Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitor MBQ-167 and paclitaxel.

Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN): An introduction to the Urinary Urgency Phenotyping Protocol LURN II.

AIMS: The Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) is undertaking a new cohort study in LURN II including cases and controls. METHODS: This new cohort was enrolled to specifically study urinary urgency and urgency urinary incontinence, lower urinary tract symptoms (LUTSs) that are often difficult to treat due to a lack of understanding of their phenotypes and pathophysiologies. RESULTS: This paper will focus on the motivation for the second iteration of LURN and highlight the new research techniques and plans for more thorough phenotyping of this population. CONCLUSIONS: This paper will outline the gaps in understanding in treating LUTSs, specifically urinary urgency.

Effects on dentin nanomechanical properties, cell viability and dentin wettability of a novel plant-derived biomodification monomer.

OBJECTIVES: To evaluate the effects of dentin biomodification agents (Proanthocyanidin (PAC), Cardol (CD) and Cardol-methacrylate (CDMA) on dentin hydrophilicity by contact angle measurement, viability of dental pulp stem cells (DPSCs) and nanomechanical properties of the hybrid layer (HL). METHODS: CDMA monomer was synthesized from cardol through methacrylic acid esterification. Human extracted third molars were used for all experiments. For nanomechanical tests, specimens were divided in four groups according to the primer solutions (CD, CDMA, PAC and control) were applied before adhesive and composite coating. Nanomechanical properties of the HL were analyzed by nanoindentation test using a Berkovich probe in a nanoindenter. Wettability test was performed on dentin surfaces after 1 min biomodification and measured by contact angle analysis. Cytotoxicity was assessed by a MTT assay with DPSCs after 48 and 72 h. Data were analyzed with Student's t test or Two-way ANOVA and Tukey HSD test (p < 0.05). RESULTS: CD and CDMA solutions achieved greater hydrophobicity and increased the water-surface contact angles when compared to PAC and control groups (p < 0.05). PAC group showed a greater reduction of elastic modulus in nanoindentation experiments when compared to CD and CDMA groups (p < 0.05) after 4 months of aging. CD inhibited cell proliferation compared to all further materials (p < 0.05), whilst CDMA and PAC indicated no cell cytotoxicity to human DPSCs. SIGNIFICANCE: Cardol-methacrylate provided significantly higher hydrophobicity to dentin and demonstrated remarkable potential as collagen crosslinking, attaining the lowest decrease of HL's mechanical properties. Furthermore, such monomer did not affect pulp cytotoxicity, thereby highlighting promising feasibility for clinical applications.

Prognostic role of SOX2 and STAT3 expression on circulating T lymphocytes and CD44+/CD24neg cells in the locally advanced and metastatic breast cancer.

BACKGROUND: Breast cancer (BC) is associated with a continuous increase in incidence, with high mortality rates in several countries. CD44, STAT3, and SOX2 are related to regulating of somatic cell division, tumorigenesis, and metastasis in BC. METHODS: A cross-sectional study was carried out at the Hospital de Cancer de Pernambuco (HCP) between 2017 and 2018. Fifty-one women with locally advanced (LA) and 14 with metastatic BC were included in the study. RESULTS: High CD44+/CD24neg and CD44+/CD24neg/SOX2+ levels in Luminal B (LB), HER2+, and triple-negative breast cancer (TNBC) compared with controls (p < 0.05). Low CD44+/CD24negSTAT3+ levels in LB, HER2+, and TNBC compared with controls (p < 0.05). High T lymphocytes, and low STAT3 + T, and SOX2 + T levels in BC patients (p < 0.05). High SOX2 + T levels in patients with axillary lymph node-negative (N0) compared with the axillary lymph node-positives (N1 and N2 groups; p < 0.05). High SOX2 + T levels in N1 compared to N2 (p < 0.05). High T lymphocytes and low SOX2 + T levels in the LA tumor compared to metastatic disease (p = 0.0007 and p = 0.02, respectively). High CD44 + /CD24negSTAT3+, and T lymphocyte levels in TNBC patients with LA tumor compared to metastatic (p < 0.05). Low STAT3 + T levels in TBNC patients with LA tumor compared to metastatic (p = 0.0266). CONCLUSION: SOX2 and STAT3 expression on circulating T lymphocytes and CD44 + /CD24neg cells in peripheral blood have prognostic roles in breast cancer. SOX2 and STAT3 expression are potential predictive biomarkers of disease progression in breast cancer regardless of tumor subtype.

Mixed effects of climate and species richness on aboveground carbon stock in subtropical Atlantic forests.

Tropical forests are global biodiversity hotspots and are crucial in the global carbon (C) cycle. Understanding the drivers of aboveground carbon stock (AGC) in a heterogeneous and biodiverse system can shed light on the processes underlying the relationship between biodiversity and carbon accumulation. Here, we investigate how biodiversity, environment, and landscape structure affect AGC. We examined such associations in 349 plots comprising over 95,346 km2 the Atlantic Forest of southern Brazil, encompassing three forest types: Dense Ombrophylous Forest (DF), Mixed Ombrophylous Forest (MF), and Seasonal Deciduous Forest (SF). Each plot was described by environmental variables, landscape metrics, and biodiversity (species richness and functional diversity). We used diversity, environmental, and landscape variables to build generalized linear mixed models and understand which can affect the forest AGC. We found that species richness is associated positively with AGC in all forest types, combined and separately. Seasonal temperature and isothermality affect AGC in all forest types; additionally, stocks are positively influenced by annual precipitation in SF and isothermality in MF. Among landscape metrics, total fragment edge negatively affects carbon stocks in MF. Our results show the importance of species diversity for carbon stocks in subtropical forests. The climate effect was also relevant, showing the importance of these factors, especially in a world where climate change tends to affect forest stock capacity negatively.

The Presence of esat-6 and cfp10 and Other Gene Orthologs of the RD 1 Region in Non-Tuberculous Mycobacteria, Mycolicibacteria, Mycobacteroides and Mycolicibacter as Possible Impediments for the Diagnosis of (Animal) Tuberculosis.

The Esx-1 family proteins of the Type VII secretion systems of Mycobacterium bovis and Mycobacterium tuberculosis have been assessed and are frequently used as candidates for tuberculosis (TB) diagnosis in both humans and animals. The presence of ESAT-6 and CFP 10 proteins, which are the most immunogenic proteins of the Esx-1 system and have been widely investigated for the immunodiagnosis of tuberculosis, in some Mycobacteriaceae and in Mycobacterium leprae, poses limitations for their use in specific diagnoses of TB. As such, to improve the specificity of the ESAT-6/CFP 10-based cell-mediated immunity (CMI) assays, other proteins encoded by genes within and outside the RD 1 region of the esx-1 locus have been evaluated as candidate antigens for CMI, as well as to investigate humoral responses in combination with ESAT-6 and or CFP 10, with varying specificity and sensitivity results. Hence, in this study, we evaluated various non-tuberculous mycobacteria (NTM), Mycolicibacterium, Mycolicibacter and Mycobacteroides species genomes available on the NCBI database for the presence and composition of the RD1 region of the esx-1 locus. In addition, we also assayed by polymerase chain reaction (PCR) and sequencing of Mycobacteriaceae available in our culture collection for the presence and sequence diversity of esxA and esxB genes encoding ESAT-6 and CFP 10, respectively. Whole genome sequence (WGS) data analysis revealed the presence of RD 1 gene orthologs in 70 of the over 100 published genomes of pathogenic and non- pathogenic Mycobcteriaceae other than tuberculosis. Among species evaluated from our culture collection, in addition to earlier reports of the presence of esxA and esxB in certain Mycolicibacterium, Mycolicibacterium septicum/peregrinum, Mycolicibacterium porcinum and Mycobacterium sp. N845T were also found to harbour orthologs of both genes. Orthologs of esxA only were detected in Mycobacterium brasiliensis, Mycolicibacterium elephantis and Mycolicibacterium flouroantheinivorans, whereas in Mycolicibacter engbackii, Mycolicibacterium mageritense and Mycobacterium paraffinicum, only esxB orthologs were detected. A phylogenetic analysis based on esxA and esxB sequences separated slow-growing from rapidly growing bacteria. These findings strengthen previous suggestions that esxA and esxB may be encoded in the majority of Mycobacteriaceae. The role of the Esx-1 system in both pathogenic and non-pathogenic Mycobacteriaceae needs further investigation, as these species may pose limitations to immunological assays for TB.

The efficiency of micellar solubilization of naphthalene from aqueous solutions using rhamnolipid as a biological surfactant according to NMR diffusometry.

The micellar solubilization of naphthalene from its saturated aqueous solutions using the biosurfactant rhamnolipid was studied. Using the NMR diffusion method, selective measurements of the self-diffusion coefficients of molecules of all components of the solution-naphthalene, rhamnolipid, and water-were carried out at various rhamnolipid concentrations from 0.06 to 100 g/L. Based on the results of diffusometry, the distribution of naphthalene molecules between the states free in solution and states bound by micelles was found. With an increase in the concentration of rhamnolipids, the proportion of bound naphthalene molecules increases from 50% at CRL = 2 g/L to 100% at CRL ≥ 50 g/L. The micelle-water partition coefficient Km and the molar solubilization ratio MSR were calculated.

Fullerene C60 Conjugate with Folic Acid and Polyvinylpyrrolidone for Targeted Delivery to Tumor Cells.

The use of targeted drug delivery systems, including those based on selective absorption by certain receptors on the surface of the target cell, can lead to a decrease in the minimum effective dose and the accompanying toxicity of the drug, as well as an increase in therapeutic efficacy. A fullerene C60 conjugate (FA-PVP-C60) with polyvinylpyrrolidone (PVP) as a biocompatible spacer and folic acid (FA) as a targeting ligand for tumor cells with increased expression of folate receptors (FR) was obtained. Using 13C NMR spectroscopy, FT-IR, UV-Vis spectrometry, fluorometry and thermal analysis, the formation of the conjugate was confirmed and the nature of the binding of its components was established. The average particle sizes of the conjugate in aqueous solutions and cell culture medium were determined using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The FA-PVP-C60 showed antiradical activity against •DPPH, •OH and O2•-, but at the same time, it was shown to generate 1O2. It was found that the conjugate in the studied concentration range (up to 200 µg/mL) is non-toxic in vitro and does not affect the cell cycle. To confirm the ability of the conjugate to selectively accumulate through folate-mediated endocytosis, its uptake into cells was analyzed by flow cytometry and confocal microscopy. It was shown that the conjugate is less absorbed by A549 cells with low FR expression than by HeLa, which has a high level of expression of this receptor.

Peculiarities of treatment of maxillofacial polytrauma during wartime.

OBJECTIVE: Aim: Analyzing of the last-time papers in this subject in organizing, diagnostic and surgery tactic is the aim of this work. PATIENTS AND METHODS: Materials and Methods: The study analyzed the experience of treating patients with maxillofacial polytrauma before and after February 24, 2022. Research methods: bibliographic, systematic, comparative, general clinical, radiological and retrospective analysis. CONCLUSION: Conclusions: Tactic of the multidisciplinal team should based on the principles of damage control, which involves the initial performance of manipulations and surgical interventions that ensure the patient's survival. Modern strategies for infusion-transfusion therapy play a significant role in severe trauma cases. Choosing the rational management of this therapy for severe trauma remains an important issue. Reconstructive surgeries are recommended to be performer deferred, after surgical wound management, neurosurgical interventions and stabilization of the patient common status. Patients with maxillofacial polytrauma needs in specialized medical care at all the levels. Active wound management aimed at creating favorable conditions for healing, comprehensive medical treatment, prevention, early detection and timely treatment of complications.

Chromatin modifications and memory in regulation of stress-related polyphenols: finding new ways to control flavonoid biosynthesis.

The influence of epigenetic factors on plant defense responses and the balance between growth and defense is becoming a central area in plant biology. It is believed that the biosynthesis of secondary metabolites can be regulated by epigenetic factors, but this is not associated with the formation of a "memory" to the previous biosynthetic status. This review shows that some epigenetic effects can result in epigenetic memory, which opens up new areas of research in secondary metabolites, in particular flavonoids. Plant-controlled chromatin modifications can lead to the generation of stress memory, a phenomenon through which information regarding past stress cues is retained, resulting in a modified response to recurring stress. How deeply are the mechanisms of chromatin modification and memory generation involved in the control of flavonoid biosynthesis? This article collects available information from the literature and interactome databases to address this issue. Visualization of the interaction of chromatin-modifying proteins with the flavonoid biosynthetic machinery is presented. Chromatin modifiers and "bookmarks" that may be involved in the regulation of flavonoid biosynthesis through memory have been identified. Through different mechanisms of chromatin modification, plants can harmonize flavonoid metabolism with: stress responses, developmental programs, light-dependent processes, flowering, and longevity programs. The available information points to the possibility of developing chromatin-modifying technologies to control flavonoid biosynthesis.

Association of copayments with healthcare utilization and expenditures among Medicaid enrollees with a substance use disorder.

BACKGROUND: The purpose of this study was to examine the association between copayments and healthcare utilization and expenditures among Medicaid enrollees with substance use disorders. METHODS: This study used claims data (2020-2021) from a private insurer participating in Arkansas's Medicaid expansion. We compared service utilization and expenditures for enrollees in different Medicaid program structures with varying copayments. Enrollees with incomes above 100 % FPL (N = 10,240) had copayments for substance use treatment services while enrollees below 100 % FPL (N = 2478) did not. Demographic, diagnostic, utilization, and cost information came from claims and enrollment information. The study identified substance use and clinical comorbidities using claims from July through December 2020 and evaluated utilization and costs in 2021. Generalized linear models (GLM) estimated outcomes using single equation and two-part modeling. A gamma distribution and log link were used to model expenditures, and negative binomial models were used to model utilization. A falsification test comparing behavioral health telemedicine utilization, which had no cost sharing in either group, assessed whether differences in the groups may be responsible for observed findings. RESULTS: Substance use enrollees with copayments were less likely to have a substance use or behavioral health outpatient (-0.04 PP adjusted; p = 0.001) or inpatient visit (-0.04 PP; p = 0.001) relative to their counterparts without copayments, equal to a 17 % reduction in substance use or behavioral health outpatient services and a nearly 50 % reduction in inpatient visits. The reduced utilization among enrollees with a copayment was associated with a significant reduction in total expenses ($954; p = 0.001) and expenses related to substance use or behavioral health services ($532; p = 0.001). For enrollees with at least one behavioral health visit, there were no differences in outpatient or inpatient utilization or expenditures between enrollees with and without copayments. Copayments had no association with non-behavioral health or telemedicine services where neither group had cost sharing. CONCLUSION: Copayments serve as an initial barrier to substance use treatment, but are not associated with the amount of healthcare utilization conditional on using services. Policy makers and insurers should consider the role of copayments for treatment services among enrollees with substance use disorders in Medicaid programs.

Low gH/gL (Sub)Species-Specific Antibody Levels Indicate Elephants at Risk of Fatal Elephant Endotheliotropic Herpesvirus Hemorrhagic Disease.

Elephant endotheliotropic herpesviruses (EEHVs), of which eleven (sub)species are currently distinguished, infect either Asian (Elephas maximus) or African elephants (Loxodonta species). While all adult elephants are latently infected with at least one EEHV (sub)species, young elephants, specifically those with low to non-detectable EEHV-specific antibody levels, may develop fatal hemorrhagic disease (EEHV-HD) upon infection. However, animals with high antibody levels against EEHV(1A) gB, an immunodominant antigen recognized by antibodies elicited against multiple (sub)species, may also occasionally succumb to EEHV-HD. To better define which animals are at risk of EEHV-HD, gB and gH/gL ELISAs were developed for each of the Asian elephant EEHV subspecies and assessed using 396 sera from 164 Asian elephants from European zoos. Antibody levels measured against gB of different (sub)species correlated strongly with one another, suggesting high cross-reactivity. Antibody levels against gH/gL of different subspecies were far less correlated and allowed differentiation between these (sub)species. Importantly, while high gB-specific antibody levels were detected in the sera of several EEHV-HD fatalities, all fatalities (n = 23) had low antibody levels against gH/gL of the subspecies causing disease. Overall, our data indicate that (sub)species-specific gH/gL ELISAs can be used to identify animals at risk of EEHV-HD when infected with a particular EEHV (sub)species.

Scalar Relativistic All-Electron and Pseudopotential Ab Initio Study of a Minimal Nitrogenase [Fe(SH)4H]- Model Employing Coupled-Cluster and Auxiliary-Field Quantum Monte Carlo Many-Body Methods.

Nitrogenase is the only enzyme that can cleave the triple bond in N2, making nitrogen available to organisms. The detailed mechanism of this enzyme is currently not known, and computational studies are complicated by the fact that different density functional theory (DFT) methods give very different energetic results for calculations involving nitrogenase models. Recently, we designed a [Fe(SH)4H]- model with the fifth proton binding either to Fe or S to mimic different possible protonation states of the nitrogenase active site. We showed that the energy difference between these two isomers (ΔE) is hard to estimate with quantum-mechanical methods. Based on nonrelativistic single-reference coupled-cluster (CC) calculations, we estimated that the ΔE is 101 kJ/mol. In this study, we demonstrate that scalar relativistic effects play an important role and significantly affect ΔE. Our best revised single-reference CC estimates for ΔE are 85-91 kJ/mol, including energy corrections to account for contributions beyond triples, core-valence correlation, and basis-set incompleteness error. Among coupled-cluster approaches with approximate triples, the canonical CCSD(T) exhibits the largest error for this problem. Complementary to CC, we also used phaseless auxiliary-field quantum Monte Carlo calculations (ph-AFQMC). We show that with a Hartree-Fock (HF) trial wave function, ph-AFQMC reproduces the CC results within 5 ± 1 kJ/mol. With multi-Slater-determinant (MSD) trials, the results are 82-84 ± 2 kJ/mol, indicating that multireference effects may be rather modest. Among the DFT methods tested, τ-HCTH, r2SCAN with 10-13% HF exchange with and without dispersion, and O3LYP/O3LYP-D4, and B3LYP*/B3LYP*-D4 generally perform the best. The r2SCAN12 (with 12% HF exchange) functional mimics both the best reference MSD ph-AFQMC and CC ΔE results within 2 kJ/mol.

Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

PURPOSE: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction. MATERIALS AND METHODS: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis. RESULTS: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2. CONCLUSIONS: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms.

Characterization of polarization states of canine monocyte derived macrophages.

Macrophages can reversibly polarize into multiple functional subsets depending on their micro-environment. Identification and understanding the functionality of these subsets is relevant for the study of immune­related diseases. However, knowledge about canine macrophage polarization is still in its infancy. In this study, we polarized canine monocytes using GM-CSF/IFN- γ and LPS towards M1 macrophages or M-CSF and IL-4 towards M2 macrophages and compared them to undifferentiated monocytes (M0). Polarized M1 and M2 macrophages were thoroughly characterized for morphology, surface marker features, gene profiles and functional properties. Our results showed that canine M1-polarized macrophages obtained a characteristic large, roundish, or amoeboid shape, while M2-polarized macrophages were smaller and adopted an elongated spindle-like morphology. Phenotypically, all macrophage subsets expressed the pan-macrophage markers CD14 and CD11b. M1-polarized macrophages expressed increased levels of CD40, CD80 CD86 and MHC II, while a significant increase in the expression levels of CD206, CD209, and CD163 was observed in M2-polarized macrophages. RNAseq of the three macrophage subsets showed distinct gene expression profiles, which are closely associated with immune responsiveness, cell differentiation and phagocytosis. However, the complexity of the gene expression patterns makes it difficult to assign clear new polarization markers. Functionally, undifferentiated -monocytes, and M1- and M2- like subsets of canine macrophages can all phagocytose latex beads. M2-polarized macrophages exhibited the strongest phagocytic capacity compared to undifferentiated monocytes- and M1-polarized cells. Taken together, this study showed that canine M1 and M2-like macrophages have distinct features largely in parallel to those of well-studied species, such as human, mouse and pig. These findings enable future use of monocyte derived polarized macrophages particularly in studies of immune related diseases in dogs.

Differences in the health-related quality of life in patients with asthma living in urban and rural areas in the Amur Region of Russian Federation.

BACKGROUND: Asthma usually arises from an interaction between host and environmental factors. Growing attention has been paid to a place of residence as a factor shaping health-related quality of life (QoL). This study investigated the rural-urban disparity in QoL among adult asthma patients in the Amur region of Russian Federation. MATERIALS AND METHODS: This cross-sectional study included 351 randomly selected adults with asthma. We analyzed QoL (SF-36 and AQLQ scores), asthma control (ACT), and anxiety and depression (HADS) depending on the place of residence (urban vs. rural). RESULTS: The scale "Role Emotional" (RE) of SF-36 was significantly lower in patients from rural areas compared to urban residents (59.3±3.1 vs. 70.4±2.3 points; p = 0.0042). In the urban group, the correlation analysis demonstrated a clear influence of RE on patients' own assessment of their physical functioning (PF, r = 0.53; p<0.0001). Both groups demonstrated low "Social Functioning" (SF). In the group of urban residents, correlation analysis revealed the presence of positive correlations of SF-36 domains reflecting physical (PF, RP, BP) and social functioning (SF, VT) with most scales of both QoL questionnaires. The domains of the emotional sphere (RE and MH) positively correlated with all scales of both QoL questionnaires among urban residents. In the group of rural residents, a comparative analysis showed the absence of significant correlations between more of the QoL scales. Although Asthma Control Test did not differ between groups, we noted a significantly higher need for ß2-agonists in rural areas compared to urban areas (4.2±0.6 vs. 2.7±0.3 inh/day, respectively; p = 0.0221). The frequency of urban residents with a clinically significant level of anxiety (56 persons, or 25.2%) turned out to be lower compared to rural residents (45 persons, or 34.8%; χ2 = 34.08; p<0.001). CONCLUSION: The burden of asthma introduces a greater imbalance in the health-related QoL of rural residents compared to urban residents in the Amur region of the Russian Federation. The absence of interrelationships of some QoL domains in rural residents suggested a disunity of the physical, psychological and social aspects of life. The rural residents suppress physical discomfort by the more frequent use of short bronchodilators. They often showed emotional instability with a predominance of anxiety, which affected the decrease in QoL in the psycho-emotional sphere.

Copaifera langsdorffii Oleoresin-Loaded Nanostructured Lipid Carrier Emulgel Improves Cutaneous Healing by Anti-Inflammatory and Re-Epithelialization Mechanisms.

The skin is essential to the integrity of the organism. The disruption of this organ promotes a wound, and the organism starts the healing to reconstruct the skin. Copaifera langsdorffii is a tree used in folk medicine to treat skin affections, with antioxidant and anti-inflammatory properties. In our study, the oleoresin of the plant was associated with nanostructured lipid carriers, aiming to evaluate the healing potential of this formulation and compare the treatment with reference drugs used in wound healing. Male Wistar rats were used to perform the excision wound model, with the macroscopic analysis of wound retraction. Skin samples were used in histological, immunohistochemical, and biochemical analyses. The results showed the wound retraction in the oleoresin-treated group, mediated by α-smooth muscle actin (α-SMA). Biochemical assays revealed the anti-inflammatory mechanism of the oleoresin-treated group, increasing interleukin-10 (IL-10) concentration and decreasing pro-inflammatory cytokines. Histopathological and immunohistochemical results showed the improvement of re-epithelialization and tissue remodeling in the Copaifera langsdorffii group, with an increase in laminin-γ2, a decrease in desmoglein-3 and an increase in collagen remodeling. These findings indicate the wound healing potential of nanostructured lipid carriers associated with Copaifera langsdorffii oleoresin in skin wounds, which can be helpful as a future alternative treatment for skin wounds.

Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents.

Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral drugs used to treat HSV infections, acyclovir and related compounds, as well as foscarnet and cidofovir, selectively inhibit herpesvirus DNA polymerase (DNA-pol). It has been previously found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (compound 1) exhibits selective anti-herpesvirus activity against HSV-1 in cell culture, including acyclovir-resistant mutants, so we consider it as a lead compound. In this work, the selection of HSV-1 clones resistant to the lead compound was carried out. High-throughput sequencing of resistant clones and reference HSV-1/L2 parent strain was performed to identify the genetic determinants of the virus's resistance to the lead compound. We identified a candidate mutation presumably associated with resistance to the virus, namely the T321I mutation in the UL15 gene encoding the large terminase subunit. Molecular modeling was used to evaluate the affinity and dynamics of the lead compound binding to the putative terminase binding site. The results obtained suggest that the lead compound, by binding to pUL15, affects the terminase complex. pUL15, which is directly involved in the processing and packaging of viral DNA, is one of the crucial components of the HSV terminase complex. The loss of its functional activity leads to disruption of the formation of mature virions, so it represents a promising drug target. The discovery of anti-herpesvirus agents that affect biotargets other than DNA polymerase will expand our possibilities of targeting HSV infections, including those resistant to baseline drugs.

Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides.

Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.