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The discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. We analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aβ PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aβ accumulation, and thickness, accounting for age and APOE ε4 allele variations. The cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aβ deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. The study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment. • We explored the association between human glymphatic function, cMD, cortical Aβ deposition, and cortical thickness. • Significant associations were identified between glymphatic function and cMD in AD-susceptible brain regions. • Associations among DTI-ALPS, aging, and cortical thickness were noted. • We suggested the potential of DTI-ALPS as a biomarker of glymphatic function in PTSD. • Moreover, changes in DTI-ALPS occur in PTSD, possibly due to glymphatic system impairment. [ABSTRACT FROM AUTHOR]

• Diffusion in subarachnoid space was more isotropic with aging in young adults. • Other brain regions did not show an age-related decline of diffusion anisotropy. • Diffusion anisotropy in subarachnoid space was highest in the temporal lobe. • Reduced anisotropy may be relevant to reduced glymphatic transport with aging. The glymphatic system theory postulates that brain waste is removed through the cerebrospinal fluid (CSF) flow. According to this theory, CSF in the subarachnoid space (SAS) moves to the perivascular space around the penetrating arteries, flows into parenchyma to mix with interstitial fluid and brain waste, and then moves to the perivenous space to be flushed out of the brain. Despite the controversies about the glymphatic theory, it is clear that SAS plays a key role in waste clearance. For instance, the SAS around the middle cerebral artery is known to be highly involved in glymphatic influx. While diffusion tensor imaging has been used for studying the glymphatic system, there has been limited exploration of age-related changes in diffusion anisotropy within SAS and their regional variations. Given the narrow and heterogeneous morphology of SAS, the fractional anisotropy (FA) in diverse brain regions may be more relevant to glymphatic transport than mean diffusivity (MD). The goal of this study was to investigate FA in SAS to observe age-related changes across different brain regions and to interpret the results based on the glymphatic transport. We segmented SAS in the whole brain of 83 young adults and divided SAS into four cortical lobes. We demonstrated regional variations in FA and MD within SAS and an age-related decline in FA among young adults, indicating that diffusion within SAS becomes more isotropic with aging. These findings raise new questions about the factors influencing diffusion anisotropy within SAS, which are relevant to glymphatic transport. [ABSTRACT FROM AUTHOR]

The demand for glucose monitoring devices has witnessed continuous growth from the rising diabetic population. The traditional approach of blood glucose (BG) sensor strip testing generates only intermittent glucose readings. Interstitial fluid‐based devices measure glucose dynamically, but their sensing approaches remain either minimally invasive or prone to skin irritation. Here, a sweat glucose monitoring system is presented, which completely operates under rest with no sweat stimulation and can generate real‐time BG dynamics. Osmotically driven hydrogels, capillary action with paper microfluidics, and self‐powered enzymatic biochemical sensor are used for simultaneous sweat extraction, transport, and glucose monitoring, respectively. The osmotic forces facilitate greater flux inflow and minimize sweat rate fluctuations compared to natural perspiration‐based sampling. The epidermal platform is tested on fingertip and forearm under varying physiological conditions. Personalized calibration models are developed and validated to obtain real‐time BG information from sweat. The estimated BG concentration showed a good correlation with measured BG concentration, with all values lying in the A+B region of consensus error grid (MARD = 10.56% (fingertip) and 13.17% (forearm)). Overall, the successful execution of such osmotically driven continuous BG monitoring system from passive sweat can be a useful addition to the next‐generation continuous sweat glucose monitors. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) is a type of short, non-coding nucleic acid molecule that plays essential roles in diagnosing and prognosing various types of cancer. MiRNA is abundantly present in skin interstitial fluid (ISF), providing real-time and localized physiological information. Hydrogel microneedle (HMN) patches enable miRNA collection in a fast, pain-free, minimally invasive, and user-friendly manner. In this study, we introduced a fluorescence-based HMN assay, namely the HMN-miR sensor, composed of methacrylated hyaluronic acid (MeHA) and a graphene oxide–probe DNA (GO.pDNA) conjugate for miR21 and miR210 detection. The HMN-miR sensor demonstrates excellent skin penetration efficiency, rapid ISF collection capability, and sufficient miRNA detection and sequence identification specificity. The HMN-miR sensor facilitates a new assay that, with further optimization, could be applied in future clinical settings. Its simple fabrication process and excellent biocompatibility give it significant potential for various clinical uses, such as personalized cancer treatment and monitoring the healing progress of burn wounds. [ABSTRACT FROM AUTHOR]

Identification of suitable polymeric materials to fabricate microneedles (MNs) for the collection of interstitial fluid (ISF) is a challenge. Here, characterization of different carrageenan‐biopolymer composites for MN patch fabrication intended for ISF collection is reported. Systematic oscillatory rheological studies of composites containing iota‐carrageenan mixed with alginate, gelatin, or pectin are performed to determine the linear viscoelastic region, gel point, tan delta, complex viscosity, and flow transition index. A polynomial equation is derived by relating flow transition index of biopolymer composites and compression strength of fabricated MNs. The biopolymer composite of iota‐carrageenan and gelatin at 2% and 14%, respectively, and CaCl2 crosslinker (80 mm) shows the greatest compression strength sufficient for MNs insertion into the excised porcine skin. MNs swell up on application in an agarose gel model and the ex vivo excised porcine skin model to collect 36 ± 5 and 14 ± 1 µL of fluid within 10 min, respectively. Taken together, it is demonstrated that rheological analysis can be performed to select suitable polymer composites that possess sufficient strength for the skin insertion and swellability for ISF collection. [ABSTRACT FROM AUTHOR]

• Dynamic contrast MRI can be used to describe diffusive and convective flow in the brain tumor microenvironment using the Lymph4D tool. • Transport metrics measured in different planes of view for a single tumor correlate. • There is high variability in interstitial velocity magnitude and diffusion coefficient slice to slice across a single tumor. We present a comprehensive methodology for measuring heterogeneous interstitial fluid flow in murine brain tumors using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) coupled with the computational tool, Lymph4D. This four-part protocol encompasses glioma cell preparation, tumor inoculation, MRI imaging protocol, and histological verification using Evans Blue. While conventional DCE-MRI analysis primarily focuses on vascular perfusion, our methods reveal untapped potential to extract crucial information about interstitial fluid dynamics, including directions, velocities, and diffusion coefficients. This methodology extends beyond glioma research, with applicability to conditions routinely imaged with DCE-MRI, thereby offering a versatile tool for investigating interstitial fluid dynamics across a wide range of diseases and conditions. Our methodology holds promise for accelerating discoveries and advancements in biomedical research, ultimately enhancing diagnostic and therapeutic strategies for a wide range of diseases and conditions. [ABSTRACT FROM AUTHOR]

In this paper, the bone tissue was modeled as a linear viscoelastic material saturated with interstitial fluid. We considered a specific case of harmonic loading and related the mechanical stimuli to the loading frequency. In this way, we could include the inertial effect in the model while not having to deal with the perturbation during each loading period. Two types of mechanical signals were considered: strain energy and dissipation energy. A parametric study revealed the dependency of the two signals on loading frequency and material property. The evolution of the apparent mass density supported the parametric study's findings. Under the three different frequency loadings, the strain energy-stimulated samples experienced identical remodeling scenarios. The samples stimulated with dissipation energy, on the other hand, exhibited a strong frequency dependence. An additional study was performed to investigate the effect of long-term variations in the loading frequency on the remodeling process. This demonstrated the model's capabilities in designing and evaluating load regimes for rehabilitation following a bone injury or bone reconstruction. [ABSTRACT FROM AUTHOR]

It is well recognised that the rheology of an interstitial fluid has profound effects on debris flow dynamics. Existing design guidelines for multiple resisting barriers, however, do not consider the rheological behaviour of debris flows explicitly while estimating barrier spacing. A modified overflow equation is proposed, considering an improved overflow trajectory and a new yield stress-based velocity attenuation model, to estimate the overflow distance in two-phase flows. This study experimentally investigates the effects of yield stress of an interstitial fluid on the impact behaviour of two-phase flows with similar Froude numbers against dual-rigid barriers. The flow composition is varied to model a wide range of natural flows based on dimensionless yield stress. The results reveal that the hydrodynamic impact coefficient increases with increasing dimensionless yield stress and exceeds the existing international design guidelines by more than 13%. The existing guidelines underestimate the overflow distance by up to 115%. The modified formulation is verified and conservatively predicts overflow distance for water floods to debris flows. It is recommended that the dimensionless yield stress of interstitial fluid together with Froude number should be used to characterise the impact and overflow dynamics of two-phase flow for a conservative design of dual barriers. [ABSTRACT FROM AUTHOR]

Oxidative stress, orchestrated by myeloperoxidase (MPO), plays crucial roles in the progression of many diseases. Nonetheless, the role of MPO‐mediated oxidative stress in distinct factor‐induced acute liver injuries (ALI) is still up for dispute, mainly due to the lack of probes for in vivo monitoring of MPO releases. Here, a highly selective MPO probe (CSQ) based on the epoxidation biochemical reaction within the MPO‐H2O2‐Cl− system is screened to construct dual near infrared‐IIb (NIR‐IIb) ratiometric (F1550Em, 808Ex/F1550Em, 980Ex) luminescence nanoprobes by integrating CSQ onto down conversion nanoparticles (DCNPs) with and without liver‐targeting moiety (twin NIR‐IIb nanoprobes). Liver‐targeting probes are employed to monitor MPO release, whereas non‐liver‐targeting probes are utilized to assess MPO activity across all cell types. Using twin NIR‐IIb nanoprobes, the MPO‐mediated oxidative stress progressively increased are observed in carbon tetrachloride (CCl4)‐induced ALI over 12 h. In contrast, the MPO‐mediated oxidative stress in acetaminophen (APAP)‐induced ALI initially increased, peaked within 3 h, and then rapidly weakened to normal levels within 12 h. Importantly, the differential release of MPO from neutrophils/Kupfer cells to extracellular fluids in the two types of ALI is revealed. This work reveals significant differences in MPO distribution and the role of MPO‐mediated oxidative stress in CCl4 and APAP‐induced ALI. [ABSTRACT FROM AUTHOR]

During space flight, prolonged weightlessness stress exerts a range of detrimental impacts on the physiology and psychology of astronauts. These manifestations encompass depressive symptoms, anxiety, and impairments in both short-term memory and motor functions, albeit the precise underlying mechanisms remain elusive. Recent studies have revealed that hindlimb unloading (HU) animal models, which simulate space weightlessness, exhibited a disorder in memory and motor function associated with endogenous formaldehyde (FA) accumulation in the hippocampus and cerebellum, disruption of brain extracellular space (ECS), and blockage of interstitial fluid (ISF) drainage. Notably, the impairment of the blood-brain barrier (BBB) caused by space weightlessness elicits the infiltration of albumin and hemoglobin from the blood vessels into the brain ECS. However, excessive FA has the potential to form cross-links between these two proteins and amyloid-beta (Aβ), thereby obstructing ECS and inducing neuron death. Moreover, FA can inhibit N-methyl-D-aspartate (NMDA) currents by crosslinking NR1 and NR2B subunits, thus impairing memory. Additionally, FA has the ability to modulate the levels of certain microRNAs (miRNAs) such as miRNA-29b, which can affect the expression of aquaporin-4 (AQP4) so as to regulate ECS structure and ISF drainage. Especially, the accumulation of FA may inactivate the ataxia telangiectasia-mutated (ATM) protein kinase by forming cross-linking, a process that is associated with ataxia. Hence, this review presents that weightlessness stress-derived FA may potentially serve as a crucial catalyst in the deterioration of memory and motor abilities in the context of microgravity. [ABSTRACT FROM AUTHOR]

Background: The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. Methods: This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. Results: Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood–brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. Conclusions: This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings. [ABSTRACT FROM AUTHOR]

The document published in the journal "Molecular Neurodegeneration" compares the effectiveness of different anti-tau antibodies in inhibiting tau seeding from Alzheimer's disease (AD) brain extracts. The study found that an antibody targeting acetylated lysine-280 (acK280) on the microtubule-binding region (MTBR) showed the most significant decrease in tau seeding. The research suggests that targeting acK280 in the MTBR region may be a promising approach for immunotherapy in AD treatment. The study highlights the importance of epitope selection in developing effective anti-tau antibodies for combating tau pathologies. [Extracted from the article]

Potassium ions (K+) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K+ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K+ ion-rich TME, which has important implications for MDSCs-targeted therapies. [ABSTRACT FROM AUTHOR]

Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high‐throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient‐specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA‐MB‐468) and patient‐derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA‐MB‐468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient‐derived models. These microphysiological systems can thus be personalized by using patient‐derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Solid tumours are complex and heterogeneous systems, which exist in a dynamic biophysical microenvironment. Conventional cancer research methods have long relied on two-dimensional (2D) static cultures which neglect the dynamic, three-dimensional (3D) nature of the biophysical tumour microenvironment (TME), especially the role and impact of interstitial fluid flow (IFF). To address this, we undertook a transcriptome-wide analysis of the impact of IFF-like perfusion flow using a spheroid-on-chip microfluidic platform, which allows 3D cancer spheroids to be integrated into extracellular matrices (ECM)-like hydrogels and exposed to continuous perfusion, to mimic IFF in the TME. Importantly, we have performed these studies both in experimental (normoxia) and pathophysiological (hypoxia) oxygen conditions. Our data indicated that gene expression was altered by flow when compared to static conditions, and for the first time showed that these gene expression patterns differed in different oxygen tensions, reflecting a differential role of spheroid perfusion in IFF-like flow in tumour-relevant hypoxic conditions in the biophysical TME. We were also able to identify factors primarily linked with IFF-like conditions which are linked with prognostic value in cancer patients and therefore could correspond to a potential novel biomarker of IFF in cancer. This study therefore highlights the need to consider relevant oxygen conditions when studying the impact of flow in cancer biology, as well as demonstrating the potential of microfluidic models of flow to identify IFF-relevant tumour biomarkers. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumors. Recently, "physiological" cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1%-8% O2). Nonetheless, further refinement of tumor-specific culture conditions may be needed. In this study, we describe the development of a tumor microenvironment medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumor interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumor-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared with plasma-like conditions (mouse plasma medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumor-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5% O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5% O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumor microenvironment- like conditions in standard cancer research. [ABSTRACT FROM AUTHOR]

The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha‐synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti‐αSyn immunotherapy may contribute to pathology reduction in various PD‐like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti‐αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD‐like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD‐like pathology. [ABSTRACT FROM AUTHOR]

Moyamoya disease (MMD) causes cerebral arterial stenosis and hemodynamic disturbance, the latter of which may disrupt glymphatic system activity, the waste clearance system. We evaluated 46 adult patients with MMD and 33 age- and sex-matched controls using diffusivity along the perivascular space (ALPS) measured with diffusion tensor imaging (ALPS index), which may partly reflect glymphatic system activity, and multishell diffusion MRI to generate freewater maps. Twenty-three patients were also evaluated via 15O-gas positron emission tomography (PET), and all patients underwent cognitive tests. Compared to controls, patients (38.4 (13.2) years old, 35 females) had lower ALPS indices in the left and right hemispheres (1.94 (0.27) vs. 1.65 (0.25) and 1.94 (0.22) vs. 1.65 (0.19), P < 0.001). While the right ALPS index showed no correlation, the left ALPS index was correlated with parenchymal freewater (ρ = −0.47, P < 0.001); perfusion measured with PET (cerebral blood flow, ρ = 0.70, P < 0.001; mean transit time, ρ = −0.60, P = 0.003; and oxygen extraction fraction, ρ = −0.52, P = 0.003); and cognitive tests (trail making test part B for executive function; ρ = −0.37, P = 0.01). Adult patients with MMD may exhibit decreased glymphatic system activity, which is correlated with the degree of hemodynamic disturbance, increased interstitial freewater, and cognitive dysfunction, but further investigation is needed. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are considered the major cause of the occurrence, progression, chemoresistance/radioresistance, recurrence, and metastasis of cancer. Increased interstitial fluid pressure (IFP) is a key feature of solid tumors. Our previous study showed that the distribution of liver cancer stem cells (LCSCs) correlated with the mechanical heterogeneity within liver cancer tissues. However, the regulation of liver cancer's mechanical microenvironment on the LCSC stemness is not fully understood. Here, we employed a cellular pressure‐loading device to investigate the effects of normal IFP (5 mmHg), as well as increased IFP (40 and 200 mmHg) on the stemness of LCSCs. Compared to the control LCSCs (exposure to 5 mmHg pressure loading), the LCSCs exposed to 40 mmHg pressure loading exhibited significantly upregulated expression of CSC markers (CD44, EpCAM, Nanog), enhanced sphere and colony formation capacities, and tumorigenic potential, whereas continuously increased pressure to 200 mmHg suppressed the LCSC characteristics. Mechanistically, pressure loading regulated Yes‐associated protein (YAP) activity and Bcl‐2 modifying factor (BMF) expression. YAP transcriptionally regulated BMF expression to affect the stemness of LCSCs. Knockdown of YAP and overexpression of BMF attenuated pressure‐mediated stemness and tumorgenicity, while YAP‐deficient and BMF‐deletion recused pressure‐dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression. [ABSTRACT FROM AUTHOR]

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining cultures of intra-abdominal fluid in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. [ABSTRACT FROM AUTHOR]

The rapid advancement in personalized healthcare has driven the development of wearable biomedical devices for real-time biomarker monitoring and diagnosis. Traditional invasive blood-based diagnostics are painful and limited to sporadic health snapshots. To address these limitations, microneedle-based sensing platforms have emerged, utilizing interstitial fluid (ISF) as an alternative biofluid for continuous health monitoring in a minimally invasive and painless manner. This review aims to provide a comprehensive overview of microneedle sensor technology, covering microneedle design, fabrication methods, and sensing strategy. Additionally, it explores the integration of monitoring electronics for continuous on-body monitoring. Representative applications of microneedle sensing platforms for both monitoring and therapeutic purposes are introduced, highlighting their potential to revolutionize personalized healthcare. Finally, the review discusses the remaining challenges and future prospects of microneedle technology. Highlights: • Microneedle sensors enable minimally invasive and continuous biomarker monitoring through dermal interstitial fluid. • This review offers a comprehensive overview of microneedle sensing technology. • Key topics covered include skin physiology, microneedle design, sensing mechanisms, monitoring electronics, and applications. [ABSTRACT FROM AUTHOR]

[Objective] Electroporation has been widely used in biomedical applications, which is a typical medical--engineering cross-field. Currently, in the application of irreversible electroporation, the assessment of the ablation outcome in real time by medical imaging methods has become an issue. To solve this problem from the engineering field and create a teaching program for students in related majors, this study describes in detail how to build the electroporation platform and measure the ablation results and tissue impedance. The characteristics of the impedance variation are extracted by the equivalent circuit model. Finally, the correlation between the ablation outcome and the impedance change is discussed, which might be the new method to assess the ablation outcome in real-time. [Methods] This study investigated the tissue impedance changes and the ablation outcome induced by high-voltage pulsed electric fields. The pulsed voltage and current waveforms were recorded by an oscilloscope and used to analyze the electroporation process. The tissue impedance change induced by different pulse amplitudes was measured by an impedance analyzer, and the load characteristics were analyzed based on the impedance spectrum. To extract the characteristics of impedance change during treatment, the equivalent circuit model of tissue was proposed according to the features of the tissue structure. The measured impedance data were fitted to the circuit model to determine the value of every element in the circuit. The potato tube, which is the commonly used tissue model in irreversible electroporation, was used to detect the ablation outcome for different pulse parameters. The ablation outcome was quantified by the length and area of the ablated zone. [Results] The experimental results of the response current showed that: (1) At the first pulse, the increase in the current during pulse on time caused by electroporation could be easily identified. (2) As more pulses were applied, the current change during the pulse seemed to be saturated, indicating the saturation of electroporation. The measured impedance and the equivalent circuit model yielded the following results: (1) The impedance of the tissue started from the capacitive load, reflecting the polarization process between electrode and tissue. (2) As the frequency increased, the impedance could reflect the resistive characteristics of the extracellular fluid, the capacitive characteristics of the cell membrane, and the resistive characteristics of the intracellular fluid in sequence. (3) The circuit model could fit the impedance spectrum well, and the variation of the element value caused by the pulsed electric field could be explained by tissue electroporation. (4) The changing trends of the extracellular and cell membrane parameters were consistent with the ablation outcome, which had the potential to be used to assess the irreversible electroporation outcome in real-time. [Conclusions] By investigating the electrical and biomedical changes in the tissue after treatment by pulsed electric fields, the changes in the response current and impedance spectra are measured and correlated with the electroporation process. The equivalent circuit model can describe the tissue property well, and the changes in the extracellular resistance and cell membrane impedance are consistent with the ablation results. This study provides the potential electrical indicators to evaluate the ablation outcomes of irreversible electroporation in real-time. This teaching program helps students understand the connections between medicine and engineering, enhancing their skills in the application of theoretical knowledge in electrical engineering. [ABSTRACT FROM AUTHOR]

The glymphatic system is a functional cerebrospinal fluid circulatory system that uses peri-arterial space for inflow of cerebrospinal fluid and peri-venous space for efflux of cerebrospinal fluid from brain parenchyma. This brain-wide fluid transport pathway facilitates the exchange between cerebrospinal fluid and interstitial fluid and clears metabolic waste from the metabolically active brain. Multiple lines of work show that the glymphatic system is crucial to normal brain functions, and the dysfunction of the glymphatic system is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury. Currently, it is common to explore the functional and molecular mechanisms of the glymphatic system based on animal models. The function of glymphatic system during perioperative period is affected by many factors such as physiological, pathological, anesthetic and operative methods. To provide a reference for the interpretation of the results of glymphatic system studies during perioperative period, this article comprehensively reviews the physiological and pathological factors that interfere with the function of the glymphatic system during perioperative period, investigates the effects of anesthetic drugs on glymphatic system function and the potential underlying mechanisms, describes operative methods that interfere with the function of the glymphatic system, and potential intervention strategies based on the glymphatic system. Future, these variables should be taken into account as critical covariates in the design of functional studies on the glymphatic system. [ABSTRACT FROM AUTHOR]

The vascular and lymphatic systems are integral to maintaining skeletal homeostasis and responding to pathological conditions in bone and joint tissues. This review explores the interplay between blood vessels and lymphatic vessels in bones and joints, focusing on their roles in homeostasis, regeneration, and disease progression. Type H blood vessels, characterized by high expression of CD31 and endomucin, are crucial for coupling angiogenesis with osteogenesis, thus supporting bone homeostasis and repair. These vessels facilitate nutrient delivery and waste removal, and their dysfunction can lead to conditions such as ischemia and arthritis. Recent discoveries have highlighted the presence and significance of lymphatic vessels within bone tissue, challenging the traditional view that bones are devoid of lymphatics. Lymphatic vessels contribute to interstitial fluid regulation, immune cell trafficking, and tissue repair through lymphangiocrine signaling. The pathological alterations in these networks are closely linked to inflammatory joint diseases, emphasizing the need for further research into their co-regulatory mechanisms. This comprehensive review summarizes the current understanding of the structural and functional aspects of vascular and lymphatic networks in bone and joint tissues, their roles in homeostasis, and the implications of their dysfunction in disease. By elucidating the dynamic interactions between these systems, we aim to enhance the understanding of their contributions to skeletal health and disease, potentially informing the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions We aim to compare the burden of Level 1 (<4 mmol/L) and Level 2 (<3 mmol/L) hypoglycaemia between type 2 diabetes (T2D) patients with and without chronic kidney disease (CKD).T2D subjects with and without CKD (eGFR<60 mL/min/1.73 m2) were recruited from a tertiary‐care hospital. Subjects wore the Freestyle Libre‐Pro sensor for 2 weeks. The number of hypoglycaemic events and intra‐day difference in Level 1 and 2 hypoglycaemias were compared between the cohorts.We recruited 134 subjects: 74 with CKD (44 M:30F) and 60 without CKD (36 M:24F), with no difference in HbA1c between the two cohorts (66 ± 20 vs 64 ± 16 mmol/mol, p = 0.529). The CKD cohort had increased level 1 (OR 1.73, p = 0.011), level 2 hypoglycaemias (OR 2.16, p = 0.002), and glycaemic variability than the non‐CKD cohort (35.3 ± 9.5 vs 32.3 ± 6.8%). The CKD cohort had more level 2 hypoglycaemia events nocturnally compared to day at 1.9 ± 3.1 vs. 1.4 ± 2.5 events/person within the two week sensor wearing period (p = 0.022), whereas there was no significant intra‐day difference in the number of such events within the non‐CKD cohort.The CKD cohort has a greater burden of hypoglycaemia despite being treated to similar HbA1c targets. The greater number of nocturnal events warrants safety concern. Interstitial fluid glucose targets should be incorporated into the glycaemic guidelines for T2D patients with CKD. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to interstitial fluid into the ventricles of the brain. CSF acts as a growth medium for the developing cerebral cortex and a source of nutrients and signalling throughout life. Together with perivascular glymphatic and interstitial fluid movement through the brain and into CSF, it also acts to remove toxins and maintain metabolic balance. In this study, we focused on cerebral folate status, measuring CSF concentrations of folate receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, also known as 10-formyl tetrahydrofolate dehydrogenase (ALDH1L1 and FDH); and total folate. These demonstrate the transport of folate from blood across the blood–CSF barrier and into CSF (FOLR1 + folate), and the transport of folate through the primary FDH pathway from CSF into brain FDH + ve astrocytes. Based on our hypothesis that CSF flow, drainage issues, or osmotic forces, resulting in fluid accumulation, would have an associated cerebral folate imbalance, we investigated folate status in CSF from neurological conditions that have a severity association with enlarged ventricles. We found that all the conditions we examined had a folate imbalance, but these folate imbalances were not all the same. Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions. [ABSTRACT FROM AUTHOR]

• Higher free-water index in bipolar group suggests neuroinflammation links. • ALPS index and disease duration are inversely related suggesting glymphatic issues. • FW-corrected measures linked with DRS indicate severe bipolar impacts myelin. The glymphatic system, an expansive cerebral waste-disposal network, harbors myriad enigmatic facets necessitating elucidation of their nexus with diverse pathologies. Murine investigations have revealed a relationship between the glymphatic system and affective disorders. This study aimed to illuminate the interplay between bipolar disorder and the glymphatic system. Fifty-eight individuals afflicted with bipolar disorder were identified through meticulous psychiatric assessment. These individuals were juxtaposed with a cohort of 66 comparably aged and sex-matched, mentally stable subjects. Subsequent analysis entailed the application of covariance analysis to evaluate along with the perivascular space (ALPS) index, a novel magnetic resonance imaging method for assessing brain interstitial fluid dynamics via diffusion tensor imaging within the bipolar and control cohorts. We also evaluated the correlation between the ALPS index and clinical parameters, which included the Hamilton Depression scale scores, disease duration, and other clinical assessments. Moreover, partial correlation analyses, incorporating age and sex as covariates, were performed to investigate the relationships between the ALPS index and clinical measures within the two cohorts. A noteworthy adverse correlation was observed between the ALPS index and illness duration. A free-water imaging analysis revealed a substantial elevation in the free-water index within the white-matter tracts, prominently centered on the corpus callosum, within the bipolar cohort relative to that in the control group. In analogous cerebral regions, a conspicuous affirmative correlation was observed between the free-water–corrected radial diffusivity and depression rating scales. Our results showed that the protracted course of bipolar disorder concomitantly exacerbated glymphatic system dysregulation. [ABSTRACT FROM AUTHOR]

Introduction: The interstitial space harbours two fluid compartments linked serially to the plasma. This study explores conditions that lead to fluid accumulation in the most secluded compartment, termed the "third space". Methods: Retrospective data was collected from 326 experiments in which intravenous crystalloid fluid was administered to conscious volunteers as well as a small group of anaesthetized patients. The urinary excretion and plasma dilution derived from haemoglobin served as input variables in nine population volume kinetic analyses representing subtly different settings. Results: An infusion of 250-500 mL of Ringer's solution expanded only the central fluid space (plasma), whereas the infusion of 500-1,000 mL extended into a rapidly exchanging interstitial fluid space. When more than 1 L was infused over 30 min, it was distributed across plasma and both interstitial fluid compartments. The remote space, characterized by slow turnover, abruptly accommodated fluid upon accumulation of 700-800 mL in the rapidly exchanging space, equivalent to an 11%-13% volume increase. However, larger expansion was necessary to trigger this event in a perioperative setting. The plasma half-life of crystalloid fluid was 25 times longer when 2,000-2,700 mL expanded all three fluid compartments compared to when only 250-500 mL expanded the central space (14 h versus 30 min). Conclusion: As the volume of crystalloid fluid increases, it apparently occupies a larger proportion of the interstitial space. When more than 1 L is administered at a high rate, there is expansion of a remote "third space", which considerably extends the intravascular half-life. [ABSTRACT FROM AUTHOR]

Macropinocytosis mediates the non-selective bulk uptake of extracellular fluid, enabling cells to survey the environment and obtain nutrients. A conserved set of signaling proteins orchestrates the actin dynamics that lead to membrane ruffling and macropinosome formation across various eukaryotic organisms. At the center of this signaling network are Ras GTPases, whose activation potently stimulates macropinocytosis. However, how Ras signaling is initiated and spatiotemporally regulated during macropinocytosis is not well understood. By using the model system Dictyostelium and a proteomics-based approach to identify regulators of macropinocytosis, we uncovered Leep2, consisting of Leep2A and Leep2B, as a RasGAP complex. The Leep2 complex specifically localizes to emerging macropinocytic cups and nascent macropinosomes, where it modulates macropinosome formation by regulating the activities of three Ras family small GTPases. Deletion or overexpression of the complex, as well as disruption or sustained activation of the target Ras GTPases, impairs macropinocytic activity. Our data reveal the critical role of fine-tuning Ras activity in directing macropinosome formation. [ABSTRACT FROM AUTHOR]

Background: Microcirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA−I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock. Methods: The present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA−I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA−I interval was analyzed. Results: A total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6–16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9–40), of whom 18 died during ICU stay. The GA−I levels were negative correlation with CRT (r = 0.369, P < 0.001), Lac (r = -0.269, P < 0.001), skin mottling score (r=-0.223, P < 0.001), and were positively associated with urine volume (r = 0.135, P < 0.05). The ICU mortality rate of patients with septic shock presenting GA−I ≤ 0.30 mmol/L and ≥ 2.14 mmol/L was significantly higher than that of patients with GA−I at 0.30–2.14 mmol/L [65.2% vs. 15.0%, odds ratio (OR) = 10.625, 95% confidence interval (CI): 2.355–47.503]. Conclusion: GA−I was correlated with microcirculation parameters, and with differences in survival. Future studies are needed to further explore the potential impact of GA−I on microcirculation and clinical prognosis of septic shock, and the bedside monitoring of GA−I may be beneficial for clinicians to identify high-risk patients. [ABSTRACT FROM AUTHOR]

Background The use of interstitial glucose monitoring devices such as flash glucose monitoring has been shown to be beneficial in patients with type 1 diabetes mellitus (T1DM). However, these devices have been little studied in patients with diabetes treated by chronic haemodialysis (HD). Methods The goal of this prospective, observational, multicentric study was to evaluate the analytical performance of the FreeStyle Libre 2 (FSL2) sensor in T1DM patients during HD sessions. During three HD sessions, interstitial fluid glucose (ISFG) concentrations given by the FSL2 were compared every 15 minutes with blood glucose (BG) concentrations obtained simultaneously. BG concentrations were measured by two different glucometers: the Accu-Chek Guide and StatStrip meters. Results Twelve HD patients were included, with a mean age of 54 ± 11 years and a mean diabetes duration of 36.5 ± 11.6 years. Dialysis vintage was 35 ± 22 months. A total of 565 pairs of ISFG/BG values were available for analysis. The mean absolute relative difference, defined as the mean of the absolute relative differences between the ISFG and BG measurements, was 17.4% and 20.9% when the ISFG was compared with the StatStrip meter or Accu-Chek Guide, respectively. Interstitial results tend to underestimate blood results, but all values were classified as having clinically acceptable error. The differences observed remained stable during the dialysis session and were not associated with the ultrafiltration rate. Conclusion Use of the FSL2 interstitial glucose monitoring device in HD patients with T1DM is clinically acceptable, even though the accuracy of the device is generally poorer than in studies including non-dialysis patients. [ABSTRACT FROM AUTHOR]

Introduction. Fluid therapy is an intervention widely used in clinical practice. However, its application is not without risks and requires a careful evaluation of patient’s tolerance and response to volume. The empirical practice of fluid resuscitation can be potentially lethal. The purpose of this review was to provide an overview of the physiological and therapeutic principles for the administration of intravenous fluids in critically ill patients, addressing special populations, such as surgical, septic, and trauma patients. Methods. A narrative review was carried out based on articles published in PUBMED, ScienceDirect, and LILACS between 2001 and 2023. MESH terms fluid therapy, crystalloid solutions, and colloids were employed. Results. A total of 371 articles were found, of which randomized clinical trials studies, narrative reviews, systematic reviews, and meta-analyses that analyzed the role of crystalloids and colloids were selected. Manuscripts published on dates outside the search range, which were considered relevant for the description of the pathophysiology and the rationale for the use of intravenous fluids, were included. Conclusion. Reflective resuscitation is based on a holistic understanding of physiology and individualization of fluid therapy. The liberal use of intravenous fluids has potential harmful effects and resuscitation strategies should be guided by individual dynamic and static measures, which provide a safe framework for fluid management. [ABSTRACT FROM AUTHOR]

Maintaining extracellular potassium (K+) within narrow limits, critical for membrane potential and excitability, is accomplished through the internal redistribution of K+ between extracellular fluid (ECF) and intracellular fluid (ICF) in concert with the regulation of renal K+ output to balance K+ intake. Here we present evidence from high-precision analyses of stable K+ isotopes in rats maintained on a control diet that the tissues and organs involved in the internal redistribution of K+ differ in their speed of K+ exchange with ECF and can be grouped into those that exchange K+ with ECF either rapidly or more slowly ("fast" and "slow" pools). After 10 days of K+ restriction, a compartmental analysis indicates that the sizes of the ICF K+ pools decreased but that this decrease in ICF K+ pools was not homogeneous, rather occurring only in the slow pool (15% decrease, p < 0.01), representing skeletal muscles, not in the fast pool. Furthermore, we find that the dietary K+ restriction is associated with a decline in the rate constants for K+ effluxes from both the "fast" and "slow" ICF pools (p < 0.05 for both). These results suggest that changes in unidentified transport pathways responsible for K+ efflux from ICF to ECF play an important role in buffering the internal redistribution of K+ between ICF and ECF during K+ restriction. Thus, the present study introduces novel stable isotope approaches to separately characterize heterogenous ICF K+ pools in vivo and assess K+ uptake by individual tissues, methods that provide key new tools to elucidate K+ homeostatic mechanisms in vivo. [ABSTRACT FROM AUTHOR]

In landfill cover, geosynthetic packages are often used to fulfil different and simultaneous functions: drainage, waterproofing, separation, reinforcement, and soil protection. In this regard, various types of geosynthetics are combined in succession to allow for water and biogas drainage and to waterproof, reinforce, and provide protection from erosion over the useful lifetime, ranging over many decades if we consider the long phases of disposal, closure, and quiescence of the landfill itself. The creation of the composite cover barrier requires the evaluation of various interfaces' frictional strength under low contact stresses, both in static and seismic cases. The main purpose of this study is to summarize the results of past laboratory tests carried out on different geosynthetic–geosynthetic and geosynthetic–soil–geosynthetic interfaces using experimental instrumentation developed at the geotechnical laboratory of the University of Padua, which allows for the characterization of the interface geosynthetic friction at low contact stresses. The main aspects highlighted are the kinematic mode of failure, the wearing of the contact surfaces, the presence or absence of interstitial fluid, and, finally, the density level of the granular soil in contact with the geosynthetics. [ABSTRACT FROM AUTHOR]

Adapting the mechanical strength between the implant materials and the brain tissue is crucial for the postoperative treatment of glioblastoma. However, no related study has been reported. Herein, we report an injectable lipoic acid‑iron (LA-Fe) hydrogel (LFH) that can adapt to the mechanical strength of various brain tissues, including human brain tissue, by coordinating Fe3+ into a hybrid hydrogel of LA and its sodium salt (LANa). When LFH, which matches the mechanical properties of mouse brain tissue (337 ± 8.06 Pa), was injected into the brain resection cavity, the water content of the brain tissue was maintained at a normal level (77%). Similarly, LFH did not induce the activation or hypertrophy of glial astrocytes, effectively preventing brain edema and scar hyperplasia. Notably, LFH spontaneously degrades in the interstitial fluid, releasing LA and Fe3+ into tumor cells. The redox couples LA/DHLA (dihydrolipoic acid, reduction form of LA in cells) and Fe3+/Fe2+ would regenerate each other to continuously provide ROS to induce ferroptosis and activate immunogenic cell death. As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the efficacy of tumor-immunotherapy and promoted tumor ferroptosis. The injectable hydrogel that adapted the mechanical strength of tissues shed a new light for the tumor postoperative treatment. TOC Graph: The first injectable hydrogel that can adapt the mechanical strength of different brain tissues including human brain has been developed for the GBM postoperative treatment without the involvement of anti-tumor drugs by coordinating Fe3+ into the hybrid hydrogel of B vitamin lipoic acid (LA) and its sodium salt (LANa). [Display omitted] • By coordinating Fe3+ into the hybrid hydrogel of lipoic acid (LA) and its sodium salt (LANa) formed an injectable hydrogel. • The LA-Fe hydrogel (LFH) can adapt the mechanical strength of multiple brain tissues including human brain. • The LFH circumvented the foreign body reaction caused by material implantation, and effectively inhibited tumor recurrence. • As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the tumor-immunotherapy efficacy and promoted the tumor ferroptosis. [ABSTRACT FROM AUTHOR]

Nile tilapia Oreochromis niloticus is an important aquaculture species worldwide, and understanding its behavior and growth performance under variable culture conditions is essential for optimizing culture. Light as an environmental factor profoundly affects fish development, growth, food consumption, hormone secretion, and other life processes. This study investigated the effects of different light colors (blue, green, and red) on the stress response of individually reared Nile tilapia using a wireless biosensor system for real-time glucose monitoring. The biosensor system effectively measured glucose concentration (stress indicator) by enzymatic oxidation, allowing continuous monitoring of fish eyeball interstitial sclera fluid (EISF), providing longer and more accurate data. Air exposure and ammonia exposure were used as stressors, and stress responses were monitored under different light colors. Nile tilapia exhibited lower quiescent blood glucose levels, lower blood glucose elevations, and faster stress recovery under blue light. Green light induced more significant glucose elevations during acute physical stress, but showed similar fluctuations to blue light during chronic chemical stress, indicating potential benefits for fish welfare. In contrast, whether exposed to air or ammonia, red light induced large fluctuations in blood glucose levels, which may be detrimental to the fish. The study highlights the importance of light color in influencing stress responses and recovery in Nile tilapia, providing valuable insights for improving aquaculture practices and promoting fish welfare. [ABSTRACT FROM AUTHOR]

Physiological age-related alterations in the interstitial flow in the brain, which plays an important role in waste product removal, remain unclear. Using [15O]H 2 O positron emission tomography (PET), water dynamics were evaluated in 63 healthy adult participants aged between 20 and 80 years. Interstitial flow was assessed by influx ratio (IR) and drain rate (DR), using time-activity concentration data. Participants were divided into four age groups with 15-year ranges, to evaluate age-related functional alterations. At least one of the indices declined significantly with age across all groups. A significant linear negative correlation between age and both indicators was found in the scatter plots (IR: R2 = 0.54, DR: R2 = 0.44); both indicators were predominantly lower after age 50 years. These results suggest interstitial flow decreases with age, especially after 50 years. These important findings can contribute to devising therapeutic interventions for neurological diseases characterized by abnormal accumulation of waste products, and suggest the need for taking measures to maintain interstitial flow starting around the age of 50 years. [ABSTRACT FROM AUTHOR]

Vaccines play a critical role in combating infectious diseases and cancers, yet improving their efficacy remains challenging. Here, we introduce a separable nanocomposite hydrogel microneedle (NHMN) patch designed for intradermal and sustained delivery of ovalbumin (OVA), a model antigen, to enhance adaptive immune responses. The NHMN patch consists of an array of OVA-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite (LAP), supported by a hyaluronic acid backing. The incorporation of LAP not only enhances the mechanical strength of the pure hydrogel microneedles but also significantly prolongs OVA release. Furthermore, in vitro cell experiments demonstrate that NHMNs effectively activate dendritic cells without compromising cell viability. Upon skin penetration, NHMNs detach from the backing as the hyaluronic acid rapidly dissolves upon contact with the skin interstitial fluid, thereby acting as antigen reservoirs to release antigens to abundant skin dendritic cells. NHMNs containing 0.5% w/v LAP achieved a 15-day OVA release in vivo. Immunization studies demonstrate that the intradermal and sustained release of OVA via NHMNs elicited stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. Given its easy to use, painless and minimally invasive features, the NHMN patch shows promise in improving vaccination accessibility and efficacy against a range of diseases. The study introduces a separable nanocomposite hydrogel microneedle (NHMN) patch. This patch consists of an array of ovalbumin (OVA, a model antigen)-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite, with a hyaluronic acid backing, designed for intradermal and sustained delivery of antigens. This patch addresses several key challenges in traditional vaccination methods, including poor antigen uptake and presentation, and rapid systematic clearance. The incorporation of laponite enhances mechanical strength of microneedles, promotes dendritic cell activation, and significantly slows down antigen release. NHMN-based vaccination elicits stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. This NHMN patch holds great potential for improving the efficacy, accessibility, and patient comfort of vaccinations against a range of diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Authors have expressed reservations regarding the use of base deficit measured in umbilical artery blood samples to assess fetal well-being during the course of labor and to predict neonatal neurologic morbidity. Despite its integration into clinical practice for more than 50 years, obstetricians and maternal-fetal medicine specialists may not realize that this marker has significant limitations in accurately identifying neonatal metabolic acidosis as a proxy for fetal well-being. In brief, there are 2 large families of base deficit, namely whole blood and extracellular fluid. Both rely on equations that use normal adult acid-base characteristics (pH 7.40 and partial CO 2 pressure of 40 mm Hg) that overlook the specificity of the normal in utero acid-base status of pH 7.27 and partial CO 2 pressure of 54 mm Hg. In addition, it ignores the unique characteristic of the in utero fetal response to acute hypoxia. The dependence on placental circulation for CO 2 elimination may lead to extremely high values (up to 130 to 150 mm Hg) during hypoxic events, a phenomenon that is absent in adults with acute metabolic acidosis who can hyperventilate. The dispute over if to include a correction for high partial CO 2 pressure in the bicarbonate estimation, as presented in the Great Trans-Atlantic Debates, remains unresolved. The key constants computed for adult acid-base physiology in the current base deficit algorithms, without accounting for the impact of high partial CO 2 pressure or other fetal characteristics of buffering capacity (eg, differences in body water content composition, plasma protein, and hemoglobin attributes), may lead to an overestimation of metabolic acidosis, especially in newborns who are experiencing hypercarbia during the early stages of the hypoxic response. These unrecognized limitations impact the base deficit results and may mislead clinicians on fetal well-being assessments when discussing the management of fetal heart rate monitoring and neonatal outcomes. Based on our arguments, we believe that it is prudent to consider an alternative to base deficit for drawing conclusions regarding fetal well-being during the course of birth management. We propose a marker specifically related to the newborn acid-base physiology––the neonatal eucapnic pH correction. This marker can be added to arterial cord blood gas analysis, and we have described how to interpret it as a marker of neonatal metabolic acidosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) plays a critical role in metabolic waste clearance from the brain, requiring its circulation throughout various brain pathways, including the ventricular system, subarachnoid spaces, para‐arterial spaces, interstitial spaces, and para‐venous spaces. The complexity of CSF circulation has posed a challenge in obtaining noninvasive measurements of CSF dynamics. The assessment of CSF dynamics throughout its various circulatory pathways is possible using diffusion magnetic resonance imaging (MRI) with optimized sensitivity to incoherent water movement across the brain. This review presents an overview of both established and emerging diffusion MRI techniques designed to measure CSF dynamics and their potential clinical applications. The discussion offers insights into the optimization of diffusion MRI acquisition parameters to enhance the sensitivity and specificity of diffusion metrics on underlying CSF dynamics. Lastly, we emphasize the importance of cautious interpretations of diffusion‐based imaging, especially when differentiating between tissue‐ and fluid‐related changes or elucidating structural versus functional alterations. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) lacks traditionally defined lymphatic vasculature. However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis. Pathways involved in this system have been under investigation for centuries and continue to be the source of considerable interest and debate. Modern imaging and microscopy technologies have led to important breakthroughs pertaining to various elements of CNS fluid circuitry and exchange over the past decade, thus enhancing knowledge on mechanisms of mammalian CNS maintenance and disease. Yet, to better understand precise anatomical routes, the physiology and clinical significance of these CNS pathways, and potential therapeutic targets in humans, fluid conduits, flow‐regulating factors, and tissue effects must be analyzed systematically and in a global manner in persons across age, demographical factors, and disease states. Here, we illustrate the system‐wide nature of intermixing CNS fluid networks, summarize historical and clinical studies, and discuss anatomical and physiological similarities and differences that are relevant for translation of evidence from mice to humans. We also review Cushing's classical model of cerebrospinal fluid flow and present a new framework of this "third circulation" that emphasizes previously unexplained complexities of CNS fluid circulation in humans. Finally, we review future directions in the field, including emerging theranostic techniques and MRI studies required in humans. [ABSTRACT FROM AUTHOR]

During anatomical dissection of a female body donor at the Howard University College of Medicine, a rare renal anomaly was discovered. Detailed anatomical and histological analyses on this anomaly were compared to a normal kidney from another donor and previously published reports from a comprehensive literature review. Anatomical assessment confirmed the condition of pancake kidney, a rare form of completely fused, ectopic kidneys without an isthmus. Due to the lack of symptoms in patients with this condition and the limited number of published case reports, very little information is available regarding the anatomy, development, and histology of pancake kidneys, making it difficult to determine an accurate estimate of the number of individuals who are affected. In the case presented here, a single kidney was located in the pelvis, below the bifurcation of the abdominal aorta into the common iliac arteries. The histological analysis of the pancake kidney revealed focal segmental glomerulosclerosis, dilated renal tubules, and increased interstitial fluid, all common characteristics of renal disease and not present in the normal kidney of the other donor. Future studies are needed to compare the histology of pancake kidneys and typical kidneys in order to help determine potential pathologies. [ABSTRACT FROM AUTHOR]

Introduction. Avoiding solid foods and liquids before surgery is a common practice in elective surgery in pediatric, however, there is a risk of dehydration.The objective was to assess the distribution of fluid across the water sectors of the body in children according to the duration of refusal of food and liquids before elective surgery.Materials and methods. A single-center prospective cohort study. 104 children were examined, the average age was 12.5 ± 3.7 years. Depending on the age, patients were divided into three groups: group I: 3–7 years old, group II: 7–12 years old and group III: 12–18 years old. In each group, taking into account the duration of preoperative refusal of food and fluid, there were two subgroups: subgroup I – less than 12 hours; subgroup II – more than 12 hours. The average fasting time was 13.3 ± 2.7 hours. The condition of the water sectors of the body was assessed 30 minutes before surgery, 30 minutes and 24 hours after surgery.Results. Before the operation, the distribution of fluid across the water sectors in groups I and II, depending on the duration of fasting, did not differ; in group III, when fasting for more than 12 hours, all indicators were significantly lower. 30 minutes and 24 hours after the intervention, an increase in the volume of total water and extracellular fluid was observed, however, significant changes were only in group III (p < 0.05). In group III, when fasting for more than 12 hours before surgery, lower systolic BP values were observed (p < 0.05).Conclusion. The duration of preoperative refusal of solid food and liquids in the range of 12–15 hours does not adversely affect the indicators of water metabolism and is not associated with arterial hypotension during the induction of anesthesia.

Therapeutic antibodies (Abs) have been anticipated as promising alternatives to conventional treatments such as topical minoxidil and oral finasteride for androgenetic alopecia (AGA). Due to the high molecular weight of typical Abs, the half-life of subcutaneous Abs exceeds 2 weeks, allowing an administration intervals of once a month or longer. Direct injection into the areas of hair loss is also feasible, potentially enhancing treatment efficacy while minimizing systemic side effects. However, therapeutic Abs are rarely developed for AGA therapy due to the requirement to be responsiveness to androgens and to exist in the extracellular fluid or cell surface surrounding the hair follicle. In this review, we introduce recent progress of antibody therapeutics in AGA targeting the prolactin receptor, Interleukin-6 receptor, C-X-C motif chemokine ligand 12, and dickkopf 1. As therapeutic Abs for AGA are still in the early stages, targets need further validation and optimization for clinical application. [ABSTRACT FROM AUTHOR]

Diabetes is a common chronic metabolic disease with a wide range of clinical symptoms and consequences and one of the main causes of death. For the management of diabetes, painless and continuous interstitial fluid (ISF) glucose monitoring is ideal. Here, we demonstrate continuous diabetes monitoring using an integrated microneedle (MN) biosensor with an emergency alert system. MNs are a novel technique in the field of biomedical engineering because of their ability to analyze bioinformation with minimal invasion. In this work we developed a poly(methyl methacrylate) (PMMA) based MN glucose sensor. The device was produced by the 3D printing technique, microfabrication, electrodeposition, and enzyme immobilization step. The in vitro test for the glucose MN sensor showed a linear range from 1.5 to 14 mM with a sensitivity of 1.51 μA mM−1, limit of detection (LOD) of 0.35 mM and good selectivity. Highly repeatable sensing is observed with good reproducibility. The interference-free detection of glucose in the presence of physiologically relevant concentrations of ascorbic acid, uric acid, and mannose is demonstrated, along with the operational stability of the array. After resolving the biofouling consequences linked to on-body sensing, this MN platform would be appealing for minimally invasive electrochemical glucose monitoring. An alert is sent to confidants via email or SMS when the values are abnormal. The application is also able to display the recorded values in the form of a graph to help determine the state of health of the user over a period of time. It can be concluded that continuous monitoring and an emergency alert system are important for keeping an eye on diabetic patients and can send alert in case of an abnormal situation of the patient. [ABSTRACT FROM AUTHOR]

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents. Editor's summary: Tumors often have abnormal and dysfunctional blood vessels that are in part responsible for poor drug delivery and thus reduced efficacy of treatment. Here, Lu et al. have developed a derivative of the C-type natriuretic peptide (dCNP) to normalize vascular structures of tumors to improve therapy efficacy. They demonstrated that this modified dCNP had superior pharmacokinetic and pharmacodynamic properties as compared with native CNP. In addition, administration of dCNP to multiple mouse models remodeled tumor blood vessels and improved antitumorigenic activity of standard monotherapies. This represents a promising compound that could improve therapeutic efficacy of multiple therapies for patients with cancer that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood–brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood–brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further. [ABSTRACT FROM AUTHOR]

As cutting‐edge technologies applied for the study of body fluid molecular biomarkers are continuously evolving, clinical applications of these biomarkers improve. Diverse forms of circulating molecular biomarkers have been described, including cell‐free DNA (cfDNA), circulating tumor cells (CTCs), and cell‐free microRNAs (cfmiRs), although unresolved issues remain in their applicability, specificity, sensitivity, and reproducibility. Translational studies demonstrating the clinical utility and importance of cfmiRs in multiple cancers have significantly increased. This review aims to summarize the last 5 years of translational cancer research in the field of cfmiRs and their potential clinical applications to diagnosis, prognosis, and monitoring disease recurrence or treatment responses with a focus on solid tumors. PubMed was utilized for the literature search, following rigorous exclusion criteria for studies based on tumor types, patient sample size, and clinical applications. A total of 136 studies on cfmiRs in different solid tumors were identified and divided based on tumor types, organ sites, number of cfmiRs found, methodology, and types of biofluids analyzed. This comprehensive review emphasizes clinical applications of cfmiRs and summarizes underserved areas where more research and validations are needed. [ABSTRACT FROM AUTHOR]

The rapid advancements in nucleic acid-based electrochemical sensors for implantable and wearable applications have marked a significant leap forward in the domain of personal healthcare over the last decade. This technology promises to revolutionize personalized healthcare by facilitating the early diagnosis of diseases, monitoring of disease progression, and tailoring of individual treatment plans. This review navigates through the latest developments in this field, focusing on the strategies for nucleic acid sensing that enable real-time and continuous biomarker analysis directly in various biofluids, such as blood, interstitial fluid, sweat, and saliva. The review delves into various nucleic acid sensing strategies, emphasizing the innovative designs of biorecognition elements and signal transduction mechanisms that enable implantable and wearable applications. Special perspective is given to enhance nucleic acid-based sensor selectivity and sensitivity, which are crucial for the accurate detection of low-level biomarkers. The integration of such sensors into implantable and wearable platforms, including microneedle arrays and flexible electronic systems, actualizes their use in on-body devices for health monitoring. We also tackle the technical challenges encountered in the development of these sensors, such as ensuring long-term stability, managing the complexity of biofluid dynamics, and fulfilling the need for real-time, continuous, and reagentless detection. In conclusion, the review highlights the importance of these sensors in the future of medical engineering, offering insights into design considerations and future research directions to overcome existing limitations and fully realize the potential of nucleic acid-based electrochemical sensors for healthcare applications. [ABSTRACT FROM AUTHOR]

Recent research has extensively explored the intricate mechanisms that underlie the effectiveness of acupuncture, highlighting the importance of stimulating acupoints, the role of acupuncture techniques in managing diseases, and the interaction between meridian pathways and molecular processes. Studies have underscored the crucial role of acupuncture in activating neurons, modulating the immune system, and influencing vascular activity, all of which contribute significantly to its therapeutic benefits across a wide range of symptoms and conditions. Utilization of imaging modalities enables the identification of changes in cerebral blood flow, brain function, and regional glucose metabolism following acupuncture sessions. The interstitial fluid circulation network within meridians adheres to specific laws that facilitate the transportation of materials. Acupuncture initiates the release of neurotransmitters, neuropeptides, and immune factors, impacting pain perception, inflammation, and physiological functions. It influences the complex neuro–endocrine–immune network by activating pathways involving the nervous system, the hypothalamic-pituitary-adrenal axis, and immune responses. Moreover, acupuncture induces molecular modifications such as phosphorylation, methylation, and histone modification, leading to key molecular changes that ultimately result in anti-inflammatory effects and the regulation of immune responses. [ABSTRACT FROM AUTHOR]