Insufficient Concentrations Research Articles

Development of a time-resolved fluoroimmunoassay for rituximab and its application to therapeutic drug monitoring.

Rituximab pharmacokinetics in patients with membranous nephropathy (MN) exhibit significant interindividual variability. Accurate measurement of serum rituximab concentrations is essential for effective therapeutic monitoring. This study develops a highly sensitive time-resolved fluoroimmunoassay (TRFIA) for rituximab (rituximab-TRFIA) with a wide detection range, aimed at enhancing therapeutic drug monitoring in MN treatment. A capture -type rituximab-TRFIA was developed using streptavidin-coated microplates, biotinylated anti-rituximab idiotypic antibodies, and Eu3+-labeled mouse anti-human IgG targeting the Fc fragment of rituximab. The assay was used to measure rituximab serum concentrations in MN patients treated with rituximab. The linear range of rituximab-TRFIA is 0.50 to 2500ng/mL, with a limit of detection (LOD) of 0.062ng/mL. The intra-assay coefficient of variation (CV) ranges from 1.97% to 9.50%, while the inter-assay CV ranges from 7.44% to 9.99%. The recovery rate ranges from 99.14% to 107.75%. No cross-reactivity was observed with other monoclonal antibody drugs (mAbs). The detection range is two orders of magnitude higher, and the sensitivity is six times greater than that of the enzyme-linked immunosorbent assay (ELISA). Rituximab-TRFIA showed strong consistency within the same measurement range compared to ELISA (P < 0.0001). The serum rituximab levels in MN patients were significantly higher than those in the control group (P < 0.0001). Among patients who did not achieve remission, 60% to 70% had insufficient drug concentrations, and rituximab pharmacokinetics followed the expected trends. The rituximab-TRFIA provides high sensitivity, a wide detection range, and reliable performance for monitoring serum rituximab concentrations in MN patients, supporting personalized treatment strategies.

Glycyrrhizinate Monoammonium Cysteine-Loaded Lipid Nanoparticles Allow for Improved Acute Liver Injury Therapy.

Background: Acute liver injury (ALI) is a prevalent and potentially lethal condition globally, where pharmacotherapy plays a vital role. However, challenges such as rapid drug excretion and insufficient concentration at hepatic lesions often impede the treatment's effectiveness. Methods: We successfully prepared glycyrrhizinate monoammonium cysteine (GMC)-loaded lipid nanoparticles (LNPs) using high-pressure homogenization. The characterization and safety of the LNPs were measured using electrophoretic light scattering (ELS), transmission electron microscopy (TEM), dynamic light scattering (DLS), cytotoxicity assays, and hemolysis tests. The distribution of LNPs in mice was explored using fluorescence labeling methods. The encapsulation efficiency of LNP-GMC was detected using High-Performance Liquid Chromatography (HPLC), and its slow-release effect on GMC was assessed through dialysis. The therapeutic effects of LNP-GMC and pure GMC on the ALI model were evaluated using fibroblast activation protein inhibitor (FAPI) PET imaging, blood biochemical indicators, and liver pathology slices. Results: The encapsulation of GMC in LNPs enhances drug stability and prolongs its hepatic retention, significantly improving its bioavailability and sustained release within the liver. This study also explores the expression of fibroblast activation protein (FAP) in ALI, employing 68Ga-FAPI PET/CT imaging for effective differentiation and assessment of liver injury. Conclusions: Our results suggest that LNPs offer an enhanced therapeutic approach for ALI treatment, reducing the required drug dosage, and 68Ga-FAPI PET/CT imaging provides a novel method for diagnosis and treatment assessment. This study contributes valuable insights into the utilization of LNPs in liver disease treatment, presenting a promising direction for future clinical applications.

DigiLoCS: A leap forward in predictive organ-on-chip simulations.

Digital twins, driven by data and mathematical modelling, have emerged as powerful tools for simulating complex biological systems. In this work, we focus on modelling the clearance on a liver-on-chip as a digital twin that closely mimics the clearance functionality of the human liver. Our approach involves the creation of a compartmental physiological model of the liver using ordinary differential equations (ODEs) to estimate pharmacokinetic (PK) parameters related to on-chip liver clearance. The objectives of this study were twofold: first, to predict human clearance values, and second, to propose a framework for bridging the gap between in vitro findings and their clinical relevance. The methodology integrated quantitative Organ-on-Chip (OoC) and cell-based assay analyses of drug depletion kinetics and is further enhanced by incorporating an OoC-digital twin model to simulate drug depletion kinetics in humans. The in vitro liver clearance for 32 drugs was predicted using a digital-twin model of the liver-on-chip and in vitro to in vivo extrapolation (IVIVE) was assessed using time series PK data. Three ODEs in the model define the drug concentrations in media, interstitium and intracellular compartments based on biological, hardware, and physicochemical information. A key issue in determining liver clearance appears to be the insufficient drug concentration within the intracellular compartment. The digital twin establishes a connection between the hardware chip structure and an advanced mapping of the underlying biology, specifically focusing on the intracellular compartment. Our modelling offers the following benefits: i) better prediction of intrinsic liver clearance of drugs compared to the conventional model and ii)explainability of behaviour based on physiological parameters. Finally, we illustrate the clinical significance of this approach by applying the findings to humans, utilising propranolol as a proof-of-concept example. This study stands out as the biggest cross-organ-on-chip platform investigation to date, systematically analysing and predicting human clearance values using data obtained from various in vitro liver-on-chip systems. Accurate prediction of in vivo clearance from in vitro data is important as inadequate understanding of the clearance of a compound can lead to unexpected and undesirable outcomes in clinical trials, ranging from underdosing to toxicity. Physiologically based pharmacokinetic (PBPK) model estimation of liver clearance is explored. The aim is to develop digital twins capable of determining better predictions of clinical outcomes, ultimately reducing the time, cost, and patient burden associated with drug development. Various hepatic in vitro systems are compared and their effectiveness for predicting human clearance is investigated. The developed tool, DigiLoCs, focuses explicitly on accurately describing complex biological processes within liver-chip systems. ODE-constrained optimisation is applied to estimate the clearance of compounds. DigiLoCs enable differentiation between active biological processes (metabolism) and passive processes (permeability and partitioning) by incorporating detailed information on compound-specific characteristics and hardware-specific data. These findings signify a significant stride towards more accurate and efficient drug development methodologies.

Association Between Serum Folate Concentrations and 10-Year Stroke Risk in a Prospective Community Cohort: Mediation and Interaction Analyses.

The relationship between folate concentrations and stroke risk remains unestablished, and the mediation effect of homocysteine (Hcy) and interaction effect of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has yet to be investigated. This cohort study involved 4903 subjects derived from a Chinese community population. The association between folate and first stroke was examined in Cox proportional hazard regression models. The mediation analyses involving Hcy and the undiscovered modification of the MTHFR C677T genotype were assessed. The mean (SD) age of subjects was 56.7 (8.8) years old, and 37.0% were male. A total of 407 strokes, 375 ischemic strokes and 47 hemorrhagic strokes occurred during the mean (SD) follow-up of 9.3 (1.8) years. The participants in the highest folate quartile (≥8.2 ng/mL) exhibited a lower stroke risk compared to those in the lowest quartile (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.50-0.93, p = 0.017; p for trend = 0.009). Hcy significantly mediated 14.51% of the relationship between folate and stroke in the fully adjusted model. Only in individuals with the MTHFR 677CC genotype but not CT/TT genotype was folate adversely correlated with stroke (HR: 0.88, 95% CI: 0.79-0.97, p for interaction = 0.026) and ischemic stroke (HR: 0.88, 95% CI: 0.80-0.98, p for interaction = 0.035). Insufficient folate concentrations were associated with a heightened 10-year stroke risk, in which Hcy concentrations played a crucial mediating role. MTHFR C677T gene polymorphism could potentially modify the folate-stroke relationship.

ОСОБЕННОСТИ МОДЕЛЕЙ ТРАНСПОРТНОЙ ДОСТУПНОСТИ В РЕГИОНАЛЬНОМ И МЕСТНОМ МАСШТАБЕ ГОРОДСКИХ АГЛОМЕРАЦИЙ (ЗАРУБЕЖНЫЙ ОПЫТ)

The article presents the results of studies of existing methods for determining the need for supporting infrastructure, an analysis of foreign experience in creating transport accessibility models and a proposal for an ameliorated approach to improve the accuracy and efficiency of planning urban development of territories. To determine the need for supporting infrastructure, the following methods (criteria) were defined: access to regional centers, availability of jobs, regional potential accessibility, access to medical institutions, the presence of schools and potential accessibility to basic health care. In the comparative table of foreign experience in creating transport accessibility models, the criteria of potential accessibility were not included. In the comparative table the regions of Europe are considered, namely: Finland, Bavaria, Northern Italy. As a result of the analysis, it was concluded that in each of the regions under consideration, transport accessibility models have their own shortcomings. In Finland, there are remote peripheries in the central and eastern parts, where accessibility models are underdeveloped, and in some areas of northern Finland they are not developed at all. In Bavaria, the differences between the regional accessibility models are very small, but outside the major Bavarian metropolitan areas there are areas with insufficient spatial concentration of schools. In Northern Italy there are also areas with deficiencies in the transport model (mountainous areas). Therefore, it is necessary to implement improved approaches to improve the efficiency of spatial planning, such as the use of modern geographic information systems (GIS).

Assembly of a biomimetic copper-based nanocomplex for alleviating hypoxia to enhance cuproptosis against osteosarcoma and lung metastasis.

Osteosarcoma tissues demonstrated elevated expression of proteins (FDX1 and DLAT) integral to cuproptosis in our preliminary study, indicating the potential effectiveness of anti-tumor strategies predicated on this process. Nevertheless, the overexpression of copper export proteins and the challenge of copper ion penetration may contribute to insufficient local copper ion concentration for inducing cuproptosis. Herein, we engineered a biomimetic copper-elesclomol-polyphenol network for the efficient delivery of copper ions and the copper ionophore elesclomol. Simultaneously, we integrated catalase (CAT) to alleviate tumor hypoxia, thereby inducing a greater reliance of tumor cells on aerobic respiration and enhancing cuproptosis sensitivity. In vitro analyses revealed that the nanocomplex exhibited potent cytotoxicity and displayed hallmark characteristics of cuproptosis. In vivo trials further validated targeted tumor accumulation, resulting in the suppression of tumor growth and lung metastasis. An augmentation in the proportion of activated immune cells in both tumor and draining lymph nodes was observed. The improvement of immunosuppressive microenvironment facilitated a synergistic antitumor effect with cuproptosis. The therapeutic efficacy was further evidenced in two osteosarcoma models, highlighting the potential as a safe and effective strategy against osteosarcoma and lung metastasis. STATEMENT OF SIGNIFICANCE: Osteosarcoma tissues exhibit a marked increase in the expression of proteins FDX1 and DLAT, which are crucial for cuproptosis. Moreover, cells that depend on mitochondrial respiration are more susceptible to cuproptosis. Here we developed a biomimetic copper-based nanocomplex to trigger cuproptosis against osteosarcoma and lung metastases. The nanocomplex demonstrated excellent biocompatibility and tumor targeting. Catalase incorporating facilitated oxygen generation within tumor microenvironment and alleviated hypoxia, thereby inducing a greater reliance of tumor cells on aerobic respiration and enhancing cuproptosis sensitivity. Simultaneously, the released Cu-elesclomol complexes induced proteotoxic stress responses and efficiently elicited cuproptosis, leading to increased release of proinflammatory factors and triggering anti-tumor immune activation. Our strategy holds promise for osteosarcoma treatment by inducing cuproptosis and achieving potent tumor suppression.

Trans-nasal brain delivery of anti-TB drugs by methyl-β-cyclodextrin microparticles show efficient mycobacterial clearance from central nervous system.

Central nervous system tuberculosis (CNS-TB) is the most severe extra-pulmonary manifestation of tuberculosis (TB), facing significant challenges due to the limited penetration of anti-TB drugs (ATDs) across the blood-brain barrier (BBB) and their insufficient concentrations at the site of infection. This study aimed to enhance the efficacy of ATDs by encapsulating them in methyl-β-cyclodextrin (M-β-CD) microparticles (ATD-MP) using spray drying, intended for intranasal delivery to manage CNS-TB. M-β-CD microparticles loaded with isoniazid (INH) and rifampicin (RIF) exhibited spherical shapes with slightly deflated surfaces and particle sizes of 6.24 ± 0.77 μm and 5.97 ± 0.50 μm, respectively. M-β-CD improved the permeation of ATDs through RPMI-2650 cell monolayers while reducing drug cytotoxicity. Pharmacokinetic and biodistribution analysis demonstrated that intranasal administration of ATD-MP significantly enhanced the trans-nasal brain delivery of ATDs and their distribution in the brain, achieving the minimum inhibitory concentration. In a murine model of CNS-TB, intranasal insufflation of ATD-MP for four weeks led to a significant reduction (~0.78 Log10 CFU) in mycobacterial burden in the brain compared to the untreated group (~3.60 Log10 CFU). These preclinical results underscore the potential of intranasal administration of M-β-CD microparticles as an effective therapeutic strategy for combating brain inflammation in CNS-TB.

Socio-Demographic Determinant Factors for Serum Iron, Copper, Zinc, and Selenium Concentrations Among U.S. Women of Childbearing Age.

Trace elements (TEs) are essential nutrients for the human body and have a significant impact on fertility and hormone levels in women of reproductive age, underscoring the importance of understanding sociodemographic variations in their concentrations within this population. To investigate the socio-demographic factors influencing blood concentrations of four essential TEs, including iron, zinc, copper, and selenium among women of reproductive age. A cross-sectional analysis of women aged 20-44 years was performed using the National Health and Nutrition Examination Survey, 1999-2018. Serum iron data were analyzed for 9211 women across 10 cycles, while serum copper, zinc, and selenium data were available for 1027 women across 3 cycles. Generalized linear and logistic regressions examined the individual associations of socio-demographic factors, including age, race and ethnicity, education, and poverty index ratio, with iron, zinc, copper, and selenium concentrations treated as continuous and categorical outcomes, respectively. A qualitative heatmap explored the joint associations between the socio-demographic factors and the four essential TEs. Reduced iron concentrations and increased risks of insufficiency occurred in older, Black, low-education, or low-income women. Black women were more likely to have lower zinc and selenium concentrations and an increased risk of zinc insufficiency but higher copper concentrations. The qualitative heatmap found that older, Black, low-education, and low-income women generally had lower concentrations of the four TEs, particularly iron (β = -0.10; p < 0.01). Socially disadvantaged women are more likely to present with lower TE concentrations, and these specific population groups should be targeted by replenishment planning by public health initiatives.

Validation of the technological process for the production of riamilovir-based solution for aerodispersible administration

BACKGROUND: An important step in the production of riamilovir-based solution for inhalation administration is the validation of critical stages of the technological process. First, a detailed study of all production steps, from the preparation of the initial ingredients to the final packaging, is carried out. Control tests are then conducted, including measuring key process parameters and analyzing the physical and chemical properties of the solution. One of the important aspects of process validation is also the training of production personnel. Proper understanding and adherence to all process instructions and requirements ensures that the process is followed correctly. AIM: Carry out validation activities throughout the stages of the technological process for the production of a solution for inhalation administration based on the active substance “riamilovir”. MATERIALS AND METHODS: The study was carried out using the developed Pilot Industrial Regulations for the production of the medicina. The quality assessment of pharmaceutical substances, excipients and pilot samples was carried out in accordance with the requirements of the State Pharmacopoeia of the Russian Federation and GMP rules. RESULTS: It has been established that the technological scheme for the production of a solution based on the active substance “riamilovir” contains 6 main stages. The greatest risk is observed at the following stages: Auxiliary work 3. Obtaining water — risk of bacterial contamination. Тechnological process 4. Preparation and sterilizing filtration of the solution — risks of insufficient concentration and unsterility of the solution. Тechnological process 5. Dosing the solution into vials is a risk due to underfilling, as well as violation of sterility. CONCLUSION: Validation of the technological process of production of solution for inhalation administration based on the active substance “riamilovir” has been carried out. Critical stages in the technological production process have been identified. The optimal parameters of the technological process have been determined and documented, leading to a predictable result — the release of a high-quality and safe drug.

Seasonal dynamics of 25-OH vitamin D and biogenic amines in the blood of apparently healthy men living in the city of Arkhangelsk

BACKGROUND: The Arctic zone territories of the Russian Federation have the risk of developing 25-OH vitamin D deficiency, which is aggravated by low levels of insolation and nutrition low in vitamins and minerals. Along with low levels of insolation and reduced vitamin D concentrations during periods of minimal daylight hours, manifestations of seasonal affective disorder may occur, which is characterized by circadian dysregulation and monoaminergic functions of neurotransmitters (serotonin, dopamine, noradrenaline). The scientific challenge lies in estimating 25-OH vitamin D and biogenic amines sufficiency and detecting associative changes in 25-OH vitamin D and biogenic amines levels during various photoperiods of the year in the population of Arkhangelsk, as well as in further identification of typological variations in the intra-individual dynamics of the studied indicators depending on gender and daylight hours.AIM. The purpose is to assess the seasonal sufficiency of vitamin D and biogenic amines for apparently healthy men of working age living in the city of Arkhangelsk.METHODS. An analytical prospective uncontrolled study was conducted with the participation of 20 clinically healthy men from the city of Arkhangelsk (64°32’24.4’’N). Blood samples were collected every season (March, June, September, December) during the year with subsequent determination of the concentrations of vitamin D, serotonin, dopamine, adrenaline and noradrenaline in the blood. Statistical analysis of endocrine parameters was performed using the Wilcoxon rank test with the Bonferroni correction.RESULT: According to the revealed annual dynamics, the concentration of 25-OH vitamin D in the blood of men who live in the city of Arkhangelsk reached a minimum level during an increase in daylight hours (March), followed by an increase in vitamin concentration in summer (June) and a maximum concentration level during a decrease in daylight hours (September). The largest percentage of people (45%) with insufficient (below 30 ng /ml) vitamin D concentration in the blood is noted during the period of increasing daylight (March), while in summer and autumn this percentage decreases to 10, and in winter no insufficient concentrations of vitamin D are detected.CONCLUSION: In terms of vitamin D concentration in the blood of men, the period of increase in daylight hours (March) is the most critical season, whereas the period of decrease in daylight hours (September) is a more favourable one. Seasonal dynamics of serotonin concentrations were associated with changes in vitamin D levels during the year. Seasonal variations of dopamine, adrenaline and noradrenaline concentrations were similar to each other and different from the annual dynamics of vitamin D concentration in the blood.

7328 A case of Adrenal Calcifications in a Patient with Familial Cerebral Cavernous Malformations

Abstract Disclosure: R.I. Dorin: None. L.E. Aguirre: None. M. Bomgardner: None. Background: Familial syndromes of cerebral cavernous malformation (fCCM) having autosomal dominant inheritance and variable penetrance and expression have been linked to loss of function mutations at three genetic loci. The association of small focal adrenal calcifications with fCCM was only recently recognized in a New Mexican cohort of subjects predominately carrying the founder common Hispanic mutation in the CCM1 locus (stop codon Q455X in the Krev1 interaction trapped gene 1 [KRIT1]). We report a case of bilateral, focal adrenal calcifications in a patient affected by fCCM. Clinical Case: A 72-year-old Hispanic male with past medical history of intracranial CCM was referred for osteoporosis and hyperthyroidism due to multinodular goiter. Small focal calcifications of the adrenal glands were incidentally noted on prior imaging studies. There was no history of anticoagulant use, adrenal hemorrhage, or systemic/adrenal infection. The patient was without clinical manifestations of adrenal insufficiency, morning cortisol and plasma ACTH concentrations were normal, and exam was negative for hyperpigmentation or cutaneous vascular malformations. Brain MRI revealed the presence of over 100 parenchymal CCM lesions. A family history of CCM was reported in multiple family members, including 7/10 siblings. Conclusion: In addition to cutaneous malformations, small focal adrenal calcifications are now recognized as one of the extra-neurological manifestations of fCCM, particularly in patients harboring the common Hispanic CCM1/KRIT1 mutation. Whether adrenal calcifications are observed in fCCM patients having other mutations of KRIT1 or other genetic loci of fCCM (CCM2 or PDCD10) remains to be determined. The focal adrenal calcifications are believed to be result of dyssynchronous, subclinical hemorrhagic events related to vascular malformations in the adrenal gland. These findings implicate a role for KRIT1 in endothelial development in the adrenal gland in addition to established role in CNS, spinal cord, and skin. Our patient appeared had normal adrenocortical function, as expected for the focal nature of the adrenal lesions. Though adrenal function has not been evaluated in fCCM patients, there are no reports of primary adrenal insufficiency in fCCM in the literature. Adrenal calcifications may be considered to represent an imaging biomarker for fCCM, and fCCM should be included in the differential diagnosis of adrenal calcifications. The incidental recognition of characteristic small, focal adrenal calcifications in either bilateral or unilateral adrenal glands should prompt evaluation for fCCM.

In Vitro Digestion of Vacuum-Impregnated Yam Bean Snacks: Pediococcus acidilactici Viability and Mango Seed Polyphenol Bioaccessibility.

This study investigates the in vitro digestion of vacuum-impregnated yam bean snacks enriched with Pediococcus acidilactici and mango seed polyphenols, focusing on bacterial survival and polyphenol bioaccessibility. The snacks were prepared by vacuum impregnation (VI) with solutions containing either mango seed extract, P. acidilactici, or a combination of both, followed by dehydration. The antimicrobial activity of the treatments was assessed against pathogens, revealing limited effectiveness, likely due to insufficient concentrations of mango seed extract and the intrinsic resistance of the bacteria. VI of mango seed extract improved the total soluble phenols (TSP) content up to 400% and maintained the initial probiotic concentration (106 cell/mL). In vitro digestion was performed to simulate gastrointestinal conditions, measuring the stability of TSP and the survival of P. acidilactici. The results indicated that the viability of P. acidilactici fluctuated throughout the digestion process (106 to 104 log UFC/g), the polyphenols showed varying degrees of bioaccessibility (11 to 30%), and the TSP content in the intestinal fraction ranged from 1.95 to 6.54 mg GAE/g. The study highlights the potential of VI for incorporating functional components into plant-based snacks, though further optimization is necessary to enhance the stability of P. acidilactici and the effectiveness of the bioactive ingredients.

Bio-inspired catalysts for enhanced N₂ electroreduction to NH3: Architecting molecular screening interfaces via active sites microenvironment engineering

The electrochemical nitrogen reduction reaction (ENRR) promises a sustainable route for ammonia (NH3) production but faces hurdles from competing hydrogen evolution reaction (HER) and insufficient N2 concentration. Drawing inspiration from Tropical Lizards’ unique mechanism of creating a thin air layer on their hydrophobic skin, we modify the catalyst-water interface using alkyl thiols of different chain lengths on VS2 (Cx-VS2, x = 4,8,12). This novel approach suppresses HER and increases N2 availability. Among the tailored catalysts, C8-VS2 exhibits superior ENRR performance, with an ammonia yield of 58.43 μg h−1 mgcat−1 and a Faradaic efficiency of 34.69 % that surpasses unmodified VS2 (21.05 μg h−1 mgcat−1 and 8.87 %). Supporting measurements and density functional theory (DFT) calculations confirm the pivotal role of the modified interface in optimizing NH3 production. Our findings offer fresh perspectives for designing efficient electrocatalysts via tailoring interface microenvironments, with potential implications for various applications.

Stress corrosion behavior and mechanism of Ti6321 alloy in seawater with different dissolved oxygen concentrations

AbstractThe stress corrosion behavior of Ti‐6Al‐3Nb‐2Zr‐1Mo (Ti6321, in wt%) alloy in seawater with different dissolved oxygen (DO) concentrations was investigated using X‐ray photoelectron spectroscopy, energy dispersive spectrometer, electrochemical measurements, and other advanced methodologies. The results indicate that when the DO concentration in seawater is insufficient, the passivation film will preferentially form on the α‐phase surface. Meanwhile, insufficient DO concentration leads to incomplete oxidation of the surface passivation film, resulting in an increase in surface defects. Hydrogen produced by reactions at crack tips is more likely to enter the surface of the titanium alloy through these defects, and under the influence of HEDE and HELP mechanisms, promote crack propagation.

The spatial spillover impact and transmission mechanisms of logistics agglomeration on eco-efficiency: A case study in China

This study employs spatial durbin model (SDM) and spatial mediation model to empirically investigate the relationship between logistics agglomeration (LA) and logistics eco-efficiency (LEE), as well as the transmission mechanism role of technological innovation (TI) and advanced industrial structure (AIS), using panel data on inter-provincial logistics in China from 2008 to 2020. The findings indicate a U-shaped relationship between LA and LEE. The early development of LA in China was accompanied by environmental sacrifices. Further analysis of the curves reveals that LA has spatial spillover effect on LEE. That is, insufficient concentration of LA has a siphon effect on the LEE of surrounding areas, whereas appropriate concentration of LA has a radiation effect on the LEE of surrounding areas. Spatial mediation analysis indicates that enhancing TI and developing AIS are essential channels through which LA bolsters LEE. Additionally, this study innovatively incorporates topography ruggedness and altitude as instrumental variables to account for potential endogeneity issues in the empirical model. Theoretical and practical significance is attributed to this research for China's logistics industry, particularly shedding light on the optimization of efficiency and long-term improvement of LEE through spatial reform via agglomeration zones.

Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity

Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

Acidity-Responsive Fe-PDA@CaCO3 Nanoparticles for Photothermal-Enhanced Calcium-Overload- and Reactive-Oxygen-Species-Mediated Tumor Therapy.

Calcium-overload-mediated tumor therapy has received considerable interest in oncology. However, its efficacy has been proven to be inadequate due to insufficient calcium ion concentration at the tumor site coupled with challenges in facilitating efficient calcium uptake by tumors, leading to unsatisfactory therapeutic outcomes. In the present study, calcium carbonate nanoshell mineralized ferric polydopamine nanoparticles (Fe-PDA@CaCO3 NPs) were prepared for achieving Ca2+-overload-mediated tumor therapy. Upon entering the tumor site, the pH-responsive CaCO3 layer, acting as a "Ca2+ storage pool", rapidly degraded and released high quantities of free Ca2+ within the weakly acidic environment. The Fe-PDA core, with its excellent photothermal conversion properties, could significantly increase the temperature upon exposure to near-infrared (NIR) light irradiation, thereby activating the TRPV1 channel and leading to a large influx of released Ca2+ into the cytoplasm. Furthermore, the exposed Fe-PDA core could react with the tumor-overexpressed hydrogen peroxide (H2O2) to efficiently produce hydroxyl radicals (•OH), significantly increasing intracellular reactive oxygen species (ROS) levels and thus inhibiting the activity of the Ca2+ efflux pump, resulting in a high intracellular Ca2+ concentration. Ultimately, the increase in calcium/ROS levels could disrupt mitochondrial homeostasis and activate the apoptosis pathway. The current work presents a promising approach for tumor therapy using photothermal-enhanced calcium-overload-mediated ion interference therapy and chemodynamic therapy.

Rational Regulation of Optimal Oxygen Vacancy Concentrations on VO2 for Superior Aqueous Zinc-Ion Battery Cathodes.

VO2 with its special tunnel structure and high theoretical capacity is an ideal candidate for cathode materials for aqueous zinc-ion batteries (ZIBs). However, the slow kinetics and structural instability due to the strong electrostatic interactions between the host structure of VO2 and Zn2+ hinder its application. Defect engineering is a well-recognized strategy for improving the intrinsic ion-electron dynamics and structural stability of this material. However, the preparation of oxygen vacancies poses significant difficulties, and it is challenging to control their concentration effectively. Excessive or insufficient vacancy concentration can have a negative effect on the cathode material. Herein, we propose electrode materials with controlled oxygen vacancies prepared in situ on carbon nanofibers (CNF) by a simple, one-step hydrothermal process (Ov-VO2@CNF). This method can balance the adsorption energy and migration energy barrier easily, and we maximized the adsorption energy of Zn2+ while minimizing the adsorption energy barrier. Notably, the Ov2-VO2@CNF electrode delivered a high specific capacity (over 450 mAh g-1 at 0.1 A g-1) and excellent cycle stability (318 mAh g-1 at 5 A g-1 capacity after 2000 cycles with a capacity retention of 85%). This rational design of precisely regulated defect engineering provides a way to obtain advanced electrode materials with excellent comprehensive properties.

The therapeutic efficacy of 5-ALA based photodynamic therapy and chemotherapy combination in triple negative breast cancer cells

Triple negative breast cancer (TNBC) is one of the subtypes of breast cancer characterized by a heterogeneous and aggressive nature. Photodynamic therapy (PDT) has drawn significant attention in cancer treatment. However, solubility of photosensitizer, penetration problems into a target tissue and insufficient oxygen concentration limit the effectiveness of PDT. To overcome these limitations and to reduce the side effects of chemotherapy, combination treatment modalities play an essential role in cancer treatment. In this study, we aimed to investigate the combination efficacy of cisplatin-based chemotherapy and 5-Aminolevulinic acid (5-ALA)/PDT in TNBC cells and healthy breast cells in vitro. To determine the effect of the combination effects of cisplatin and 5-ALA/PDT on TNBC cells, two treatment protocols (simultaneous and sequential combination therapy) were evaluated compared with cisplatin and 5-ALA/PDT monotherapy and WST-1, Annexin V assay, acridine orange (AO) and mitochondrial staining were performed. Our findings showed that MDA-MB-231 TNBC cell viability was significantly decreased following simultaneous combination treatment compared to cisplatin and 5-ALA/PDT monotherapy. Additionally, simultaneous combination treatment was more effective than sequential combination treatment. The simultaneous combination treatment of 2.5 µM cisplatin and 5-ALA/PDT at 6 J/cm2 and 9 J/cm2 induced 46.78% and 53.6% total apoptotic death, respectively in TNBC cells compared with monotherapies (cisplatin (37.88%) and 5-ALA/PDT (6 J/cm2: 31.48% and 9 J/cm2: 37.78%). Additionally, cisplatin and 5-ALA/PDT combination treatment resulted in nuclear fragmentation and mitochondrial damage due to apoptosis. Our results suggest that cisplatin and 5-ALA/PDT simultaneous combination therapy could be a promising new alternative strategy for treating TNBC. However, further studies are required to assess the underlying molecular mechanisms of cisplatin and 5-ALA/PDT combination treatment at the molecular level.

Development of a novel critical nitrogen concentration–cumulative transpiration curve for optimizing nitrogen management under varying irrigation conditions in winter wheat

Accurate nitrogen (N) nutrition diagnosis is essential for improving N use efficiency in crop production. The widely used critical N (Nc) dilution curve traditionally depends solely on agronomic variables, neglecting crop water status. With three-year field experiments with winter wheat, encompassing two irrigation levels (rainfed and irrigation at jointing and anthesis) and three N levels (0, 180, and 270 kg ha−1), this study aims to establish a novel approach for determining the Nc dilution curve based on crop cumulative transpiration (T), providing a comprehensive analysis of the interaction between N and water availability. The Nc curves derived from both crop dry matter (DM) and T demonstrated N concentration dilution under different conditions with different parameters. The equation Nc = 6.43T−0.24 established a consistent relationship across varying irrigation regimes. Independent test results indicated that the nitrogen nutrition index (NNI), calculated from this curve, effectively identifies and quantifies the two sources of N deficiency: insufficient N supply in the soil and insufficient soil water concentration leading to decreased N availability for root absorption. Additionally, the NNI calculated from the Nc-DM and Nc-T curves exhibited a strong negative correlation with accumulated N deficit (Nand) and a positive correlation with relative grain yield (RGY). The NNI derived from the Nc-T curve outperformed the NNI derived from the Nc-DM curve concerning its relationship with Nand and RGY, as indicated by larger R2 values and smaller AIC. The novel Nc curve based on T serves as an effective diagnostic tool for assessing winter wheat N status, predicting grain yield, and optimizing N fertilizer management across varying irrigation conditions. These findings would provide new insights and methods to improve the simulations of water-N interaction relationship in crop growth models.