Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions.

BACKGROUND: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown. METHODS: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS: Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aß) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. CONCLUSIONS: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA. HIGHLIGHTS: Long-term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD-specific pathophysiological pathways.

RecQ dysfunction contributes to social and depressive-like behavior and affects aldolase activity in mice.

RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.

Distribution and transformation of organophosphate esters in moving bed biofilm reactor.

A moving bed biofilm reactor (MBBR) process in wastewater treatment plants (WWTPs) uses plastic carriers, called biofilm carrier, to increase their treatment efficiency. Biofilm carrier is made up of plastic, containing the OPEs as flame retardants or plasticizers, so OPEs in biofilm carrier are possible to release from WWTPs to the river. This study investigated the effect of the MBBR process in WWTP on aquatic environments, focusing on OPEs. OPE eluted from the biofilm carrier by leaching test was tris(2-chloroethyl) phosphate (TCEP), and the concentration of the effluent compared to the influent was increased in the WWTP of the MBBR process. 3609 mg/day of TCEP would be discharged into the water using the second-order model with rate constant [Formula: see text] = 0.000451 (ng L-1)-1 h-1, which is the most suitable for the leaching concentration of TCEP. It was identified that TCEP in biofilm carrier was transformed into oxidative dechlorinated compounds and oxidative compounds by microorganisms in the bioreactor. As a result of the study, it was confirmed that not only TCEP but also transformation products of TCEP emitted into the water from the MBBR process of WWTP.

Dynamic Transformation of a Ag+-Coordinated Supramolecular Nanostructure from a 1D Needle to a 1D Helical Tube via a 2D Ribbon Accompanying the Conversion of Complex Structures.

We report a unique dynamic morphology transformation of a Ag+-coordinated supramolecular nanostructure accompanying the conversion of complex structures in aqueous solution. In the presence of AgNO3 (1.0 equiv), the achiral bipyridine-based ligand 1G, possessing hydrazine and glycine moieties, preferentially generated a 1D needle-like structure (nanostructure I) based on the 1GAgNO3 complex (1G:Ag+ = 1:1) as a metastable product. Nanostructure I was then transformed into nanostructure II, which was composed of the 1G3Ag2(NO3)2 complex (1G:Ag+ = 3:2) as the thermodynamically stable product. This nanostructure exhibited a 1D helical tubular structure with a uniform diameter via a 2D ribbon as an intermediator, which led to the generation of a circular dichroism (CD) signal with right-handed (P-type) helicity. The observed dynamic transformation was attributed to formation of the thermodynamically favored helical 1G3Ag2(NO3)2 complex. In addition, the helical 1G3Ag2(NO3)2 complex acted as an initiator in the transformation from the 1D needle-like structure to the 1D helical tube via a 2D ribbon. The enhanced ΔG° value of nanostructure II compared to that of nanostructure I confirmed that nanostructure II is thermodynamically stable. More importantly, the transformation of supramolecular nanostructure I to nanostructure II occurred via an "on" pathway, even though the 1GAgNO3 complex was converted to the 1G3Ag2(NO3)2 complex, which did not involve dissociation from nanostructure I into the monomeric 1GAgNO3 complex species. In the kinetic study, the NO3- anion was found to act as an accelerator for the dynamic transformation from nanostructure I to nanostructure II. This result provides the first example of a dynamic transformation of a 1D needle-like structure into a 1D tubular structure via a 2D ribbon structure, accompanied by the conversion of a complex structure and the generation of a large CD signal for the metallo-supramolecular nanostructure. This study may open up new avenues to the understanding of a dynamic morphology transformation process in biological systems.

Dynamic one-shot target detection and classification using a pseudo-Siamese network and its application to Raman spectroscopy.

Target detection and classification by Raman spectroscopy are important techniques for biological and chemical defense in military operations. Conventionally, these techniques preprocess the observed spectra using smoothing or baseline correction and apply detection algorithms like the generalized likelihood ratio test, independent component analysis, nonnegative matrix factorization, etc. These conventional detection algorithms need preprocessing and multiple shots of Raman spectra to get a reasonable accuracy. Recently, techniques based on deep learning are being used for target detection and classification due to its great adaptability and high accuracy over other methods and due to no requirement for preprocessing. Deep learning may give a good performance, but need retraining when untrained class targets are introduced which is time-consuming and bothersome. We devise a novel algorithm using a variant of the pseudo-Siamese network, one of the deep learning algorithms, that does not need retraining to detect and classify untrained class targets. Our algorithm detects and classifies targets with only one shot. In addition, our algorithm does not need preprocessing. We verify our algorithm with Raman spectra measured using a Raman spectrometer.

Chemoradiotherapy with hyperthermia versus chemoradiotherapy alone in locally advanced cervical cancer: a systematic review and meta-analysis.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is recommended as the standard treatment for locally advanced cervical cancer (LACC). However, the synergistic effect of hyperthermia (HT) with CCRT remains unclear. Therefore, we performed a meta-analysis to evaluate the effect of HT with CCRT on LACC patients. METHODS AND MATERIALS: A systematic literature search was conducted on the MEDLINE, PubMed, Embase, Cochrane library and SCOPUS databases for articles that compared CCRT with HT and CCRT alone as treatments for LACC. Hazard ratios (HRs) and risk ratios (RRs) were used to compare five-year overall survival (OS), local relapse-free survival (LRFS) and incidence of acute and chronic toxicity between the two treatments. RESULTS: Two articles out of 2860 were finally selected for analysis. A total of 536 patients were evaluated (CCRT with HT group: 268, CCRT group: 268). FIGO stages I-II and III-IV were found in 295 (55.0%) and 241 patients (45.0%), respectively. The CCRT with HT group had significantly better five-year OS than the CCRT group (HR 0.67, 95% confidence interval [CI] 0.47-0.96, p = 0.03). LRFS of patients was superior in the CCRT with HT group than in the CCRT group, but without significance (HR 0.74, 95% CI 0.49-1.12; p = 0.16). Moreover, there was no difference between the two groups regarding acute and chronic toxicity. CONCLUSION: This systematic review and meta-analysis showed that CCRT with HT significantly improved OS in LACC patients without increasing acute and chronic toxicity. Therefore, tri-modality treatment could be a feasible approach for patients with LACC.

Bispicolyamine-Based Supramolecular Polymeric Gels Induced by Distinct Different Driving Forces with and Without Zn2.

Metal-coordination polymeric gels are interesting areas as organic/inorganic hybrid supramolecular materials. The bispicolylamine (BPA) based gelator (1) showed excellent gelation with typical fibrillar morphology in acetonitrile. Upon complexing 1 with Zn2+, complexes ([1 + Zn + ACN]2+ and [1 + zinc trifluoromethanesulfonate (ZnOTf)]+) with four coordination numbers were formed, which determine the gel structure significantly. A gel-sol transition was induced, driven by the ratio of the two metal complexes produced. Through nuclear magnetic resonance analysis, the driving forces in the gel formation (i.e., hydrogen-bonding and π-π stacking) were observed in detail. In the absence and the presence of Zn2+, the intermolecular hydrogen-bonds and π-π stacking were the primary driving forces in the gel formation, respectively. In addition, the supramolecular gels exhibited a monolayer lamellar structure irrespective of Zn2+. Conclusively, the gels' elasticity and viscosity reduced in the presence of Zn2+.

Origin of Both Right- and Left-Handed Helicities in a Supramolecular Gel with and without Ni2+ at the Supramolecular Level.

We demonstrate the different origins of helical directions in polymeric gels derived from a hydrazone reaction in the absence and presence of Ni2+. The right-handed helicity of polymeric gels without Ni2+ originates from the enantiomeric d-form alanine moiety embedded in the building block. However, the right-handed helicity is inverted to a left-handed helicity upon the addition of Ni2+, indicating that added Ni2+ greatly affects the conformation of the polymeric gel by overcoming the influence of the enantiomer embedded in the building block on the helicity at the supramolecular level. More interestingly, the ratio of the right-toleft-handed helical fibers varies with the concentration of Ni2+, which converts from 100% right-handed helical fiber to 90% left-handed helical fiber. In the presence of Ni2+, both right- and left-handed helical fibers coexist at the supramolecular level. Some fibers also exhibit both right- and left-handed helicities in a single fiber.

A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore.

The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to 'dial out' the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors.

Luminescent calix[4]arene-based metallogel formed at different solvent composition.

We have synthesized a calix[4]arene derivative (1) containing terpyridine and showed that gelation occurred in the presence of Pt(2+) in DMSO/H2O of varying compositions. Gelation was presumably mediated by the Pt-Pt and π-π stacking interactions. The scanning electron microscopy image of the xerogel showed a spherical structure with diameter of 1.8-2.1 µm. Interestingly, the metallogel showed strong luminescence enhancement, which was dependent on the DMSO/H2O ratio of the solvent. We examined the effects of concentration, temperature, and time resolution on the luminescence emission of both the gel 1-Pt(2+) and the sol 1-Pt(2+). The luminescence lifetimes of the metallogel were particularly long, on the order of several microseconds. The luminescence lifetimes were also strongly dependent on the solvent composition. We also determined the thermodynamic parameters for the self-assembly of the gel by the Birks kinetic scheme. Furthermore, the rheological properties of the metallogels in the presence of more than 4.0 equiv of Pt(2+) were independent of the concentration of Pt(2+) applied.

AI-based betting anomaly detection system to ensure fairness in sports and prevent illegal gambling.

This study develops a solution to sports match-fixing using various machine-learning models to detect match-fixing anomalies, based on betting odds. We use five models to distinguish between normal and abnormal matches: logistic regression (LR), random forest (RF), support vector machine (SVM), the k-nearest neighbor (KNN) classification, and the ensemble model-a model optimized from the previous four. The models classify normal and abnormal matches by learning their patterns using sports betting odds data. The database was developed based on the world football league match betting data of 12 betting companies, which offered a vast collection of data on players, teams, game schedules, and league rankings for football matches. We develop an abnormal match detection model based on the data analysis results of each model, using the match result dividend data. We then use data from real-time matches and apply the five models to construct a system capable of detecting match-fixing in real time. The RF, KNN, and ensemble models recorded a high accuracy, over 92%, whereas the LR and SVM models were approximately 80% accurate. In comparison, previous studies have used a single model to examine football match betting odds data, with an accuracy of 70-80%.

Cysteine protease I29 propeptide from Calotropis procera R. Br. As a potent cathepsin L inhibitor and its suppressive activity in breast cancer metastasis.

Breast cancer metastasis is associated with a poor prognosis and a high rate of mortality. Cathepsin L (CTSL) is a lysosomal cysteine protease that promotes tumor metastasis by degrading the extracellular matrix. Gene set enrichment analysis revealed that CTSL expression was higher in tumorous than in non-tumorous tissues of breast cancer patients and that high-level CTSL expression correlated positively with the epithelial-mesenchymal transition. Therefore, we hypothesized that inhibiting CTSL activity in tumor cells would prevent metastasis. In this study, we characterized the inhibitory activity of SnuCalCpI15, the I29 domain of a CTSL-like cysteine protease from Calotropis procera R. Br., and revealed that the propeptide stereoselectively inhibited CTSL in a reversible slow-binding manner, with an inhibitory constant (Ki) value of 1.38 ± 0.71 nM, indicating its potency as an exogenous inhibitor in anti-cancer therapy. SnuCalCpI15 was localized intracellularly in MDA-MB-231 breast cancer cells and suppressed tumor cell migration and invasion. These results demonstrate the potential of SnuCalCpI15 as a novel agent to prevent breast cancer metastasis.

Evaluating the Efficacy of Machine Performance Checks as an Alternative to Winston-Lutz Quality Assurance Testing in the TrueBeam Linear Accelerator with HyperArc.

HyperArc is a preferred technique for treating brain metastases, employing a single isocenter for multiple lesions. Geometrical isocentricity in the TrueBeam linear accelerator with HyperArc is crucial. We evaluated machine performance checks (MPCs) as an alternative to the Winston-Lutz (WL) test to verify the treatment isocenter. Between January and July 2023, we assessed 53 data points using MPC and Winston-Lutz tests. The isocenter size obtained from the MPC and its sum, including the rotation-induced couch shift, were compared with the maximum total delta value from the Winston-Lutz test. The maximum total delta was 0.68 ± 0.10 mm, while the isocenter size was 0.28 ± 0.02 mm. The sum of the isocenter size and rotation-induced couch shift measured by MPC was 0.61 ± 0.03 mm. During the Winston-Lutz test (without couch rotation), the maximum total delta value was 0.56 ± 0.13 mm. A t-test analysis revealed a significant difference in the isocenter size averages between the Winston-Lutz and MPC outcomes, whereas the Pearson's correlation coefficient yielded no correlation. Our study highlights the necessity for separate MPC and Winston-Lutz tests for isocenter verification. Therefore, the Winston-Lutz test should precede stereotactic radiosurgery for isocenter verification.

Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen.

Semen liquefaction is a postejaculation process that transforms semen from a gel-like (coagulated) form to a water-like consistency (liquefied). This process is primarily regulated by serine proteases from the prostate gland, most prominently, prostate-specific antigen (PSA; KLK3). Inhibiting PSA activity has the potential to impede liquefaction of human semen, presenting a promising target for nonhormonal contraception in the female reproductive tract. This study employed triazole B1 as a starting compound. Through systematic design, synthesis, and optimization, we identified compound 20 (CDD-3290) as a 216 nM inhibitor of PSA with better stability in media than triazole B1. Further, we also evaluated the selectivity profile of compound 20 (CDD-3290) by testing against closely related proteases and demonstrated excellent inhibition of PSA versus α-chymotrypsin and elastase and similar potency versus thrombin. Thus, compound 20 is an improved PSA inhibitor that can be tested for efficacy in vitro or in the female reproductive tract.

Early-Onset Hearing Loss in Mouse Models of Alzheimer's Disease and Increased DNA Damage in the Cochlea.

There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polß+/-. The 3xTgAD/Polß+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polß+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.

A Validation Study of a Deep Learning-Based Doping Drug Text Recognition System to Ensure Safe Drug Use among Athletes.

This study aimed to develop an English version of a doping drug-recognition system using deep learning-based optical character recognition (OCR) technology. A database of 336 banned substances was built based on the World Anti-Doping Agency's International Standard Prohibited List and the Korean Pharmaceutical Information Center's Drug Substance Information. For accuracy and validity analysis, 886 drug substance images, including 152 images of prescriptions and drug substance labels collected using data augmentation, were used. The developed hybrid system, based on the Tesseract OCR model, can be accessed by both a smartphone and website. A total of 5379 words were extracted, and the system showed character recognition errors regarding 91 words, showing high accuracy (98.3%). The system correctly classified all 624 images for acceptable substances, 218 images for banned substances, and incorrectly recognized 44 of the banned substances as acceptable. The validity analysis showed a high level of accuracy (0.95), sensitivity (1.00), and specificity (0.93), suggesting system validity. The system has the potential of allowing athletes who lack knowledge about doping to quickly and accurately check whether they are taking banned substances. It may also serve as an efficient option to support the development of a fair and healthy sports culture.

Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.

Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.

Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice.

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Enhanced spin Seebeck effect via oxygen manipulation.

Spin Seebeck effect (SSE) refers to the generation of an electric voltage transverse to a temperature gradient via a magnon current. SSE offers the potential for efficient thermoelectric devices because the transverse geometry of SSE enables to utilize waste heat from a large-area source by greatly simplifying the device structure. However, SSE suffers from a low thermoelectric conversion efficiency that must be improved for widespread application. Here we show that the SSE substantially enhances by oxidizing a ferromagnet in normal metal/ferromagnet/oxide structures. In W/CoFeB/AlOx structures, voltage-induced interfacial oxidation of CoFeB modifies the SSE, resulting in the enhancement of thermoelectric signal by an order of magnitude. We describe a mechanism for the enhancement that results from a reduced exchange interaction of the oxidized region of ferromagnet, which in turn increases a temperature difference between magnons in the ferromagnet and electrons in the normal metal and/or a gradient of magnon chemical potential in the ferromagnet. Our result will invigorate research for thermoelectric conversion by suggesting a promising way of improving the SSE efficiency.