Carotenoid Bioaccessibility and Caco-2 Cell Uptake Following Novel Encapsulation Using Medium Chain Triglycerides.

Carotenoids are especially hydrophobic and dissolve poorly in water. Encapsulation is used to increase their solubility in water-based food products. However, it is not yet known whether encapsulation with a combination of lecithin and medium-chain triglycerides improves carotenoid bioaccessibility and intestinal cell uptake. The relative bioaccessibility and Caco-2 cell uptake of two water-soluble carotenoid (i.e. lutein and astaxanthin) dispersions in a liquid form (VitaSperse®) and a powdered form (VitaDry®) were compared to the carotenoid ingredient alone. An in vitro digestion model was used to assess bioaccessibility, measuring the micellarized fraction postdigestion. The micelle fraction was incubated with Caco-2 cells to assess intestinal uptake of carotenoids. Encapsulation (by either VitaDry® or Vitasperse®) increased total astaxanthin bioaccessibility 2-2.4× and cell uptake by ∼2× relative to control. Encapsulation also increased total lutein bioaccessibility by 3-5× and cell uptake 2.3× relative to control. There was no significant difference between VitaDry® and VitaSperse® products in regards to Caco-2 cell uptake. Increased bioaccessibility largely drove increased carotenoid cell uptake from the encapsulated formulations. These results suggest further study is warranted to determine if this encapsulation approach increases carotenoid bioavailability in human studies.

Mechanical properties and water vapour corrosion behaviour of Al x CoCrFeNi high-entropy alloys.

Al x CoCrFeNi (x = 0.1, 0.5 and 1) high-entropy alloys (HEAs) were prepared using a spark plasma sintering (SPS) technique combined with aerosol powder. Their microstructure and phase constituents were characterized using an X-ray diffractometer and SEM, and their tensile properties, hardness and compactness were tested. The results show that the crystal structure of the Al x CoCrFeNi HEAs changed significantly with the Al content, from the original single face-centered cubic FCC phase (Al0.1CoCrFeNi) to an FCC + BCC structure (Al0.5CoCrFeNi), and then to FCC + BCC + sigma (σ) phase structures (AlCoCrFeNi). Chemical composition analysis showed that the crystal structure transformation was related to the segregation caused by the increased Al content. The hardness of the Al x CoCrFeNi HEAs increases with increasing Al content, and the hardness of AlCoCrFeNi reaches a maximum of 507.3 HV. The tensile properties of the alloy show a trend of first increasing and then decreasing with increasing Al content, and the yield strength, ultimate tensile strength and elongation of the Al0.5CoCrFeNi alloy reach maximum values of 527.4 MP, 943.3 MPa and 28.2%, respectively. The fracture mechanism of the Al0.1CoCrFeNi and Al0.5CoCrFeNi alloys is typical ductile fracture, while that of the AlCoCrFeNi alloy is cleavage fracture. The compactness of the alloy increases with the Al content. The samples were also subjected to high-temperature water vapour corrosion, and corrosion products such as Al3Fe5O12, CoCr2O4 and NiCr2O4 were found in the Al0.1 and Al0.5 alloys, whereas no oxide peaks were detected using XRD for the Al1 alloy. It was also presumed that a very thin alumina film was generated on the surface of the Al1 alloy, preventing the oxidation of the sample, in combination with the analysis of SEM, EDS and XPS behaviour.

ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.

Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated ß-galactosidase (SA-ß-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.

Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice.

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Stereospecific Enzymatic Conversion of Boronic Acids to Amines.

Boronic acids and esters are highly regarded for their safety, unique reactivity, and versatility in synthesizing a wide range of small molecules, bioconjugates, and materials. They are not exploited in biocatalytic synthesis, however, because enzymes that can make, break, or modify carbon-boron bonds are rare. We wish to combine the advantages of boronic acids and esters for molecular assembly with biocatalysis, which offers the potential for unsurpassed selectivity and efficiency. Here, we introduce an engineered protoglobin nitrene transferase that catalyzes the new-to-nature amination of boronic acids using hydroxylamine. Initially targeting aryl boronic acids, we show that the engineered enzyme can produce a wide array of anilines with high yields and total turnover numbers (up to 99% yield and >4000 TTN), with water and boric acid as the only byproducts. We also demonstrate that the enzyme is effective with bench-stable boronic esters, which hydrolyze in situ to their corresponding boronic acids. Exploring the enzyme's capacity for enantioselective catalysis, we found that a racemic alkyl boronic ester affords an enantioenriched alkyl amine, a transformation not achieved with chemocatalysts. The formation of an exclusively unrearranged product during the amination of a boronic ester radical clock and the reaction's stereospecificity support a two-electron process akin to a 1,2-metallate shift mechanism. The developed transformation enables new biocatalytic routes for synthesizing chiral amines.

Mask structure optimization for beyond EUV lithography.

Beyond extreme ultraviolet (BEUV) lithography with a 6 × nm wavelength is regarded as a future technique to continue the pattern shirking in integrated circuit (IC) manufacturing. This work proposes an optimization method for the mask structure to improve the imaging quality of BEUV lithography. Firstly, the structure of mask multilayers is optimized to maximize its reflection coefficient. Then, a mask diffraction near-field (DNF) model is established based on the Born series algorithm, and the aerial image of BEUV lithography system can be further calculated. Additionally, the mask absorber structure is inversely designed using the particle swarm optimization (PSO) algorithm. Simulation results show a significant improvement of the BEUV lithography imaging obtained by the proposed optimization methods. The proposed workflow can also be expanded to areas of EUV and soft x ray imaging.

Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp 3 -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme's remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst's compatibility with diverse functional groups and tertiary C-H bonds. Mechanistic studies elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

Recent Progress in Thermally Activated Delayed Fluorescence Photosensitizers for Photodynamic Therapy.

Photodynamic therapy (PDT) is a rapidly growing discipline that is expected to become an encouraging noninvasive therapeutic strategy for cancer treatment. In the PDT process, an efficient intersystem crossing (ISC) process for photosensitizers from the singlet excited state (S1) to the triplet excited state (T1) is critical for the formation of cytotoxic reactive oxygen species and improvement of PDT performance. Thermally activated delayed fluorescence (TADF) molecules featuring an extremely small singlet-triplet energy gap and an efficient ISC process represent an enormous breakthrough for the PDT process. Consequently, the development of advanced TADF photosensitizers has become increasingly crucial and pressing. The most recent developments in TADF photosensitizers aimed at enhancing PDT efficiency for bio-applications are presented in this review. TADF photosensitizers with water dispersibility, targeting ability, activatable ability, and two-photon excitation properties are highlighted. Furthermore, the future challenges and perspectives of TADF photosensitizers in PDT are proposed.

Correlation between vessel density and thickness in the retina and choroid of severe non-proliferative diabetic retinopathy patients.

Objectives: To explore the correlation between the vessel density (VD) of the retina and choroid vascular plexuses and the thicknesses of their respective retinal layers and choroid membranes in participants with severe non-proliferative diabetic retinopathy (NPDR). Methods: We retrospectively analyzed the data of 42 eyes of 42 participants with diabetes mellitus (DM) and severe NPDR. In addition, 41 eyes of 41 healthy controls were evaluated. Measurements were taken for both groups using optical coherence tomography angiography (OCTA), including the area and perimeter of the foveal vascular zone (FAZ) and the vascular density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choroid capillary (CC). These measurements were compared with the retinal thickness (RT) of the inner/intermediate retinal layers and choroidal thickness (CT). The study evaluated the correlation between RT or CT and VD in the respective vascular networks, namely superficial capillary plexus (SCP), deep capillary plexus (DCP), or CC. Results: The inner RT and VD in all plexuses were significantly lower in the severe NPDR group than in the healthy controls. Furthermore, the FAZ area and perimeter were larger in the severe NPDR group. Inner RT was correlated with VD in the SCP group (r=0.67 and r=0.71 in the healthy control and severe NPDR groups, respectively; p<0.05). CT negatively correlated with VD in the CC (r=-0.697 and r=-0.759 in the healthy control and severe NPDR groups, respectively; p<0.05). Intermediate RT significantly correlated with VD in the DCP of the severe NPDR group (r=-0.55, p<0.05), but not in the healthy control group. Conclusions: Retinal or choroidal thickness strongly correlated with VD. Therefore, patients with severe NPDR must consider the distinct anatomical and functional entities of the various retinal layers and the choroid.

Clinical implications of haemodynamics in symptomatic intracranial atherosclerotic stenosis by computational fluid dynamics modelling: a systematic review.

BACKGROUND: Recently, computational fluid dynamics (CFD) has been used to simulate blood flow of symptomatic intracranial atherosclerotic stenosis (sICAS) and investigate the clinical implications of its haemodynamic features, which were systematically reviewed in this study. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology statements, we searched PubMed and Embase up to March 2024 and screened for articles reporting clinical implications of haemodynamic parameters in sICAS derived from CFD models. RESULTS: 19 articles met the inclusion criteria, all studies recruiting patients from China. Most studies used CT angiography (CTA) as the source image for vessel segmentation, and generic boundary conditions, rigid vessel wall and Newtonian fluid assumptions for CFD modelling, in patients with 50%-99% sICAS. Pressure and wall shear stress (WSS) were quantified in almost all studies, and the translesional changes in pressure and WSS were usually quantified with a poststenotic to prestenotic pressure ratio (PR) and stenotic-throat to prestenotic WSS ratio (WSSR). Lower PR was associated with more severe stenosis, better leptomeningeal collaterals, prolonged perfusion time and internal borderzone infarcts. Higher WSSR and other WSS measures were associated with positive vessel wall remodelling, regression of luminal stenosis and artery-to-artery embolism. Lower PR and higher WSSR were both associated with the presence and severity of cerebral small vessel disease. Moreover, translesional PR and WSSR were promising predictors for stroke recurrence in medically treated patients with sICAS and outcomes after acute reperfusion therapy, which also provided indicators to assess the effects of stenting treatment on focal haemodynamics. CONCLUSIONS: CFD is a promising tool in investigating the pathophysiology of ICAS and in risk stratification of patients with sICAS. Future studies are warranted for standardisation of the modelling methods and validation of the simulation results in sICAS, for its wider applications in clinical research and practice.

Room-Temperature Geometrical Circular Photocurrent in Few-Layer MoS2.

Valleytronics, i.e., the manipulation of the valley degree of freedom, offers a promising path for energy-efficient electronics. One of the key milestones in this field is the room-temperature manipulation of the valley information in thick-layered material. Using scanning photocurrent microscopy, we achieve this milestone by observing a geometrically dependent circular photocurrent in a few-layer molybdenum disulfide (MoS2) under normal incidence. Such an observation shows that the system symmetry is lower than that of bulk MoS2 material, preserving the optical chirality-valley correspondence. Moreover, the circular photocurrent polarity can be reversed by applying electrical bias. We propose a model where the observed photocurrent results from the symmetry breaking and the built-in field at the electrode-sample interface. Our results show that the valley information is still retained even in thick-layered MoS2 at room temperature and opens up new opportunities for exploiting the valley index through interface engineering in multilayer valleytronics devices.

TAK-3 Inhibits Lipopolysaccharide-Induced Neuroinflammation in Traumatic Brain Injury Rats Through the TLR-4/NF-κB Pathway.

Purpose: The activation of the inflammatory response is regarded as a pivotal factor in the pathogenesis of TBI. Central nervous system infection often leads to the exacerbation of neuroinflammation following TBI, primarily caused by Gram-negative bacteria. This study aims to elucidate the effects of the novel anti-inflammatory drug TAK-3 on LPS-induced neuroinflammation in TBI rats. Methods: In conjunction with the rat controlled cortical impact model, we administered local injections of Lipopolysaccharide to the impact site. Subsequently, interventions were implemented through intraperitoneal injections of TAK-3 and NF-κB activitor2 to modulate the TLR4/NF-κB axis The impact of LPS on neurological function was assessed using mNSS, open field test, and brain water content measurement. Inflammatory markers, including TNF-α, IL-1ß, IL-6 and IL-10 were assessed to evaluate the condition of neuritis by Elisa. The activation of the TLR-4/NF-κB signaling pathway was detected by immunofluorescence staining and Western blot to assess the anti-inflammatory effects of TAK-3. Results: The administration of LPS exacerbated neurological damage in rats with TBI, as evidenced by a reduction in motor activity and an increase in anxiety-like behavior. Furthermore, LPS induced disruption of the blood-brain barrier integrity and facilitated the development of brain edema. The activation of microglia and astrocytes by LPS at the cellular and molecular levels has been demonstrated to induce a significant upregulation of neuroinflammatory factors. The injection of TAK-3 attenuated the neuroinflammatory response induced by LPS. Conclusion: The present study highlights the exacerbating effects of LPS on neuroinflammation in TBI through activation of the TLR-4/NF-κB signaling pathway. TAK-3 can modulate the activity of this signaling axis, thereby attenuating neuroinflammation and ultimately reducing brain tissue damage.

Rathke's Cleft Cyst Leads to Stunted Growth in Children: A Case Report Written With the Help of ChatGPT.

In recent times, ChatGPT has become a globally renowned AI tool, revolutionizing academic research by offering innovative methods and opportunities. The integration of AI into various domains is a prevailing topic, focusing on optimizing its utility. This article presents a case study of a child with Rathke's cyst, primarily exhibiting symptoms of growth and developmental delay. The patient's self-perception of stunted growth, coupled with previous assessments indicating partial growth hormone deficiency, prompted further investigation. Laboratory assessments revealed low growth hormone and insulin-like growth factor levels, while imaging disclosed a pituitary lesion. Rathke's cyst was postulated as the probable cause of the growth hormone deficiency. Rathke's cyst remains a rare medical condition with substantial research knowledge gaps. In this article, we synergize ChatGPT responses with a comprehensive case report of a child with Rathke's cyst as the primary symptom-growth and developmental delay. We explore the methods and feasibility of employing ChatGPT within this case report.

Stereodivergent, Kinetically Controlled Isomerization of Terminal Alkenes via Nickel Catalysis.

Because internal alkenes are more challenging synthetic targets than terminal alkenes, metal-catalyzed olefin mono-transposition (i.e., positional isomerization) approaches have emerged to afford valuable E- or Z- internal alkenes from their complementary terminal alkene feedstocks. However, the applicability of these methods has been hampered by lack of generality, commercial availability of precatalysts, and scalability. Here, we report a nickel-catalyzed platform for the stereodivergent E/Z-selective synthesis of internal alkenes at room temperature. Commercial reagents enable this one-carbon transposition of terminal alkenes to valuable E- or Z-internal alkenes via a Ni-H-mediated insertion/elimination mechanism. Though the mechanistic regime is the same in both systems, the underlying pathways that lead to each of the active catalysts are distinct, with the Z-selective catalyst forming from comproportionation of an oxidative addition complex followed by oxidative addition with substrate and the E-selective catalyst forming from protonation of the metal by the trialkylphosphonium salt additive. In each case, ligand sterics and denticity control stereochemistry and prevent over-isomerization.

Impact of manufacturing processes on glycerolipid and polar lipid composition and ultrastructure in infant formula.

The introduction of exogenous lipids in the production of infant formula induces significant alterations in milk lipid composition, content, and membrane structure, thus affecting the lipid digestion, absorption, and utilization. This study meticulously tracks these changes throughout the manufacturing process. Pasteurization has a significant effect on phosphatidylcholine and sphingomyelin in the outer membrane, decreasing their relative contents to total polar lipids from 12.52% and 17.34% to 7.72% and 12.59%, respectively. Subsequent processes, including bactericidal-concentration and spray-drying, demonstrate the thermal stability of sphingomyelin and ceramides, while glycerolipids with arachidonic acid/docosahexaenoic acid and glycerophospholipids, particularly phosphatidylethanolamine, diminish significantly. Polar lipids addition and freeze-drying technology significantly enhance the polar lipid content and improve microscopic morphology of infant formula. These findings reveal the diverse effects of technological processes on glycerolipid and polar lipid compositions, concentration, and ultrastructure in infant formulas, thus offering crucial insights for optimizing lipid content and structure within infant formula.

Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.

BACKGROUND: Despite the substantial impact of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) on cancer progression, its significance in the regulation of hepatocellular carcinoma (HCC) cell proliferation and chemosensitivity remains poorly defined. METHODS: We evaluated MTHFD2 expression in a total of 95 HCC tissues by immunohistochemistry and analyzed the association of MTHFD2 with clinicopathologic features. qRT-PCR and Western blotting were conducted to verify MTHFD2 expression levels. Bioinformatics analysis such as gene set enrichment analysis (GSEA) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were used to predict the signaling pathways involved in MTHFD2. In addition, to investigate the anti-tumor effects of MTHFD2 knockdown, Cell Counting Kit-8 (CCK-8) and EdU assays were used. RESULTS: We found that MTHFD2 was frequently upregulated in HCC, and the combination of increased expression of MTHFD2 and Ki67 was associated with poor HCC prognosis. MTHFD2 knockdown significantly inhibited HCC cell proliferation and effectively sensitized HCC cells to sorafenib and lenvatinib. PI3K/AKT pathway was involved in MTHFD2-mediated modulation of proliferation and chemosensitivity. CONCLUSIONS: These findings indicate that MTHFD2 plays an important role in proliferation and chemosensitivity of HCC, indicating that it may serve as a novel pharmacological target for improving HCC therapy.

SIRT1-Mediated HMGB1 Deacetylation Suppresses Neutrophil Extracellular Traps Related to Blood-Brain Barrier Impairment After Cerebral Venous Thrombosis.

Cerebral venous thrombosis (CVT) is a neurovascular disease with recently increasing incidence. Aseptic inflammatory responses play an important role in the pathology of CVT. Recent studies report that neutrophil extracellular traps (NETs) are major triggers of thrombosis and inflammation in stroke, but their effect on brain injury in CVT requires further validation. In this study, two CVT animal models were used to simulate superior sagittal sinus thrombosis and cortical vein thrombosis. The effects of brain tissue infiltration of NETs and the molecular mechanisms associated with NET formation were deeply explored in combination with proteomics, histology, and serology. The results showed that the cortical vein thrombosis model could be combined with more severe blood-brain barrier (BBB) disruption and showed more severe cerebral hemorrhage. Decreased Sirtuin 1 (SIRT1) expression promotes high mobility group box 1 (HMGB1) acetylation, causing increased cytosolic translocation and extracellular release, and HMGB1 can promote NET formation and recruitment. In addition, corticocerebral accumulation of NETs contributes to BBB damage. This establishes a vicious cycle between BBB damage and NET accumulation. SIRT1 mediated-HMGB1 deacetylation may play a critical role in attenuating BBB damage following CVT. This study employed a combined validation using models of venous sinus thrombosis and cortical vein thrombosis to investigate the deacetylation role of SIRT1, aiming to offer new insights into the pathological mechanisms of brain injury following CVT.

Deficiency of TOP1MT enhances glycolysis through the stimulation of PDK4 expression in gastric cancer.

BACKGROUND: Abnormal glucose metabolism is one of the determinants of maintaining malignant characteristics of cancer. Targeting cancer metabolism is regarded as a new strategy for cancer treatment. Our previous studies have found that TOP1MT is a crucial gene that inhibits glycolysis and cell metastasis of gastric cancer (GC) cells, but the mechanism of its regulation of glycolysis remains unclear. METHODS: Transcriptome sequencing data, clinic-pathologic features of GC from a variety of public databases, and WGCNA were used to identify novel targets of TOP1MT. Immunohistochemical results of 250 patients with GC were used to analyze the relative expression relationship between TOP1MT and PDK4. The function of TOP1MT was investigated by migration assays and sea-horse analysis in vitro. RESULTS: We discovered a mitochondrial topoisomerase I, TOP1MT, which correlated with a higher risk of metastasis. Functional experiments revealed that TOP1MT deficiency promotes cell migration and glycolysis through increasing PDK4 expression. Additionally, the stimulating effect of TOP1MT on glycolysis may be effectively reversed by PDK4 inhibitor M77976. CONCLUSIONS: In brief, our work demonstrated the critical function of TOP1MT in the regulation of glycolysis by PDK4 in gastric cancer. Inhibiting glycolysis and limiting tumor metastasis in GC may be accomplished by suppressing PDK4.