Miracle-dz/UniFAR-FTUs huggingface dataset:
Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric cis- and trans-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies

Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic PIII-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen–halogen exchange at PIV-halogenide. Their conformation and configuration at the C4-ring carbon and phosphorus stereocentres were studied by NMR (1H, 31P) methods, X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reactions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown to depend on the nature of halogen. Cyclic cis- and trans-isomers of chlorides and bromides react with nucleophiles (HO−, CH3O−, Me2NH) with inversion of configuration at phosphorus. DFT calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds according to the SN2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides proceeds stepwise according to the A–E mechanism with formation of a pentacoordinate intermediate since a PES with two transition states was observed.
Impact of Sugar Type Addition and Fermentation Temperature on Pomegranate Alcoholic Beverage Production and Characteristics

The present study focuses on the production of pomegranate alcoholic beverage (PAB) from juice of the Wonderful variety. The effect of fermentation temperature (15 and 25 °C) and type of sugar added (adjustment to 20 °Brix) on the physicochemical characteristics, bioactive compounds, and volatile composition were studied. Sucrose, concentrated pomegranate juice, concentrated grape juice, and honey were used to increase the initial sugar content. The produced PABs contained ethanol in concentrations ranging from 7.9 to 10.0% v/v and glycerol from 4.8 to 6.1 g L−1. A decrease in total phenolics content, free radical-scavenging activity, and total monomeric anthocyanin content was observed following fermentation. Total flavonoids content appeared to increase after fermentation only in the cases of concentrated pomegranate and grape juice addition. In general, 22 volatile compounds were identified in PABs (13 esters, 2 fatty acids, and 7 alcohols). Major compounds detected were 3-methyl-1-butanol, 2-methyl-1-butanol, 2-phenylethanol, and ethyl acetate. These findings demonstrate the production prospect of PABs with increased ethanol content, while elaborating on the importance of fermentation temperature and the differences between the selected types of added sugars on end-product composition.
Synergistic Activation of Bovine CD4+ T Cells by Neutrophils and IL-12

CD4+ T cell activation requires inflammatory cytokines to provide a third signal (3SI), such as interleukin-12 (IL-12). We recently reported that bovine neutrophils can enhance the activation of bovine CD4+ T cells. To explore the interactions between neutrophils and third signal cytokines in bovine CD4+ T cell activation, naïve CD4+ T cells were isolated from cattle lymph nodes and stimulated for 3.5 days with anti-bovine CD3 (first signal; 1SI), anti-bovine CD28 (second signal; 2SI), and recombinant human IL-12 (3SI) in the presence or absence of neutrophils harvested from the same animals. Indeed, the strongest activation was achieved in the presence of all three signals, as demonstrated by CD25 upregulation, IFNγ production in CD4+ T cells, and secretion of IFNγ and IL-2 in cell supernatants. More importantly, 1SI plus neutrophils led to enhanced CD25 expression that was further increased by IL-12, suggesting synergistic action by IL-12 and neutrophils. Consistently, neutrophils significantly increased IFNγ production in 1SI plus IL-12-stimulated CD4+ T cells. Our data suggest the synergy of neutrophils and IL-12 as a novel regulator on bovine CD4+ T cell activation in addition to three signals. This knowledge could assist the development of immune interventions for the control of infectious diseases in cattle.
CEACAM6’s Role as a Chemoresistance and Prognostic Biomarker for Pancreatic Cancer: A Comparison of CEACAM6’s Diagnostic and Prognostic Capabilities with Those of CA19-9 and CEA

Survival rates from pancreatic cancer have remained stagnant for decades due to the heterogenic nature of the disease. This study aimed to find a new advanced biomarker and evaluate its clinical capabilities, thus enabling more individualised pancreatic cancer management. Between 2013 and 2020, 267 patients were included in the study. Surgically collected pancreatic tissue samples were analysed via high-definition mass spectrometry. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was discovered as a possible promising pancreatic cancer biomarker. The predominance of CEACAM6 to pancreatic cancer was validated using antibodies in tissue samples. CEACAM6, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) blood serum concentrations were evaluated for clinical evaluation and comparison. Kaplan–Meier survival analyses were used to evaluate disease-free survival (DFS) and overall survival (OS). Poorer overall survival was significantly dependent on increased CEACAM6 blood serum concentrations (17.0 vs. 12.6 months, p = 0.017) in pancreatic cancer patients after radical treatment and adjuvant chemotherapy. Increased CEA and CA19-9 concentrations showed no significant dependencies with survival. Thus, CEACAM6 is a promising new biomarker with significant prognostic value and prediction of chemoresistance properties, enabling the improvement of individualised approaches to patients with pancreatic cancer.
PESIN Conjugates for Multimodal Imaging: Can Multimerization Compensate Charge Influences on Cell Binding Properties? A Case Study †

Recently, anionic charges were found to negatively influence the in vitro gastrin-releasing peptide receptor (GRPR) binding parameters of dually radioisotope and fluorescent dye labeled GRPR-specific peptide dimers. From this, the question arose if this adverse impact on in vitro GRP receptor affinities could be mitigated by a higher valency of peptide multimerization. For this purpose, we designed two different hybrid multimodal imaging units (MIUs), comprising either one or two click chemistry-compatible functional groups and reacted them with PESIN (PEG3-BBN7–14, PEG = polyethylene glycol) dimers to obtain a dually labeled peptide homodimer or homotetramer. Using this approach, other dually labeled peptide monomers, dimers, and tetramers can also be obtained, and the chelator and fluorescent dye can be adapted to specific requirements. The MIUs, as well as their peptidic conjugates, were evaluated in terms of their photophysical properties, radiolabeling efficiency with 68Ga and 64Cu, hydrophilicity, and achievable GRP receptor affinities. Here, the hydrophilicity and the GRP receptor binding affinities were found to be especially strongly influenced by the number of negative charges and peptide copies, showing logD (1-octanol-water-distribution coefficient) and IC50 (half maximal inhibitory concentration) values of −2.2 ± 0.1 and 59.1 ± 1.5 nM for the homodimer, and −1.9 ± 0.1 and 99.8 ± 3.2 nM for the homotetramer, respectively. From the obtained data, it can be concluded that the adverse influence of negatively charged building blocks on the in vitro GRP receptor binding properties of dually labeled PESIN multimers can, at least partly, be compensated for by the number of introduced peptide binding motives and the used molecular design.
A Positive Dermcidin Expression Is an Unfavorable Prognostic Marker for Extramammary Paget’s Disease

Extramammary Paget’s disease is recognized as an apocrine-origin cutaneous tumor and is localized in the intraepithelial skin lesion. However, its advanced form is intractable, and there is currently no therapeutic option with a satisfactory level of clinical outcome. Therefore, it is of great importance to identify a potential biomarker to estimate tumor advancement in extramammary Paget’s disease. Dermcidin is an antimicrobial peptide derived from the eccrine gland and is identified as a biomarker in various malignancies. To investigate the potential of dermcidin in extramammary Paget’s disease, we investigated dermcidin expression in tumors using the immunostaining technique. Although previous studies have reported that extramammary Paget’s disease has no positive staining against dermcidin, 14 out of 60 patients showed positive staining of dermcidin in our study. To clarify the characteristics of positive dermcidin in extramammary Paget’s disease, we investigated the clinical characteristics of positive dermcidin extramammary Paget’s disease patients. Positive dermcidin patients showed a significantly high frequency of lymph node metastasis. We next investigated the impact of positive dermcidin on overall survival. Univariate analysis identified that positive dermcidin showed a significantly increased hazard ratio in overall survival, suggesting that dermcidin might be a prognostic factor for extramammary Paget’s disease.
Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

Simple Summary RAD51 is an essential gene for cell survival. Its function is central to DNA repair and it protects cells from life-threatening damage to the genome. Interestingly, RAD51 is expressed at high levels in a large proportion of cancers, and elevated RAD51 expression is associated with a bad outcome and reduced response to treatment. Hence, reducing RAD51 expression and/or interfering with its function could be of great therapeutic value. We review here the multiple levels of regulation of RAD51 expression and function and explore potential therapeutic leads. Abstract The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.
The Effects of a Fermented Rapeseed or/and Soybean Meal Additive on Antioxidant Parameters in the Blood and Tissues of Piglets

Simple Summary The use of fermented products, including fermented soybean meal, and recently also fermented rapeseed meal, in the diet of pigs and other animals is becoming increasingly popular. A diet containing protein components from which anti-nutrients and allergenic substances have been eliminated by means of fermentation stimulates beneficial gastrointestinal microflora, resulting in improvement in metabolic processes and thus improved animal health. Abstract The aim of the study was to assess the effect of fermented soybean meal (FSBM) and/or rapeseed meal (FRSM) on the redox status of blood and tissues in piglets. The experiment was conducted on 150 28-day-old weaned piglets divided into five groups. Piglets in the control group received standard diets with soybean meal. Animals in the experimental groups received diets in which a portion of the soybean meal was replaced with FRSM and/or FSBM: group FR—8% FRSM; group FR/FS—6% FRSM and 2% FSBM; group FS/FR—2% FRSM and 6% FSBM; and group FS—8% FSBM. Group FR/FS showed an increase in total antioxidant potential of plasma (FRAP) and low-molecular-weight antioxidants, i.e., vitamin C, urea, uric acid, and albumin, as well as an increase in catalase activity. Blood levels of lipid hydroperoxides (LOOH) and malonyl dialdehyde (MDA) were decreased. A reduction in lipid peroxidation due to the use of FR/FS was also indicated by a decrease in liver MDA and jejunum wall LOOH levels. Increases in superoxide dismutase (SOD) and catalase (CAT) activity and vitamin C levels in these tissues were also noted. The results of the study indicate that the inclusion of fermented rapeseed meal in the diet (6%) in combination with soybean meal (2%), improved the redox status of the weaners.
Natural Polymer Chitosan as Super Disintegrant in Fast Orally Disintegrating Meloxicam Tablets: Formulation and Evaluation

The aim of the present investigation was to formulate fast disintegrating tablets of meloxicam by wet granulation technique using medium molecular weight chitosan. The orally disintegrating tablets of meloxicam with chitosan showed good mechanical and disintegration properties and good dissolution rate when prepared in tablet press using 10.8 kN and 11.0 kN compression force. Chitosan is a suitable biopolymer to moderate the disintegration process in orally disintegrating tablets.
Safety and Efficacy of Specially Designed Texture-Modified Foods for Patients with Dysphagia Due to Brain Disorders: A Prospective Study

Providing texture-modified food for patients with dysphagia is a cornerstone of dysphagia treatment. This study aimed to evaluate the safety and efficacy of a specially designed texture-modified food that can be easily swallowed while maintaining the unique taste by adjusting hardness and adhesiveness in patients with brain disorders using a videofluoroscopic swallowing study. We included 101 patients with oropharyngeal dysphagia due to brain disorders who were referred to the rehabilitation department. To evaluate the safety and efficacy of a specially designed texture-modified food, rice gruel was compared with a regular instant rice porridge, and bulgogi mousse was compared with ground bulgogi, which normally serves as a texture-modified diet for patients with dysphagia in our hospital during the videofluoroscopic swallowing study. The Penetration–Aspiration Scale score, oropharyngeal transit time, number of swallows required to maximally eliminate food materials from the oropharyngeal space, and vallecular and pyriform sinus residue after swallowing scale score were compared. Rice gruel required a shorter oropharyngeal transit time and fewer number of swallowing per the given amount of food than regular instant rice porridge; however, no statistical difference was found in the vallecular and pyriform sinus residue after swallowing scale scores and the Penetration–Aspiration Scale scores. Bulgogi mousse required more swallowing and had lower Penetration–Aspiration Scale scores than ground bulgogi; however, no significant difference was found in the oropharyngeal transit time and the vallecular and pyriform sinus residue after swallowing scale scores. The study foods were safe and efficacious compared to control foods usually provided for patients with dysphagia from various brain disorders.
Hand Erosive Osteoarthritis and Distal Interphalangeal Involvement in Psoriatic Arthritis: The Place of Conservative Therapy

Hand erosive osteoarthritis (HEOA) and Psoriatic Arthritis (PsA) with DIP involvement are common diseases affecting the hand. Both of them evolve with a progressive limitation in grip due to limited range of motion of the affected joints and stenosing tenosynovitis. Pharmacological options currently available (corticosteroids and clodronate or Idrossicloroquine) for the treatment of EHOA are mostly symptomatic and currently there are no effective drugs able to modify the course of the disease. In addition, data on drug effectiveness of PsA with DIP involvement are lacking. Conservative therapy should be considered in order to reduce pain and improve hand functionality. There are many studies debating a wide range of non-pharmacological intervention in the management of HEOA: joint protection program, range of motion and strengthening exercise, hand exercise with electromagnetic therapy, application of heat with paraffin wax or balneotherapy, occupational therapy and education. Concerning conservative treatment strategies to treat PsA, on the contrary, current evidence is still weak. Further research is needed to find the correct place of physical therapy to prevent stiffness and ankylosis due to the vicious circle of inflammation-pain-immobility-rigidity.
Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (cPIP) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as cPIP of 32–64 mg/L (2–4× the ‘MIC breakpoint’ of Pseudomonas aeruginosa). Of the 1544 patients screened, we included 179 patients (335 serum concentrations), of whom 89% achieved the minimum therapeutic exposure of >32 mg/L and 12% achieved potentially harmful cPIP > 96 mg/L within the first 48 h. Therapeutic exposure was achieved in 40% of the patients. Subsequent TDM-guided dose adjustments significantly enhanced therapeutic exposure to 65%, and significantly reduced cPIP > 96 mg/L to 5%. Mortality in patients with cPIP > 96 mg/L (13/21; 62%) (OR 5.257, 95% CI 1.867–14.802, p = 0.001) or 64–96 mg/L (30/76; 45%) (OR 2.696, 95% CI 1.301–5.586, p = 0.007) was significantly higher compared to patients with therapeutic exposure (17/72; 24%). Given the observed variability in critically ill patients, combining the application of dosing software and consecutive TDM increases therapeutic drug exposure of piperacillin in patients with sepsis and septic shock.
A Comparative Study of Biocompatibility in Rat Connective Tissue of a New Mineral Trioxide Compound (Theracal) versus MTA and a Bioactive G3 Glass

The aim of this paper was to assess the differences in tissue response to implantation during 15, 30 and 45 days in the subcutaneous connective tissue of Wistar rats from three biomaterials: Angelus MTA®, Theracal LC®, and Angelus MTA® to which 25% bioglass G3 was added. Twenty-four Wistar rats were used, the materials were inserted into the rat’s dorsal area in silicone tubes 5 mm long by 1.5 mm diameter. Histological reaction was assessed at 15, 30, and 45 days after implantation. They were then stained with hematoxylin eosin and evaluated by two observers. Data were analyzed using Fisher’s exact test and Mann–Whitney’s U test was used to determine the association between variables. Angelus MTA induced the formation of dystrophic calcifications twice as much as Theracal LC (p < 0.05). The addition of G3 did not affect the greater or lesser occurrence of calcifications (p > 0.05). Theracal LC and MTA plus G3 caused an inflammatory reaction, which was chronic at 15 days and decreased in intensity, almost disappearing after 45 days. Theracal LC, as well as Angelus MTA plus G3, were well tolerated when implanted in the subcutaneous connective tissue of rat. Histologically, no inconvenience was found for the use by direct contact of Theracal LC, and the mixture of MTA with 25% bioactive glass G3, in the tissue of Wistar rats.
New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action

This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported.