Relevant Sites Research Articles

Machine Learning Approach for Detection of Phishing Website

Abstract: Phishing attacks are the easiest way to get sensitive information from innocent users. The purpose of phishing is to obtain critical information like the private information of users. Phishing sites pretend to be relevant sites and it is more difficult to distinguish these sites. It is one of the greatest threats that every individual and management has ever faced. URLs are referred to as web pages through which users locate pieces of information on the Internet. This paper focuses on phishing website detection which is important for the prevention of our sensitive information. There are different types of websites with different features. Therefore, we need to use a specific set of features on websites to protect against phishing. A machine learning model has been proposed to detect phishing websites. To detect phishing sites, we proposed the machine learning model. The essential objective of this paper is to classify the various algorithm of machine learning by extracting and analyzing various features of legitimate and phishing URLs.

P-562 Elective egg freezers’ disposition decisions: A qualitative study

Abstract Study question What are the factors that influence elective egg freezers’ (EEF) disposition decisions towards their surplus frozen oocytes? Summary answer Achieving motherhood or dealing with grief if motherhood was not achieved, the complexities of donating to others, and a lack of information and professional advice. What is known already Most women who undergo EEF do not use their oocytes. Consequently, there is an abundant, but unquantified, number of women with surplus oocytes in storage globally. Many women are deciding about the disposition of their surplus oocytes due to storage limits in countries such as Australia, Belgium, Finland, and Taiwan. However, no studies have examined the factors that influence EEF oocyte disposition decisions. Research exploring factors relevant to embryo disposition and planned oocyte donation may not be relevant. Consequently, women are making the challenging and stressful decision regarding the fate of their oocytes with limited research available to support them. Study design, size, duration Thirty-one structured interviews took place in Australia between October 2021 and March 2022. Recruitment was via: Facebook (paid advertising, posts on relevant groups and organisation sites), newsletters and emails from universities and professional organizations, emails to eligible patients from an IVF clinic, and snowballing. A reflexive thematic approach was planned; data collection and analysis occurred concurrently. Recruitment occurred until the process of analysis did not identify any new themes and saturation have been reached. Participants/materials, setting, methods Eligible participants (EEF with surplus frozen eggs, 18+, living in Australia) were interviewed and included women who had previously made a disposition decision (n = 7), were currently deciding (n = 6), or who not yet considered the decision (n = 18). Interviews took place on recorded teleconference, were transcribed verbatim and anonymised. Transcripts were iteratively coded via NVivo and analysed, and themes developed inductively. The researcher reflected on their subjectivity with co-authors to ensure accuracy and clarity of data interpretation. Main results and the role of chance Six inter-related themes were identified related to the decision-making process: ‘decisions are dynamic’; ‘triggers for the final decision’; ‘achieving or not achieving motherhood’; ‘conceptualisation of oocytes’; ‘the impacts of egg donation on others’; and ‘external factors affecting the final disposition outcome’. All women reported a type of trigger ‘event’ for making a final decision (e.g. completing their family). Women who achieved motherhood were more open to donating their oocytes to others, wanting to share the joy of motherhood, but were concerned about the implications for their child (e.g. donor-conceived half-siblings) and also felt responsibility for potential donor children. Women who did not achieve motherhood were less likely to donate to others due to the grief of not becoming a mother, often feeling alone, misunderstood, and unsupported. Reclaiming oocytes (e.g. taking them home) and closure ceremonies helped some women process their grief. Donating to research was viewed as an altruistic option as oocytes would not be wasted and did not have the “complication” of a genetically linked child. Decisions were often made based on misinformation and a lack of knowledge of the available disposition options and their consequences, with few women seeking professional advice on their decision. Limitations, reasons for caution Most participants had not considered the decision and their stated intentions may not reflect their final decision. Women who had previously made disposition decisions were difficult to recruit despite comprehensive study advertising. Other limitations were the use of convenience sampling and conduct of interviews via teleconference (due to COVID). Wider implications of the findings Due to a lack of understanding of the disposition options, their impacts, and women not seeking professional advice, decision support (e.g. counselling, decision aids) is suggested. Counselling should occur at least at the beginning and end of the process, address disposition options, impacts, grief, and gaining support from others. Trial registration number Not applicable

Cost-effectiveness of screening for chronic kidney disease in the general adult population: a systematic review.

Chronic kidney disease (CKD) is a significant public health problem, with rising incidence and prevalence worldwide, and is associated with increased morbidity and mortality. Early identification and treatment of CKD can slow its progression and prevent complications, but it is not clear whether CKD screening is cost-effective. The aim of this study is to conduct a systematic review of the cost-effectiveness of CKD screening strategies in general adult populations worldwide, and to identify factors, settings and drivers of cost-effectiveness in CKD screening. Studies examining the cost-effectiveness of CKD screening in the general adult population were identified by systematic literature search on electronic databases (MEDLINE OVID, Embase, Cochrane Library and Web of Science) for peer-reviewed publications, hand-searched reference lists and grey literature of relevant sites, focusing on the following themes: (i) CKD, (ii) screening and (iii) cost-effectiveness. Studies comprising health economic evaluations performed for CKD screening strategies, compared with no CKD screening or usual-care strategy in adult individuals, were included. Study characteristics, model assumptions and CKD screening strategies of selected studies were identified. The primary outcome of interest is the incremental cost-effectiveness ratio (ICER) of CKD screening, in cost per quality-adjusted life year (QALY) and life-year gained (LYG), expressed in 2022 US dollars equivalent. Twenty-one studies were identified, examining CKD screening in general and targeted populations. The cost-effectiveness of screening for CKD was found to vary widely across different studies, with ICERs ranging from $113 to $430 595, with a median of $26 662 per QALY and from $6516 to $38 372, with a median of $29 112 per LYG. Based on the pre-defined cost-effectiveness threshold of $50 000 per QALY, the majority of the studies found CKD screening to be cost-effective. CKD screening was especially cost-effective in those with diabetes ($113 to $42 359, with a median of $27 471 per QALY) and ethnic groups identified to be higher risk of CKD development or progression ($23 902 per QALY in African American adults and $21 285 per QALY in Canadian indigenous adults), as indicated by a lower ICER. Additionally, the cost-effectiveness of CKD screening improved if it was performed in older adults, populations with higher CKD risk scores, or when setting a higher albuminuria detection threshold or increasing the interval between screening. In contrast, CKD screening was not cost-effective in populations without diabetes and hypertension (ICERs range from $117 769 to $1792 142, with a median of $202 761 per QALY). Treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were identified to be the most common influential drivers of the ICERs. Screening for CKD is especially cost-effective in patients with diabetes and high-risk ethnic groups, but not in populations without diabetes and hypertension. Increasing the age of screening, screening interval or albuminuria detection threshold, or selection of population based on CKD risk scores, may increase cost-effectiveness of CKD screening, while treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were influential drivers of the cost-effectiveness.

Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease.

The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.

Optimized real-time parking management framework using deep learning

Today’s modern world has seen massive population growth in the past few decades, causing the automobile industry to expand rapidly. The exponential increase has disrupted the seamless flow of traffic globally and has fashioned significant problems such as traffic congestion and its mismanagement. To tackle these issues, some hardware and data-driven-based solutions have been previously proposed. The hardware-based solutions utilize different types of sensors installed at relevant sites to monitor the status of parking slots which makes them less scalable, complex, costly to install and maintain. In contrast, the data-driven solutions utilize the already available infrastructure of surveillance cameras installed at parking lots, thus overcoming the limitations of sensor-based solutions. However, currently only classification-based approaches are prevalent and adopted to monitor the status of the parking slots which makes the systems less generalized for scalability with slower performance. This paper proposes an intelligent parking management system which employs deep learning to alleviate the limitations in the data driven solutions by leveraging the high performance and fast inference capability of YOLO v5 for vehicles detection instead of parking slot classification. The model was evaluated using the PKLot dataset which is a benchmark for identifying the status of the parking lot with state of the art performance achieved having an accuracy of 99.5%. To augment the performance of the algorithm in real-time, a pretrained model of YOLO v5 on MS COCO dataset was employed to detect and assign vacant parking slots and generate vehicle statistics. The performance of the proposed system was evaluated on our custom dataset with an accuracy of 96.8% achieved and a nearly real-time performance of 45 Fps which makes it more efficient, scalable, and generalized.

Inventory and assessment of geoarchaeosites in the Middle Eure Valley (Paris Basin, France): An integrated approach to geoarchaeological heritage

For the last decade, there has been an abundance of scattered case studies on geoarchaeological heritage in the scientific literature. Yet, there is a lack of methodological guidelines to inventory and numerically assess a collection of “geoarchaeosites” for heritage conservation and/or tourism purposes. The aim of this paper is to propose an innovative and integrated methodology for the inventory and assessment of geoarchaeological heritage, with an example of application in the Middle Eure Valley (Paris Basin, France). In this work, we suggest the use of the “geoarchaeosite” concept as a contraction of geoarchaeological sites, i.e., sites of particular relevance in understanding past society-environment interactions at the Quaternary or historical time scale. In our approach, archaeological and geomorphological components of a site have the same level of importance, in contrast to the classical approaches on geomorphosites that consider the cultural, archaeological, and/or historical significance of a site as an “additional” value. In the study area, the results provide a selection of 19 geoarchaeosites with contrasted scientific values, ranging from sites of national (fossiliferous site of Saint-Prest, loess-paleosol sequence of Chaudon) and regional rank (Chartres Cathedral and its historical quarry at Berchères-les-Pierres, French Royal Canal Louis XIV-Aqueduct of Maintenon, Megaliths of Changé at Saint-Piat and Eure palaeochannels) to more confidential sites of local interest, with various degrees of vulnerability and potential use. A network analysis of “disconnected geoarchaeosites” according to spatial, chronological, and functional relationships contributes to improving the overall scientific value of the geoarchaeological heritage. Among the prospects that are emerging in the scope of promotional activities, comes the interest of building a digital geoarchaeoheritage platform with a collaborative/participatory aim in order to reinforce heritage ownership by local residents and stakeholders.

The Impact of Termination of Cooperation between the Indonesian Government and the World Wide Fund for Nature (WWF) on Nature Conservation

This study aims to explain the reasons why the Indonesian government decided to cooperate with World Wide Fund for Nature (WWF) and the impact of the termination of the Indonesian government's cooperation with WWF on Nature Conservation in Indonesia. Data was collected through a literature study (library research) which aims to collect secondary data from books, journals, reports, official government websites, and other relevant internet sites to support this research. The data is then analyzed in three stages: data reduction, data presentation, and drawing conclusions. The findings show that the reasons why the Indonesian government, represented by the Ministry of Environment, decided to partner or end the collaboration with the WWF foundation, namely, first, a change in landscape or the scope of WWF's performance which is increasingly being expanded. Second, WWF's activities, especially in the field of climate change, environmental and forestry law enforcement and waste management in the field, do not have a legal basis for legal cooperation. Third, violations of the principle of cooperation and violations of field work and unilateral claims that do not match the facts that occur in the field. Fourth, violations of the substance of the cooperation agreement, including through a series of social media campaigns and publication of reports that are not in accordance with the facts. Meanwhile, the impact of the termination of this collaboration resulted in aspects of the natural environment that were increasingly not maintained and many other projects that were concerned with nature and ecosystem conservation became worse. The limitation of this research is that the researchers did not have time to conduct interviews with WWF to examine in more detail the impact of the termination of cooperation on nature conservation in Indonesia. Subsequent research needs to use the interview method for more comprehensive results.

In vitro validation of an in vivo phenotyping drug cocktail for major drug transporters in humans

PurposeCocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on transporter activities should be ruled out. Here, for a clinically tested cocktail consisting of adefovir, digoxin, metformin, sitagliptin, and pitavastatin, inhibition of major transporters by individual probe substrates was investigated in vitro. MethodsTransporter transfected HEK293 cells were used in all evaluations. Cell-based assays were applied for uptake by human organic cation transporters 1/2 (hOCT1/2), organic anion transporters 1/3 (hOAT1/3), multidrug and toxin extrusion proteins 1/2K (hMATE1/2K), and organic anion transporter polypeptide 1B1/3 (hOATP1B1/3). For P-glycoprotein (hMDR1) a cell-based efflux assay was used whereas an inside-out vesicle-based assay was used for the bile salt export pump (hBSEP). All assays used standard substrates and established inhibitors (as positive controls). Inhibition experiments using clinically achievable concentrations of potential perpetrators at the relevant transporter expression site were carried out initially. If there was a significant effect, the inhibition potency (Ki) was studied in detail. ResultsIn the inhibition tests, only sitagliptin had an effect and reduced hOCT1- and hOCT2- mediated metformin uptake and hMATE2K mediated MPP+ uptake by more than 70%, 80%, and 30%, respectively. The ratios of unbound Cmax (observed clinically) to Ki of sitagliptin were low with 0.009, 0.03, and 0.001 for hOCT1, hOCT2, and hMATE2K, respectively. ConclusionThe inhibition of hOCT2 in vitro by sitagliptin is in agreement with the borderline inhibition of renal metformin elimination observed clinically, supporting a dose reduction of sitagliptin in the cocktail.

PO-04-230 IMPROVED VISUALIZATION OF LOW AMPLITUDE LATE POTENTIALS WITH VT SUBSTRATE MAPPING USING A NOVEL EP RECORDING SYSTEM

Accurate identification of low-voltage electrograms (EGMs) suffer from artifacts that often interfere with physiological signals in the <0.1-0.5mV range. For substrate based ablation of ventricular tachycardia (VT), dense scar is defined as regions of myocardium with EGM amplitudes below 0.5 mV. Within these regions, current EP recording systems can fail at identifying low-voltage late potentials that are effective targets of ablation therapy. More recently, new EP amplifiers designed specifically to reduce the impact of interference on the fidelity of signals have been introduced. This study used a novel EP recording system (ECGenius System, CathVision, Copenhagen, DK) to identify low amplitude (<0.5mV) late potentials in regions of scar, and quantify their characteristics in a head-head comparison to a standard recording system (LabSystem Pro, Boston Scientific, MA). We collected recordings in parallel from four patients (30-250 Hz bipolar recording bandwidth) referred to our center for an EP study and ablation for VT. We performed substrate mapping during sinus rhythm with a standard 4mm irrigated ablation catheter (SmartTouch, Biosense Webster, Diamond Bar, CA) and a multi-spline mapping catheter (PentaRay, Biosense Webster). In regions of dense scar (< 0.5 mV, delineated with 3-D electroanatomical mapping) we identified late potentials that were above the baseline noise level of the CathVision system that were otherwise not clearly visible with the LabSystem Pro system. In four patients we identified fourteen sites with late potentials (110 beats) that were only identified with the CathVision System (see figure). The average amplitude of the late signals was 0.079 +/- 0.063 mV, which was above the baseline mean noise of 0.008 mV (range 0.006 to 0.015 mV). In contrast, the baseline mean noise of the LabSystem Pro was 0.060 mV (range 0.040 to 0.090 mV). The mean delay of the late potentials (after the start of the surface ECG QRS) was 377ms (range 198 to 470ms). Improved visualization of low voltage EGMs and late potentials can improve upon substrate-based ablation of ischemic VT. With a novel, and state-of-the art recording amplifier, we demonstrate an improved ability to detect clinically relevant sites for ablation that were not visible with a standard recording system. This technology could improve upon current ablation strategies, and may be particularly useful in the current era of micro-electrodes and relatively smaller recording voltages.

Unclearing the Air: The Pneumatological Dalliances of Jacques Derrida

Abstract In the 1980s, Luce Irigaray accused Western philosophy of “forgetting” about the role that the materiality of air and the act of breathing played in pre-Socratic metaphysics. This essay explores how Jacques Derrida maintained a complicated but insightful relationship to the air throughout his career through the mediating influence of pneuma, a word with long and complicated connections to the air. I highlight two relevant sites of engagement. The first was found in Of Grammatology (1968), where he connected the breathy logocentrism of “natural writing” to a concept of pneumatology (a “science of spirit” with some interesting connections to Leibniz) that served as grammatology’s Janus face. The second stemmed from Of Spirit (1991), in which Derrida emphasized the combustible, fiery face of pneuma to lambast Heidegger’s use of translation to mediate away the historical presence of the word pneuma for ideological purposes. This body of work, en toto, presents a subtle and oblique critique of Irigaray’s position. For Derrida, the air cannot function as the medium for an alternative metaphysics of presence because, historically, its space has already been infused with a pneumatic specter that cannot be ignored.

Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions.

Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.

Choose what suits you best: reproductive patterns and livestock management in the Iron Age Iberian Peninsula (3rd c. BC)

Isotopic analyses have proven to be an essential tool for obtaining more comprehensive and precise knowledge about past livestock strategies. Nevertheless, biogeochemical data for the Iron Age and, in particular, for the Iberian Peninsula are still very scarce. This study aims to provide a first and pivotal glimpse of sheep reproductive strategies adopted by north-eastern Iberian societies during the Middle and Late Iron Age, a period in which a process of urbanisation and agricultural expansion took place. Birth seasonality and the duration of the lambing period are here investigated through sequential oxygen isotope analyses performed on sheep’s second and third lower molars from four relevant Catalan sites (Mas Castellar de Pontós, Tossal de Baltarga, Sant Esteve d’Olius, Turó de la Rovira). These are contemporary (third century BC) and are located in different ecological and cultural areas. Results display diversified sheep reproductive patterns and distinct demographical management in the four settlements, with manipulations both on the season and on the duration of the lambing period. Thus, we propose that herd management and exploitation were determined by specific economic demands and the social organisation and environmental conditions of each area. Therefore, through this biogeochemical approach, we have been able to demonstrate that the resources, knowledge and time involved in the organisation of sheep husbandry were much more complex and planned than classical zooarchaeological studies have so far documented, highlighting the importance of livestock farming as a key activity in the economy of the Iron Age Iberian communities.

A qualitative approach to the conservation and valorization of abandoned rural heritage: case study of the Traras Mountains (NW-Algeria)

ABSTRACT Several threats are affecting the abandoned vernacular houses of the Traras Mountains region (NW Algeria). The disappearance of this heritage, reflecting the culture of the Traras ancient community is near. Thus, this empirical research aims at producing useful and practical information to avoid the disappearing of a valuable knowledge. It should raise awareness about Traras cultural resources and offer a context for preservation programmes. Our research approach is exploratory, with which general information about the built environment was collected through a windshield and web-mapping survey. An in-depth inquiry is carried out in the most relevant sites, gathering more accurate information. Also, Informal talks and interviews were essential to our research to understand the locals’ interpretations. This study revealed that Traras is homogeneous in terms of vernacular-built features; two typologies are found.

Maternal transfer of IgA and IgG SARS-CoV-2 specific antibodies transplacentally and via breast milk feeding.

Although there have been many studies on antibody responses to SARS-CoV-2 in breast milk, very few have looked at the fate of these in the infant, and whether they are delivered to immunologically relevant sites in infants. Mother/infant pairs (mothers who breast milk fed and who were SARS-CoV-2 vaccinated before or after delivery) were recruited for this cross-sectional study. Mother blood, mother breast milk, infant blood, infant nasal specimen, and infant stool was tested for IgA and IgG antibodies against SARS-CoV-2 spike trimer. Thirty-one mother/infant pairs were recruited. Breast milk fed infants acquired systemic anti-spike IgG antibodies only if their mothers were vaccinated antepartum (100% Antepartum; 0% Postpartum; P<0.0001). Breast milk fed infants acquired mucosal anti-spike IgG antibodies (in the nose) only if their mothers were vaccinated antepartum (89% Antepartum; 0% Postpartum; P<0.0001). None of the infants in either group had anti-spike IgA in the blood. Surprisingly, 33% of the infants whose mothers were vaccinated antepartum had high titer anti-spike IgA in the nose (33% Antepartum; 0% Postpartum; P = 0.03). Half-life of maternally transferred plasma IgG antibodies in the Antepartum infant cohort was ~70 days. Vaccination antepartum followed by breast milk feeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants. The presence of high titer SARS-CoV-2-specific IgA in the nose of infants points to the potential importance of breast milk feeding early in life for maternal transfer of mucosal IgA antibodies. Expectant mothers should consider becoming vaccinated antepartum and consider breast milk feeding for optimal transfer of systemic and mucosal antibodies to their infants.

Promotional effect of Co cations on the catalytic activity of Co/ZSM-5 in 1,2-dichloroethane dehydrochlorination for the production of vinyl chloride monomer

In the catalytic dehydrochlorination of 1, 2-dichloroethane (DCE) for Vinyl chloride monomer (VCM) production, it is important to design catalysts with appropriate acid properties which can activate DCE, while inhibiting the further reaction of VCM. In this study, Co species were introduced into ZSM-5 through an ion-exchange method to change acid site distribution of ZSM-5. The introduction of Co cations significantly improved DCE conversion and VCM selectivity, achieving 6 and 2-fold greater than bare HZSM-5, respectively. Postmortem analyses allowed us to delineate the role of acid sites: Lewis acid sites are the major active sites, whereas Brønsted acid sites give rise to undesired secondary reactions. Thus, our results demonstrate that the introduction of Co cations increases the number of relevant active sites, and simultaneously eliminates undesirable sites. These findings help understand the effect of Brønsted and Lewis acid sites in zeolites on the DCE dehydrochlorination, providing useful information for designing rational catalysts.

Abstract 4141: Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model

Abstract Recent studies have begun to demonstrate the therapeutic capacity of physical exercise on cancer treatment outcomes. While this research suggests exercise may improve health in cancer patients, the specific mechanisms by which exercise influences tumor progression remain largely unknown. We hypothesized that exercise alters the gut microbiome and promotes immune cell activation in relevant immune sites. Therefore, we utilized BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine), a carcinogen that mimics human muscle invasive bladder cancer conditions, and voluntary exercise wheels to determine the effect of exercise on bladder carcinogenesis, gut microbiome, and the immune system. Ultrasound imaging revealed that the average tumor volume of female exercising mice was 11.9% of the total bladder volume at time of sacrifice, while the tumor volume of their non-exercising counterparts was 56.4%, a difference determined to be significant using a two-tailed t-test with p-value of 0.05. A similar trend was seen in male mice, though the difference between groups was not significant. Immune cell analysis did not show significant variation in cytotoxic T cell, helper T cell, macrophage, or dendritic cell populations between exercising and non-exercising mice in spleen, colon, or bladder tissues as measured by FACS. Standardization of the amount exercised, as evaluated by expression of myosin and actin levels in the tibialis anterior muscle, and sequencing of the gut microbiome are in progress and could better indicate the mechanism of exercise-induced tumor suppression. Citation Format: Joseph P. LaMorte, Brittany Tian, Rashida Ginwala, Laura Bukavina, Philip Abbosh. Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4141.

Molecular Basis of Unequal Alternative Splicing of Human SCD5 and Its Alteration by Natural Genetic Variations.

Alternative splicing (AS) is a major means of post-transcriptional control of gene expression, and provides a dynamic versatility of protein isoforms. Cancer-related AS disorders have diagnostic, prognostic and therapeutic values. Changes in the expression and AS of human stearoyl-CoA desaturase-5 (SCD5) are promising specific tumor markers, although the transcript variants (TVs) of the gene have not yet been confirmed. Our in silico, in vitro and in vivo study focuses on the distribution of SCD5 TVs (A and B) in human tissues, the functionality of the relevant splice sites, and their modulation by certain single-nucleotide variations (SNVs). An order of magnitude higher SCD5A expression was found compared with SCD5B. This unequal splicing is attributed to a weaker recognition of the SCD5B-specific splicing acceptor site, based on predictions confirmed by an optimized minigene assay. The pronounced dominance of SCD5A was largely modified (rs1430176385_A, rs1011850309_A) or even inverted (rs1011850309_C) by natural SNVs at the TV-specific splice sites. Our results provide long missing data on the proportion of SCD5 TVs in human tissues and reveal mutation-driven changes in SCD5 AS, potentially affecting tumor-associated reprogramming of lipid metabolism, thus having prognostic significance, which may be utilized for novel and personalized therapeutic approaches.

Long-Term Degradation Assessment of a Polyurethane-Based Surgical Adhesive—Assessment and Critical Consideration of Preclinical In Vitro and In Vivo Testing

Tissue adhesives constitute a great possibility to improve conventional wound closure. In contrast to sutures, they enable nearly immediate hemostasis and can prevent fluid or air leaks. In the present study, a poly(ester)urethane-based adhesive was investigated which already proved to be suitable for different indications, such as reinforcing vascular anastomosis and sealing liver tissue. Using in vitro and in vivo setups, the degradation of the adhesives was monitored over a period of up to 2 years, to evaluate long-term biocompatibility and determine degradation kinetics. For the first time, the complete degradation of the adhesive was documented. In subcutaneous locations, tissue residues were found after 12 months and in intramuscular locations, tissue degradation was complete after about 6 months. A detailed histological evaluation of the local tissue reaction revealed good biocompatibility throughout the different degradation stages. After full degradation, complete remodeling to physiological tissue was observed at the implant locations. In addition, this study critically discusses common issues related to the assessment of biomaterial degradation kinetics in the context of medical device certification. This work highlighted the importance and encouraged the implementation of biologically relevant in vitro degradation models to replace animal studies or at least reduce the number of animals in preclinical testing prior to clinical studies. Moreover, the suitability of frequently used implantation studies based on ISO 10993-6 at standard locations was critically discussed, especially in light of the associated lack of reliable predictions for degradation kinetics at the clinically relevant site of implantation.

Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X-ray structures.

Catalytic activity and function of acetylcholinesterase (AChE; EC 3.1.1.7) have been recognized and studied for over a century and its quaternary and primary structures for about half a century, and its tertiary structure has been known for about 33 years. Clear understanding of relationships between the structure and the function is still pending for this enzyme. Hundreds of crystallographic, static snapshots of AChEs from different sources reveal largely one general backbone conformation with narrow entry into the active center gorge, tightly fit to accept one acetylcholine (ACh) molecule, in contrast to its high catalytic turnover. This short review of available X-ray structures of AChEs from electric ray Torpedo californica, mouse and human, finds some limited, yet consistent deviations in conformations of selected secondary structure elements of AChE relevant for its function. The observed conformational diversity of the acyl pocket loop of AChE, unlike the large Ω-loop, appears consistent with structurally dynamic INS data and solution-based SAXS experiments to explain its dominant role in controlling the size of the active center gorge opening, as well as connectivity between the immediate surroundings of the buried active Ser, and catalytically relevant sites on the AChE surface.

Crystal structure, DFT calculation, molecular docking, in vitro biological activity evaluation and in silico drug-likeness prediction of (E)-N-(4-bromophenyl)-4-(2-(2-hydroxybenzylidene) hydrazine-1-carbonyl) benzenesulfonamide

Herein, a novel Mtb LeuRS inhibitor compound 1A was synthesized and crystallized. And compound 1A was found to be active targeting Mtb LeuRS with IC50 values =21.37 ± 0.2 μM and against Mtb H37Ra with MIC values =18.85 ± 0.2 μM. Therefore, compound 1A was selected to conduct deeply research on molecular structure information and interaction with Mtb LeuRS. Firstly, quantum chemical calculation was used to predict spectral properties of the compound 1A, such as, structure optimization, IR, Raman, 1HNMR and 13CNMR . What's more, Hirshfeld surface analysis was used to explain multiple interactions of compound 1A, and 2D fingerprint was used to quantify intermolecular interactions accurately. Molecular electrostatic potential (MEP), reduced density gradient (RDG) and Electron localization function (ELF) were used to describe the relevant sites that can form electrostatic interaction. FMOs were used to determine chemical stability of compound 1A. At last, molecular docking were conducted to elaborate the interactions between Mtb LeuRS and compound 1A, and ADMET prediction indicates compound 1A has perfect druggability and pharmacokinetic properties.