The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges.

In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including ß-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional ß-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional ß-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional ß-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional ß-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional ß-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

Traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine.

Although pancreas and islet cell transplantation are the only ways to prevent the late complications of insulin-dependent diabetes, a shortage of donors is a major obstacle to tissue and organ transplantation. Stem cell therapy is an effective treatment for diabetes and other pancreatic-related diseases, which can be achieved by inducing their differentiation into insulin-secreting cells. The liver is considered an ideal source of pancreatic cells due to its similar developmental origin and strong regenerative ability as the pancreas. This article reviews the traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine and evaluates their advantages and challenges. Gene reprogramming and chemical reprogramming technologies are traditional strategies with potential to improve the efficiency and specificity of cell reprogramming and promote the transformation of hepatocytes into islet cells. At the same time, organoid technology, as an emerging strategy, has received extensive attention. Biomaterials provide a three-dimensional culture microenvironment for cells, which helps improve cell survival and differentiation efficiency. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology has brought new opportunities and challenges to the development of organoid technology.

Chromosome-level genome assembly of the predatory stink bug Arma custos.

The stink bug Arma custos (Hemiptera: Pentatomidae) is a predatory enemy successfully used for biocontrol of lepidopteran and coleopteran pests in notorious invasive species. In this study, a high-quality chromosome-scale genome assembly of A. custos was achieved through a combination of Illumina sequencing, PacBio HiFi sequencing, and Hi-C scaffolding techniques. The final assembled genome was 969.02 Mb in size, with 935.94 Mb anchored to seven chromosomes, and a scaffold N50 length of 135.75 Mb. This genome comprised 52.78% repetitive elements. The detected complete BUSCO score was 99.34%, indicating its completeness. A total of 13,708 protein-coding genes were predicted in the genome, and 13219 of them were annotated. This genome provides an invaluable resource for further research on various aspects of predatory bugs, such as biology, genetics, and functional genomics.

Dynamic clustering via branched deep learning enhances personalization of stress prediction from mobile sensor data.

College students experience ever-increasing levels of stress, leading to a wide range of health problems. In this context, monitoring and predicting students' stress levels is crucial and, fortunately, made possible by the growing support for data collection via mobile devices. However, predicting stress levels from mobile phone data remains a challenging task, and off-the-shelf deep learning models are inapplicable or inefficient due to data irregularity, inter-subject variability, and the "cold start problem". To overcome these challenges, we developed a platform named Branched CALM-Net that aims to predict students' stress levels through dynamic clustering in a personalized manner. This is the first platform that leverages the branching technique in a multitask setting to achieve personalization and continuous adaptation. Our method achieves state-of-the-art performance in predicting student stress from mobile sensor data collected as part of the Dartmouth StudentLife study, with a ROC AUC 37% higher and a PR AUC surpassing that of the nearest baseline models. In the cold-start online learning setting, Branched CALM-Net outperforms other models, attaining an average F1 score of 87% with just 1 week of training data for a new student, which shows it is reliable and effective at predicting stress levels from mobile data.

A palladium-catalyzed synthesis of cyclic alkenyl boronates from alkenyl chlorides.

A palladium-catalyzed borylation of cyclic alkenyl chlorides with B2pin2 is reported. This transformation allows for the conversion of diverse cyclic alkenyl chlorides into synthetically versatile alkenyl boronates with moderate to excellent yields. The utility of this reaction has been demonstrated with practical Suzuki-Miyaura coupling and aziridination reactions, which allow access to functionalized olefins and valuable boron-substituted aziridines.

Ultrasensitive enhanced Raman spectroscopy by hybrid surface-enhanced and interference-enhanced Raman scattering with metal-insulator-metal structures.

High-sensitivity, reproducible, and low-cost substrate has been a major obstacle for practical sensing application of surface-enhancement Raman scattering (SERS). In this work, we report a type of simple SERS substrate which is composed of metal-insulator-metal (MIM) structure of Ag nanoisland (AgNI)-SiO2-Ag film (AgF). The substrates are fabricated by only evaporation and sputtering processes, which are simple, fast and low-cost. By combining the hotspots and interference-enhanced effects in AgNIs and the plasmonic cavity (SiO2) between AgNIs and AgF, the proposed SERS substrate shows an enhancement factor (EF) of 1.83 × 108 with limit of detection (LOD) down to 10-17 mol/L for rhodamine 6 G (R6G) molecules. The EFs are ∼18 times higher than that of conventional AgNIs without MIM structure. In addition, the MIM structure shows excellent reproducibility with relative standard deviation (RSD) less than 9%. The proposed SERS substrate is fabricated only with evaporation and sputtering technique and the conventionally used lithographic methods or chemical synthesis are not required. This work provides a simple way to fabricate ultrasensitive and reproducible SERS substrates which show great promise for developing various biochemical sensors with SERS.

A comprehensive SERS, SEM and EDX study of individual atmospheric PM2.5 particles in Chengdu, China.

Characterization of atmospheric fine particulate matter (PM2.5) in large cities has important implications for the study of their sources and formation mechanisms, as well as in developing effective measures to control air pollution. Herein, we report a holistic physical and chemical characterization of PM2.5 by combining surface-enhanced Raman scattering (SERS) with scanning electron microscopy (SEM) and electron-induced X-ray spectroscopy (EDX). PM2.5 particles were collected in a suburban area of Chengdu, a large city in China with a population over 21 million. A special SERS chip composed of inverted hollow Au cone (IHAC) arrays was designed and fabricated to allow direct loading of PM2.5 particles. SERS and EDX were used to reveal the chemical composition, and particle morphologies were analyzed from SEM images. SERS data of atmospheric PM2.5 indicated qualitatively the presence of carbonaceous particulate matter, sulfate, nitrate, metal oxides and bioparticles. The EDX showed the presence of the elements C, N, O, Fe, Na, Mg, Al, Si, S, K, and Ca in the collected PM2.5. Morphology analysis showed that the particulates were mainly in the form of flocculent clusters, spherical, regular crystal shaped or irregularly shaped particles. Our chemical and physical analyses also revealed that the main sources of PM2.5 are automobile exhaust, secondary pollution caused by photochemical reactions in the air, dust, emission from nearby industrial exhaust, biological particles, other aggregated particles, and hygroscopic particles. SERS and SEM data collected during three different seasons showed that carbon-containing particles are the principal sources of PM2.5. Our study demonstrates that the SERS based technique, when combined with standard physicochemical characterization methods, is a powerful analytical tool to determine the sources of ambient PM2.5 pollution. Results obtained in this work may be valuable to the prevention and control of PM2.5 pollution in air.

A water-soluble NIR fluorescent probe capable of rapid response and selective detection of hydrogen sulfide in food samples and living cells.

DDAO (1,3-Dichloro-7-hydroxy-9,9-dimethyl-2(9H)-acridone) is a near-infrared (NIR) fluorophore that has received increasing attention in recent years, exhibiting near-infrared emission at 658 nm, low pKa (∼5.0), good water solubility and high quantum yield (Φ = 0.39). The reported DDAO-based fluorescent probes can be applied to biological imaging ofenzymes and other substances in vivo with high sensitivity and selectivity. Herein, using -OCN as the detection group, a novel NIR H2S fluorescent probe DDAO-CN based on DDAO was designed and synthesized. In PBS buffer (10 mM, pH 7.4), probe DDAO-CN displayed specific selection, short response time (within 10 s) and low detection limit (4.3 nM) towards to H2S under the catalysis of CTAB. At the same time, the probe is able to sense H2S gas produced by food spoilage via the fluorescent test strip loaded with DDAO-CN. Moreover, since the probe has optimal pH range (6.0-9.0), it has been successfully used for bioimaging H2S in the HeLa cells with low cytotoxicity.

Rh-Catalyzed [3+2] Annulation of Cyclic Ketimines and Alkynyl Chloride: A Strategy for Accessing Unsymmetrically Substituted and Highly Functionalizable Indenes.

Alkynyl chlorides were found to be extraordinarily novel electrophiles, which could afford a single regioisomer of the [3+2] annulation adducts with cyclic ketimines by rhodium catalysis. The alkenyl chloride moiety in the products provided a valuable functional handle for further diverse transformations. Therefore, this research provided not only a synthetic protocol for accessing unsymmetrically substituted indenyl amines but also a highly divergent solution for decorating the substituting group by postmanipulation of the chloride.

Identification and classification of particle contaminants on photomasks based on individual-particle Raman scattering spectra and SEM images.

Particle contamination of photo masks is a significant issue facing the micro-nanofabrication process. It is necessary to analyze the particulate matter so that the contamination can be effectively controlled and eliminated. In this study, Raman spectroscopy was used in combination with scanning electron microscopy with energy analysis (SEM-EDX) techniques to study the contamination of individual particles on the photomask. From Raman spectroscopic analysis, the Raman bands of particles mainly contributed to the vibrational modes of the elements C, H, O, and N. Their morphology and elemental composition were determined by SEM-EDX. The sizes of the particles are mostly less than 0.8 µm according to the SEM image analysis. Hierarchical clustering analysis (HCA) of the Raman spectra of particles have shown that the particles can be classified into six clusters which are assigned to CaCO3, hydrocarbon and hydrocarbon polymers, mixture of NH4NO3 and few (NH4)2SO4, mixtures metal oxides, D and G peaks of carbon, fluorescent and (NH4)2SO4 clusters. Finally, principal component analysis (PCA) was used to verify the correctness of the classification results. The identification and classification analysis of individual particles of photomask contamination illustrate the chemical components of the particles and provide insights into mask cleaning and how to effectively avoid particle contamination.

A planar ultraviolet objective lens for optical axis free imaging nanolithography by employing optical negative refraction.

Lithography is one of the most key technologies for integrated circuit (IC) manufacturing and micro/nano-functional device fabrication, while the imaging objective lens plays one important role. Due to the curved surface of the conventional objective lens, the imaging field of view is limited and the objective lens system is complex. In this paper, a planar objective lens based on the optical negative refraction principle is demonstrated for achieving optical axis free and long depth of focus imaging nanolithography. Through employing a hyperbolic metamaterial composed of silver/titanium dioxide multilayers, plasmonic waveguide modes could be generated in multilayers, which results in optical negative refraction and then flat imaging at ultraviolet wavelength. The corresponding imaging characteristics are investigated in simulation and experiment. At the I-line wavelength of 365 nm, the highest imaging resolution of 165 nm could be realized in the 100 nm photoresist layer under the working gap of 100 nm between the objective lens and substrate. Moreover, this planar objective lens has good ability for cross-scale and two-dimensional imaging lithography, and is similar to a conventional projection objective lens. It is believed that this kind of planar objective lens will provide a promising avenue for low-cost nanofabrication scenarios in the near future.

PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2.

Phosphatidylethanolamine binding protein 4 (PEBP4) is an understudied multifunctional small protein. Previous studies have shown that the expression of PEBP4 is increased in many cancer specimens, which correlates to cancer progression. The present study explored the mechanism by which PEBP4 regulates the growth and progression of hepatocellular carcinoma cells. Thus, we showed that knockdown of PEBP4 in MHCC97H cells, where its expression was relatively high, diminished activities of serine/threonine protein kinase B (PKB, also known as Akt), mammalian target of rapamycin complex 1(mTORC1), and mTORC2, events that were not restored by insulin-like growth factor 1 (IGF-1). Conversely, overexpression of PEBP4 in MHCC97L cells with the low endogenous level yielded opposite effects. Furthermore, physical association of PEBP4 with Akt, mTORC1, and mTORC2 was observed. Interestingly, introduction of AktS473D mutant, bypassing phosphorylation by mTORC2, rescued mTORC1 activity, but without effects on mTORC2 signaling. In contrast, the effect of PEBP4 overexpression on the activity of mTORC1 but not that of mTORC2 was suppressed by MK2206, a specific inhibitor of Akt. In conjunction, PEBP4 knockdown-engendered reduction of cell proliferation, migration and invasion was partially rescued by Akt S473D while increases in these parameters induced by overexpression of PEBP4 were completely abolished by MK2206, although the expression of epithelial mesenchymal transition (EMT) markers appeared to be fully regulated by the active mutant of Akt. Finally, knockdown of PEBP4 diminished the growth of tumor and metastasis, whereas they were enhanced by overexpression of PEBP4. Altogether, our study suggests that increased expression of PEBP4 exacerbates malignant behaviors of hepatocellular cancer cells through cooperative participation of mTORC1 and mTORC2.

Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver.

Obesity often concurs with nonalcoholic fatty liver disease (NAFLD), both of which are detrimental to human health. Thus far, exercise appears to be an effective treatment approach. However, its effects cannot last long and, moreover, it is difficult to achieve for many obese people. Thus, it is necessary to look into alternative remedies. The present study explored a noninvasive, easy, tolerable physical alternative. In our experiment, C57BL/6 mice were fed with a high-fat diet (HFD) to induce overweight/obesity and were exposed to 10% oxygen for one hour every day. We found that hypoxia exerted protective effects. First, it offset HFD-induced bodyweight gain and insulin resistance. Secondly, hypoxia reversed the HFD-induced enlargement of white and brown adipocytes and fatty liver, and protected liver function. Thirdly, HFD downregulated the expression of genes required for lipolysis and thermogenesis, such as UCP1, ADR3(beta3-adrenergic receptor), CPT1A, ATGL, PPARα, and PGC1α, M2 macrophage markers arginase and CD206 in the liver, and UCP1 and PPARγ in brown fat, while these molecules were upregulated by hypoxia. Furthermore, hypoxia induced the activation of AMPK, an energy sensing enzyme. Fourthly, our results showed that hypoxia increased serum levels of epinephrine. Indeed, the effects of hypoxia on bodyweight, fatty liver, and associated changes in gene expression ever tested were reproduced by injection of epinephrine and prevented by propranolol at varying degrees. Altogether, our data suggest that hypoxia triggers stress responses where epinephrine plays important roles. Therefore, our study sheds light on the hope to use hypoxia to treat the daunting disorders, obesity and NAFLD.

Surface-enhanced Raman Scattering of Au-Ag bimetallic nanopillars fabricated using surface-plasmon lithography.

Arrays of gold-silver (Au-Ag) bimetallic nanopillars were fabricated by a newly developed surface-plasmon lithography (SPL) and their enhancement properties as surface-enhanced Raman scattering (SERS) substrates have been studied. We demonstrated that the SPL is a low-cost and high efficiency method for the fabrication of SERS substrates with both high sensitivity and reproducibility. The nanopillars showed a good response in the detection of methylene blue molecules at a low concentration of 1.0 × 10-11mol· l-1. The SERS enhancement factors (EFs) are on the orders of 107and the relative standard deviation of SERS intensity is <8% over an area of 50µm × 50µm. The EFs increase fast with the height increasing from 200 to 530 nm, then increase slowly when further increase the height of the nanopillars to 1100 nm. In addition, the Au-Ag bimetallic coating has shown much higher SERS enhancement than the coatings of either the pure Au or Ag. The excellent SERS enhancement and reproducibility of the Au-Ag coated nanopillars indicated that the fabricated SERS substrates can be used for the detection of biochemical molecules at trace level and the SPL is a promising method for fabrication of SERS substrates.

Surface-enhanced Raman scattering with gold-coated silicon nanopillars arrays: The influence of size and spatial order.

Nanopillars have been extensively explored as promising substrates for surface-enhanced Raman scattering (SERS) owing to their high sensitivity and excellent reproducibility. Most of the researches have been focused on the fabrication methods of nanopillars, and the dependences of SERS effects on geometrical size and spatial order are rarely investigated. In this work, SERS properties of nanopillars with different sizes (115-185 nm) and spatial orders (square and rhombus orders) have been studied. The work has shown that the nanopillars not only have high enhancement capability and high signal reproducibility, but also the enhancement is insensitive to the size and spatial orders. The measured enhancement factors (EFs) are 2.3-4.0 × 106 and signal reproducibility (relative standard deviation, RSD) are âˆ¼ 5.2%-6.9%, which are among the best of the similar SERS substrates reported. The variation of SERS intensity was as low as approximately 4.8% with the variation of pillar size from 115, 135, 145, to 160 nm. The insensitiveness and high reproducibility have been ascribed to the combined excitation of localized surface plasmon resonance (LSPR) and propagating surface plasmons (SPPs) of the nanopillars. Optical properties of the nanopillars are studied both experimentally and numerically to understand the physics behind the SERS performance.

AMP-activated protein kinase re-sensitizes A549 to paclitaxel via up-regulating solute carrier organic anion transporter family member 1B3 expression.

Paclitaxel (PTX) is a common antineoplastic drug whose functionality is often restricted by drug resistance. Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a PTX influx transporter and its low expression has been proved to be relevant with PTX resistance. It has been widely reported that AMP-activated protein kinase (AMPK) could re-sensitize tumor cells to PTX. Our gene array result demonstrates AMPK up-regulated SLCO1B3. In this paper, we have tried to explain the relationships between PTX, SLCO1B3 and AMPK. First, we have verified the proliferative inhibition of PTX on A549 and found that PTX could inhibit A549 cells proliferation. Then, we have explored the relationship between SLCO1B3 and PTX: SLCO1B3 expression significantly decreased when A549 cells were treated with PTX or in A549 PTX resistant cells (A549-PTX) and the intracellular PTX concentration in A549-PTX was also lower. When treated with metformin/LKB1, both SLCO1B3 expression and intracellular PTX concentration have increased. Knockdown of AMPK has induced decreased SLCO1B3 expression. Moreover, in vitro and in vivo experiments have showed that metformin not only obviously inhibited A549-PTX tumor xenograft and A549-PTX proliferation alone, but also enhanced PTX efficacy to A549-PTX and this may be relevant to SLCO1B3. To verify it, we have treated A549 cells with AMPK both activators and an inhibitor, and then found that AMPK activators could weaken the PTX effect in inhibiting SLCO1B3 while its inhibitor has opposite effect. With knockdown of SLCO1B3, the effect of AMPK in re-sensitizing A549 to paclitaxel has decreased. To sum up, activation of AMPK can up-regulate SLCO1B3 expression, enhance the sensitivity of A549 cells to PTX, providing a new way to re-sensitize PTX resistance.

Metformin Affects Gut Microbiota Composition and Diversity Associated with Amelioration of Dextran Sulfate Sodium-Induced Colitis in Mice.

Background: Inflammatory bowel disease (IBD) is an increasingly common and globally emergent immune-mediated disorder. The etiology of IBD is complex, involving multiple factors such as immune dysregulation, environmental factors, genetic mutations, and microbiota dysbiosis, exacerbated by a lack of effective clinical therapies. Recently, studies hypothesized that dysbiosis of intestinal flora might participate in the onset of IBD. Metformin is widely used to treat type 2 diabetes and has shown beneficial effects in mouse models of IBD, although its underlying mechanisms remain poorly understood. Accumulating studies found that metformin shows beneficial effects for diabetes by affecting microbiota composition. This study explores possible regulatory effects of metformin on intestinal microecology during treatment for IBD. Methods: Inflammation was induced using 3% Dextran Sulfate Sodium (DSS) solution to generate mice models of IBD. Metformin treatments were assayed by measuring body weights and colon lengths of mice and H&E staining to observe histological effects on colon tissue structures. Changes in bacterial community composition and diversity-related to IBD and metformin treatment were assessed by high-throughput metagenomic sequencing analysis. Results: Metformin administration significantly ameliorated body weight loss, inhibited colon shrinking, and contributed to preserving the integrity of colon histological structures. The gut microbiota profiles revealed that the biodiversity of intestinal flora lost during inflammation was restored under metformin treatment. Metformin administration was also associated with decreased pathogenic Escherichia shigella and increased abundance of Lactobacillus and Akkermansia. Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.

Inflammation initiates a vicious cycle between obesity and nonalcoholic fatty liver disease.

Low-level of chronic inflammation activation is characteristic of obesity. Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity and is an emerging health problem, it originates from abnormal accumulation of triglycerides in the liver, and sometimes causes inflammatory reactions that could contribute to cirrhosis and liver cancer, thus its pathogenesis needs to be clarified for more treatment options. Once NAFLD is established, it contributes to systemic inflammation, the low-grade inflammation is continuously maintained during NAFLD causing impaired resolution of inflammation in obesity, which subsequently exacerbates its severity. This study focuses on the effects of obesity-induced inflammations, which are the underlying causes of the disease progression and development of more severe inflammatory and fibrotic stages. Understanding the relationship between obesity and NAFLD could help in establishing attractive therapeutic targets or diagnostic markers in obesity-induced inflammation response and provides new approaches for the prevention and treatment of NAFLD in obesity.

Engineering a homochiral metal-organic framework based on an amino acid for enantioselective separation.

A chiral metal-organic framework possessing an open amphiphilic channel is constructed from a dicarboxylate ligand derived from an amino acid and is shown to be an efficient and recyclable chiral solid adsorbent, which is capable of separating racemic secondary alcohols, epoxides, and ibuprofen with very high enantioselectivity.

Remarkable Ligand Effect on Rh-Catalyzed C-H-Active [3 + 2] Annulation of Ketimines and Alkynes.

Externally added ligands were first found to have a significant impact on the Rh-catalyzed C-H-active [3 + 2] annulation of ketimines and alkynes. Olefin ligands have shown remarkable promotion effect for this reaction. The olefin promoted the reaction by increasing both the turnover rate and conversion of [Cp*RhCl2]2 in the formation of rhodacycle in the C-H activation step.