Peptidoglycan-Targeted [18F]3,3,3-Trifluoro-d-alanine Tracer for Imaging Bacterial Infection.

Imaging is increasingly used to detect and monitor bacterial infection. Both anatomic (X-rays, computed tomography, ultrasound, and MRI) and nuclear medicine ([111In]-WBC SPECT, [18F]FDG PET) techniques are used in clinical practice but lack specificity for the causative microorganisms themselves. To meet this challenge, many groups have developed imaging methods that target pathogen-specific metabolism, including PET tracers integrated into the bacterial cell wall. We have previously reported the d-amino acid derived PET radiotracers d-methyl-[11C]-methionine, d-[3-11C]-alanine, and d-[3-11C]-alanine-d-alanine, which showed robust bacterial accumulation in vitro and in vivo. Given the clinical importance of radionuclide half-life, in the current study, we developed [18F]3,3,3-trifluoro-d-alanine (d-[18F]-CF3-ala), a fluorine-18 labeled tracer. We tested the hypothesis that d-[18F]-CF3-ala would be incorporated into bacterial peptidoglycan given its structural similarity to d-alanine itself. NMR analysis showed that the fluorine-19 parent amino acid d-[19F]-CF3-ala was stable in human and mouse serum. d-[19F]-CF3-ala was also a poor substrate for d-amino acid oxidase, the enzyme largely responsible for mammalian d-amino acid metabolism and a likely contributor to background signals using d-amino acid derived PET tracers. In addition, d-[19F]-CF3-ala showed robust incorporation into Escherichia coli peptidoglycan, as detected by HPLC/mass spectrometry. Based on these promising results, we developed a radiosynthesis of d-[18F]-CF3-ala via displacement of a bromo-precursor with [18F]fluoride followed by chiral stationary phase HPLC. Unexpectedly, the accumulation of d-[18F]-CF3-ala by bacteria in vitro was highest for Gram-negative pathogens in particular E. coli. In a murine model of acute bacterial infection, d-[18F]-CF3-ala could distinguish live from heat-killed E. coli, with low background signals. These results indicate the viability of [18F]-modified d-amino acids for infection imaging and indicate that improved specificity for bacterial metabolism can improve tracer performance.

Performance of the BD MAX MDR-TB assay in a clinical setting and its impact on the clinical course of patients with pulmonary tuberculosis: a retrospective before-after study.

Background: Missing isoniazid (INH) resistance during tuberculosis (TB) diagnosis can worsen the outcomes of INH-resistant TB. The BD MAX MDR-TB assay (BD MAX) facilitates the rapid detection of TB and INH and rifampin (RIF) resistance; however, data related to its performance in clinical setting remain limited. Moreover, its effect on treatment outcomes has not yet been studied. Methods: We compared the performance of BD MAX for the detection of INH/RIF resistances to that of the line probe assay (LPA) in patients with pulmonary TB (PTB), using the results of a phenotypic drug sensitivity test as a reference standard. The treatment outcomes of patients who used BD MAX were compared with those of patients who did not. Results: Of the 83 patients included in the study, the BD MAX was used for an initial PTB diagnosis in 39 patients. The sensitivity of BD MAX for detecting PTB was 79.5%. The sensitivity and specificity of BD MAX for INH resistance were both 100%, whereas these were 50.0% and 95.8%, respectively, for RIF resistance. The sensitivity and specificity of BD MAX were comparable to those of LPA. The BD MAX group had a shorter time interval from specimen request to the initiation of anti-TB drugs (2.0 days vs. 5.5 days, p=0.001). Conclusion: BD MAX showed comparable performance to conventional tests for detecting PTB and INH/RIF resistances. The implementation of BD MAX as a diagnostic tool for PTB resulted in a shorter turnaround time for the initiation of PTB treatment.

Angiogenesis and Apoptosis: Data Comparison of Similar Microenvironments in the Corpus Luteum and Tumors.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in animal reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in terms of the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities between the apoptotic-regulated signaling pathways involved in apoptosis in the corpus luteum and tumors. However, the regulation of apoptosis in both can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis.

Deep learning framework for bovine iris segmentation.

Iris segmentation is an initial step for identifying the biometrics of animals when establishing a traceability system for livestock. In this study, we propose a deep learning framework for pixel-wise segmentation of bovine iris with a minimized use of annotation labels utilizing the BovineAAEyes80 public dataset. The proposed image segmentation framework encompasses data collection, data preparation, data augmentation selection, training of 15 deep neural network (DNN) models with varying encoder backbones and segmentation decoder DNNs, and evaluation of the models using multiple metrics and graphical segmentation results. This framework aims to provide comprehensive and in-depth information on each model's training and testing outcomes to optimize bovine iris segmentation performance. In the experiment, U-Net with a VGG16 backbone was identified as the optimal combination of encoder and decoder models for the dataset, achieving an accuracy and dice coefficient score of 99.50% and 98.35%, respectively. Notably, the selected model accurately segmented even corrupted images without proper annotation data. This study contributes to the advancement of iris segmentation and the establishment of a reliable DNN training framework.

Blood vessel organoids generated by base editing and harboring single nucleotide variation in Notch3 effectively recapitulate CADASIL-related pathogenesis.

Human blood vessel organoids (hBVOs) offer a promising platform for investigating vascular diseases and identifying therapeutic targets. In this study, we focused on in vitro modeling and therapeutic target finding of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary stroke disorder caused by mutations in the NOTCH3 gene. Despite the identification of these mutations, the underlying pathological mechanism is elusive, and effective therapeutic approaches are lacking. CADASIL primarily affects the blood vessels in the brain, leading to ischemic strokes, migraines, and dementia. By employing CRISPR/Cas9 base-editing technology, we generated human induced pluripotent stem cells (hiPSCs) carrying Notch3 mutations. These mutant hiPSCs were differentiated into hBVOs. The NOTCH3 mutated hBVOs exhibited CADASIL-like pathology, characterized by a reduced vessel diameter and degeneration of mural cells. Furthermore, we observed an accumulation of Notch3 extracellular domain (Notch3ECD), increased apoptosis, and cytoskeletal alterations in the NOTCH3 mutant hBVOs. Notably, treatment with ROCK inhibitors partially restored the disconnection between endothelial cells and mural cells in the mutant hBVOs. These findings shed light on the pathogenesis of CADASIL and highlight the potential of hBVOs for studying and developing therapeutic interventions for this debilitating human vascular disorder.

Bioorthogonal Radiolabeling of Azide-Modified Bacteria Using [18F]FB-sulfo-DBCO.

Purpose: This study was motivated by the need for better positron emission tomography (PET)-compatible tools to image bacterial infection. Our previous efforts have targeted bacteria-specific metabolism via assimilation of carbon-11 labeled d-amino acids into the bacterial cell wall. Since the chemical determinants of this incorporation are not fully understood, we sought a high-throughput method to label d-amino acid derived structures with fluorine-18. Our strategy employed a chemical biology approach, whereby an azide (-N3) bearing d-amino acid is incorporated into peptidoglycan muropeptides, with subsequent "click" cycloaddition with an 18F-labeled strained cyclooctyne partner. Procedures: A water-soluble, 18F-labeled and dibenzocyclooctyne (DBCO)-derived radiotracer ([18F]FB-sulfo-DBCO) was synthesized. This tracer was incubated with pathogenic bacteria treated with azide-bearing d-amino acids, and incorporated 18F was determined via gamma counting. In vitro uptake in bacteria previously treated with azide-modified d-amino acids was compared to that in cultures treated with amino acid controls. The biodistribution of [18F]FB-sulfo-DBCO was studied in a cohort of healthy mice with implications for future in vivo imaging. Results: The new strain-promoted azide-alkyne cycloaddition (SPAAC) radiotracer [18F]FB-sulfo-DBCO was synthesized with high radiochemical yield and purity via N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB). Accumulation of [18F]FB-sulfo-DBCO was significantly higher in several bacteria treated with azide-modified d-amino acids than in controls; for example, we observed 7 times greater [18F]FB-sulfo-DBCO ligation in Staphylococcus aureus cultures incubated with 3-azido-d-alanine versus those incubated with d-alanine. Conclusions: The SPAAC radiotracer [18F]FB-sulfo-DBCO was validated in vitro via metabolic labeling of azide-bearing peptidoglycan muropeptides. d-Amino acid-derived PET radiotracers may be more efficiently screened via [18F]FB-sulfo-DBCO modification.

Exploring the role of loop tunnels in enhancing termite food transport efficiency: A simulation approach.

Subterranean termites construct a network of tunnels beneath the ground, comprising a main tunnel and branch tunnels. While termites do not construct tunnels that turn back in a "U" shape, the intersection of main and branch tunnels often forms closed curved structures (a loop). The loop structure can have either a positive or negative effect on the transport efficiency of termites in food transportation. However, little research has been conducted on the impact of loop tunnels on transport efficiency (E) due to the technical difficulties associated with direct observation. In this study, we used an individual-based model to simulate termite behavior during food transportation within a tunnel composed of a main tunnel and a loop tunnel. The model incorporates four control variables: the number of introduced simulated termites (k1), the probability of a simulated termite using a loop tunnel when walking towards a food or nest site (k2 or k3), and the length of the loop tunnel (k4). The simulation results reveal that the E value is high for (k2, k3) = (high, high), (low, low), (high, low), and (low, high) when the length of the loop tunnel is relatively short. However, when the length of the loop tunnel is relatively long, E is high only for (k2, k3) = (high, low) and (low, high). We found that these results are primarily influenced by the frequency of traffic jams. Therefore, termites would benefit from adopting strategies that reduce the occurrence of traffic jams during food transportation. In the Discussion section, we briefly touch on the strategy from an ecological perspective.

Elucidation of critical chemical moieties of metallo-ß-lactamase inhibitors and prioritisation of target metallo-ß-lactamases.

The urgent demand for effective countermeasures against metallo-ß-lactamases (MBLs) necessitates development of novel metallo-ß-lactamase inhibitors (MBLIs). This study is dedicated to identifying critical chemical moieties within previously developed MBLIs, and critical MBLs should serve as the target in MBLI evaluations. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic literature analysis was conducted, and the NCBI RefSeq genome database was exploited to access the abundance profile and taxonomic distribution of MBLs and their variant types. Through the implementation of two distinct systematic approaches, we elucidated critical chemical moieties of MBLIs, providing pivotal information for rational drug design. We also prioritised MBLs and their variant types, highlighting the imperative need for comprehensive testing to ensure the potency and efficacy of the newly developed MBLIs. This approach contributes valuable information to advance the field of antimicrobial drug discovery.

Podocyte disease following treatment with intravenous ibandronate in an older patient.

Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.

A novel histologic description of the fibrous networks in the lid-cheek junction and infraorbital region.

The aim of this study was to identify the anatomical feature of retaining ligament and fat compartment on the lower eyelid and infraorbital region using a histological method, and to investigate clear definitions for them which could be used generally in the clinical area. Eighteen specimens from eight fresh Korean cadavers were stained with Masson trichrome or hematoxylin and eosin. The ligamentous and fascial fibrous tissue were clearly identified. The ligamentous fibrous tissue which traversed in the superficial and deep fat layer was skin ligament and orbicularis retaining ligament (ORL). The fascial fibrous tissue enclosed the orbicularis oculi muscle (OOc) and circumferencial adipose tissue. Based on the ligamentous and fascial structure, three fat compartments, septal, suborbicularis oculi and infraorbital fat compartment, could be identified. The OOc attached to orbital rim and dermis by ORL and skin ligament, and the muscle fascicle and fat fascicle provided the connection point to the ORL and skin ligament as enclosing all muscle and fat tissue. The combination of the force made by the skin ligament in the lower eyelid and ORL may decide the level and form of the infraorbital grooves.

A novel description of the supporting system of the orbicularis oculi muscle in the infraorbital area: Tear trough muscle fiber.

BACKGROUND: The aim of this study was to elucidate the anatomical structures of supporting system of the infraorbital area. MATERIALS AND METHODS: Forty-four hemifaces from eleven Korean and eleven Thai cadavers were used to dissect the infraorbital area. Based on the dissection and previous histologic results, they were analyzed. RESULTS: The orbicularis oculi muscle (OOc) had two portions (palpebral and orbital portion) and four subparts (pretarsal, preseptal, prezygomatic, and premaxillary part). The elliptical muscle fiber of OOc was supported by circumferential connective tissue including skin ligament, orbicularis retaining ligament, zygomatic ligament, and zygomatic cutaneous ligament. The vertical muscle fiber, the tear trough muscle fiber, and medial muscular band directly attached to the skin. CONCLUSION: Full of subcutaneous tissue in the tear trough groove, strong attachment to the bone by tear trough ligament and to the skin by tear trough muscle fiber would multiply result in the tear trough on the face.

Beta-lapachone ameliorates the progression of primary sclerosing cholangitis pathogenesis in rodent models.

AIMS: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and severe fibrosis for which effective treatment options are currently lacking. In this study, we explored the potential of beta-lapachone (ßL) as a drug candidate for PSC therapy. MATERIALS AND METHODS: We employed an animal model fed a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to assess the preventive and therapeutic effects of ßL. The beneficial effects of ßL on PSC pathogenic characteristics, including blood biomarkers, inflammation, and fibrosis, were determined by assessing relevant parameters. Differential gene expression between each group was analyzed by RNA sequencing of liver tissues. Mdr2-/- mice were utilized to explore the involvement of Abcb4 in the ßL-induced improvement of PSC pathogenesis. KEY FINDINGS: ßL effectively inhibited key features of PSC pathogenesis, as demonstrated by reduced blood biomarkers and improved pathogenic characteristics. Treatment with ßL significantly mitigated DDC-induced apoptosis, cell proliferation, inflammation, and fibrosis. Analysis of differential gene expression confirmed a new insight that ßL could stimulate the expression of genes related to NAD synthesis and Abcb4. Indeed, ßL-induced NAD exhibited effective functioning, as evidenced by enhanced sirt1/3 and acetyl-lysine levels, leading to improved mitochondrial stability. The role of Abcb4 in response to ßL was confirmed in Mdr2/Abcb4 KO mice, where the beneficial effects of ßL were abolished. SIGNIFICANCE: This study provided a new concept for PSC treatment, suggesting that pharmacological stimulation of the NAD synthetic pathway and Abcb4 via ßL ameliorates PSC pathogenesis.

Radiosynthesis and whole-body distribution in mice of a 18 F-labeled azepino[4,3-b]indole-1-one derivative with multimodal activity for the treatment of Alzheimer's disease.

Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent as BChE inhibitors (half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance, threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18 F-labeled congener 2a was synthesized, by applying the aromatic 18 F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positron emission tomography imaging. [18 F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g-1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood-brain barrier crossing. After a transient liver accumulation of [18 F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.

Chrysanthemum coronarium L. Extract Attenuates Homocysteine-Induced Vascular Inflammation in Vascular Smooth Muscle Cells.

Hyperhomocysteinemia is a main risk factor for phenotypic modulation of vascular smooth muscle cells (VSMCs) and atherosclerosis. Phenotypic switching and proliferation of VSMCs are related to the progression of vascular inflammation. Chrysanthemum coronarium L. is a leafy vegetable with various biological functions, such as antioxidative, anti-inflammatory, and antiproliferative effects. In this study, we aimed to identify the mechanisms underlying the therapeutic and preventive effects of C. coronarium L. extract (CC) in regulating homocysteine (Hcy)-induced vascular inflammation in human aortic VSMCs. CC did not exhibit cytotoxicity and inhibited Hcy-stimulated VSMC proliferation and migration. In addition, CC promoted Hcy-induced expression of VSMC contractile phenotype proteins, including alpha-smooth muscle actin, calponin, and smooth muscle 22α. CC also decreased Hcy-induced accumulation of reactive oxygen species and expression of inflammatory markers nicotinamide adenine dinucleotide phosphate oxidase-4 and soluble epoxide hydrolase. These results showed that CC attenuates Hcy-induced inflammatory responses, highlighting its potential as a therapeutic or preventive target for Hcy-induced vascular inflammation.

Imaging the Bacterial Cell Wall Using N-Acetyl Muramic Acid-Derived Positron Emission Tomography Radiotracers.

Imaging infections in patients is challenging using conventional methods, motivating the development of positron emission tomography (PET) radiotracers targeting bacteria-specific metabolic pathways. Numerous techniques have focused on the bacterial cell wall, although peptidoglycan-targeted PET tracers have been generally limited to the short-lived carbon-11 radioisotope (t1/2 = 20.4 min). In this article, we developed and tested new tools for infection imaging using an amino sugar component of peptidoglycan, namely, derivatives of N-acetyl muramic acid (NAM) labeled with the longer-lived fluorine-18 (t1/2 = 109.6 min) radioisotope. Muramic acid was reacted directly with 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP) to afford the enantiomeric NAM derivatives (S)-[18F]FMA and (R)-[18F]FMA. Both diastereomers were easily isolated and showed robust accumulation by human pathogens in vitro and in vivo, including Staphylococcus aureus. These results form the basis for future clinical studies using fluorine-18-labeled NAM-derived PET radiotracers.

Hermetia illucens Fermented with Lactobacillus plantarum KCCM12757P Alleviates Dextran Sodium Sulfate-Induced Colitis in Mice.

Inflammatory bowel disease (IBD) can severely affect humans and animals and is difficult to treat. Black soldier fly (Hermetia illucens; Hi) larvae (BSFL) are a sustainable source of protein. However, no studies exist on the antioxidant and anti-inflammatory functions of BSFL or fermented BSFL with respect to IBD. In this study, riboflavin-producing Lactobacillus plantarum KCCM12757P was isolated from a fish farm tank, and in conjunction with hot water-extracted Hi (HeHi) (termed HeHi_Lp), was used to determine optimal fermentation conditions to increase vitamin B2 concentration. This in vivo study investigated the therapeutic effects and mechanistic role of HeHi_Lp in chronic colitis-induced murine models. Histological changes, inflammatory cytokine levels, and intestinal barrier function were explored. Gut microbial communities and gene expression in the nuclear factor (NF)-κB signaling pathway were also studied. HeHi_Lp remarkably reduced the disease activity index, inflammatory cytokine (inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, interleukin (IL-6 and IL-1ß) levels, and increased body weight and colon length. HeHi_Lp administration significantly raised zonula occludens 1, occludin and claudin 1 and improved the composition of the gut microbiota and beneficial intestinal bacteria. These results suggest that HeHi_Lp can be used as a dietary supplement in pet food to alleviate colitis.

Prioritization of Critical Factors for Surveillance of the Dissemination of Antibiotic Resistance in Pseudomonas aeruginosa: A Systematic Review.

Pseudomonas aeruginosa is the primary opportunistic human pathogen responsible for a range of acute and chronic infections; it poses a significant threat to immunocompromised patients and is the leading cause of morbidity and mortality for nosocomial infections. Its high resistance to a diverse array of antimicrobial agents presents an urgent health concern. Among the mechanisms contributing to resistance in P. aeruginosa, the horizontal acquisition of antibiotic resistance genes (ARGs) via mobile genetic elements (MGEs) has gained recognition as a substantial concern in clinical settings, thus indicating that a comprehensive understanding of ARG dissemination within the species is strongly required for surveillance. Here, two approaches, including a systematic literature analysis and a genome database survey, were employed to gain insights into ARG dissemination. The genome database enabled scrutinizing of all the available sequence information and various attributes of P. aeruginosa isolates, thus providing an extensive understanding of ARG dissemination within the species. By integrating both approaches, with a primary focus on the genome database survey, mobile ARGs that were linked or correlated with MGEs, important sequence types (STs) carrying diverse ARGs, and MGEs responsible for ARG dissemination were identified as critical factors requiring strict surveillance. Although human isolates play a primary role in dissemination, the importance of animal and environmental isolates has also been suggested. In this study, 25 critical mobile ARGs, 45 critical STs, and associated MGEs involved in ARG dissemination within the species, are suggested as critical factors. Surveillance and management of these prioritized factors across the One Health sectors are essential to mitigate the emergence of multidrug-resistant (MDR) and extensively resistant (XDR) P. aeruginosa in clinical settings.

Deep Learning-Based Precision Analysis for Acrosome Reaction by Modification of Plasma Membrane in Boar Sperm.

The analysis of AR is widely used to detect loss of acrosome in sperm, but the subjective decisions of experts affect the accuracy of the examination. Therefore, we develop an ARCS for objectivity and consistency of analysis using convolutional neural networks (CNNs) trained with various magnification images. Our models were trained on 215 microscopic images at 400× and 438 images at 1000× magnification using the ResNet 50 and Inception-ResNet v2 architectures. These models distinctly recognized micro-changes in the PM of AR sperms. Moreover, the Inception-ResNet v2-based ARCS achieved a mean average precision of over 97%. Our system's calculation of the AR ratio on the test dataset produced results similar to the work of the three experts and could do so more quickly. Our model streamlines sperm detection and AR status determination using a CNN-based approach, replacing laborious tasks and expert assessments. The ARCS offers consistent AR sperm detection, reduced human error, and decreased working time. In conclusion, our study suggests the feasibility and benefits of using a sperm diagnosis artificial intelligence assistance system in routine practice scenarios.

Inhibition of pyruvate dehydrogenase kinase 4 ameliorates kidney ischemia-reperfusion injury by reducing succinate accumulation during ischemia and preserving mitochondrial function during reperfusion.

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.

Exploring the effects of high curvature section distribution and density in termite tunnels on food transport efficiency: A simulation study.

This study explores the food transport efficiency of termite using an individual-based model. Termites are believed to have evolved tunneling patterns that optimize food search and transport efficiency. However, few studies have investigated transport efficiency due to the difficulty of field observations. The model is characterized by four control variables: the number of simulated termites participating in transport (k1), the distribution of high curvature sections of the termite tunnel (k2), a quantity related to the density of the tunnel sections (k3), and the duration of traffic jams (k4). As k3 increases, the total length of the high curvature section decreases. Our simulation results show that the E(k1, k2) maps for k3 and k4 contain two modes: Mode A shows that E decreases with increasing k1 due to an increase in traffic jams, while Mode B shows E increasing with increasing k1 due to a decrease in the density of curved sections and an increase in jamming resolution time. The partial rank correlation coefficient analysis reveals that k1 and k2 have a negative effect on E, while k3 and k4 have a positive effect, with k1 having the greatest influence on E, followed by k3, k4, and k2. The ecological implications of the simulation results are briefly described, and the limitations of the model are discussed.