Background: Ongoing molecular profiling studies enabled by advances in biomedical technologies are producing vast amounts of ‘omic’ data for early detection, monitoring, and prognosis of diverse diseases. A major common limitation is the scarcity of biological samples, necessitating integrative modeling frameworks that can make optimal use of available data for disease classification tasks. Related data sets are often available from different studies, but may have been generated using different technology platforms. Thus, there is a critical need for flexible modeling methods that can handle data from diverse sources to facilitate the discovery of robust biomarkers that underlie disease regulatory processes. Results: In this paper, we introduce a novel framework called Knowledge Augmented Rule Learning (KARL), which incorporates two sources of knowledge, domain, and data, for pattern discovery from small and high-dimensional datasets, such as transcriptomic data. We propose KARL as a transfer rule learning framework in which knowledge of the domain is transferred to the learning process on data in order to 1) improve the reliability of the discovered patterns, and 2) study the knowledge of the domain when used along with data for modeling. In this work, we generated KARL models on gene expression datasets for five types of cancer, including brain, breast, colon, lung, and prostate. As our knowledge of the domain, we used the Ingenuity Knowledge Base (IKB) to extract genes related to hallmarks of cancer and annotated these prior relationships before learning classifiers from these datasets. Conclusions: Our results show that KARL produces, on average, rule models that are more robust classifiers than the baseline without such background knowledge, for our tasks of cancer prediction using 25 publicly available gene expression datasets. Moreover, KARL helped us learn insights about previously known relationships in these gene expression datasets, along with new relationships not input as known, to enable informed biomarker discovery for cancer prediction tasks. KARL can be applied to modeling similar data from any other domain and classification task. Future work would involve extensions to KARL to handle hierarchical knowledge to derive more general hypotheses to drive biomedicine.

It is necessary to address the scarcity of crushed stones for pavement structural layers. So fly ash can be proved to be promising solution as more than 270 tonnes of fly ash is generated in India. Though, numerous research has been conducted for the use of fly ash intreated and untreated form, high volume of fine particles and brittleness of the stabilized fly ash pose a great problem for its use in subbase and base. Moreover, stiffness or modulus of stabilized fly ash is vital elastic parameter which is used for mechanistic pavement design. Hence, in this study an extensive experimental investigation is carried out to study its strength and stiffness properties such as compressive strength, indirect tensile strength and flexural strength, cyclic indirect tensile modulus and flexural modulus of fiber reinforced cement stabilized fly ash, stone dust, aggregate mixtures. The stone dust and aggregates have been added to enhance the gradation of the composite’s mixture. The study presents the effect of fiber on strength and stiffness properties. The experimental result reveals that addition of polypropylene (PP) fibers up to 0.25 wt.% enhances the compressive strength and any further addition of fiber results in decrease of the strength. However, indirect tensile strength and flexural strength increases with increase in fiber percentage up to 0.5 wt.%. Cement content is observed to be the dominant parameter for stabilized materials. Suitable relationships have been developed between strength and modulus parameters for stabilized mixtures. Based on the strength and stiffness study, 70% fly ash and 30% stone dust-aggregate and 60% fly ash and 40% stone dust-aggregate with 6% cement can be considered for the base layer. Based on the indirect tensile strength and flexural strength behavior, 0.35% is considered as the optimum fiber percentage.

The RNA-guided endonuclease system CRISPR-Cas9 has been extensively modified since its discovery, allowing its capabilities to be extending far beyond double-stranded cleavage to high fidelity insertions, deletions, and single base edits. Such innovations have been possible due to the modular architecture of CRISPR-Cas9 and the robustness of its component parts to modifications and the fusion of new functional elements. Here, we review the broad toolkit of CRISPR-Cas9-based systems now available for diverse genome editing tasks. We provide an overview of their core molecular structure and mechanism and distil the design principles used to engineer their diverse functionalities. We end by looking beyond the biochemistry and towards the societal and ethical challenges that these CRISPR-Cas9 systems face if their transformative capabilities are to be deployed in a safe and acceptable manner.

Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins that work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases resulting in abasic sites. Many DNA glycosylases are product inhibited by binding to the abasic site more avidly than the damaged base. Traditionally apurinic/apyrimidinic endonuclease, APE1, was believed to help turnover the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three-to-five-fold. Moreover, we have shown UV-DDB can assist chromatin decompaction facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER.

Base excision repair (BER) is the predominant pathway to remove most forms of hydrolytic, oxidative and alkylative DNA damage. The precise functioning of BER is achieving by the regulation of each step by regulatory/accessory proteins, with the most important of which being poly(ADP-ribose) polymerase 1 (PARP1). The PARP1 regulatory functions extend to many cellular processes including regulation of mRNA stability and decay. PARP1 can therefore affect BER both at the level of the BER proteins and at the level of their mRNAs. Systematic data on how the PARP1 content affects the activities of key BER proteins and the levels of their mRNAs in human cells are extremely limited. In this study the CRISPR/Cas9 based technique has been used to knocked out the PARP1 gene in the human HEK 293FT line. The obtained cell clones with putative PARP1 deletion were characterized by several approaches including: PCR analysis of deletions in genomic DNA, Sanger sequencing of genomic DNA, qPCR analysis of PARP1 mRNA, western-blot analysis of whole-cell-extract proteins with anti-PARP1 antibodies, and the PAR synthesis in the whole-cell-extracts. qPCR analysis of mRNAs coding the BER related proteins: PARP2, uracil DNA glycosylase 2, AP endonuclease 1, DNA polymerase β, DNA ligase III and XRCC1 did not reveal crucial influence of PARP1 knockout. The corresponding catalytic activities in the whole-cell extracts (WCEs) evaluated in parallel did not differ significantly between mutant and parental cell lines. No considerable influence of poly(ADP-ribose) synthesis on the activity of the above WCE enzymes was revealed.

The paper discusses the classification of fuzzy metrics based on their continuity conditions, dividing them into Erceg, Deng, Yang-Shi, and Chen metrics. It explores the relationships between these types of fuzzy metrics, concluding that a Deng metric in [0,1]-topology must also be Erceg, Chen, and Yang-Shi metrics. The paper also proves that the product of countably many Deng pseudo-metric spaces remains a Deng pseudo-metric space, and demonstrates some σ-locally finite properties of Deng metric space. Additionally, the paper constructs two interrelated mappings based on normal space and concludes that if a [0,1]-topological space is T1 and regular, and its topology has a σ-locally finite base, then it is Deng metrizable, and thus Erceg, Yang-Shi, and Chen metrizable as well.

The study of the surface thermodynamic properties of solid materials is primordial for the determination of the dispersive surface energy, polar enthalpy of adsorption and Lewis’s acid base properties of solid particles. Inverse gas chromatography technique (IGC) at infinite dilution is the best surface technique for the determination of the surface physicochemical properties of materials. (1) Background: This paper was devoted to study the surface properties of solid materials such as alumina particles by using IGC technique. (2) Methods: Different methods and molecular models such as spherical, cylindrical, van der Waals, Redlich-Kwong, Kiselev and geometric models, were used to determine the London dispersive surface energy of solid surfaces. Hamieh model was also used and highlighted the thermal effect on the surface area of solvents. (3) Results: The variations of the dispersive surface energy and the free energy of adsorption were determined for alumina particles as a function of the temperature as well as their Lewis’s acid base constants. Alumina surfaces were proved to exhibit a strong Lewis amphoteric character three time more basic than acidic (4) Conclusions: The new methodology based on Hamieh model gave the more accurate results of the physicochemical properties of the particle surfaces.

Blood gas analysis is a diagnostic tool to evaluate the partial pressures of gas in blood and acid-base content. The use of blood gas analysis enables to clear understanding the respiratory, circulatory, and metabolic disorders. The arterial blood gas (ABG) explicitly analyzes blood taken from an artery, assessing the patient's partial pressure of oxygen (PaO2), carbon dioxide (PaCO2) pH (acid/base). PaO2 indicates the oxygenation status, and PaCO2 indicates the ventilation status (chronic or acute respiratory failure). PaCO2 is affected by hyperventilation characterized by rapid or deep breathing, and hypoventilation characterized by slow or shallow breathing. The acid-base balance tested by the ABG procedure measures the pH and PaCO2 directly while the use of the Hasselbach equation gives the serum bicarbonate (HCO3) and base deficit or excess. The measured HCO3is based on strong alkali that frees all CO2 in serum, including dissolved CO2, carbamino compounds, and carbonic acid the calculation uses a standard chemistry analysis giving the amount of "total CO2", the difference will amount to around 1.2 mmol/L. Though ABG is frequently ordered in emergency medicine contests for acute conditions it may also be needed in other clinical settings. The ABG analysis shows to be an exceptional diagnostic tool including the group of those diseases known as acid-base diseases (ABDs) which include a great variety of conditions as such severe sepsis, septic shock, hypovolemic shock, diabetic ketoacidosis, renal tubular acidosis, chronic respiratory failure, chronic heart failure, and diverse metabolic diseases.

Surface processes such as coatings, corrosion, photocatalysis, and tribology are greatly diversified by acid-base interaction at the surface overlayer. This study focuses on the action of metallic copper surface as an electron donor/acceptor related to inactivation of viruses; it was found that regarding Cu2O or Cu materials electrostatic interaction plays a major role in virus inactivation. We applied TPPE method to clarify the mechanism of electron transfer (ET) occurring at light irradiated copper surfaces. The TPPE characteristics was strongly influenced by the environments, which correspond to the temperature and environment dependence of the total count of emitted electrons in the incident light wavelength scan (PE total count, NT), the photothreshold, and further the activation energy (E) analyzed from Arrhenius plot of NT values obtained in the temperature-increase and subsequent temperature-decrease processes. In this study we reexamined the dependence of the TPPE data from two types of Cu metal surfaces: Sample A, which was mechanically abraded in alcohols, water, and air, and Sample C, which was only ultrasonically cleaned in these liquids. The NT for both Samples slowly increased with increasing temperature, reached a maximum (NTmax) at 250C (maximum temperature, Tmax), and after that decreased. For Sample A the NTmax value decreased in the order H2O > CH3OH > C2H5OH > (CH3)2CHOH > C3H7OH, although the last alcohol gave Tmax = 100C, while with Sample C the NTmax value decreased in the order: C3H7OH > (CH3)2CHOH > C2H5OH > CH3OH > H2O. Interestingly, both orders of the liquids were completely opposite: this means that Cu surface can possess two-way character. The NT intensity was found to be strongly associated with the change of the hydroxyl group (Cu-OH) to the oxide oxygen (O2) in the O1s spectra in the XPS measurement. The difference between the above orders was explained by the acid-base interaction mode of the Cu-OH group with the adsorbed molecule on the surfaces. The H2O adsorbed on Sample A produces the electric dipole Cu-OH+---:OH2 (--- hydrogen bond), while the C3H7OH and (CH3)2CHOH adsorbed on Sample C produce ROH+---:O(H)-Cu (R = alkyl groups). Gutmann’s acceptor number (AN) representing the basicity of the liquid molecules was found to be related to the TPPE characteristics: (CH3)2CHOH (33.5), C2H5OH (37.1), CH3OH (41.3), H2O (54.8) (the AN of C3H7OH could not be confirmed). With Sample A the values of NTmaxa and EaUp1 both increased with increasing AN (Up1 means the 1st temperature-increase process). On the other hand, with Sample C the values of NTmaxc and EcUp1 both decreased with increasing AN. These findings suggest that Sample A acts as an acid, while Sample C functions as a base. However, in the case of both types of Samples A and C the NTmax values were found to increase with increasing EUp1. It was explained that the EUp1 values depending on the liquids originate from the difference in the energy level of the hydroxyl group radical at the surface denoted. This is able to attract electrons in the neighborhood of the Fermi level of the base metal by tunnelling. After that due to Auger emission electrons are released, leading to the ET in the overlayer. These electrons are considered to have a strong ability of reducibility.

Hexakis(2-alkoxy-1,5-phenyleneimine) macrocycles were synthesized using a simple one−pot procedure through by precipitation−driven cyclization. The acetal−protected AB−type monomers, 2-alkoxy-5-aminobenzaldehyde diethyl acetals, underwent polycondensation in water or acid−containing tetrahydrofuran. The precipitation−driven cyclization based on imine dynamic covalent chemistry and π−stacked columnar aggregation played a decisive role in the one−pot synthesis. The progress of the reaction was analyzed by MALDI−TOF mass spectrometry. The macrocycles with alkoxy chains were soluble in specific organic solvents such as chloroform, allowing their structures to be analyzed by NMR. The shape−anisotropic, nearly planar, and persistent macrocycles aggregated into columnar assemblies in polymerization solvents, driven by aromatic π−stacking. The octyloxylated macrocycle OcO−Cm6 exhibited an enantiotropic columnar liquid crystal−like mesophase between 165°C and 197°C. In the SEM image of (S)-(−)-3,7-dimethyloctyloxylated macrocycle (−)BCO-Cm6, columnar substances with a diameter of 100−200 nm were observed. The polymerization solution for 2-(2-methoxyethoxy)ethoxy)ethoxylated macrocycle (TEGO−Cm6) gelled and showed thixotropic properties by forming a hydrogen bond network.

Chatbots have gained widespread popularity for their task automation capabilities and consistent availability in various domains, including education. However, their ability to adapt to the continuously evolving and dynamic nature of knowledge is limited. This research investigates the implementation of an internet wizard to enhance the knowledge base of an open-domain question-answering chatbot. The proposed approach leverages search engines, particularly Google, and its features, including feature snippets, knowledge graph, and organic search, in conjunction with data science and natural language models. This mechanism empowers the chatbot to dynamically access the extensive and up-to-date knowledge available on the web, enabling the provision of real-time and pertinent answers to user queries sourced from web documents. A pilot study in a higher education context evaluated the chatbot's mechanism and features, confirming its proficiency in generating responses across a broad range of educational and non-educational topics. Positive feedback and high user satisfaction validate these findings. Notably, the chatbot's dynamic feature of retrieving related or follow-up questions from search engines significantly enhances student engagement and facilitates exploration of supplementary information beyond the curriculum.

The absolute time and relative time are defined in terms of the 4-D Euclidean space. Our universe is the 3-D x₁x₂x₃ quantized photon space which follows the absolute time simultaneity when the universe moves along the absolute time axis of ct. The length expansion of Dx = gDx₀ is derived under the condition of the absolute time (ct) simultaneity. From the similarity between this length expansion of Dx = gDx₀ and the energy increasing of E = gE₀, it is assumed that the energy is proportional to the particle size of Dx. The extension of this assumption to the 4-D Euclidean space gives the new definition that the particle energy (E) is the 4-D volume. Then, the particle mass energy is defined as E= mc² = cDtDV = gE₀. The masses of the elementary particles are originated from the 4-D warped volume of the photon space because the particle is the warped photon space with the velocity of v < c. Therefore, the Higgs boson concept in the standard model (SM) is not needed in the present 3-D quantized space model (TQSM). The scalar boson with the spin of zero, photon with the spin of 1 and graviton with the spin of 2 are the two-boson states. Therefore, the observed Higgs boson is reinterpreted as the two-boson state of the scalar boson with the spin of zero. The cosmic muon observation and twin paradox are explained by using the absolute time and relative time. The relative time is the observed time in the twin paradox and cosmic muon observation. In the twin paradox, a person who travels the long distance is more aged than a person on the earth in terms of the relative time ages because of the space and time conversion effect (STCE effect) of the moving space distance (x). But twins are in the same ages in terms of the absolute time without STCE effect. The fast-moving cosmic muon has the expanded half-life from the time expansion of the relative time. Also, the quantum entanglement and Pauli exclusion principle are explained. The quantum base of the photon space line connects two entangled particles. Two particles and quantum base system is fluctuated along the absolute time axis by the time clicking when one particle is measured. Another particle is instantly selected by the time clicking. This is called as the quantum entanglement. The photons which are the flat photon space with the constant speed of c along the space axis and absolute time axis have the 4-D photon velocity of c_eff = 2^0.5 c. Total 10-D Euclidean space including three 3-D quantized spaces and one absolute time axis is required for the electric charges (EC), lepton charges (CC) and color charges (CC) of the elementary particles. The 3-D photon space is very stiff along the absolute time (ct) axis and very soft along the space axes. The Coulomb force through the photons (2EM waves) of the space fluctuations is much stronger than the Gravitational force through the gravitons (G waves) of the time fluctuations between two electrons.

Coronavirus Disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm,” and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy Bodies made of α-Synuclein protein encoded by synuclein alpha (SNCA). This study presents the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis, the study identifies the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream Effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

Emulsion stabilisation of base layers surfaced with chip seals often proves problematic with chips punching into the base and early distress. This can be aggravated by the use of modified binders that restricts the evaporation of moisture from pavement layers. The introduction of New-age (Nano) Modified Emulsion (NME) stabilisation has the advantage that water is chemically repelled from the stabilised layer resulting in an accelerated development of strength. A need was identified to evaluate the early life performance of selected chip seals, together with identified binders. Three different chip seal surfacings with unconventional modified binders were constructed and evaluated using Accelerated Pavement Testing (APT) with the MMLS3. The objectives of the experimental design and testing were to evaluate binder performance, early loss of chips before chip orientation at low temperatures, punching of the chips into the NME stabilised base, deformation characteristics of a Cape seal and the effect of the use of a standard normal modified binder. This paper contains details of the NME base layer, the binder and seal selection and the test results. It is shown that a cost-effective thin chip seal in combination with a suitable binder can be used on a NME stabilised base with confidence.