Search

Acid-base disorders are currently analyzed and treated using a bicarbonate-centered approach derived from blood studies prior to the advent of digital computers, which could solve computer models capable of quantifying the complex physicochemical nature governing distribution of water and ions between fluid compartments. An alternative is the Stewart approach, which can predict the pH of a simple mixture of ions and electrically charged proteins; hence, the role of extravascular fluids has been largely ignored. The present study uses a new, comprehensive computer model of four major fluid compartments, based on a recent blood model, which included ion binding to proteins, electroneutrality constraints, and other essential physicochemical laws. The present model predicts quantitative respiratory acid-base buffering behavior in the whole body, as well as determining roles of each compartment and their species, particularly compartmental electrically charged proteins, largely responsible for buffering. The model tested an early theory that H+ was conserved in the body fluids; hence, when changing P co 2 states, intracellular buffering could be predicted by net changes in bicarbonate and protein electrical charge in the remaining fluids. Even though H+ is not conserved in the model, the theory held in simulated respiratory disorders. Model results also agreed with a second part of the theory, that ion movements between cells and interstitial fluid were linked with H+ buffering, but by electroneutrality constraints, not necessarily by some membrane-related mechanisms, and that the strong ion difference (SID), an amalgamation of ionic electrical charges, was approximately conserved when going between equilibrium states caused by P co 2 changes in the body-fluid system. NEW & NOTEWORTHY: For the first time, a physicochemically based, whole body, four-compartment, computer model was used to study respiratory whole body acid-base buffering. An improved approach to quantify acid-base buffering, previously used by this author, was able to determine contributions of the various compartmental fluids to whole body buffering. The model was used to test, for the first time, three fundamental theories of whole body acid-base homeostasis, namely, H+-conservation, its linkage to ion transport, and strong ion difference conservation. [ABSTRACT FROM AUTHOR]

In recent times, the demand for innovative, insignificantly invasive diagnostic and therapeutic biomedical tools has reached enhanced attention. Rapid Diagnostic Tests (RDTs) for diagnosis, which are non-invasive, inexpensive, simple, and deliver results accurately in less than 20 minutes, have heightened the accessibility to parasite-based analysis globally. Microneedle (MN) arrays are a fast-developing and promising technology for drug delivery and extraction of Interstitial fluid (ISF) employed for numerous diagnostic and clinical therapies. This review gives a broad overview of the characteristics and history of Microneedles (MNs) patches together with their applications in drug delivery and transdermal rapid diagnostic purposes, classifications, and categories based on the design of fabrication from previous works of literature spanning the period 2018-2023. Utilizing PubMed, Scopus, Google Scholar, and Wiley online library search engines, an online search for scientific publications published between 2018 and 2023 was conducted using the keywords "microneedle patch" and "rapid diagnostic tests." 175 articles in all were found when the search terms were used. The acquired results were then narrowed to 64 citations in this review by applying the inclusion principle. Pictorial and tabular representations highlight the various features of Microneedle patches used in interstitial fluid testing and extraction that have been documented experimentally, including numerous applications of Microneedle patches, showing their dimensions, applications, fabrication methods, and findings made. Finally, research on bio-microneedles and bio-inspired MN are reviewed. The research findings indicate that dissolving microneedles has become increasingly popular since they have several benefits over other microneedles. It is among the most well-known microneedles, and since it degrades naturally, it is a superior option for diagnosis and long-term treatment. [ABSTRACT FROM AUTHOR]

Elevated interstitial fluid pressure (IFP) within pathological tissues (e.g., tumors, obstructed kidneys, and cirrhotic livers) creates a significant hindrance to the transport of nanomedicine, ultimately impairing the therapeutic efficiency. Among these tissues, solid tumors present the most challenging scenario. While several strategies through reducing tumor IFP have been devised to enhance nanoparticle delivery, few approaches focus on modulating the intrinsic properties of nanoparticles to effectively counteract IFP during extravasation and penetration, which are precisely the stages obstructed by elevated IFP. Herein, we propose an innovative solution by engineering nanoparticles with a fusiform shape of high curvature, enabling efficient surmounting of IFP barriers during extravasation and penetration within tumor tissues. Through experimental and theoretical analyses, we demonstrate that the elongated nanoparticles with the highest mean curvature outperform spherical and rod-shaped counterparts against elevated IFP, leading to superior intratumoral accumulation and antitumor efficacy. Super-resolution microscopy and molecular dynamics simulations uncover the underlying mechanisms in which the high curvature contributes to diminished drag force in surmounting high-pressure differentials during extravasation. Simultaneously, the facilitated rotational movement augments the hopping frequency during penetration. This study effectively addresses the limitations posed by high-pressure impediments, uncovers the mutual interactions between the physical properties of NPs and their environment, and presents a promising avenue for advancing cancer treatment through nanomedicine. [ABSTRACT FROM AUTHOR]

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPStreated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin- NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors. [ABSTRACT FROM AUTHOR]

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10−3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min−1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies. [ABSTRACT FROM AUTHOR]

Background: First metatarsophalangeal joint arthrodesis is a typical medical treatment performed in cases of arthritis or joint deformity. The gold standard for this procedure is arthrodesis stabilisation with the dorsally positioned plate. However, according to the authors' previous studies, medially positioned plate provides greater bending stiffness. It is worth to compare the mechanical conditions for bone formation in the fracture callus for both placements of the locking plate. Methods: Two finite element models of the first metatarsophalangeal joint with the dorsally and medially positioned plate were defined in the Abaqus software to simulate differentiation of the fracture callus. A simplified load application, i.e. one single step per each day and the diffusion of the mesenchymal stem cells into the fracture region were assumed in an iterative hardening process. The changes of the mesenchymal stem cells into different phenotypes during the callus stiffening were governed by the octahedral shear strain and interstitial fluid velocity according to Prendergast mechanoregulation theory. Basing on the obtained results the progress of the cartilage and bone tissues formation and their distribution within the callus were compared between two models. Findings: The obtained results suggest that after 6 weeks of simulation the healing progress is in general comparable for both plates. However, earlier closing of external callus was observed for the medially positioned plate which had greater vertical bending stiffness. This process enables faster internal callus hardening and promotes symmetrical bridging. [ABSTRACT FROM AUTHOR]

Bioaccessibility of metals from substances and alloys is increasingly used as part of the assessment to predict potential toxicity. However, data are sparse on the metal bioaccessibility from nanoparticle (NP) size metal substances. This study examines nickel ion release from metallic nickel and nickel oxide micron particles (MPs) and NPs in simulated biological fluids at various timepoints including those relevant for specific routes of exposure. The results suggest that MPs of both metallic nickel and nickel oxide generally released more nickel ions in acidic simulated biological fluids (gastric and lysosomal) than NPs of the same substance, with the largest differences being for nickel oxide. In more neutral pH fluids (interstitial and perspiration), nickel metal NPs released more nickel ions than MPs, with nickel oxide results showing a higher release for MPs in interstitial fluid yet a lower release in perspiration fluid. Various experimental factors related to the particle, fluid, and extraction duration were identified that can have an impact on the particle dissolution and release of nickel ions. Overall, the results suggest that based on nickel release alone, nickel NPs are not inherently more hazardous than nickel MPs. Moreover, analyses should be performed on a case-by-case basis with consideration of various experimental factors and correlation with in vivo data. [ABSTRACT FROM AUTHOR]

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern. [ABSTRACT FROM AUTHOR]

Prostate cancer is frequently diagnosed and the leading cause of death in men worldwide. Prostate-specific antigen (PSA) blood tests and biopsies are the primary methods for diagnosing prostate cancer; however, their accuracy is less than 50%. Therefore, there is a need to develop diagnostic tests that minimize patient discomfort during examination and adequate biomarkers that are more accurate, sensitive, and specific for the detection of prostate cancer. This study investigated the application of metabolomics to identify biomarkers in prostate cancer biofluids. In addition, changes in prostate cancer metabolite levels induced by chrysin, a natural anticancer compound, were evaluated and compared with those in non-treated prostate cancer cells. Gas chromatography-mass spectrometry (GC-MS)-based metabolomic profiling was performed to investigate the differences in metabolic alterations among prostate cancer, normal prostate, and chrysin-treated prostate cancer cells. Pairwise comparisons of the extracellular fluid metabolomes were performed using principal component analysis (PCA), partial least squares–discriminant analysis (PLS-DA), and Student's t-test. The results revealed significantly different patterns among the metabolite groups, including alcohols, amino acids, carboxylic acids, organic acids, sugars, and urea. The RWPE-1- and chrysin-treated PC-3 (PC-3 Chr) cell groups showed similar tendencies for 23 metabolites, while the groups showed significant differences from the PC-3 group. Most amino acids showed higher concentrations in PC-3 cells than in the normal cell line RWPE-1 cells and PC-3 Chr cells. Our results revealed that GC-MS might be an effective diagnostic tool to detect prostate cancer and contribute to finding new tumor markers for prostate cancer as the basis for new ideas. [ABSTRACT FROM AUTHOR]

Hearing loss is a pivotal risk factor for dementia. It has recently emerged that a disruption in the intercommunication between the cochlea and brain is a key process in the initiation and progression of this disease. However, whether the cochlear properties can be influenced by pathological signals associated with dementia remains unclear. In this study, using a mouse model of Alzheimer's disease (AD), we investigated the impacts of the AD-like amyloid β (Aβ) pathology in the brain on the cochlea. Despite little detectable change in the age-related shift of the hearing threshold, we observed quantitative and qualitative alterations in the protein profile in perilymph, an extracellular fluid that fills the path of sound waves in the cochlea. Our findings highlight the potential contribution of Aβ pathology in the brain to the disturbance of cochlear homeostasis. [ABSTRACT FROM AUTHOR]

Background: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. Results: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. Conclusions: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy. [ABSTRACT FROM AUTHOR]

Endometriosis is a common gynaecological condition, with a long diagnostic delay. Surgery is required to confirm a diagnosis, highlighting the need for a non‐invasive biomarker. Extracellular vesicles (EVs) may have a role in endometriosis pathogenesis, yet there is limited EV biomarker literature available. This study aimed to investigate the feasibility of isolating cervico‐vaginal fluid EVs sampled using cervical brushes and vaginal swabs and to compare these methods. After providing informed consent, patients undergoing surgery for suspected endometriosis had cervical brush and vaginal swab samples collected under general anaesthetic. Isolated EVs were characterised through negative stain transmission electron microscopy (TEM), Western blotting (TSG101, CD63, Calnexin, ApoB, Albumin), tunable resistive pulse sensing (TRPS), microBCA assays and RT‐qPCR of miRNAs. PCR was performed on samples prior to EV isolation to assess bacteria present in samples. Cervical brush and vaginal swab EVs were intact vesicles with limited co‐isolated contaminants. Cervical brushes had higher concentrations of particles compared to match vaginal swabs, although both samples had low concentrations. Protein and miRNA yield were similar between matched samples. PCR demonstrated only a small amount DNA within samples was bacterial (>0.5%). Cervico‐vaginal fluids EVs were successfully isolated from cervical brushes and vaginal swabs, demonstrating a new method of sampling reproductive EVs. EV yield from both sample types was low. Similar protein and miRNA levels suggest either sampling method may be suitable for biomarker studies. [ABSTRACT FROM AUTHOR]

Aims: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium‐glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods: This was a post‐hoc analysis of the PROCEED trial, which evaluated the effect of 24‐week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post‐treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium‐glucose co‐transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. Results: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3‐0.8; p <.001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3‐3.1; p <.001) and erythropoietin (estimated log‐transformed group difference, 0.1; 95% CI, 0.01‐0.3; p =.036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (β = 0.253, p <.001) or haematocrit (β = 0.278, p <.001). Reductions in estimated plasma volume (estimated group difference, −7.94%; 95% CI, −11.6 to −4.26%; p <.001) and estimated extracellular volume (estimated group difference, −181.6 ml; 95% CI, −275.7 to −87.48 ml; p <.001) were significantly greater in the ipragliflozin group than those in the control group. Conclusions: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. Clinical trial: PROCEED trial (registration number: jRCTs071190054). [ABSTRACT FROM AUTHOR]

Introduction: Microfluidic resistive pulse sensing (MRPS) can determine the concentration and size distribution of extracellular vesicles (EVs) by measuring the electrical resistance of single EVs passing through a pore. To ensure that the sample flows through the pore, the sample needs to contain a wetting agent, such as bovine serum albumin (BSA). BSA leaves EVs intact but occasionally results in unstable MRPS measurements. Here, we aim to find a new wetting agent by evaluating Poloxamer-188 and Tween-20. Methods: An EV test sample was prepared using an outdated erythrocyte blood bank concentrate. The EV test sample was diluted in Dulbecco's phosphate-buffered saline (DPBS) or DPBS containing 0.10% BSA (w/v), 0.050% Poloxamer-188 (v/v) or 1.00% Tween-20 (v/v). The effect of the wetting agents on the concentration and size distribution of EVs was determined by flow cytometry. To evaluate the precision of sample volume determination with MRPS, the interquartile range (IQR) of the particles transit time through the pore was examined. To validate that DPBS containing Poloxamer-188 yields reliable MRPS measurements, the repeatability of MRPS in measuring blood plasma samples was examined. Results: Flow cytometry results show that the size distribution of EVs in Tween 20, in contrast to Poloxamer-188, differs from the control measurements (DPBS and DPBS containing BSA). MRPS results show that Poloxamer-188 improves the precision of sample volume determination compared to BSA and Tween-20, because the IQR of the transit time of EVs in the test sample is 11 μs, which is lower than 56 μs for BSA and 16 μs for Tween-20. Furthermore, the IQR of the transit time of particles in blood samples with Poloxamer-188 are 14, 16, and 14 μs, which confirms the reliability of MRPS measurements. Conclusion: The solution of 0.050% Poloxamer-188 in DPBS does not lyse EVs and results in repeatable and unimpeded MRPS measurements. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the molecular composition of follicular fluid (FF) extracellular vesicles (EVs) in women of different reproductive ages and its possible relationship to sperm fertilizing ability. FF EVs were obtained by differential centrifugation. The concentration and size distribution of FF EVs were analyzed by nanoparticle tracking analysis. The lipidome and proteome were analyzed by liquid chromatography–mass spectrometry. The isolated FF EVs had a variety of shapes and sizes; their concentration and size distribution did not differ significantly between the age groups. In women younger than 35 years, the concentration of vesicular progesterone was 6.6 times higher than in women older than 35 years, and the total levels of the main lipid classes were increased in younger women. A proteomic analysis revealed that not only FF EV-specific proteins, but also proteins involved in sperm activation were present. New data were obtained on the composition of FF EVs, confirming their importance as molecular indicators of age-related changes in the female reproductive system. In addition, these results shed light on the possible interaction between the FF EVs of women in different age groups and male germ cells. Therefore, studying the transcriptomic and metabolomic profile of FF EVs may be a crucial approach to evaluate the efficacy of ART. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic foot infection (DFI) is one of the complications of diabetes mellitus. Clindamycin (CLY) is one of the antibiotics recommended to treat DFI, but CLY given orally and intravenously still causes many side effects. Methods: In this study, we encapsulated CLY in a bacteria sensitive microparticle system (MP-CLY) using polycaprolactone (PCL) polymer. MP-CLY was then delivered in a separable effervescent microarray patch (MP-CLY-SEMAP), which has the ability to separate between the needle layer and separable layer due to the formation of air bubbles when interacting with interstitial fluid in the skin. Result: The characterization results of MP-CLY proved that CLY was encapsulated in large amounts as the amount of PCL polymer used increased, and there was no change in the chemical structure of CLY. In vitro release test results showed increased CLY release in media cultured with Staphylococcus aureus bacteria and showed controlled release. The characterization results of MPCLY-SEMAP showed that the developed formula has optimal mechanical and penetration capabilities and can separate in 56 ± 5.099 s. An ex vivo dermatokinetic test on a bacterially infected skin model showed an improvement of CLY dermatokinetic profile from MP-CLY SEMAP and a decrease in bacterial viability by 99.99%. Conclusion: This research offers proof of concept demonstrating the improved dermatokinetic profile of CLY encapsulated in a bacteria sensitive MP form and delivered via MP-CLY-SEMAP. The results of this research can be developed for future research by testing MP-CLY-SEMAP in vivo in appropriate animal models. [ABSTRACT FROM AUTHOR]

Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and hormone secretion and action. Indeed, maintaining K+ balance is critical for normal cell function, as too high or too low K+ levels can have serious and potentially deadly health consequences. K+ homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K+ intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na+-K+-ATPase uptake, and hormone and electrolyte impacts on renal K+ handling. We recently developed a mathematical model of whole body K+ regulation to unravel the individual impacts of these regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high-K+ diet. We conducted model simulations and sensitivity analyses to investigate how these renal alterations impact whole body K+ regulation. Model predictions quantify the sensitivity of K+ regulation to various levels of proximal tubule K+ reabsorption adaptation and tubuloglomerular feedback. Our results suggest that the reduced proximal tubule K+ reabsorption under a high-K+ diet could achieve K+ balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K+ excretion.NEW & NOTEWORTHY Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective. [ABSTRACT FROM AUTHOR]

Here, we theoretically and computationally study the frequency dependence of phase speed and attenuation for marine sediments from the perspective of granular mechanics. We leverage recent theoretical insights from the granular physics community as well as discrete-element method simulations, where the granular material is treated as a packing of discrete objects that interact via pairwise forces. These pairwise forces include both repulsive contact forces as well as dissipative terms, which may include losses from the fluid as well as losses from inelasticity at grain–grain contacts. We show that the structure of disordered granular packings leads to anomalous scaling laws for frequency-dependent phase speed and attenuation that do not follow from a continuum treatment. Our results demonstrate that granular packing structure, which is not explicitly considered in existing models, may play a crucial role in a complete theory of sediment acoustics. While this simple approach does not explicitly treat sound propagation or inertial effects in the interstitial fluid, it provides a starting point for future models that include these and other more complex features. [ABSTRACT FROM AUTHOR]

Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. WT and MR-deficient mice were exposed to lipopolysaccharide, after which the protein content in their lung epithelial lining fluid was compared by tandem mass tag-based mass spectrometry. More than 1200 proteins were identified in the epithelial lining fluid using this unbiased approach, but only six showed a statistically different abundance. Among these, an unexpected potential new ligand, thrombospondin-4 (TSP-4), displayed a striking 17-fold increased abundance in the MR-deficient mice. Experiments using exogenous addition of TSP-4 to MRtransfected CHO cells or MR-positive alveolar macrophages confirmed that TSP-4 is a ligand for MR-dependent endocytosis. Similar studies revealed that the molecular interaction with TSP-4 depends on both the lectin activity and the fibronectin type-II domain of MR and that a closely related member of the TSP family, TSP-5, is also efficiently internalized by the receptor. This was unlike the other members of this protein family, including TSPs −1 and −2, which are ligands for a close MR homologue known as urokinase plasminogen activator receptor-associated protein. Our study shows that MR takes part in the regulation of TSP-4, an important inflammatory component in the injured lung, and that two closely related endocytic receptors, expressed on different cell types, undertake the selective endocytosis of distinct members of the TSP family. [ABSTRACT FROM AUTHOR]

Adequate tissue perfusion and cellular function is dependent on the maintenance of effective circulatory volume and serum osmolality, respectively. As sodium is the principal extracellular cation with the inability to pass freely across the cellular membrane, it therefore has the greatest effect on extracellular fluid osmolality. The extracellular fluid (ECF) volume can increase or decrease independent of the surrounding osmolality indicating that control of plasma osmolality and volume occur through distinct physiological processes. Disorders in sodium balance with consequent effect on osmolality come about mainly due to disturbances in water homeostasis rather than an abnormality of sodium intake or excretion. [ABSTRACT FROM AUTHOR]

Malignant melanoma (MM) is the most aggressive form of skin cancer. The delay in treatment will induce metastasis, resulting in a poor prognosis and even death. Here, a two‐step strategy for on‐site diagnosis of MM is developed based on the extraction and direct visual quantification of S100A1, a biomarker for melanoma. First, a swellable microneedle is utilized to extract S100A1 in skin interstitial fluid (ISF) with minimal invasion. After elution, antibody‐conjugated magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) are introduced. A high expression level of S100A1 gives rise to a robust binding between MMPs and PMPs and reduces the number of free PMPs. By loading the reacted solution into the device with a microfluidic particle dam, the quantity of free PMPs after magnetic separation is displayed with their accumulation length inversely proportional to S100A1 levels. A limit of detection of 18.7 ng mL−1 for S100A1 is achieved. The animal experiment indicates that ISF‐based S100A1 quantification using the proposed strategy exhibits a significantly higher sensitivity compared with conventional serum‐based detection. In addition, the result is highly comparable with the gold standard enzyme‐linked immunosorbent assay based on Lin's concordance correlation coefficient, suggesting the high practicality for routine monitoring of melanoma. [ABSTRACT FROM AUTHOR]

Wearable devices are gaining popularity in the fields of health monitoring, diagnosis, and drug delivery. Recent advances in wearable technology have enabled real-time analysis of biofluids such as sweat, interstitial fluid, tears, saliva, wound fluid, and urine. The integration of microfluidics and emerging smart technologies, such as artificial intelligence (AI), machine learning (ML), and Internet of Things (IoT), into wearable devices offers great potential for accurate and non-invasive monitoring and diagnosis. This paper provides an overview of current trends and developments in microfluidics and smart technologies in wearable devices for analyzing body fluids. The paper discusses common microfluidic technologies in wearable devices and the challenges associated with analyzing each type of biofluid. The paper emphasizes the importance of combining smart technologies with microfluidics in wearable devices, and how they can aid diagnosis and therapy. Finally, the paper covers recent applications, trends, and future developments in the context of intelligent microfluidic wearable devices. [ABSTRACT FROM AUTHOR]

The advent of digital technologies has spurred the development of wearable sensing devices marking a significant shift in obtaining real-time physiological information. The principal objective is to transition from blood-centric monitoring to minimally invasive modalities, which will enable movement from specialised settings to more accessible environments such as the practices of general practitioners or even home settings. While subcutaneously implanted continuous monitoring devices have demonstrated this transition, detection of analytes from sample matrices like skin interstitial fluid (ISF), is a frontier that offers attractive minimally invasive routes for detection of biomarkers. This manuscript presents a comprehensive overview of our work in subdermal wearable biosensing patches for the simultaneous monitoring of glucose and lactate from ISF in ambulatory conditions. The performance of the subdermal wearable glucose monitoring patch was evaluated over a duration of three days, which is the longest reported duration reported till date. The subdermal wearable lactate sensing patch was worn for the duration of the exercise. Our findings highlight a critical observation that biofouling effects become apparent after a 24 h period. The data presented in this manuscript extends on the knowledge in the areas of continuous metabolite monitoring by introducing multifunctional polyphenol polymer films that can be used for both glucose and lactate monitoring with appropriate modifications. This study underscores the potential of subdermal wearable patches as versatile tools for real-time metabolite monitoring, positioning them as valuable assets in the evolution of personalised healthcare in diverse settings. [ABSTRACT FROM AUTHOR]

Objective. An elevated interstitial fluid pressure (IFP) can lead to strain-induced stiffening of poroelastic biological tissues. As shear wave elastography (SWE) measures functional tissue stiffness based on the propagation speed of acoustically induced shear waves, the shear wave velocity (SWV) can be used as an indirect measurement of the IFP. The underlying biomechanical principle for this stiffening behavior with pressurization is however not well understood, and we therefore studied how IFP affects SWV through SWE experiments and numerical modeling. Approach. For model set-up and verification, SWE experiments were performed while dynamically modulating IFP in a chicken breast. To identify the confounding factors of the SWV-IFP relationship, we manipulated the material model (linear poroelastic versus porohyperelastic), deformation assumptions (geometric linearity versus nonlinearity), and boundary conditions (constrained versus unconstrained) in a finite element model mimicking the SWE experiments. Main results. The experiments demonstrated a statistically significant positive correlation between the SWV and IFP. The model was able to reproduce a similar SWV-IFP relationship by considering an unconstrained porohyperelastic tissue. Material nonlinearity was identified as the primary factor contributing to this relationship, whereas geometric nonlinearity played a smaller role. The experiments also highlighted the importance of the dynamic nature of the pressurization procedure, as indicated by a different observed SWV-IFP for pressure buildup and relaxation, but its clinical relevance needs to be further investigated. Significance. The developed model provides an adaptable framework for SWE of poroelastic tissues and paves the way towards non-invasive measurements of IFP. [ABSTRACT FROM AUTHOR]

Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fcreceptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fcfusion protein (MDTCS-Fc). Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions ("accepted" parameter sets) to nonlinear least-squares problems. Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo. Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time. [ABSTRACT FROM AUTHOR]

Background: Breast cancer-related lymphedema (BCRL) is a potentially disabling and often irreversible consequence of breast cancer treatment, caused by the mechanical incompetence of the lymphatic system, resulting in reduced drainage capacity and functional overload due to an excessive volume of interstitial fluid surpassing the system's transport capacity in the arm. We wanted to determine the impact and explore the differences in independent risk factors for the occurrence of BCRL; incidence of BCRL over a five-year period at the Institute of Oncology Vojvodina in Sremska Kamenica and to answer the research question regarding the influence of the prehabilitation program on the overall incidence of BCRL during the observed five-year period. Methods: From 2014 to 2018, a retrospective study was conducted at the Institute of Oncology of Vojvodina in Sremska Kamenica, analyzing female patients who had undergone breast cancer surgery. Results: The study included 150 breast cancer patients who developed secondary lymphedema following surgery with the mean age of 59.2 ± 11.3 years. Fluctuations in hospitalization rates were observed over the five-year period, with the highest number of admissions in 2014 (24.0%) and a decline in 2018 (14.0%). The most common surgical procedure performed was left quadrantectomy (24.0%), followed by right quadrantectomy (20.0%) and left amputation (15.3%). The mean number of removed lymph nodes was 15.2 ± 6.1, with no statistically significant association between the number of removed lymph nodes and the manifestation of secondary lymphedema. The severity of secondary lymphedema varied based on patient age, with a higher incidence of moderate and severe lymphedema observed in patients aged 61 years and older. Patients who underwent radical surgery were more likely to experience severe lymphedema compared to those who had conservative surgery, although this difference was not statistically significant. Conclusion: In our study, the type of surgery, elapsed time since surgery, and the number of removed lymph nodes were not influencing factors for the occurrence of BCRL. However, concerning its severity, a greater number of systemic therapy modalities combined with radiotherapy were associated with a more frequent occurrence of mild and moderate BCRL. Also, the severity of BCRL varied among different age groups, with a higher incidence of moderate and severe lymphedema observed in patients aged 61 years and older. Ultimately, improving the quality of life for individuals affected by secondary lymphedema remains a crucial goal in the field of oncology. [ABSTRACT FROM AUTHOR]

Chronic overloading of the cartilage can lead to its irreversible destruction, as observed in people with osteoarthritis. The floating skeleton model previously introduced postulates that overloading begins and progresses when a joint is isolated from the hydrostatical connection with other joints. Such a connection occurs via the interstitial fluid in subperiosteal space and allows for pressure transmission between synovial capsules modulating intra-articular pressure. In the current study, a simple experiment was performed to model an obstruction in the subperiosteal hydrostatic pressure conductivity between joints to illustrate the effect of that obstruction on loads borne by the joint. When the obstruction was removed, the load experienced by the joint was reduced as it was redistributed throughout the model structure. The experiment demonstrated that contact pressures can be redistributed when the conditions of Pascal's Law are met. [ABSTRACT FROM AUTHOR]

Background: Oxidative/nitrosative stress in the oocyte microenvironment could have an impact on intracytoplasmic sperm injection (ICSI) outcomes. The presence of reactive oxygen species (ROS) and reactive nitrogen species (RNS) can stimulate the secretion of pro-inflammatory cytokines, leading to chronic inflammation and potentially affecting embryo as well as oocyte quality. This study aimed to examine the relationship of lipid peroxidation [measured by the malondialdehyde (MDA) assay] with protein carbonyl [measured by the 2,4 dinitrophenylhydrazine (DNPH) assay] levels in cumulus cells (CCs), as well as nitric oxide (NO), peroxynitrite (ONOO-), and C-reactive protein (CRP) levels in follicular fluid (FF). The potential relationship of these levels with ICSI outcome was also evaluated. Materials and Methods: In this prospective study, 63 FF samples and their corresponding CCs were collected for ICSI procedures. Spectrophotometry was used to assess levels of DNPH, MDA, NO, and ONOO-. CRP levels were evaluated using an immunoturbidimetric assay. Results: The patients under 37 years with normal ovarian reserve had significantly lower levels of MDA, DNPH, NO, ONOO-, and CRP compared to those over 37 years. Additionally, we observed higher levels of MDA, DNPH, NO, ONOO-, and CRP in the group with an oocyte maturity rate of less than 60%. No significant difference was observed between the DNPH levels and factors such as infertility duration, embryo quality, pregnancy, or the number of retrieved oocytes. A higher level of MDA, NO, ONOO-, and CRP was found to be significantly related to the lower number of retrieved oocytes, longer periods of infertility, poor embryo quality, and negative pregnancy outcomes. Conclusion: Oxidative/nitrosative stress, linking to inflammation in the oocyte microenvironment, can be considered as a potentially useful biomarker for assessing the development and competence of oocytes and embryos and predicting ICSI outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. Methods: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration–time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model. Results: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage. Conclusions: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens. [ABSTRACT FROM AUTHOR]

Background: Poor responders are those with poor ovarian reserve test, usually old age group however, there are some young patients with adequate ovarian reserve test are unexpectedly poorly responding to Controlled Ovarian Stimulation protocol ( COS) through In Vitro Fertilization (IVF) program. Follicular fluid and serum Prostaglandin D2 (PGD2) level has a role in ovarian function and response to COS protocol. Aim of study: To find whether follicular fluid and serum PGD2 level is a potential biomarker of ovarian reserve and a predictor of ovarian response to hyper stimulation and to show a possibility in developing a therapeutic factor for poor ovarian responders. Methods: The study included eighty infertile females less than 42 years old, their BMI less than 30 undergone Controlled Ovarian Stimulation (COS) protocol through IVF program. Forty of them with poor ovarian reserve (study group) defined according to ESHRE guidelines 2019; low Ati Mullerian hormones (AMH) and or low Antral Follicle Count (AFC), adding to them in my study Follicular Stimulating Hormone (FSH) level. Other forty with normal ovarian reserve test (control group). A third group extracted from control group, eight in number involving those with adequate ovarian reserve test and young age less than 35 years old, though showed unexpectedly poor response to COS protocol(total oocytes retrieved less than four). In our study we excluded women with endometriosis, immune disorder, endocrine disorders, women with endometriosis, women with polycystic ovarian syndrome and male factor infertility. We analysed PGD2 level using ELISA in both follicular fluid and patients serum on day of ovum pick up in both study group and control group, then we correlated the patients clinical parameters (age, BMI, ovarian reserve test),controlled ovarian stimulation / IVF program outcome (total oocytes retrieved, fertilisation rate and total embryos obtained) with follicular and serum PGD2 level. Finally we did comparison of all parameters mentioned above including follicular and serum PGD2 level among: (1) study group (poor ovarian reserve test) (2) new control group (normal ovarian reserve test and normal response with four oocytes retrieved and above) and (3) unexpected poorly responding group (normal ovarian reserve test, young less than 35 year and total oocytes retrieved less than four). Results: Showed significant lowered PGD2 level in both follicular fluid and patient's serum in study group (poor ovarian reserve group) in comparison with control group (normal reserve test). When we do the comparison among the three groups, the result showed significant lower follicular fluid PGD2 level, non-significant lower serum PGD2 level in unexpected poor responder group (age less than 35yr, normal ovarian reserve test, and poor response, less than four total oocytes retrieved) in comparison to group(normal ovarian reserve test and normal responder with equal or more than four total oocytes retrieved). There was no significant difference in follicular fluid and serum PGD2 level between study group (poor ovarian reserve test) and the unexpected poor responder group. Conclusion: We suggest that PGD2 is a potential biomarker to aid the tests of ovarian reserve and to enhance the diagnosis of poor ovarian response and this data may show the possibility of developing a therapeutic factor for poor ovarian responders by enhancing follicular function that can be used to establish new individualised COS protocol in women with poor ovarian response [ABSTRACT FROM AUTHOR]

Articular cartilage's remarkable low-friction properties are essential to joint function. In osteoarthritis (OA), cartilage degeneration (e.g. , proteoglycan loss and collagen damage) decreases tissue modulus and increases permeability. Although these changes impair lubrication in fully depressurized and slowly slid cartilage, new evidence suggests such relationships may not hold under biofidelic sliding conditions more representative of those encountered in vivo. Our recent studies using the convergent stationary contact area (cSCA) configuration demonstrate that articulation (i.e. , sliding) generates interfacial hydrodynamic pressures capable of replenishing cartilage interstitial fluid/pressure lost to compressive loading through a mechanism termed tribological rehydration. This fluid recovery sustains in vivo -like kinetic friction coefficients (µ k <0.02 in PBS and <0.005 in synovial fluid) with little sensitivity to mechanical properties in healthy tissue. However, the tribomechanical function of compromised cartilage under biofidelic sliding conditions remains unknown. Here, we investigated the effects of OA-like changes in cartilage mechanical properties, modeled via enzymatic digestion of mature bovine cartilage, on its tribomechanical function during cSCA sliding. We found no differences in sliding-driven tribological rehydration behaviors or µ k between naïve and digested cSCA cartilage (in PBS or synovial fluid). This suggests that OA-like cartilage retains sufficient functional properties to support naïve-like fluid recovery and lubrication under biofidelic sliding conditions. However, OA-like cartilage accumulated greater total tissue strains due to elevated strain accrual during initial load application. Together, these results suggest that elevated total tissue strains—as opposed to activity-mediated strains or friction-driven wear—might be the key biomechanical mediator of OA pathology in cartilage. Osteoarthritis (OA) decreases cartilage's modulus and increases its permeability. While these changes compromise frictional performance in benchtop testing under low fluid load support (FLS) conditions, whether such observations hold under sliding conditions that better represent the joints' dynamic FLS conditions in vivo is unclear. Here, we leveraged biofidelic benchtop sliding experiments—that is, those mimicking joints' native sliding environment—to examine how OA-like changes in mechanical properties effect cartilage's natural lubrication. We found no differences in sliding-mediated fluid recovery or kinetic friction behaviors between naïve and OA-like cartilage. However, OA-like cartilage experienced greater strain accumulation during load application, suggesting that elevated tissue strains (not friction-driven wear) may be the primary biomechanical mediator of OA pathology. [Display omitted] [ABSTRACT FROM AUTHOR]

When caring for people with venous leg ulceration, exudate management is commonly seen as one of the main challenges for clinicians. However, unfortunately, the reason for this wound-related symptom is often not identified or fully understood and therefore the clinical interventions necessary to address the problem are not implemented (Tickle, 2016). This results in people living with wounds that are failing to heal and producing a volume of exudate that has a significant impact on their quality of life (Cunha et al, 2017). Commonly, the words 'leaky legs' or 'wet legs' are documented in patient notes as the presenting problem -- this is not a clinical diagnosis; it is a symptom of an underlying condition which more than likely is venous disease. Unless this is recognised and treated correctly, those 'leaky legs' will continue to be a problem and potentially could have a devastating impact on the patient. It is therefore important to have a good understanding of venous disease as well as the role that exudate plays in wound healing, from initial wounding, through the stages of healing, and when (and why) it becomes a problem. [ABSTRACT FROM AUTHOR]

Sodium is the main osmotically active ion in the extracellular fluid and its concentration goes hand in hand with fluid volume. Under physiological conditions, homeostasis of sodium and thus amount of fluid is regulated by neural and humoral interconnection of body tissues and organs. Both heart and kidneys are crucial in maintaining volume status. Proper kidney function is necessary to excrete regulated amount of water and solutes and adequate heart function is inevitable to sustain renal perfusion pressure, oxygen supply etc. As these organs are bidirectionally interconnected, injury of one leads to dysfunction of another. This condition is known as cardiorenal syndrome. It is divided into five subtypes regarding timeframe and pathophysiology of the onset. Hemodynamic effects include congestion, decreased cardiac output, but also production of natriuretic peptides. Renal congestion and hypoperfusion leads to kidney injury and maladaptive activation of renin-angiotensin-aldosterone system and sympathetic nervous system. In cardiorenal syndromes sodium and water excretion is impaired leading to volume overload and far-reaching negative consequences, including higher morbidity and mortality of these patients. [ABSTRACT FROM AUTHOR]

Reverse iontophoresis (RI) technology has the advantages of wearable and painless in the field of continuous glucose monitoring. However, there are still challenges in optimizing the extraction throughput and consistency of RI. Here, we study an extraction and detection system based on microneedles, which integrates hollow microneedles and constant current adjustable circuits to achieve efficient RI extraction of glucose from interstitial fluid and improve the electrochemical performance of glucose sensor. High sensitivity and limit of detection were achieved in the same glucose sensor. The integrated device has the advantages of simple preparation, high sensitivity, high accuracy and electrical controllability, and has practical application potential in glucose sensing. [ABSTRACT FROM AUTHOR]

There are several ways in which viruses can spread at the cellular level within biological tissues. Some viruses can infect neighboring cells by binding to specific receptors on their surface while remaining suspended in the interstitial fluid between cells. In this study, we investigate a theoretical model based on graphs to understand viral contamination. This model is closely related to the well-known power dominating set problems in graphs. To be specific, we define a contaminating set of vertices in a graph G based on a predetermined system of vertex contamination. A set S of vertices is considered a contaminating set of G if, by following the contamination system starting with the affected vertices in S, all vertices in the graph can be contaminated. The contaminating number of a graph, denoted by c(G), is the minimum cardinality of a contaminating set for that graph. In this paper, our focus is on studying the contaminating number of n x m King graphs, which we represent as c(Pn x Pm). [ABSTRACT FROM AUTHOR]

Despite the crucial role of lymphangiogenesis during development and in several diseases with implications for tissue regeneration, immunity, and cancer, there are significantly fewer tools to understand this process relative to angiogenesis. While there has been a major surge in modeling angiogenesis with microphysiological systems, they have not been rigorously optimized or standardized to enable the recreation of the dynamics of lymphangiogenesis. Here, a Lymphangiogenesis‐Chip (L‐Chip) is engineered, within which new sprouts form and mature depending upon the imposition of interstitial flow, growth factor gradients, and pre‐conditioning of endothelial cells with growth factors. The L‐Chip reveals the independent and combinatorial effects of these mechanical and biochemical determinants of lymphangiogenesis, thus ultimately resulting in sprouts emerging from a parent vessel and maturing into tubular structures up to 1 mm in length within 4 days, exceeding prior art. Further, when the constitution of the pre‐conditioning cocktail and the growth factor cocktail used to initiate and promote lymphangiogenesis are dissected, it is found that endocan (ESM‐1) results in more dominant lymphangiogenesis relative to angiogenesis. Therefore, The L‐Chip provides a foundation for standardizing the microfluidics assays specific to lymphangiogenesis and for accelerating its basic and translational science at par with angiogenesis. [ABSTRACT FROM AUTHOR]

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity. Editor's summary: Immunotherapies targeting T cells are a promising approach to treating many cancer types, but their success is limited by the immunosuppressive nature of the tumor microenvironment (TME). Regulatory T cells (Treg) play a key role in immune suppression, but whether nutrient availability in the TME influences Treg differentiation is unclear. Ma et al. profiled metabolites in the tumor interstitial fluid of tumor-bearing mice and identified an enrichment of substrates for the sphingolipid synthesis pathway. The intermediate metabolite sphinganine was required for Treg differentiation and immune suppression by directly interacting with the transcription factor c-Fos, promoting the transcription of c-Fos target genes including Pdcd1. These findings demonstrate that nutrient availability in the TME influences Treg cell accumulation and immune suppression. —Hannah Isles [ABSTRACT FROM AUTHOR]

Point‐of‐care (POC) has the capacity to support low‐cost, accurate and real‐time actionable diagnostic data. Microneedle sensors have received considerable attention as an emerging technique to evolve blood‐based diagnostics owing to their direct and painless access to a rich source of biomarkers from interstitial fluid. This review systematically summarizes the recent innovations in microneedle sensors with a particular focus on their utility in POC diagnostics and personalized medicine. The integration of various sensing techniques, mostly electrochemical and optical sensing, has been established in diverse architectures of "lab‐on‐a‐microneedle" platforms. Microneedle sensors with tailored geometries, mechanical flexibility, and biocompatibility are constructed with a variety of materials and fabrication methods. Microneedles categorized into four types: metals, inorganics, polymers, and hydrogels, have been elaborated with state‐of‐the‐art bioengineering strategies for minimally invasive, continuous, and multiplexed sensing. Microneedle sensors have been employed to detect a wide range of biomarkers from electrolytes, metabolites, polysaccharides, nucleic acids, proteins to drugs. Insightful perspectives are outlined from biofluid, microneedles, biosensors, POC devices, and theragnostic instruments, which depict a bright future of the upcoming personalized and intelligent health management. [ABSTRACT FROM AUTHOR]

Background: It is well described that circulating progesterone (P4) plays a key role in several reproductive events such as oocyte maturation. However, during diestrus, when circulating P4 is at the highest concentrations, little is known about its local impact on the follicular cells such as intrafollicular P4 concentration due to corpus luteum (CL) presence within the same ovary. Based on that, our hypothesis is that the CL presence in the ovary during diestrus alters intrafollicular P4 concentrations, oocyte competence acquisition, follicular cells gene expression, and small extracellular vesicles (sEVs) miRNAs contents. Results: P4 hormonal analysis revealed that ipsilateral to the CL follicular fluid (iFF) presented higher P4 concentration compared to contralateral follicular fluid (cFF). Furthermore, oocyte maturation and miRNA biogenesis pathways transcripts (ADAMTS-1 and AGO2, respectively) were increased in cumulus and granulosa cells of iFF, respectively. Nevertheless, a RT-PCR screening of 382 miRNAs showed that three miRNAs were upregulated and two exclusively expressed in sEVs from iFF and are predicted to regulate cell communication pathways. Similarly, seven miRNAs were higher and two exclusively expressed from cFF sEVs and are predicted to modulate proliferation signaling pathways. Conclusion: In conclusion, intrafollicular P4 concentration is influenced by the presence of the CL and modulates biological processes related to follicular cell development and oocyte competence, which may influence the oocyte quality. Altogether, these results are crucial to improve our knowledge about the follicular microenvironment involved in oocyte competence acquisition. [ABSTRACT FROM AUTHOR]

The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed. [ABSTRACT FROM AUTHOR]

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy. [ABSTRACT FROM AUTHOR]

Microfluidic devices began to be used to facilitate sweat and interstitial fluid (ISF) sensing in the mid-2010s. Since then, numerous prototypes involving microfluidics have been developed in different form factors for sensing biomarkers found in these fluids under in vitro, ex vivo, and in vivo (on-body) settings. These devices transport and manipulate biofluids using microfluidic channels composed of silicone, polymer, paper, or fiber. Fluid flow transport and sample management can be achieved by controlling the flow rate, surface morphology of the channel, and rate of fluid evaporation. Although many devices have been developed for estimating sweat rate, electrolyte, and metabolite levels, only a handful have been able to proceed beyond laboratory testing and reach the stage of clinical trials and commercialization. To further this technology, this review reports on the utilization of microfluidics towards sweat and ISF management and transport. The review is distinguished from other recent reviews by focusing on microfluidic principles of sweat and ISF generation, transport, extraction, and management. Challenges and prospects are highlighted, with a discussion on how to transition such prototypes towards personalized healthcare monitoring systems. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this cross-sectional evaluation was to determine the associations between raw bioelectrical impedance and cardiometabolic health parameters in a sample of young non-Hispanic White and African American adults. Methods: A total of 96 (female: 52, male: 44) non-Hispanic White (n = 45) and African American adults (n = 51) between the ages of 19 and 37 yr (22.7 ± 3.83 yr) completed several fasted assessments including resting systolic blood pressure (rSBP), blood glucose (FBG), blood lipids, and bioelectrical impedance spectroscopy. Bioelectrical impedance spectroscopy–derived measurements included phase angle, bioimpedance index (BI), impedance ratio (IR), reactance index (XCi), fat-free mass (FFM), FFM index (FFMi), and absolute (a) and relative (%) total body water (TBW) and extracellular (ECF) and intracellular fluid (ICF). All bioelectric variables were collected at 50 kHz other than IR (250 kHz/5 kHz). Multiple regressions were conducted and adjusted for sex, age, and body mass index. Results: rSBP was positively, and HDL was inversely, associated with all bioelectrical impedance and absolute hydration variables (all P ≤ 0.050) other than XCi for rSBP and XCi and FFMi for HDL. rSBP (P < 0.001) was inversely, and HDL (P = 0.034) was positively, associated with IR. FBG was positively associated with BI, XCi, FFM, TBWa, and ECFa (all P < 0.050). Metabolic syndrome severity was positively associated with BI, FFM, TBWa, and ECFa for women (all P ≤ 0.050) and with ICFa for African American women (P = 0.016). Conclusions: Given the rapid increase in the prevalence of cardiometabolic health risks among young adults and the broad use of bioelectrical impedance in practice, the conflicting associations we observed in this age group suggest that bioelectrical impedance parameters should be used with caution in the context of cardiometabolic health risks and age. [ABSTRACT FROM AUTHOR]

The monitoring of acidosis and hypoxia is crucial because both factors promote cancer progression and impact the efficacy of anti-cancer treatments. A phosphonated tetrathiatriarylmethyl (pTAM) has been previously described to monitor both parameters simultaneously, but the sensitivity to tackle subtle changes in oxygenation was limited. Here, we describe an innovative approach combining the pTAM radical and lithium phthalocyanine (LiPc) crystals to provide sensitive simultaneous measurements of extracellular pH (pH e) and pO 2. Both parameters can be measured simultaneously as both EPR spectra do not overlap, with a gain in sensitivity to pO 2 variations by a factor of 10. This procedure was applied to characterize the impact of carbogen breathing in a breast cancer 4T1 model as a proof-of-concept. No significant change in pH e and pO 2 was observed using pTAM alone, while LiPc detected a significant increase in tumor oxygenation. Interestingly, we observed that pTAM systematically overestimated the pO 2 compared to LiPc. In addition, we analyzed the impact of an inhibitor (UK-5099) of the mitochondrial pyruvate carrier (MPC) on the tumor microenvironment. In vitro , the exposure of 4T1 cells to UK-5099 for 24 h induced a decrease in pH e and oxygen consumption rate (OCR). In vivo , a significant decrease in tumor pH e was observed in UK-5099-treated mice, while there was no change for mice treated with the vehicle. Despite the change observed in OCR, no significant change in tumor oxygenation was observed after the UK-5099 treatment. This approach is promising for assessing in vivo the effect of treatments targeting tumor metabolism. [Display omitted] • Acidosis and hypoxia are detrimental factors in cancer progression. • Innovative EPR procedure to measure extracellular pH and pO 2 simultaneously. • Using both LiPc with pTAM allows a gain in sensitivity to oxygen variations by a factor of 10. • Proof-of-concept studies using carbogen breathing and MPC inhibition. [ABSTRACT FROM AUTHOR]

Objective: To analyze effects of tectorigenin on improving cognitive deficits in rats with vascular dementia (VD) by regulating Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. Methods: A total of 72 rats were randomly divided into sham operation group, model group, low, medium and high doses [25, 50, 100 mg/(kg⋅d)] tectorigenin groups and positive control group [piracetam 324 mg/(kg⋅d], with 12 rats in each group. Except for sham operation group, VD models were replicated in other groups. After successful modeling, different doses tectorigenin groups and positive control group were administered intragastrically with different doses of tectorigenin and piracetam, while other groups were administered intragastrically with same volume of normal saline for 28 d. Spatial learning and memory ability were detected by Morris water maze. Neurotransmitter levels in hippocampus interstitial fluid were detected by high performance liquid chromatography-electro-chemical. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor b (TrkB) expressions in hippocampus were detected by RT-qPCR and Western blot. TLR4/MyD88/NF-κB pathway-related proteins in hippocampus were detected by Western blot. Results: Compared with sham operation group, escape latency was longer, while stay time in target area and times of crossing platform were lower in model group (P<0.05). Compared with model group, escape latency was shorter, while stay time in target area and times of crossing platform were higher in medium and high doses tectorigenin groups (P<0.05). NE, DA, 5-HT and 5-HIAA levels in model group were lower than those in sham operation group (P<0.05), which were higher in medium and high doses tectorigenin groups than model group (P<0.05). Compared with sham operation group, BDNF and TrkB mRNA and proteins levels were lower, while TLR4, MyD88 and p-NF-κB p65/NF-κB p65 proteins levels were higher in model group (P<0.05). Compared with model group, BDNF and TrkB mRNA and proteins levels were higher, while TLR4, MyD88 and p-NF-κB p65/NF-κB p65 proteins levels were lower in medium and high doses tectorigenin groups (P<0.05). Conclusion:Tectorigenin can improve cognitive deficits in VD rats, which may be related to regulating TLR4/MyD88/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

The bone lacunar-canalicular system (LCS) is a unique complex 3D microscopic tubular network structure within the osteon that contains interstitial fluid flow to ensure the efficient transport of signaling molecules, nutrients, and wastes to guarantee the normal physiological activities of bone tissue. The mass transfer laws in the LCS under microgravity and hypergravity are still unclear. In this paper, a multi-scale 3D osteon model was established to mimic the cortical osteon, and a finite element method was used to numerically analyze the mass transfer in the LCS under hypergravity, normal gravity and microgravity and combined with high-intensity exercise conditions. It was shown that hypergravity promoted mass transfer in the LCS to the deep lacunae, and the number of particles in lacunae increased more significantly from normal gravity to hypergravity the further away from the Haversian canal. The microgravity environment inhibited particles transport in the LCS to deep lacunae. Under normal gravity and microgravity, the number of particles in lacunae increased greatly when doing high-intensity exercise compared to stationary standing. This paper presents the first simulation of mass transfer within the LCS with different gravity fields combined with high-intensity exercise using the finite element method. The research suggested that hypergravity can greatly promote mass transfer in the LCS to deep lacunae, and microgravity strongly inhibited this mass transfer; high-intensity exercise increased the mass transfer rate in the LCS. This study provided a new strategy to combat and treat microgravity-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Microcirculatory variations have been observed in the normal-appearing white matter (NAWM) of individuals affected by cerebral small vessel disease (CSVD). These variations collectively possess the potential to trigger neuroinflammation and edema, ultimately leading to an elevation in extracellular fluid (ECF). Nevertheless, the specific alterations in ECF within the NAWM of CSVD patients have remained inadequately understood. Methods: We reviewed the clinical and imaging characteristics of a cohort comprising 129 patients diagnosed with CSVD to investigate alterations in the ECF within NAWM. The severity of CSVD was assessed by total CSVD magnetic resonance (MR) score according to the four imaging markers, namely perivascular space, lacunar infarction, white matter hyperintensities and cerebral microbleed. ECF was evaluated by the parameter free water (FW), ranging from 0 to 1 generated from diffusion tensor imaging. Results: Significant differences in NAWM FW were observed in relation to the total CSVD MR score (p < 0.05). Patients with a total CSVD MR score of 0 exhibited significantly lower NAWM free water (FW) values compared to those with a score greater than 0 (p < 0.05). Similarly, patients with a total CSVD MR score of 1 also demonstrated notably lower NAWM FW values than those with a score greater than 1 (p < 0.05). After conducting multivariate regression analysis, age and total CSVD MR score was independently associated with FW in NAWM (p < 0.001). Further, the total CSVD MR score served as a partial mediator in the relationship between age and FW in the NAWM among patients with CSVD. Conclusions: ECF in NAWM is increased in CSVD patients, even during the early course of CSVD. [ABSTRACT FROM AUTHOR]