Chiral Flipping in Viedma Deracemization.

Understanding deracemization is crucial for progress in chiral chemistry, especially for improving separation techniques. Here, we first report the phenomenon of chiral flipping (or reverse deracemization) in a chiral material (i.e., sodium chlorate crystals) during Viedma deracemization, employing a small-volume reactor system for precise analysis. We observe considerable chiral flipping, influenced by the initial imbalance in the numbers of L- and D-form particles. We developed a simple probabilistic model to further elucidate this behavior. We find that the fluctuation in the populations of chiral crystal particles resulting from their random dissolution and regeneration is the key factor behind chiral flipping. This study not only brings to light this intriguing observation of chiral flipping but also contributes to the enhancement of deracemization techniques.

Low initial cell density promotes the differentiation and maturation of human pluripotent stem cells into erythrocytes.

Human pluripotent stem cell (hPSC)-derived red blood cells (RBCs) possess great potential for compensating shortages in transfusion medicine. For better RBC generation from hPSCs, we compared the cell seeding density in the embryoid body formation-based hPSC induction protocol. In the selection of low- and high-density inoculation conditions, we found that low-density culture performed better in the final RBC product with more cell output and increased average cellular hemoglobin content. An elaborate study using flow cytometry demonstrated that low inoculation density promoted endothelial-to-hematopoietic transition, followed by improved hematopoietic progenitor formation and erythrocyte generation. The improved transformation from glycolysis to mitochondrial oxidation and reduced apoptosis might be responsible for this effect. Hints from RNA sequencing suggested that molecules involved in microenvironment interaction and metabolic regulation might respond for the different developmental potential. The possible mediators between outer message and intracellular response could be the nutrition sensors FOXO, PRKAA1 (AMPK) and MTOR genes. It is possible that low inoculation density triggered metabolic regulation signals, promoted mitochondrial oxidation, and resulted in enhanced cell amplification and hematopoietic differentiation. The low cell culture density will improve RBC generation from human PSCs.

Droplet-based proteomics reveals CD36 as a marker for progenitors in mammary basal epithelium.

Deep proteomic profiling of rare cell populations has been constrained by sample input requirements. Here, we present DROPPS (droplet-based one-pot preparation for proteomic samples), an accessible low-input platform that generates high-fidelity proteomic profiles of 100-2,500 cells. By applying DROPPS within the mammary epithelium, we elucidated the connection between mitochondrial activity and clonogenicity, identifying CD36 as a marker of progenitor capacity in the basal cell compartment. We anticipate that DROPPS will accelerate biology-driven proteomic research for a multitude of rare cell populations.

Bistable Electrochromic Ionogels via Supramolecular Interactions for Energy-Efficient Displays.

Bistable electrochromic (EC) materials and systems offer significant potential for building decarbonization through their optical modulation and energy efficiency. However, challenges such as limited design strategies and bottlenecks in cost, fabrication, and color have hindered the full commercialization of energy-saving EC windows and displays, with few materials achieving true bistability. Herein, a novel strategy for designing bistable electrochromic materials is proposed by leveraging supramolecular interactions. These interactions facilitate reversible color transitions, stabilize the colored structure, and enable spatial confinement to inhibit diffusion, thereby achieving bistable electrochromism. The mechanisms and materials underlying these unconventional electrochromic systems are substantiated through detailed characterization. This strategy enables the preparation of low-cost and sustainable transparent electrochromic displays with high performance. Notably, the display information remains clearly visible for more than 2 hours without consuming energy. Involving biomass materials and removable device structures also enhances the sustainability and scalability of EC technology applications and development. Our results demonstrate the crucial role of supramolecular chemistry in the development of cutting-edge materials for applications such as energy-saving smart windows. This article is protected by copyright. All rights reserved.

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids.

Amorphous solids exhibit enhanced solubility and dissolution rates relative to their crystalline counterparts. However, attaining optimal bioavailability presents a challenge, primarily due to the need to maintain the physical stability of amorphous solids. Moreover, the precise manner in which precipitation parameters, including the feeding rate of the anti-solvent, agitation speed, and aging time, influence the physical stability of amorphous solids remains incompletely understood. Consequently, this study aimed to investigate these three parameters during the precipitation process of the anticancer drug, nilotinib free base. The physical stability of the resultant samples was evaluated by employing characterization techniques including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), focused beam reflectance measurement (FBRM), and data analysis methods such as pair distribution function (PDF), reduced crystallization temperature (Rc), and principal component analysis (PCA). This study's findings indicated that amorphous solids exhibited the greatest physical stability under particular conditions, namely a feeding rate of 5 mL/min, an agitation speed of 500 rpm, and an aging time of 10 min. Furthermore, the physical stability of the amorphous solids was primarily influenced by particle size and distribution, molecular interactions, microstructure, surface area, and interfacial energy. Notably, the parameters involved in the anti-solvent precipitation process, including the feeding rate of the anti-solvent, agitation speed, and aging time, exerted a significant impact on these factors. Consequently, they directly affected the physical stability of amorphous solids. Hence, this study comprehensively elucidated the mechanistic influence of these operational parameters on the physical stability of amorphous solids during the anti-solvent precipitation process.

TGF-ß1-triggered BMI1 and SMAD2 cooperatively regulate miR-191 to modulate bone formation.

Transforming growth factor ß 1 (TGF-ß1), as the most abundant signaling molecule in bone matrix, is essential for bone homeostasis. However, the signaling transduction of TGF-ß1 in the bone-forming microenvironment remains unknown. Here, we showed that microRNA-191 (miR-191) was downregulated during osteogenesis and further decreased by osteo-favoring TGF-ß1 in bone marrow mesenchymal stem cells (BMSCs). MiR-191 was lower in bone tissues from children than in those from middle-aged individuals and it was negatively correlated with collagen type I alpha 1 chain (COL1A1). MiR-191 depletion significantly increased osteogenesis and bone formation in vivo. Hydrogels embedded with miR-191-low BMSCs displayed a powerful bone repair effect. Mechanistically, transcription factors BMI1 and SMAD2 coordinately controlled miR-191 level. In detail, BMI1 and pSMAD2 were both upregulated by TGF-ß1 under osteogenic condition. SMAD2 activated miR-191 transcription, while BMI1 competed with SMAD2 for binding to miR-191 promoter region, thus disturbing the activation of SMAD2 on miR-191 and reducing miR-191 level. Altogether, our findings reveal that miR-191 regulated by TGF-ß1-induced BMI1 and SMAD2 negatively modulated bone formation and regeneration, and inhibition of miR-191 might be therapeutically useful to enhance bone repair in clinic.

Flexible scaffold-based cheminformatics approach for polypharmacological drug design.

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

Evaluating the Efficiency of Boron Nitride Coating in Single-Walled Carbon-Nanotube-Based 1D Heterostructure Films by Optical Spectroscopy.

Single-walled carbon nanotube (SWCNT) films exhibit exceptional optical and electrical properties, making them highly promising for scalable integrated devices. Previously, we employed SWCNT films as templates for the chemical vapor deposition (CVD) synthesis of one-dimensional heterostructure films where boron nitride nanotubes (BNNTs) and molybdenum disulfide nanotubes (MoS2NTs) were coaxially nested over the SWCNT networks. In this work, we have further refined the synthesis method to achieve precise control over the BNNT coating in SWCNT@BNNT heterostructure films. The resulting structure of the SWCNT@BNNT films was thoroughly characterized using a combination of electron microscopy, UV-vis-NIR spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and Raman spectroscopy. Specifically, we investigated the pressure effect induced by BNNT wrapping on the SWCNTs in the SWCNT@BNNT heterostructure film and demonstrated that the shifts of the SWCNT's G and 2D (G') modes in Raman spectra can be used as a probe of the efficiency of BNNT coating. In addition, we studied the impact of vacuum annealing on the removal of the initial doping in SWCNTs, arising from exposure to ambient atmosphere, and examined the effect of MoO3 doping in SWCNT films by using UV-vis-NIR spectroscopy and Raman spectroscopy. We show that through correlation analysis of the G and 2D (G') modes in Raman spectra, it is possible to discern distinct types of doping effects as well as the influence of applied pressure on the SWCNTs within SWCNT@BNNT heterostructure films. This work contributes to a deeper understanding of the strain and doping effect in both SWCNTs and SWCNT@BNNTs, thereby providing valuable insights for future applications of carbon-nanotube-based one-dimensional heterostructures.

ATG5 nonautophagically regulates inflammation and differentiation in mouse embryonic stem cells.

Embryonic stem cells (ESCs), with abilities of infinite proliferation (self-renewal) and to differentiate into distinct cell types (pluripotency), show attenuated inflammatory response against cytokines or pathogens, which is recognized as a unique characteristic of ESCs compared with somatic cells. However, the underlying molecular mechanisms remain unclear, and whether the attenuated inflammatory state is involved in ESC differentiation is completely unknown. Our recent study demonstrated that macroautophagy/autophagy-related protein ATG5 inhibits the inflammatory response of mouse ESCs (MmESCs) by promoting the degradation of BTRC/ß-TrCP1 and further the downregulation of NFKB/NF-κB signaling. In addition, maintenance of an attenuated inflammation status in MmESCs is required for their differentiation. In conclusion, ATG5 is a key regulator for the regulation of inflammatory response and differentiation of MmESCs.

Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1ß dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1ß and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

Research on lightweight algorithm for gangue detection based on improved Yolov5.

In order to solve the problems of slow detection speed, large number of parameters and large computational volume of deep learning based gangue target detection method, we propose an improved algorithm for gangue target detection based on Yolov5s. First, the lightweight network EfficientVIT is used as the backbone network to increase the target detection speed. Second, C3_Faster replaces the C3 part in the HEAD module, which reduces the model complexity. once again, the 20 × 20 feature map branch in the Neck region is deleted, which reduces the model complexity; thirdly, the CIOU loss function is replaced by the Mpdiou loss function. The introduction of the SE attention mechanism makes the model pay more attention to critical features to improve detection performance. Experimental results show that the improved model size of the coal gang detection algorithm reduces the compression by 77.8%, the number of parameters by 78.3% the computational cost is reduced by 77.8% and the number of frames is reduced by 30.6%, which can be used as a reference for intelligent coal gangue classification.

Probing the Impact of Surface Functionalization Module on the Performance of Mitoxantrone Prodrug Nanoassemblies: Improving the Effectiveness and Safety.

Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.

Response of tree growth to nutrient addition is size dependent in a subtropical forest.

Understanding how nutrient addition affects the tree growth is critical for assessing forest ecosystem function and processes, especially in the context of increased nitrogen (N) and phosphorus (P) deposition. Subtropical forests are often considered N-rich and P-poor ecosystems, but few existing studies follow the traditional "P limitation" paradigm, possibly due to differences in nutrient requirements among trees of different size classes. We conducted a three-year fertilization experiment with four treatments (Control, N-treatment, P-treatment, and NP-treatment). We measured soil nutrient availability, leaf stoichiometry, and relative growth rate (RGR) of trees across three size classes (small, medium and large) in 64 plots. We found that N and NP-treatments increased the RGR of large trees. P-treatment increased the RGR of small trees. RGR was mainly affected by N addition, the total effect of P addition was only 10 % of that of N addition. The effect of nutrient addition on RGR was mainly regulated by leaf stoichiometry. This study reveals that nutrient limitation is size dependent, indicating that continuous unbalanced N and P deposition will inhibit the growth of small trees and increase the instability of subtropical forest stand structure, but may improve the carbon sink function of large trees.

Proton-selective coating enables fast-kinetics high-mass-loading cathodes for sustainable zinc batteries.

The pressing demand for sustainable energy storage solutions has spurred the burgeoning development of aqueous zinc batteries. However, kinetics-sluggish Zn2+ as the dominant charge carriers in cathodes leads to suboptimal charge-storage capacity and durability of aqueous zinc batteries. Here, we discover that an ultrathin two-dimensional polyimine membrane, featured by dual ion-transport nanochannels and rich proton-conduction groups, facilitates rapid and selective proton passing. Subsequently, a distinctive electrochemistry transition shifting from sluggish Zn2+-dominated to fast-kinetics H+-dominated Faradic reactions is achieved for high-mass-loading cathodes by using the polyimine membrane as an interfacial coating. Notably, the NaV3O8·1.5H2O cathode (10 mg cm-2) with this interfacial coating exhibits an ultrahigh areal capacity of 4.5 mAh cm-2 and a state-of-the-art energy density of 33.8 Wh m-2, along with apparently enhanced cycling stability. Additionally, we showcase the applicability of the interfacial proton-selective coating to different cathodes and aqueous electrolytes, validating its universality for developing reliable aqueous batteries.

The Progress and Prospects of Immune Cell Therapy for the Treatment of Cancer.

Immune cell therapy as a revolutionary treatment modality, significantly transformed cancer care. It is a specialized form of immunotherapy that utilizes living immune cells as therapeutic reagents for the treatment of cancer. Unlike traditional drugs, cell therapies are considered "living drugs," and these products are currently customized and require advanced manufacturing techniques. Although chimeric antigen receptor (CAR)-T cell therapies have received tremendous attention in the industry regarding the treatment of hematologic malignancies, their effectiveness in treating solid tumors is often restricted, leading to the emergence of alternative immune cell therapies. Tumor-infiltrating lymphocytes (TIL) cell therapy, cytokine-induced killer (CIK) cell therapy, dendritic cell (DC) vaccines, and DC/CIK cell therapy are designed to use the body's natural defense mechanisms to target and eliminate cancer cells, and usually have fewer side effects or risks. On the other hand, cell therapies, such as chimeric antigen receptor-T (CAR-T) cell, T cell receptor (TCR)-T, chimeric antigen receptor-natural killer (CAR-NK), or CAR-macrophages (CAR-M) typically utilize either autologous stem cells, allogeneic or xenogeneic cells, or genetically modified cells, which require higher levels of manipulation and are considered high risk. These high-risk cell therapies typically hold special characteristics in tumor targeting and signal transduction, triggering new anti-tumor immune responses. Recently, significant advances have been achieved in both basic and clinical researches on anti-tumor mechanisms, cell therapy product designs, and technological innovations. With swift technological integration and a high innovation landscape, key future development directions have emerged. To meet the demands of cell therapy technological advancements in treating cancer, we comprehensively and systematically investigate the technological innovation and clinical progress of immune cell therapies in this study. Based on the therapeutic mechanisms and methodological features of immune cell therapies, we analyzed the main technical advantages and clinical transformation risks associated with these therapies. We also analyzed and forecasted the application prospects, providing references for relevant enterprises with the necessary information to make informed decisions regarding their R&D direction selection.

Digitization method for a photonic analog-to-digital converter with phase-shifted optical quantization.

This Letter proposes a novel, to the best of our knowledge, matrix digitization method for a photonic analog-to-digital converter with phase-shifted optical quantization (PSOQ-ADC). This method overcomes the issues of excessive bit width of the output code and the generation of invalid codes encountered by the traditional direct digitization method. A PSOQ-ADC was fabricated on a lithium niobate on insulator (LNOI) platform, and an experimental platform was built. The results show that RF signals at 1/2/5 GHz, which were sampled by a 50GS/s optical pulse train, were digitized successfully with the matrix digitization method, producing 5-bit codes without invalid codes. In comparison, the direct digitization method yields 10-bit codes, and as the optical signal-to-noise ratio (OSNR) decreases, the ratio of invalid codes increases in the direct digitization method; even with Hamming distance correction, its effective number of bits (ENOB) remains smaller than that of the matrix digitization.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic ß cells.

Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.

DNA framework signal amplification platform-based high-throughput systemic immune monitoring.

Systemic immune monitoring is a crucial clinical tool for disease early diagnosis, prognosis and treatment planning by quantitative analysis of immune cells. However, conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing, especially in mass health screenings, because of time-consuming, technical-sensitive and high-cost features. However, the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology. To address this bottleneck, we constructed a generally applicable DNA framework signal amplification platform (DSAP) based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells, including CD4+, CD8+ T-lymphocytes, and monocytes (down to 1/100 µl). Based on this advanced detection platform, we present a novel high-throughput immune-cell phenotyping system, DSAP, achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost. As a proof-of-concept, DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients (AUC > 0.97) within 30 min, which can be applied in HIV infection monitoring and screening. Therefore, we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.

Tolerance Factor and Phase Stability of the KCoO2-Type AMN2 Nitrides.

In order to help understand the structural stability of KCoO2-type ternary nitrides AMN2, referring to perovskite structure, a tolerance factor t is proposed to describe the size effect on the phase/symmetry options of the experimentally accessible AMN2 nitrides. This leads to a range of t values above 0.946 for structurally stable KCoO2-type AMN2 nitrides with t values around 0.970 for the orthorhombic and tetragonal phase boundary. In contrast, most of AMN2 nitrides exhibit α-NaFeO2-type structure with t ∼ 0.898-0.946 and cations ordered or disordered rocksalt structure while t below 0.898. Employing the proposed criterion, the structure formation for other ternary AMN2 compositions with lanthanum and alkaline earth cations for the A sites were predicted, which was testified through the synthesis attempts and complemented by formation energy evaluations. The efforts to synthesize the ternary Lanthanide and alkaline earth-based AMN2 nitrides were unsuccessful, which could associate the structural instability with the large formation energies of lanthanide nitrides LaMN2 and the greater tolerance factor of 1.048 for BaTiN2. The experimentally already synthesized AMN2 nitrides could be categorized into three types with different tolerance factors, and scarce AMN2 nitrides with lower formation energies would be accessible using different synthetic routes beyond the traditional solid-state synthesis method.

Efficacy of Oral Appliance for Mild, Moderate, and Severe Obstructive Sleep Apnea: A Meta-analysis.

OBJECTIVE: Oral appliances (OA) are the recommended first-line option for mild-to-moderate obstructive sleep apnea (OSA)-hypopnea. However, there is a lack of evidence to compare the effectiveness of OA in different severities of OSA. The purpose of this study was to investigate the therapeutic effects of preferred OA (tongue retention devices [TRD] and mandibular advancement device [MAD]) in different severities of OSA. DATA SOURCES: PubMed/MEDLINE, The Cochrane Library, and Web of Science. REVIEW METHODS: Concentrating on the efficacy of OA, 2 authors searched 3 databases up to November 10, 2022, independently and systematically, following the requirements and steps of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Ultimately, 42 studies with 2265 patients met the criteria for inclusion in OA. Overall, the apnea-hypopnea index improved by 48% (5.6), 67% (14.92), and 62% (32.1) in mild, moderate, and severe OSA, respectively. Subgroup analysis showed a significant difference between MAD and TRD efficacy in mild OSA (58% vs 21%). However, no significant difference was seen between MAD and TRD efficacy in moderate (67% vs 66%) and severe OSA (66% vs 51%). There was no significant difference across groups in the Epworth Sleepiness Scale, oxygen desaturation index (ODI), and lowest oxygen saturation (LSAT). CONCLUSION: Overall, both TRD and MAD are effective treatments for moderate and severe OSA. MAD is efficacious in mild OSA, while TRD requires further validation. Furthermore, mild-moderate and severe OSA received similar improvements in sleepiness, ODI, and LSAT. This study complements the evidence for the efficacy of OA.