Advanced Research Institute

Abstract The Char Dham, the four sacred abodes of Lord Vishnu, hold profound religious and mythological significance, attracting millions of Hindu pilgrims across the Indian subcontinent. Despite its spiritual prominence, the Jagannath Temple in Puri has recorded a substantial number of negative visitor reviews from September 2016 to May 2022. This study aims to analyze and interpret the critical feedback from TripAdvisor, focusing exclusively on poor and terrible ratings to identify service gaps and enhance the quality of pilgrimage experiences. Out of 2,842 available reviews, only the most negative ones were considered to develop a Temple Administrative Quality (TAQ) model based on user-generated content (UGC). The model, designed for all four Char Dham sites, places special emphasis on Jagannath Temple, which reported the highest number of negative reviews over the past decade. The study integrates extensive literature reviews, official temple website analyses, and TripAdvisor UGC to construct the TAQ model. Its accuracy, precision, and sensitivity were tested using a confusion matrix. Findings underscore the need for differentiated pilgrimage tourism planning, recognizing distinctions among domestic and international tourists, pilgrims and leisure travelers, and spiritual versus cultural visitors. Notably, spiritual devotion often outweighs service shortcomings, fostering a tolerant attitude among pilgrims. JEL Classification: L83, M10, L15

Background Exercise in older age improves depressive symptoms and prevents the onset of geriatric depression. Additionally, exercise in adolescence also enhances cognitive function, which may contribute to the prevention of geriatric depression. Therefore, the combination of exercise habits in adolescence and older age may be more effective in preventing geriatric depression.

The cytoskeleton, comprising intracellular filamentous structures composed of polymerized proteins, is crucial for the survival of both eukaryotes and prokaryotes. Although bacterial cytoskeletal proteins have diverged, they generally do not drive cellular motility. Spiroplasma, a genus of wall-less helical bacteria, swims by propagating a helicity-switching point (kink) along its cell axis. Unlike typical walled bacteria, whose motility depends on widespread motility machineries such as flagella and pili, Spiroplasma swimming is powered by the coordinated dynamics of five isoforms of bacterial actin MreB (SMreB1–5), which are grouped into three phylogenetic classes: SMreB1 and 4, SMreB2 and 5, and SMreB3. Despite the efforts to understand Spiroplasma swimming, its molecular mechanism remains unclear. In this review, we summarize how in vitro analyses of SMreBs have provided mechanistic insights into Spiroplasma swimming. While all SMreBs conserve the canonical actin fold, each SMreB class exhibits unique characteristics in its polymerized structures, ATPase activities, polymerization dynamics, and membrane binding. Studies of an essential SMreB subset for Spiroplasma swimming, i.e. SMreB1 and SMreB5, have revealed that SMreB1 binds to polymerized SMreB5 and disassembles it depending on the nucleotide state. These results challenge the previous model in which Spiroplasma swimming is driven by the coordinated extension and contraction of two distinct SMreB filaments. Finally, we discuss potential molecular mechanisms underlying Spiroplasma swimming and highlight key questions that must be answered to validate these models.

Plastics are used broadly for various applications, and their degradation and fragmentation have led to widespread accumulation of nanoplastics in the environment. Although nanoplastics are ubiquitous and intractable in the environment and in organisms, their potential health impacts remain unclear. Emerging evidence showed that nanoplastics can cross the blood-brain barrier and accumulate in the brain. However, the effects of nanoplastics on neuronal health and functions in the brain are poorly understood. Here, we examined the effects of nanoplastic exposure on neurotransmitter release by measuring FM 4-64 (a lipophilic styryl dye) release from synaptic vesicles during electrical stimulation after exposing rat hippocampal neurons to 1-10 μg/mL of fluorescent polystyrene nanoplastics with an average diameter of 42 nm. We found that nanoplastics accumulated in the presynaptic terminal of hippocampal neurons and reduced stimulation-induced FM 4-64 release in a dose-dependent manner. Furthermore, nanoplastics decreased Ca2+ elevation in the presynaptic terminal of hippocampal neurons during electrical stimulation. Our results suggest that accumulated nanoplastics in the brain can impair neuronal functions by disrupting neurotransmitter release and Ca2+ dynamics in the presynaptic terminal of neurons, which could eventually lead to neurodegeneration.

The WRN helicase has recently emerged as a promising therapeutic target for microsatellite instability (MSI)-high cancers. Here, we report LXW-P1, a potent WRN degrader derived from marine bromotyrosine alkaloids. Its molecular target was identified using an AI-guided, pathway-informed perturbation transcriptomics strategy, which prioritized candidate targets from complex phenotypic responses, focusing on WRN and accelerating mechanistic discovery. Through the first total synthesis of purpuramine D, aplysamine 3, and purealidin C, coupled with systematic derivatization, we identified LXW-P1 as a synthetic intermediate with exceptional antitumor activity. Guided by AI predictions, extensive validation revealed that LXW-P1 induces proteasome-dependent WRN degradation. Mechanistic studies demonstrated that LXW-P1 directly binds to WRN, triggering its degradation and subsequently inducing DNA damage and cell cycle arrest in MSI-high cancer cells. In vivo, LXW-P1 exhibited selective inhibition of MSI tumor growth while maintaining a favorable safety profile. This work bridges marine natural product chemistry with targeted protein degradation, providing a novel therapeutic strategy for MSI-high cancers and underscoring the strategic and efficiency advantages of AI in modern drug discovery.

We analyzed TESS archival data of three novae after recent outbursts, searching the orbital and white dwarf (WD) rotation period and possible variations of these periods. In V1405 Cas, we detected a period of $\sim$116.88 seconds, which we identified as due to the WD spin, and measured a rate of increase of 0.00165$\pm0.000006\, {\rm s\, d}^{-1}$, one of the fastest spin-down rates ever recorded. The rapid spin-down coupled with an X-ray luminosity several orders of magnitude lower than the available spin-down power, strongly indicates that the system is in a magnetic ``propeller'' state, namely the rotational energy powers the system's X-ray luminosity. We measured a previously unknown orbital period of 1.357$\pm0.005\,{\rm days}$ for V1716 Sco. If the X-ray flux modulation with a period of 77.9 s detected in outburst for this nova is due to the rotation of an strongly magnetized white dwarf as in other novae with similar modulations of the supersoft X-ray source in outburst, the system is in a parameter space that challenges standard models of cataclysmic variable evolution. For V1674 Her, which has already been classified as an intermediate polar (IP), we confirm the known spin period of 501.328$\pm0.024\,{\rm s}$ and the orbital period of $0.15293 \pm 0.00004$ days, suggesting that the spin modulation was also the root cause of the periodicity in X-rays in outburst, and that the WD atmosphere in the supersoft X-ray phase was not thermally homogeneous. Our results highlight the power of high-cadence, continuous observations in revealing extreme and unexpected characteristics of accreting white dwarfs.

An efficient oxidative ring-opening reaction of catechols to afford cis,cis-muconic acid mononitriles was established under mild conditions with a broad substrate scope. The transformation enables most catechols containing asymmetric substituents to generate a single or major product. The reaction can be scaled to gram quantities, highlighting its practical utility. Experimental studies and density functional theory calculations support a mechanism involving pyrocatechol oxidation, quinone-amine condensation, nucleophilic addition, and subsequent aromatic ring cleavage.

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide, necessitating the development of more precise diagnostic strategies beyond conventional biomarker detection and imaging techniques, which often suffer from limited specificity and sensitivity. Here, we report the design and evaluation of a mitochondria-targeting accumulation probe, 5MEF, for MI diagnosis. In vitro assays demonstrated that 5MEF exhibits high specificity and selective accumulation in H9c2 cells compared to that in HUVECs. In the rat MI model, 5MEF showed significant differences between the infarcted area and the noninfarcted area, indicating that 5MEF has diagnostic potential. Biosafety assessments conducted in vitro and in vivo revealed no significant cytotoxicity or adverse effects. In conclusion, our findings demonstrate that 5MEF is a highly promising molecular probe for the early detection of MI, providing a highly specific and safe diagnostic tool with a significant potential for clinical translation.

<title>Abstract</title> 4 September, 2025. Research Square has withdrawn this preprint due to significant concerns regarding the integrity of the work. Maintaining high standards of ethical conduct is essential to our platform.