Modification the biodegradable matrix was carried by graft-copolymerization polylactide with methacrylic acid of various concentrations. Ultraviolet irradiation with different exposure times to the samples was chosen as the initiator of copolymerization. In the experiment the effect of ultraviolet light on polylactide and graft copolymerization was investigated: the resulting samples were studied by viscosimetry, gravimetry, FTIR, static cation- exchange capacity analysis . The conditions for obtaining grafted copolymers and the dependence of the characteristics on the reaction conditions are established.

In eukaryotes, the Dph1•Dph2 dimer is a non-canonical radical SAM enzyme. Using iron-sulfur (FeS) clusters, it cleaves the cosubstrate S-adenosyl-methionine (SAM) to form a 3-amino-3-carboxy-propyl (ACP) radical for synthesis of diphthamide. The latter decorates a histidine residue on elongation factor 2 (EF2) conserved from archaea to yeast and humans and is important for accurate mRNA translation and protein synthesis. Guided by evidence from archaeal orthologues, we searched for a putative SAM binding pocket in Dph1•Dph2 from Saccharomyces cerevisiae. We predict a SAM binding pocket near the FeS cluster domain that is conserved across eukaryotes in Dph1 but not Dph2. Site-directed DPH1 mutagenesis and functional characterization by assays diagnostic for loss of diphthamide reveal the SAM pocket is essential for synthesis of the décor on EF2 in vivo. Further evidence from structural modeling suggests particularly critical residues close to the methionine moiety of SAM. Presumably, they facilitate a geometry specific for SAM cleavage and ACP radical formation that distinguishes Dph1•Dph2 from classical radical SAM enzymes, which generate canonical 5′-deoxyadenosyl (dAdo) radicals.

Abstract: Scavenging of electrogenerated superoxide radical anion (O2•−) by pyrogallol (PyH3) was investigated on the basis of cyclic voltammetry and in situ electrolytic electron spin resonance spectrum in N,N-dimethylformamide with the aid of density functional theory (DFT) calculations. Quasi-reversible dioxygen/O2•− redox coupe was modified by the presence of PyH3, suggesting that O2•− was scavenged by PyH3 through proton-coupled electron transfer (PCET) involving two proton transfer and one electron transfer. The DFT calculation suggested that the formation of hydrogen bond (HB) complex and the subsequent concerted-two-proton coupled electron transfer (2PCET) characterized by catechol moiety in PyH3 is plausible mechanism which embodies the superior kinetics of the O2•− scavenging by PyH3 as shown in the electrochemical results. Furthermore, it was clarified that three hydroxyl groups of PyH3 promote the formation of prereactive HB complex, in comparative analyses using related compounds, resulting the promotion of the O2•− scavenging.

The accuracy of multi-parametric MRI (mpMRI) in pre-operative staging of prostate cancer (PCa) remains controversial. Objective: To evaluate the ability of mpMRI to accurately predict PCa extra-prostatic extension (EPE) on a side-specific basis using a risk-stratified 5-point Likert scale. This study also aimed to assess the influence of mpMRI scan quality on diagnostic accuracy. Patients and Methods: We included 124 men who underwent robot-assisted RP (RARP) as part of the NeuroSAFE PROOF study at our centre. Three radiologists retrospectively reviewed mpMRI blinded to RP pathology and assigned a Likert score (1-5) for EPE on each side of the prostate. Each scan was also ascribed a Prostate Imaging Quality (PI-QUAL) score for assessing the quality of the mpMRI scan, where 1 represents poorest and 5 represents best diagnostic quality. Outcome measurements and statistical analyses: Diagnostic performance is presented for binary classification of EPE including 95% confidence intervals and area under the receiver operating characteristic curve (AUC). Results: A total of 231 lobes from 121 men (mean age 56.9 years) were evaluated. 39 men (32.2%), or 43 lobes (18.6%) had EPE. Likert score ≥3 had sensitivity (SE), specificity (SP), NPV, PPV of 90.4%, 52.3%, 96%, 29.9%, respectively, and AUC was 0.82 (95% CI: 0.77-0.86). AUC was 0.63 (95% CI: 0.37-0.9), 0.77 (0.71-0.84) and 0.92 (0.88-0.96) for biparametric scans, PI-QUAL 1-3 and PI-QUAL 4-5 scans, respectively. Conclusions: MRI can be used effectively by genitourinary radiologists to rule out EPE and help inform surgical planning for men undergoing RARP. EPE prediction was more reliable when the MRI scan was a) multi-parametric and b) of a higher image quality according to the PI-QUAL scoring system.

Abstract: Elimination of superoxide radical anion (O2•−) by tocopherols (TOH), and related compounds was investigated on the basis of cyclic voltammetry and in situ electrolytic electron spin resonance spectral measurements in N,N-dimethylformamide (DMF) with the aid of density functional theory (DFT) calculations. Quasi-reversible O2/O2•− redox was modified by the presence of TOHs, suggesting that the electrogenerated O2•− was eliminated by α-, β-, γ-TOH through proton-coupled electron transfer (PCET), but not by δ-TOH. The structure–activity correlation of α-, β-, γ-, and δ-TOH characterized by methyl group on the 6-chromanol ring was experimentally confirmed, where the methyl group promotes the PCET mechanism. Furthermore, comparative analyses using some related chemical analogues suggested that methoxyl group of the 6-chromanol ring is required for a successful electron transfer (ET) to O2•− through the PCET. The electrochemical and DFT results in dehydrated DMF suggested that the PCET mechanism involves preceding proton transfer (PT) forming hydroperoxyl radical followed by a concerted PCET (ET–PT). The O2•− elimination by TOH proceeds efficiently along the net PCET mechanism involving one ET and two PTs.

The elimination of superoxide radical anions (O2•−) by 5-amino-2-hydroxybenzoic acid (mesalazine, 5-ASA), 4-amino-2-hydroxybenzoic acid (4-ASA), and related compounds used for ulcerative colitis treatment was investigated using cyclic voltammetry and electron spin resonance (ESR) analyses aided by density functional theory (DFT) calculations. Quasi-reversible O2/O2•− redox was found to be modified by the compounds, suggesting that an acid-base reaction in which a hydroperoxyl radical (HO2•) is formed from O2•− occurs. However, the deprotonated 5-ASA anion can eliminate O2•− through proton-coupled electron transfer (PCET), forming a radical product. This electron transfer (ET) was confirmed by ESR analysis. The 4-aminophenol moiety in 5-ASA plays an important role in the PCET involving two proton transfers and one ET based on -conjugation. The electrochemical and DFT results indicated that O2•− elimination by 5-ASA proceeds efficiently viathrough the PCET mechanism after deprotonation of the 1-carboxyl group. Thus, 5-ASA may act as an anti-inflammatory agent in the alkali intestine through PCET-based O2•− elimination.

Wasted Green tuff powder produced by cutting Towada stone is recycled as environmental cleaning material. The optimum temperature for green tuff powder calcination to reduce the hydroxyl radical produced in hydrogen peroxide decomposition with ultraviolet light (UV) and no light. The green tuff calcined at 800 °C shows the large decomposition rate of hydrogen peroxide with no UV light when measured by using ESR. With UV light, the optimum temperature for calcinating the green tuff powder in order to reduce hydroxyl radical is also 800 °C. Next, the powder calcined at 800 °C is used to produce the tile by compression and heating, and then the formaldehyde adsorption rate was measured. The green tuff powder calcined at 800 °C showed a high adsorption rate, similar to that of the activated carbon. The tiles formed at 40 MPa and heated st 1100 °C were the strongest and also adsorbed formaldehyde. The adsorbed formaldehyde on the green tuff tile and powder might have a possibility to decompose by photocatalytic.

The detection and analysis of small molecules, typically defined as molecules under 1000 Da, is of growing interest ranging from the development of small molecule drugs and inhibitors to the sensing of toxins and biomarkers. However, due to challenges such as their small size and low mass, many biosensing technologies struggle to have the sensitivity and selectivity for the detection of small molecules. Notably, their small size limits the usage of labeled techniques that can change the properties of small molecule analytes. Furthermore, the capability of real-time detection is highly desired for small molecule biosensors’ application in diagnostics or screening. This review highlights recent advances in label-free real-time biosensing technologies utilizing different types of transducers to meet the growing demand for small molecule detection.

Bloodstream infection is a major health problem worldwide, with extremely high mortality. Detecting infection in the early stage is challenging due to the extremely low concentration of bacteria in the blood. Digital PCR provides unparalleled sensitivity and can achieve absolute quantification, but it is time-consuming. Moreover, the presence of unavoidable background signals in negative controls poses a significant challenge for single-molecule detection. Here, we propose a novel strategy called “Ultrafast flexible thin tube-based droplet digital PCR (utPCR)” that can shorten the digital PCR process from 2 hours to only 5 minutes, with primer annealing/extension time reduced from minutes to only 5 seconds. Importantly, the ultrafast PCR eliminates the nonspecific amplification and thus enables single-molecular detection. The utPCR enabled sensitive detection and digital quantification of E. coli O157 in the high background of 106-fold excess of E. coli K12 cells. Moreover, this method also displayed the potential to detect rare pathogens in blood samples, and the limit of detection (LOD) could be as low as 10 CFU per mL of blood without false positive results. Considering ultrafast (<5 min) and highly sensitive (single-molecule detection), the utPCR holds excellent prospects in the next generation of molecular diagnosis.

Cytochrome P450 monooxygenases (P450s) are promising versatile oxidative biocatalysts. However, the practical use of P450s in vitro is limited by their dependence on the co-enzyme NAD(P)H and the complex electron transport system. Using H2O2 simplifies the catalytic cycle of P450s; however, most P450s are inactive in the presence of H2O2. By mimicking the molecular structure and catalytic mechanism of natural peroxygenases and peroxidases, an artificial P450 peroxygenase system has been designed with the assistance of a dual-functional small molecule (DFSM). DFSMs, such as N-(ω-imidazolyl fatty acyl)-l-amino acids, use an acyl amino acid as an anchoring group to bind the enzyme, and the imidazolyl group at the other end functions as a general acid-base catalyst in the activation of H2O2. In combination with protein engineering, the DFSM-facilitated P450 peroxygenase system has been used in various oxidation reactions of non-native substrates, such as alkene epoxidation, thioanisole sulfoxidation, and alkanes and aromatic hydroxylation, which showed unique activities, and regio- and enantioselectivities when compared with native P450s. Moreover, the DFSM-facilitated P450 peroxygenase system can switch to the peroxidase mode by mechanism-guided protein engineering. In this short review, the design, mechanism, evolution, application, and perspective of these novel non-natural P450 peroxygenases for the oxidation of non-native substrates are discussed.

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.

With the inclusion of snakebite envenoming on the World Health Organisation’s list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Different technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins, as well as peptide and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors, varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.

Objectives: This study aimed to assess the impact of a predictive model for detecting extracapsular extension on pathology (pECE+) on biochemical recurrence-free survival (BCRFS) within 4 years after robotic-assisted radical prostatectomy (RARP). Methods: Retrospective data analysis from a single center between 2015 to 2022. Variables under consideration included prostate-specific antigen (PSA) levels, patient age, prostate volume, MRI semantic features and Gleason score (GS). We also assessed the influence of pECE+ and positive surgical margins on BCRFS. using the Kaplan-Meier survival function and Cox regression model were assessed. Additionally, we analyzed the MRI features on BCR (biochemical recurrence) in low/intermediate risk patients. Results: 177 participants with a follow-up exceeding 6 months post-RARP were included. The 1-year, 2-year, and 4-year risks of BCR after curative prostatectomy were 5%, 13%, and 21%, respectively. The survival analysis showed that adverse MRI features as macroscopic ECE on MRI (mECE+), capsular disruption, high tumor capsular contact length (TCCL), GS≥8, positive surgical margins (PSM), and pECE+ on pathology were risk factors for BCR. In low/intermediate-risk patients (pECE- and GS &lt;(4+4)) the presence of adverse MRI features, has been shown to increase the risk of BCR. Conclusions: The study highlights the importance of incorporating predictive MRI features for detecting extracapsular extension pre-surgery in influencing early outcomes and clinical decision-making; mECE+, TCCL, capsular disruption, and GS≥8 based on pre-surgical biopsy were independent prognostic factors for early BCR. The presence of adverse features on MRI can assist in identifying low/intermediate-risk patients who would benefit from closer monitoring.

The vacuum preloading method effectively strengthens the soft soil foundations with vertical drainage, which will produce a smear effect when laying sand drains. Meanwhile, the seepage of pore water and soil deformation during consolidation exhibits nonlinear characteristics. Therefore, based on Gibson's 1D large strain consolidation theory, this paper developed a more generalized large strain radical consolidation model of sand-drained soft foundations under free strain assumption. In this system, the double logarithmic compression permeability relationships for soft soils with large strain properties, the variation of the radical permeability coefficient in the smear zone, and the effect of the non-Darcy flow were all included. Then, the partial differential control equations were numerically solved by the finite difference method and validated with existing radical consolidation test results and derived analytical solutions. Finally, the influences of relevant model parameters on consolidation are discussed. The analysis shows that the greater the maximum dimensionless vacuum negative pressure P0, the faster the consolidation rate of sand-drained foundations. Meanwhile, the decrease in the negative pressure transfer coefficient k1 will result in a decreasing final settlement amount. Moreover, the consolidation rate of sand-drained foundations is slower considering the non-Darcy flow, but the final settlement is unaffected.

The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.

Poly(2-methoxyethyl acrylate) (PMEA) and poly(ethylene oxide) (PEO) have protein-antifouling properties and blood compatibility. ABA triblock copolymers (PMEAn-PEO11340-PMEAn (MEOMn)) were prepared using single-electron transfer-living radical polymerization (SET-LRP) using a bi-functional PEO macroinitiator. Two types of MEOMn composed of PMEA blocks with a degree of polymerization (DP = n) of 85 and 777 were prepared using the same PEO macroinitiator. MEOMn formed flower micelles with a hydrophobic PMEA (A) core and hydrophilic PEO (B) loop shells in diluted water with a similar appearance to petals. The hydrodynamic radii of MEOM85 and MEOM777 were 151 and 108 nm, respectively. The PMEA block with a large DP formed a tightly packed core. The aggregation number (Nagg) of the PMEA block in a single flower micelle for MEOM85 and MEOM777 was 156 and 164, respectively, which were estimated using a light scat-tering technique. The critical micelle concentrations (CMCs) for MEOM85 and MEOM777 were 0.01 and 0.002 g/L, respectively, as determined by the light scattering intensity and fluorescence probe techniques. The size, Nagg, and CMC for MEOM85 and MEOM777 were almost the same inde-pendent of hydrophobic DP of the PMEA block.

The current study aims to study the optimal fermentation conditions for producing microbial bioactive compounds. The microwave parameters consist on 2450 MHz, and 500-watt for 20, 30, and 40 seconds. The solubility of solvents was tested for the extraction of antioxidant compounds from fermented rice (Koji) by A. flavus, Ethyl acetate was the best solvent used for extraction purposes. Antioxidant properties were differentiated by blocking the oxidation of the linoleic acid with an inhibition rate of 73.13% at a concentration of 200 mg/mL, in addition to increasing its effectiveness for free radical extraction and reduction strength by increasing concentrations gradually. The bond ability to irons was lower compared to the EDTA-2Na, in addition to the obtained total content corresponding to phenolic compounds in the ethyl acetate extract of fermented rice (Koji) by A. flavus was 232.11 mg, on the basis of galic acid/mg. The stability of the antioxidant compounds of the ethyl acetate extract of fermented rice (Koji) by A. flavus was also studied; showing stability under neutral conditions, as well as at high temperatures (185 °C during two hours). However, no stability was obtained under acidic and alkaline conditions.

In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) might prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function, e.g., inhibition of GP. Herein, the Suárez radical methodology is successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not been previously constructed via a radical pathway, starting from 6-hydroxymethyl-b-D-glucopyranosyluracil. It is shown that in the rigid pyranosyl conformation the required [1,5]-radical translocation is a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the ¹H NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.

The simplistic morphological characteristics of the Carica papaya, papaya or ‘pawpaw’ should not be the cause for underestimating its potential as a nutraceutical. The market for papaya has been expanding at a staggering rate, partly due to its applicability as a biofortified product, but mostly for its phytochemical properties and traditional health benefits. Recent characterization studies have showed that the entirety of papaya or using a formulation of fermented papaya promotion (FPP) displays effective free radical scavenging abilities, thought to be influenced by its phenolic, carotenoids, flavonoid or amino acid profile. Aiming at reducing the impact of free radical-induced oxidative damage in the human system, the antioxidant properties of FPP have been found to potently target a broad spectrum of diseases ranging from neurological impairments such as senile dementia to systemic diseases, to its interference at the cellular level and support of normal biological ageing processes. FPP has thus been extensively investigated for its ability to exert cellular protective effects and reduce oxidative stress via mitigation of genetic damage, lipid peroxidation and enzymatic inactivation in diseases. Oxidative stress reduction strategies using FPP and its holistic approach in disease prevention and management, with a focus on diabetes, cancer and cognitive health, contributes unequivocally to wellness in an aging population.

From the aerial parts of Salvia ballotiflora, eleven diterpenoids were isolated, among them, four icetexanes, and one abietane (1–5), which are first reported. Their structures were established by spectroscopic means, mainly ¹H and ¹³C NMR, including 1D and 2D homo- and hetero-nuclear experiments. Most of the isolated diterpenoids were tested for their antiproliferative, anti-inflammatory, and radical scavenging activities using the sulforhodamine B assay on six cancer cell lines, the TPA induced ear edema test in mice, and the reduction of the DPPH assay, respectively. Some diterpenoids showed anti-proliferative activity, these being icetexanes 6 and 3, which were the most active with IC₅₀ (µM) = 0.27 ± 0.08 and 1.40 ± 0.03, respectively, for U251 (human glioblastoma) and IC₅₀ (µM) = 0.0.46 ± 0.05, and 0.82 ± 0.06 for SKLU-1 (human lung adenocarcinoma), when compared with adriamycin (IC₅₀ (µM) = 0.08 ± 0.003, and 0.05 ± 0.003, as the positive control, respectively. Compounds 3 and 10 showed significant reduction of the induced ear edema of 37.4 ± 2.8 and 25.4 ± 3.0% (at 1.0 µmol/ear), respectively. Compound 4 was the sole active diterpenoid in the antioxidant assay (IC₅₀ = 98. 4 ± 3.3), using α-tocopherol as positive control, IC₅₀ (µM) = 31.7 ± 1.04. The diterpenoid profile found is of chemotaxonomic relevance and reinforces the evolutionary link of S. ballotiflora with other members of the section Tomentellae.

Nitric oxide (NO) is synthesized and is involved in various physiological and developmental process regulation in all kingdoms of life. Fungi have been less explored in terms of endogenous NO biology than mammals, plants, and bacteria. In this review, we summarize and discuss the studies to date on intracellular NO biosynthesis and function in fungi. Two mechanisms for NO biosynthesis, NO synthase (NOS)-mediated arginine oxidation, and nitrate and nitrite reductase-mediated nitrite reduction, are most frequently reported. Furthermore, we summarize the multifaceted functions of NO in fungi, as well as its role as a signaling molecule in fungal growth regulation, development, abiotic stress, virulence regulation, and metabolism. Finally, we present potential directions for future research on fungal NO biology.

The rate constants of elementary processes in the atom-diatom system O(³P)+H₂(v), including the processes of vibrational relaxation and dissociation, were studied using the quasi-classical trajectory method. All calculations were carried out along the ground potential energy surface (PES) ³A′′ that was approximated by a neural network. Approximation data were obtained using ab initio quantum chemistry methods at the extended multi-configuration quasi-degenerate second-order perturbation theory XMCQDPT2 in a basis set limit. The calculated cross sections of the reaction channels are in good agreement with the literature data. A complete set of state-to-state rate constants was obtained for the metathesis reaction, the dissociation and VT relaxation of the H₂ molecule upon collision with an O atom. According to this data Arrhenius approximations over a wide temperature range were obtained for the thermal rate constants of considered processes. Data obtained on the dissociation constants and VT relaxation of vibrationally excited H₂ molecules can be used in constructing kinetic models describing the oxidation of hydrogen at high temperatures or highly nonequilibrium conditions.

Single-molecule fluorescence detection (SMFD) experiments are useful in distinguishing sub-populations of molecular species when measuring heterogeneous samples. One experimental platform for SMFD is based on a confocal microscope, where molecules randomly traverse an effective detection volume. The non-uniformity of the excitation profile and the random nature of Brownian motion, produce fluctuating fluorescence signals. For these signals to be distinguished from the background, burst analysis is frequently used. Yet, the relation between the results of burst analyses and the underlying information of the diffusing molecules is still obscure and requires systematic assessment. In this work we performed three-dimensional Brownian motion simulations of SMFD, and tested the positions at which molecules emitted photons that passed the burst analysis criteria for different values of burst analysis parameters. The results of this work verify which of the burst analysis parameters and experimental conditions influence both the position of molecules in space when fluorescence is detected and taken into account, and whether these bursts of photons arise purely from single molecules, or not entirely. Finally, we show, as an example, the effect of bursts that are not purely from a single molecule on the accuracy in single-molecule Förster resonance energy transfer measurements.

The nuclear lamina consists of a dense fibrous meshwork made of nuclear lamins, Type V intermediate filaments, and is ~14 nm thick according to recent cryo-electron tomography studies. Recent advances in light microscopy have extended the resolution to a scale allowing for the fine structure of the lamina to be imaged in the context of the whole nucleus. We review quantitative approaches to analyze the imaging data of the nuclear lamina as acquired by structured illumination microscopy (SIM) and single molecule localization microscopy (SMLM), as well as the requisite cell preparation techniques. In particular, we discuss the application of steerable filters and graph based methods to segment the structure of the four mammalian lamin isoforms (A, C, B1, and B2) and extract quantitative information.

(1) Background: Retroareolar breast tumors are common, but they rarely progress to malignancy. This report presents a case of a 41-years-old woman with a superficial breast tumor, emphasizing the significance of considering a wide range of options when evaluating breast lumps. (2) Methods: The patient presented with a steadily growing, ulcerating superficial tumor in her left breast. To determine the nature of the tumor, a diagnostic assessment was conducted, which included a positron emission tomography (PET) scan and histological analysis. (3) Results: The diagnostic assessment confirmed the presence of a malignant Grade II superficial infiltrating ductal carcinoma. Following the diagnosis, the patient underwent a modified radical mastectomy under general anesthesia. Subsequently, she received four cycles of adjuvant chemotherapy, followed by taxol administrations. (5) Conclusions: This case report underscores the importance of conducting a thorough examination and maintaining a high index of suspicion for breast tumors. By documenting this case, the report contributes to the existing knowledge on various manifestations of breast cancer and highlights the necessity of early identification and aggressive treatment. This knowledge can be applied to identify and manage similar cases in the future, leading to improved patient outcomes.

The synergic features and enhancing strategies for various photopolymerization systems are reviewed by kinetic schemes and the associated measurements. The important topics include: (i) photo crosslinking of corneas for the treatmnet of corneal deseases using UVA-light (365 nm) light and riboflavin as the photosensitizer; (ii) synergic effects by a dual-function enhancer in a 3-initiator system; (iii) synergic effects by a 3-initiator C/B/A system, having an electron-transfer and oxygen-mediated energy-transfer pathways; (iv) copper-complex (G1) photoredox catalyst in G1/Iod/NVK systems for free radiical (FRP) and cationic photopolymeriation (CP); (v) radical-mediated thiol-ene (TE) photopolymerizations; (vi) superbase photogenerator based-catalyzed thiol−acrylate Michael (TM) addition reaction; and the combined system of TE and TM usinghual wavelength; (vii) dual-wavelength (UV and blue) controlled photopolymerization confinement (PC); (viii) dual-wavelength (UV and red) selectively controlled 3D printing; and (ix) 3-wavelength selectively controlled in 3D printing and additive manufacturing (AM). With minimum mathematics, we present ( for the first time), the synergic features and enhancing strategies for various systems of multi-commponents, initiators, monomers, and under one- two- and there-wavelength light. Therefore, this Review provides not only the bridging between modeling and measurements, but also guidances for further experimantal stuides and new applications in 3D printings and additive manufacturing (AM), based on the innovative concepts (kinetics/schemes).

The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer’s Disease (AD)-like pathology in mice, although mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/ 18F]exchange reaction over IDIF in dimethylsulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7±3% radiochemical yield in a 20 minutes reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t&gt;10 min post administration), rapid accumulation in the liver, long circulation time and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.

The RNA-binding protein Human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. The protein has been progressively recognized as a relevant therapeutic target for several pathologies like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatics approaches, high throughput virtual screening and RNA–protein pull-down assays, we show that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits dose-dependent HuR inhibition in binding experiments. Importantly, the chemical scaffold is new with respect to the so-far known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Thus, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis identified two potent drugs (Cialis and Finasteride) that can efficiently inhibit AKT1 and MDM2 protein signatures respectively, and with better therapeutic properties. We proposed that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Nanometer-curved surfaces are abundant in biological systems as well as in nano-sized technologies. Properly functionalized polymer-grafted nanoparticles (PGNs) adhere to surfaces with different geometries and curvatures. This work explores some of the energetic and mechanical characteristics of the adhesion of PGNs to surfaces with positive, negative and zero curvatures using Coarse-Grained Molecular Dynamics (CGMD) simulations. Our calculated free energies of binding of the PGN to the curved and flat surfaces as a function of separation distance show that curvature of the surfaces critically impacts the adhesion strength. We find that the flat surface is the most adhesive, and the concave surface is the least adhesive surface. This somewhat counterintuitive finding suggests that while a bare nanoparticle is more likely to adhere to a positively curved surface than a flat surface, grafting polymer chains to the nanoparticle surface inverts this behavior. Moreover, we studied the rheological behavior of PGN upon separation from the flat and curved surfaces under external pulling force. The results presented herein can be exploited in drug delivery and self-assembly applications.

A Pt(II) complex featuring chelating tridentate bis-aryloxide tetrahydropyrimidinium based N-heterocyclic carbene (NHC) was synthesized and characterized by using different techniques. The electrochemical properties of the complex were investigated by cyclic voltammetry as well as differential pulse voltammetry, which revealed two reversible one-electron oxidation processes. The chemical generation and isolation of one-electron-oxidized species were performed oxidizing the initial complex by means of AgBF4. The combined UV-Vis/NIR- and EPR-spectroscopy studies supported by density functional theory (DFT) calculations suggest the formation of Pt(II)-phenoxyl radical complex. The latter open-shell derivative was structurally characterized by means of X-ray diffraction analysis. Finally, the neutral platinum complex was tested as a mediator in the process of electrocatalytic oxidation of 2-(methylamino)ethanol (MEA).

The bipartite entanglement is comprehensively investigated in the mononuclear molecular complex (Et3NH)[Ni(hfac)2L], where HL denotes 2-(2-hydroxy-3-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-3-oxide-1-oxyl and hfacH stands for hexafluoroacetylacetone. From the magnetic point of view, the molecular compound (Et3NH)[Ni(hfac)2L] consists of an exchange-coupled spin-1 Ni2+ magnetic ion and a spin-12 nitronyl-nitroxide radical substituted nitrophenol. The nickel-radical molecular complex affords an experimental realization of a mixed spin-(12, 1) Heisenberg dimer with a strong antiferromagnetic exchange coupling J/kB= 505 K and two distinct g-factors gRad=2.005 and gNi=2.275. By adopting this set of magnetic parameters we demonstrate that the Zeeman splitting of a quantum ferrimagnetic ground-state doublet due to a weak magnetic field may substantially reinforce the strength of bipartite entanglement at low temperatures. The molecular compound (Et3NH)[Ni(hfac)2L] maintains sufficiently strong thermal entanglement even at room temperature, vanishing only above 546 K. Specifically, the thermal entanglement in the nickel-radical molecular complex retains approximately 40% of the maximum value corresponding to perfectly entangled Bell states at room temperature, which implies that this magnetic compound provides suitable platform of a molecular qubit with potential implications for room-temperature quantum computation and quantum information processing.

Radical reactions in water or aqueous media are important for organic synthesis, realizing high yielding processes under non-toxic and environmentally friendly conditions. This overview includes (i) a general introduction to organic chemistry in water and aqueous media, (ii) synthetic approaches in-, on- and with-water as well as in heterogeneous phase, (iii) reaction of carbon-centered radicals with water (or deuterium oxide) activated through coordination with various Lewis acids, (iv) photocatalysis in water and aqueous media, and (v) synthetic applications bioinspired from naturally occurring processes. A wide range of chemical processes and synthetic strategies under different experimental conditions have been reviewed that lead to important functional group translocation and transformation reactions, leading to the preparation of complex molecules. These results reveal how water as a solvent/medium/reagent in radical chemistry has matured over the last two decades and how further discoveries are foreseen to come in the near future.

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.

Biological systems are highly regulated. They are also highly resistant to sudden perturbations enabling them to maintain the dynamic equilibrium essential for sustenance of life. This robustness is conferred by regulatory mechanisms that influence the activity of enzymes/proteins within their cellular context, to adapt to changing environmental conditions. However, the initial rules governing the study of enzyme kinetics were tested and implemented for mostly cytosolic enzyme systems that were easy to isolate and/or recombinantly express. Moreover, these enzymes lacked complex regulatory modalities. Now, with academic labs and pharmaceutical companies turning their attention to more complex systems (for instance, multi-protein complexes, oligomeric assemblies, membrane proteins and post-translationally modified proteins), the initial axioms defined by Michaelis-Menten (MM) kinetics are rendered inadequate and the development of a new kind of kinetic analysis to study these systems is required. The current review strives to present an overview of enzyme kinetic mechanisms that are atypical and, oftentimes, do not conform to the classical MM kinetics. Further, it presents initial ideas on the design and analysis of experiments in early drug-discovery for such systems, to enable effective screening and characterisation of small-molecule inhibitors with desirable physiological outcomes.

Modern development of high-intensity and high-resolution X-ray technology allows detailed studies of the multiphoton absorption and scattering of X-ray photons by deep and subvalent shells of molecular systems on a wide energy range. The interpretation of experimental data requires the improvement of computational methods for obtaining excited and ionized electron states of molecular systems with one or several vacancies. The specificity of solving these problems requires the use of molecular orbitals obtained in one-center representation. Slow convergence of one-center expansions is a significant disadvantage of this approach; it affects the accuracy of the calculation of spectroscopic quantities. We offer a method of including higher harmonics in one-center expansion of a molecular orbital with the use of wave functions of electrons of deep shells of a ligand (off-center atom of a molecule). The method allows one to take into account correctly electron density of a linear molecule near the ligand when describing vacancies created in a molecular core leading to radial relaxation of electron density. The analysis of the parameters of one-center expansion of the ligand functions depending on ligand’s charge is performed. The criteria for the inclusion of higher harmonics of one-center decomposition of the ligand functions in the molecular orbital are determined. The efficiency of the method is demonstrated by the example of diatomic molecules HF, LiF, and BF by estimating energy characteristics of their ground and ionized states.

The Dph1•Dph2 heterodimer from yeast is a radical SAM (RS) enzyme that generates the 3-amino-3-carboxy-propyl (ACP) precursor for diphthamide, a clinically relevant modification on eukaryotic elongation factor 2 (eEF2). ACP formation requires SAM cleavage and atypical Cys-bound Fe-S clusters in each Dph1 and Dph2 subunit. Intriguingly, the first Cys residue in each motif locates next to another, ill-defined cysteine that we show in-here is conserved across eukaryotes. As judged from structural modeling, the orientation of these tandem cysteine motifs (TCM) suggests a candidate Fe-S cluster ligand role. Hence, we generated by site-directed DPH1 and DPH2 mutagenesis, Dph1•Dph2 variants with cysteines from each TCM replaced individually or in combination by serines. Assays diagnostic for diphthamide formation in vivo reveal that while single substitutions in the TCM of Dph2 cause mild defects, double mutations almost entirely inactivate the RS enzyme. Based on enhanced Dph1 and Dph2 subunit instability in response to cycloheximide chases, the variants with Cys substitutions in their cofactor motifs are particularly prone to protein degradation. In sum, we identify a fourth functionally cooperative Cys residue within the Fe-S motif of Dph2 and show that the Cys-based cofactor binding motifs in Dph1 and Dph2 are critical for the structural integrity of the dimeric RS enzyme in vivo.

The objective of this study was to develop an ultrasonic-assisted procedure for the extraction of total phenolics from Citrus aurantium L. blossoms (CAB) and evaluate the free radical scavenging activity, anti-HMG-CoA reductase activity of total phenolics. In this work, a Box-Behnken design based on the single-factor experiments was used to explore the optimum extraction process. Under the optimum conditions (extraction solvent 70.31% ethanol, extraction temperature 61.94 °C, extraction time 51.73 min and liquid-to-solid ratio 35.63 mL/g), the extraction yield of total phenolics was 95.84 mg gallic acid equivalents (GAE)/g dry matter (DM), which was highly consistent with the theoretical value (96.12 mg GAE/g DM). The total phenolic extract showed excellent free radical scavenging properties against DPPH·, ABTS+·, ·OH and ·O2-, with the IC50 values of 197.007, 83.878, 218.643 and 158.885 μg/mL, respectively, and the extracts also showed good inhibition of HMG-CoA reductase activity, with the IC50 value of 117.165 μg/mL. Total phenolics from CAB could be a potential source of natural free radical scavenger and HMG-CoA reductase inhibitor.

Polyaromatic hydrocarbons (PAHs) are widespread in the interstellar medium (ISM). The abundance and relevance of PAHs call for a clear understanding of their formation mechanisms, which, to date, have not been completely deciphered. Of particular interest is the formation of benzene, the basic building block of PAHs. It has been shown that ionization of neutral clusters can lead to an intra-cluster ionic polymerization process that results in molecular growth. Ab initio molecular dynamics (AIMD) studies in clusters consisting of 3–6 units of acetylene modeling ionization events under ISM conditions have shown maximum aggregation of three acetylene molecules forming bonded C6H6+ species: the larger the number of acetylene molecules, the higher the production of C6H6+. These results lead to the question of whether clusters bigger than those studied thus far promote aggregation beyond three acetylene units, and whether larger clusters can result in higher C6H6+ production. In this study, we report results from AIMD simulations modeling the ionization of 10 and 20 acetylene clusters. The simulations show aggregation of up to four acetylene units producing bonded C8H8+. Interestingly, C8H8+ bicyclic species were identified, setting precedent for their astrochemical identification. Comparable reactivity rates were shown with 10 and 20 acetylene clusters.

Retrospective information about the climate system and plant ecophysiology are key inputs in climate and Earth system modelling. Dendrochronology provides such information with large spatiotemporal coverage, and stable carbon isotope (¹³C/¹²C) analysis across tree-ring series is among the most advanced dendrochronological tools. For the past seventy years, this analysis was performed on whole molecules, and, to this day, ¹³C/¹²C variation is attributed to ¹³C discrimination during CO₂ diffusion into leaves and assimilation by rubisco. By contrast, ¹³C discrimination by post-rubisco processes is presumed constant. Here, recently reported results on the first dataset of intramolecular ¹³C discrimination in tree rings were synthesised by variance component analysis. The emerging picture is not consistent with the classical (DR-discrimination-centred) concepts and practices of carbon-isotope dendrochronology. Specifically, leaf and stem post-rubisco discrimination each account for more variation in the data than diffusion-rubisco discrimination, i.e., post-rubisco discrimination is not constant. Furthermore, diffusion-rubisco discrimination is used widely as proxy of leaf intrinsic water-use efficiency (iWUE), a key determinant in the responses of global biogeochemical cycles to climate change. However, since diffusion-rubisco discrimination is a small component of the total data variance, whole-molecule analysis yields confounded iWUE estimates, yet intramolecular analysis will likely offer solutions. Lastly, all currently observed ¹³C/¹²C-climate relationships are attributed to diffusion-rubisco discrimination. However, here, relationships with temperature and radiation derive from leaf-level post-rubisco discrimination while relationships with precipitation derive from stem-level post-rubisco discrimination. That said, advances in mass spectrometry may soon make intramolecular ¹³C/¹²C analysis broadly available taking carbon-isotope dendrochronology to the next level.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI–TOF MS) is a commonly used technique for analyzing large biomolecules. However, the utilization of organic matrices limits the small-molecule analysis because of the interferences in the low-mass region and reproducibility issues. To overcome these limitations, a surface-assisted laser desorption/ionization (SALDI), which utilizes nanostructured metallic surfaces, has been developed. Herein, a novel approach for SALDI–MS was proposed using nanoengineered gold shell with nanogaps on the silica core (SiO2@Au NGS), which is an emerging material due to its excellent heat-generating capabilities. The gold shell thickness was controlled by adjusting the concentration of gold precursor for the growth of gold nanoparticles. SALDI-MS measurements were performed on a layer formed by drop-casting a mixture of SiO2@Au NGS and analytes. At the optimized process, the gold shell thickness was observed to be 17.2 nm, which showed the highest absorbance. The ion desorption efficiency was confirmed with a survival yield upon fragmentation. Based on the enhanced SALDI capability, SiO2@Au NGS was utilized to detect various small molecules including amino acids, sugars, and flavonoids. The limits of detection, reproducibility, and salt tolerance of SiO2@Au NGS demonstrate its potential as an effective and reliable SALDI material for small-molecule analyses.

Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

In this study, the optimal condition for the extraction of antioxidants from the fruit Buah Mahkota Dewa (Phaleria macrocarpa) was determined by using Response Surface Methodology (RSM). The optimization was applied using central composite design (CCD) to investigate the three independent variables, namely extraction temperature (^oC), extraction time (minutes) and extraction solvent to-feed ratio (%v/v) on the responses of free radical scavenging activity (DPPH), ferric ion reducing power assay (FRAP), total phenolic content (TPC) and total flavonoid content (TFC).The optimal conditions for the antioxidants extraction were found to be extraction temperature (64^oC), extraction time (66 minutes) and solvent to-feed ratio (75 %v/v) with the highest percentage yield of DPPH, FRAP, TPC and TFC were 86.85%, 7.47%, 292.86 mg/g and 3.22 mg/g respectively. Moreover, the data were subjected to response surface methodology (RSM) and the results showed that the polynomial equations for all models were significant, did not show lack of fit, and presented adjusted determination coefficients (R²) above 99%, proving the yield of phenolic, flavonoid and antioxidants activities obtained experimentally were close to the predicted values and the suitability of the model employed in RSM to optimize the extraction conditions. Hence, in this study, the fruit from P.macrocarpa could be considered to have the strong antioxidant ability and can be used in various cosmeceutical or medicinal applications.

Ribosome assembly is one of the most fundamental processes in gene expression and has served as a playground to investigate the molecular mechanisms of how protein-RNA complexes (RNPs) assemble. The bacterial ribosome is composed of around 50 ribosomal proteins several of which are co-transcriptionally assembled on a ~4,500 nucleotides long pre-rRNA transcript that is further processed and modified during transcription, the entire process taking around 2 minutes in vivo and assisted by dozens of assembly factors. How this complex molecular process works so efficiently to produce an active ribosome has been investigated over decades and has resulted in the development of a plethora of novel approaches that can also be used to study the assembly of other RNPs. Here we review biochemical, structural and biophysical methods that have been developed and integrated to provide a detailed and quantitative understanding of this complex and intricate molecular process of assembly. We also discuss emerging cutting-edge approaches that could be used in the future to study how transcription, rRNA processing, cellular factors and the native cellular environment shape ribosome assembly and RNP assembly at large.

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens including, viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209L family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209L family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate-recognition domain (CRD) and the neck/repeat region represent the key features of CD209L family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While, the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host-pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.

Pulmonary hypertension (PH) has a high mortality, and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type 2 and type 17 responses in C57BL/6 mice. Here, we focused on type 2 response related cytokines, specifically Resistin-like-molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild type or RELMα-/- mice. Vascular remodeling was assessed by histology, right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM2.5, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were more prominent in the C57BL/6 strain. Compared to wild type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV ST2-IL-33-receptor were significantly increased in BALB/c wild type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild type or C57BL/6-RELMα-/- mice. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- were not different from their respective wild type controls. In BALB/c mice, RELMα was a key contributor to antigen/PM2.5 induced pulmonary vascular remodeling, RV thickening and RV cytokine responses, highlighting the significance of the genetic background. The RELMα-/- animals demonstrated significantly decreased expression of RELMβ and RELM which makes these mice comparable to a situation where human RELMα levels would be significantly modified, as humans only have one RELM molecule.

Predatory research field in science is when an emerging scientific topic destroys current topics and characterizes a main scientific change. Predatory research field can be a basic driver of scientific and technological change that generates a 'creative destruction' in science and society in contexts of knowledge-based competition and rapid changes. The prediction of proposed theory of predatory research fields is that it destroys with a fast growth other research fields. The theoretical approach is tested here in research fields of large language models (LLM) by analyzing the transformers (a deep learning architecture based on the multi-head attention mechanism) proposed in 2017 and from November 2022 started main applications in generative artificial intelligence with innovations of BERT, ChatGPT, Microsoft Copilot (launched on February 7, 2023) and other natural language processing tools driven by AI technology for engaging conversations, gain insights, automate tasks, etc., etc. Statistical evidence suggests that growth rate of transformer technologies is 80.58%, a high level compared to all other research fields in machine learning (having a growth rate of 13.83%). Moreover, predatory research field of transformers has a destructive power such that all other domains in LLM from 2021 to 2023 have a general reduction of scientific growth. The impact of transformers is much more drastic of previous radical technologies such as CNN having a temporal growth rate of 0.16%, lower than 0.38% by transformers, ceteris paribus. These analysis reveals that transformers have characteristics to generate a radical scientific and technological change in a not-too-distant future. Overall, then, the study suggests that predatory research field on emerging topics and technologies can generate path-breaking innovations and the examination here can clarify the essential elements of the science dynamics for a better theory of scientific and technological change, providing also main implications for knowledge policy to support promising research fields and technologies to guide economic and social change.

Alkyl moieties—open chain or cyclic—are common in drug molecules and can be internal or terminal. The open-chain alkyls can be linear or branched; the cyclic alkyls may be substituted. Usually, the branches in open-chain alkyls and substituents in cycloalkyls influence both the pharmacokinetics and pharmacodynamics of a drug molecule. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some parent-drug equiactive hydroxy metabolites have been developed into metabolite ester prodrugs, while some of the parent-drug carboxy metabolites have been developed into metabolite drugs. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. Some subtexts found to manifest from the hydroxy and carboxy functionalization of alkyl moieties in drug molecules are presented and discussed. The review provides basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules; and (ii) whether the resulting metabolites will possess pharmacologic activity or be devoid of it.

SARS-CoV-2 Omicron variant spike RBD epitopes in complex with spike (S) -protein D614G mutations now predominate globally and increase infectivity by assembling more functional S proteins into the virion. On average, homeopathic medicine contains less than one molecule per dose on average. Single variable SphericalHarmonicY, LaguerreL, WhittakerM, SphericalBesselJ, LegendreP, LegendreQ, LaguerreL, ChebyshevT, and Hypergeometric1F1 Functions pFqarise in connection with the power series solution of the Schrodinger equation or in the summation of perturbation expansions in quantum mechanics. A quantum interpretation of the homeopathic method is presented here through a novel algebraic topology approach to supersymmetry and symmetry breaking in quantum fields and quantum gravity theory with the aim of developing a wide range of physical-based drug design applications in a Small Molecule Quantized Water Memory Network suggesting that the Hidden Black Hole Paradox of Information Loss might be solved under suitable conditions.

There are many molecules used as drug carrier. TUD-1 is a newly synthesized mesoporous silica (SM) molecule possess two important features; consists of mesoporous so it is very suitable to be drug carrier in addition to that it has the ability to induce apoptosis in cancer cells. However, the effect of TUD-1 appears to act as cell death inducer, regardless of whether it is necrosis or apoptosis. Unfortunately, recent studies indicate that a proportion of cells undergo necrosis rather than apoptosis, which limits the use of TUD-1 as a secure treatment. On the other hand, lithium considered as necrosis inhibitor element. Hence, current study based on the idea of production a new Li/TUD-1 by incorporated mesoporous silica (TUD-1 type) with lithium in order to produce a new compound that has the ability to activate apoptosis by mesoporous silica (TUD-1 type) and at the same time can inhibit the activity of necrosis by lithium. Herein, lithium was incorporated in TUD-1 mesoporous silica by using sol-gel technique in one step synthesis procedure. Moreover, lithium was incorporated in TUD-1 with different loading in order to form different active sites such as isolated lithium ions, nanoparticles of Li2O, and bulky crystals of Li2O. The ability of the new compounds to induce apoptosis and prevent necrosis was evaluated on three different types of cancer cell lines which are; liver HepG-2, Breast MCF-7 and colon HCT116. The obtained results show that Li/TUD-1has the ability to control necrosis and thus reduce the side effects of treatments containing silica in the case of lithium has been added to them, especially in chronic cases. This has been demonstrated by the significant increase in the IC50 value and cell viability comparing to control groups. Consequently, the idea is new, so it definitely needs more develop and test with materials that have more apoptotic impact than silica in order to induce apoptosis without induction of necrosis.