveratrol in the tumor microenvironment, providing new insights into future oncology drug screening, efficacy assessment, and drug delivery methods.

Wearable smart contact lenses: A critical comparison of three physiological signals outputs for health monitoring.

Smart contact lenses (SCLs) have been considered as novel wearable devices for out-of-hospital and self-monitoring applications. They are capable of non-invasively and continuously monitoring physiological signals in the eyes, including vital biophysical (e.g., intraocular of pressure, temperature, and electrophysiological signal) and biochemical signals (e.g., pH, glucose, protein, nitrite, lactic acid, and ions). Recent progress mainly focuses on the rational design of wearable SCLs for physiological signal monitoring, while also facilitating the treatment of various ocular diseases. It covers contact lens materials, fabrication technologies, and integration methods. We also highlight and discuss a critical comparison of SCLs with electrical, microfluidic, and optical signal outputs in health monitoring. Their advantages and disadvantages could help researchers to make decisions when developing SCLs with desired properties for physiological signal monitoring. These unique capabilities make SCLs promising diagnostic and therapeutic tools. Despite the extensive research in SCLs, new technologies are still in their early stages of development and there are a few challenges to be addressed before these SCLs technologies can be successfully commercialized particularly in the form of rigorous clinical trials.

Rare penetrant mutations confer severe risk of common diseases.

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

Rare penetrant mutations confer severe risk of common diseases.

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ∼10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared to common variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction. One sentence summary: Rare variant polygenic risk scores identify individuals with outlier phenotypes in common human diseases and complex traits.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence Summary: Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.

REVIEW ARTICLE Engineering bio-inks for 3D bioprinting cell mechanical microenvironment.

144Three-dimensional (3D) bioprinting has become a promising approach to constructing functional biomimetic tissues for tissue engineering and regenerative medicine. In 3D bioprinting, bio-inks are essential for the construction of cell microenvironment, thus affecting the biomimetic design and regenerative efficiency. Mechanical properties are one of the essential aspects of microenvironment, which can be characterized by matrix stiffness, viscoelasticity, topography, and dynamic mechanical stimulation. With the recent advances in functional biomaterials, various engineered bio-inks have realized the possibility of engineering cell mechanical microenvironment in vivo. In this review, we summarize the critical mechanical cues of cell microenvironments, review the engineered bio-inks while focusing on the selection principles for constructing cell mechanical microenvironments, and discuss the challenges facing this field and the possible solutions for them.

An endoscopically compatible fast-gelation powder forms Janus-adhesive hydrogel barrier to prevent postoperative adhesions.

Postoperative adhesions occur widely in various tissues, bringing the risk of secondary surgery and increased medical burden. Hydrogel barriers with Janus-adhesive ability can achieve physical isolation of adjacent tissues and are therefore considered an ideal solution. However, integrating endoscopic delivery convenience and viscoelastic Janus hydrogel formation remains a great challenge. Here, we present a report of the in situ formation of Janus-adhesive hydrogel barrier using a sprayable fast-Janus-gelation (FJG) powder. We first methacrylate the polysaccharide macromolecules to break the intermolecular hydrogen bonds and impart the ability of rapid hydration. FJG powder can rapidly absorb interfacial water and crosslink through borate ester bonds, forming a toughly adhesive viscoelastic hydrogel. The Janus barrier can be simply formed by further hydrating the upper powder with cationic solution. We construct rat models to demonstrate the antiadhesions efficiency of viscoelastic FJG hydrogels in organs with different motion modalities (e.g., intestine, heart, liver). We also developed a low-cost delivery device with a standardized surgical procedure and further validated the feasibility and effectiveness of FJG powder in minimally invasive surgery using a preclinical translational porcine model. Considering the advantages in terms of therapeutic efficacy, clinical convenience, and commercialization, our results reveal the great potential of Janus-gelation powder materials as a next-generation antiadhesions barrier.

MCAT: Motif Combining and Association Tool.

De novo motif discovery in biological sequences is an important and computationally challenging problem. A myriad of algorithms have been developed to solve this problem with varying success, but it can be difficult for even a small number of these tools to reach a consensus. Because individual tools can be better suited for specific scenarios, an ensemble tool that combines the results of many algorithms can yield a more confident and complete result. We present a novel and fast tool ensemble MCAT (Motif Combining and Association Tool) for de novo motif discovery by combining six state-of-the-art motif discovery tools (MEME, BioProspector, DECOD, XXmotif, Weeder, and CMF). We apply MCAT to data sets with DNA sequences that come from various species and compare our results with two well-established ensemble motif-finding tools, EMD and DynaMIT. The experimental results show that MCAT is able to identify exact match motifs in DNA sequences efficiently, and it has a significantly better performance in practice.

Strong coupling between chlorosomes of photosynthetic bacteria and a confined optical cavity mode.

Strong exciton-photon coupling is the result of a reversible exchange of energy between an excited state and a confined optical field. This results in the formation of polariton states that have energies different from the exciton and photon. We demonstrate strong exciton-photon coupling between light-harvesting complexes and a confined optical mode within a metallic optical microcavity. The energetic anti-crossing between the exciton and photon dispersions characteristic of strong coupling is observed in reflectivity and transmission with a Rabi splitting energy on the order of 150 meV, which corresponds to about 1,000 chlorosomes coherently coupled to the cavity mode. We believe that the strong coupling regime presents an opportunity to modify the energy transfer pathways within photosynthetic organisms without modification of the molecular structure.

Probing the spatial organization of bacteriochlorophyll C by solid-state nuclear magnetic resonance.

Green sulfur bacteria, which live in extremely low-light environments, use chlorosomes to harvest light. A chlorosome is the most efficient, and arguably the simplest, light-harvesting antenna complex, which contains hundreds of thousands of densely packed bacteriochlorophylls (BChls). To harvest light efficiently, BChls in a chlorosome form supramolecular aggregates; thus, it is of great interest to determine the organization of the BChls in a chlorosome. In this study, we conducted a (13)C solid-state nuclear magnetic resonance and Mg K-edge X-ray absorption analysis of chlorosomes from wild-type Chlorobaculum tepidum. The X-ray absorption results indicated that the coordination number of the Mg in the chlorosome must be >4, providing evidence that electrostatic interactions formed between the Mg of a BChl and the carbonyl group or the hydroxyl group of the neighboring BChl molecule. According to the intermolecular distance constraints obtained on the basis of (13)C homonuclear dipolar correlation spectroscopy, we determined that the molecular assembly of BChls is dimer-based and that the hydrogen bonds among the BChls are less extensive than commonly presumed because of the twist in the orientation of the BChl dimers. This paper also reports the first (13)C homonuclear correlation spectrum acquired for carotenoids and lipids-which are minor, but crucial, components of chlorosomes-extracted from wild-type Cba. tepidum.

D-galactose induces a mitochondrial complex I deficiency in mouse skeletal muscle: potential benefits of nutrient combination in ameliorating muscle impairment.

Accumulating research has shown that chronic D-galactose (D-gal) exposure induces symptoms similar to natural aging in animals. Therefore, rodents chronically exposed to D-gal are increasingly used as a model for aging and delay-of-aging pharmacological research. Mitochondrial dysfunction is thought to play a vital role in aging and age-related diseases; however, whether mitochondrial dysfunction plays a significant role in mice exposed to D-gal remains unknown. In the present study, we investigated cognitive dysfunction, locomotor activity, and mitochondrial dysfunction involved in D-gal exposure in mice. We found that D-gal exposure (125 mg/kg/day, 8 weeks) resulted in a serious impairment in grip strength in mice, whereas spatial memory and locomotor coordination remained intact. Interestingly, muscular mitochondrial complex I deficiency occurred in the skeletal muscle of mice exposed to D-gal. Mitochondrial ultrastructure abnormality was implicated as a contributing factor in D-gal-induced muscular impairment. Moreover, three combinations (A, B, and C) of nutrients applied in this study effectively reversed D-gal-induced muscular impairment. Nutrient formulas B and C were especially effective in reversing complex I dysfunction in both skeletal muscle and heart muscle. These findings suggest the following: (1) chronic exposure to D-gal first results in specific muscular impairment in mice, rather than causing general, premature aging; (2) poor skeletal muscle strength induced by D-gal might be due to the mitochondrial dysfunction caused by complex I deficiency; and (3) the nutrient complexes applied in the study attenuated the skeletal muscle impairment, most likely by improving mitochondrial function.

Directed self-assembly of microscale hydrogels by electrostatic interaction.

The unique benefit of electrostatic self-assembly of microscale components in solution is demonstrated for the first time. In particular, positive and negative treatment of poly(ethylene glycol) (PEG) facilitates a novel bottom-up assembly approach using electrostatic interaction from microgels with opposite charges. Fundamental investigations of electrostatic interaction of microgels reveal that the contact area of microgels determines the total energy of construct and thus the final patterns. The electrostatic self-assembly approach enables the fabrication of large and complex biological related structures (e.g., multi-layer spheroid) with accurate control. By the design of the microgels, the thickness and number of microgels in each layer can be controlled. Biological investigations of positive and negative treatments of PEG further prove the possibility of using this approach in tissue engineering, regenerative medicine and drug delivery.