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Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

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Injuries of the respiratory system caused by viral infections (e.g., by influenza virus, respiratory syncytial virus, metapneumovirus, or coronavirus) can lead to long-term complications or even life-threatening conditions. The challenges of treatment of such diseases have become particularly pronounced during the recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One promising drug is the anti-fibrinolytic and anti-inflammatory protease inhibitor aprotinin, which has demonstrated considerable inhibition of the replication of some viruses. Encapsulation of aprotinin in liposomes can significantly improve the effectiveness of the drug, however, the use of nanoparticles as carriers of aprotinin can radically change its biodistribution in the body. Here we show that the liposomal form of aprotinin accumulates more efficiently in the lungs, heart, and kidneys than the molecular form by side-by-side comparison of the ex vivo biodistribution of these two fluorescently labeled formulations in mice using bioimaging. In particular, we synthesized liposomes of different compositions and studied their accumulation in various organs and tissues. Direct comparison of the biodistributions of liposomal and free aprotinin showed that liposomes accumulated in the lungs 1.82 times more effectively, and in the heart and kidneys - 3.56 and 2.00 times, respectively. This suggests that the liposomal formulation exhibits a longer residence time in the target organ and, thus, has the potential for a longer therapeutic effect. The results reveal the great potential of the aprotinin-loaded liposomes for the treatment of respiratory system injuries and heart- and kidney-related complications of viral infections.

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The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors1. DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1-BARD1 (ref. 2). Specifically, three distinct nuclease entities-the 5'-3' exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase-act in synergy to execute the end resection process3. A major question concerns whether BRCA1-BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1-BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1-BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1-BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1-BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells.

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We develop a multiscale coarse-grain model of the NIST Monoclonal Antibody Reference Material 8671 (NISTmAb) to enable systematic computational investigations of high-concentration physical instabilities such as phase separation, clustering, and aggregation. Our multiscale coarse-graining strategy captures atomic-resolution interactions with a computational approach that is orders of magnitude more efficient than atomistic models, assuming the biomolecule can be decomposed into one or more rigid bodies with known, fixed structures. This method reduces interactions between tens of thousands of atoms to a single anisotropic interaction site. The anisotropic interaction between unique pairs of rigid bodies is precomputed over a discrete set of relative orientations and stored, allowing interactions between arbitrarily oriented rigid bodies to be interpolated from the precomputed table during coarse-grained Monte Carlo simulations. We present this approach for lysozyme and lactoferrin as a single rigid body and for the NISTmAb as three rigid bodies bound by a flexible hinge with an implicit solvent model. This coarse-graining strategy predicts experimentally measured radius of gyration and second osmotic virial coefficient data, enabling routine Monte Carlo simulation of medically relevant concentrations of interacting proteins while retaining atomistic detail. All methodologies used in this work are available in the open-source software Free Energy and Advanced Sampling Simulation Toolkit.

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The fascination with superheavy elements (SHE) spans the nuclear physics, astrophysics, and theoretical chemistry communities. Extreme relativistic effects govern these elements' chemistry and challenge the traditional notion of the periodic law. The experimental quest for SHE critically depends on theoretical predictions of these elements' properties, especially chemical homology, which allows for successful prototypical experiments with more readily available lighter homologues of SHE. This work is a comprehensive quantum-chemical investigation into astatine (At) as a non-intuitive homologue of element 113, nihonium (Nh). Combining relativistic coupled-cluster and density functional theory approaches, we model the behaviour of At and AtOH in thermochromatographic experiments on a pristine gold surface. Insights into the electronic structure of AtOH and NhOH and accurate estimates of At-gold and AtOH-gold adsorption energies rationalise recent experimental findings and justify the use of At as a chemical homologue of Nh for the successful design of future experiments on Nh detection and chemical characterisation.

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The intrinsically disordered protein MeCP2 is a global transcriptional regulator encoded by the MECP2 gene. Although the structured domains of MeCP2 have been the subject of multiple studies, its unstructured regions have not been that extensively characterized. In this work, we show that MeCP2 possesses properties akin to those of supercharged proteins. By utilizing its unstructured portions, MeCP2 can successfully transduce across cell membranes and localize to heterochromatic foci in the nuclei, displaying uptake levels a third lower than a MeCP2 construct fused to the cell-penetrating peptide TAT. MeCP2 uptake can further be enhanced by the addition of compounds that promote endosomal escape following cellular trafficking by means of macropinocytosis. Using a combination of in silico prediction algorithms and live-cell imaging experiments, we mapped the sequence in MeCP2 responsible for its cellular incorporation, which bears a striking resemblance to TAT itself. Transduced MeCP2 was shown to interact with HDAC3. These findings provide valuable insight into the properties of MeCP2 and may be beneficial for devising future protein-based treatment strategies.

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PURPOSE: The aim of this study is to evaluate and compare techniques and outcomes associated with two different technique of pelvic screw insertion in patients with caudal spine absence. METHODS: A cohort of patients with varying degrees of caudal structural regression, serves as the focal point of this investigation. Pelvic configurations were classified based on established criteria to facilitate comparative analysis. Each patient underwent spinal surgical interventions, with a follow-up period extending beyond 2 years. The primary surgical interventions predominantly involved spinal stabilization coupled with correction of scoliosis and kyphosis through one or two pairs of pelvic screws. RESULTS: In this study, we investigated a cohort of 22 patients with caudal spine absence, encompassing diverse conditions, such as lumbo-sacral aplasia, hemisacrum, and lumbar absence, with preserved sacrum. Following spinal surgery, notable improvements were observed in scoliosis and pathological lumbar kyphosis, with several patients achieving significant functional milestones such as independent ambulation. There were no significant differences in short-term complications between patients undergoing single versus double pair pelvic screw implantation. Long-term complications, primarily non-fusion, were notably more prevalent in patients undergoing fixation with a single pair of pelvic screws. CONCLUSION: Surgical intervention, particularly spinopelvic fixation, demonstrated promising outcomes in terms of improving spinal deformities. The implantation of two pairs of pelvic screws demonstrates greater reliability compared to the insertion of a single pair, diminishing the risk of non-fusion.

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Family physicians often treat patients who require urinary management with the use of external urinary devices, clean intermittent catheterization, or indwelling urinary catheterization. External urinary devices are indicated for urinary incontinence (postvoid residual less than 300 mL), urine volume measurement for hospitalized patients, nonsterile urine diagnostic testing, improved comfort for patients in hospice or palliative care, and fall prevention for high-risk patients. Indwelling urinary catheterization is indicated for severe urinary retention or bladder outlet obstruction; wound healing in the sacrum, buttocks, or perineal area; prolonged immobilization; and as a palliative measure for patients who are terminally ill. Clean intermittent catheterization is an alternative to indwelling urinary catheterization for acute or chronic urinary retention (postvoid residual greater than 300 mL) without bladder outlet obstruction, sterile urine testing, postvoid residual volume assessment, and wound healing. Suprapubic catheter placement is considered when long-term catheterization is needed or urethral catheterization is not feasible. Urinary catheters should not be used solely for staff or caregiver convenience, incontinence-related dermatitis, urine culture procurement from a voiding patient, or initial incontinence management. Common complications of urinary catheter use include obstruction, bladder spasm, urine leakage, and skin breakdown of the sacrum, buttocks, or perineum. The risk of catheter-associated urinary tract infections increases with the duration of catheter use. Urologist referral is indicated for patients requiring urinary management who have recurrent urinary tract infections, acute infectious urinary retention, suspected urethral injury, or substantial urethral discomfort or if long-term catheterization is being considered.

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Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with H2SO4 as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high Z or E geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[a]carbazoles and naphtho[2,1-a]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl. Utilization of 2-methylindoles in the reaction with 2-nitroacetophenones and performing the reaction in a sealed vial in a microwave apparatus in AcOH at 200 °C leads to 1-hydroxy-ß-carbolines. Selected compounds from each scaffold were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions, and three compounds belonging to the 3-(2-nitrovinyl)-indole and 1-hydroxy-ß-carboline series were identified to have single-digit micromolar IC50 values.

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Furin, a serine protease enzyme located in the Golgi apparatus of animal cells, plays a crucial role in cleaving precursor proteins into their mature, active forms. It is ubiquitously expressed across various tissues, including the brain, lungs, gastrointestinal tract, liver, pancreas, and reproductive organs. Since its discovery in 1990, furin has been recognized as a significant therapeutic target, leading to the active development of furin inhibitors for potential use in antiviral, antibacterial, anticancer, and other therapeutic applications. This review provides a comprehensive overview of the progress in the development and characterization of furin inhibitors, encompassing peptides, linear and macrocyclic peptidomimetics, and non-peptide compounds, highlighting their potential in the treatment of both infectious and non-infectious diseases.

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Polarization-dependent gain (PDG) effect was studied in a conventional core-pumping configuration of bismuth-doped fiber amplifiers (BDFAs) based on PANDA-type phospho- and germanosilicate core fibers. The PDG value was determined as the gain difference between the orthogonal signal polarizations, which was found to be in range of 2.5-3 dB at total gain of >20 dB in such BDFAs. This effect is more pronounced for BDFA with a germanosilicate fiber. The experimental results are in a good agreement with the calculated data derived from the simulation model, relying on the anisotropy parameter of bismuth active centers (BACs) obtained from the degree of luminescence polarization, which ranges between 9 and 12% for BACs-Si and 18 and 22% for BACs-P. The obtained data can be useful for the optimization of performance of BDFAs and studying structural peculiarities of BACs.

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Uranium fission fragments, as well as the products of 3He(n,p)3H and 10B(n,α)7Li nuclear reactions were utilized in the nuclear reactor for gas ionization and excitation. However, the 6Li(n,α)3H nuclear reaction was less examined. The use of lithium-6 as a surface source of excitation of the gas medium, due to the long path length of tritium nuclei in the gas, allows to excite large volumes of gas as opposed to using 235U or 10B. While investigating the luminescence of noble gases in the core of the IVG.1M research reactor, we noted an appearance of alkali metal lines and a sharp increase in the intensity of these lines at temperatures above 570 K. It was determined that the population of levels of lithium atoms has practically no effect on the population of the 2p-levels of atoms of noble gases. The selectivity of p- and s-levels deactivation by lithium atoms implies the possibility of creating inversion of population at 2p-1s transitions of noble gas atoms. Successful experiments to study the luminescence of gases upon excitation by 6Li(n,α)3H nuclear reaction products allow us to proceed to experiments to achieve the laser action threshold and study the lasing characteristics of gas mixtures at the IGR pulsed nuclear reactor with thermal neutron flux density up to 7∙1016 n/cm2s. For this purpose, an experimental device designs were proposed to perform experiments on the IGR reactor. A step-by-step procedure of fabrication of a nuclear-excited source for excitation of gas mixtures is provided. The results of reactor experiments aimed at determining the spectral and temporal characteristics of optical radiation during excitation of gas mixtures by 6Li(n,α)3H nuclear reaction products are presented.

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The magnetic properties of disordered Nd0.5Ba0.5Mn0.5Fe0.5O3-δ/2 and ordered NdBaMnFeO6-δ perovskites were investigated through temperature- and field-dependent DC-magnetization measurements. The temperature dependence of magnetic susceptibilities revealed that antiferromagnetic ordering occurs at temperatures below 185 K for the disordered Nd0.5Ba0.5Mn0.5Fe0.5O3-δ/2 sample, whereas the ordered NdBaMnFeO6-δ perovskite exhibited a paramagnetic state throughout the entire temperature range examined. Notably, the disordered sample exhibited a glassy state, even at room temperature, which transformed into an antiferromagnetic state under higher applied magnetic fields. The magnetic ordering in the disordered Nd0.5Ba0.5Mn0.5Fe0.5O3-δ/2 perovskite and the magnetic-disordering state in the structurally ordered NdBaMnFeO6-δ perovskite could be attributed to the alteration of the oxidation state of Mn.

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Low-cost molecular emitters that merge circularly polarized luminescence (CPL) and thermally activated delayed fluorescence (TADF) properties are attractive for many high-tech applications. However, the design of such emitters remains a difficult task. To address this challenge, here, we propose a simple and efficient strategy, demonstrated by the design of pseudochiral-at-metal complexes [Cu(L*)DPEPhos]PF6 bearing a (+)/(-)-menthol-derived 1,10-phenanthroline ligand (L*). These complexes exhibit a yellow CP-TADF with a record-high quantum yield (close to 100%) and high dissymmetry factor (|glum| ~ 1×10-2). Remarkably, the above compounds also show a negative thermal-quenching (NTQ) of luminescence in the 300-77 K range. Exploiting the designed Cu(I) emitters, we fabricated efficient CP-TADF OLEDs displaying mirror-imaged CPL bands with high |gEL| factors of 1.5×10-2  and the maximum EQE of 6.15%. Equally important, using the (+)-[Cu(L*)DPEPhos]PF6 complex, we have discovered that an external magnetic field noticeably suppresses CP-TADF of Cu(I) emitters. These findings are an important contribution to the CPL phenomenon and provide access to highly efficient, low-cost and robust CP-TADF emitters.

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Background: Noninvasive assessment of elevated filling pressure in the left ventricle (LV) remains an unresolved problem. Of the many echocardiographic parameters used to evaluate diastolic pressure, the left atrial strain and strain rate (LA S/SR) have shown promise in clinical settings. However, only a few previous studies have evaluated LA S/SR in larger populations. Methods: A total of 2033 participants from Norwegian (Tromsø 7) and Russian (Know Your Heart) population studies, equally distributed by age and sex, underwent echocardiography, including atrial and ventricular S/SR and NT-proBNP measurements. Of these, 1069 were identified as healthy (without hypertension (HT), atrial fibrillation (AF), or structural cardiac disease) and were used to define the age- and sex-adjusted normal ranges of LA S/SR. Furthermore, the total study population was divided into groups according to ejection fraction (EF) ≥50%, EF <50%, and AF. In each group, uni- and multiple regression and receiver operating characteristic curve analyses were performed to test LA and LV functional parameters as potential indicators of NT-proBNP levels above 250 ng/ml. Results: The mean LA S/SR values in this study were higher than those in previous large studies, whereas the lower references were comparable. In normal hearts, atrial total strain (ATS) and mitral valve E deceleration time (MV DT) were independent factors indicating elevated NT-proBNP levels, whereas in hearts with reduced EFs, the independent indicators were peak atrial contraction strain (PACS) and LV stroke volume. The areas under the curve for these significant indicators to discriminate elevated NT-proBNP levels were 0.639 (95% confidence interval (CI): 0.577-0.701) for normal EF and 0.805 (CI: 0.675-0.935) for reduced EF. Conclusion: The results confirm good intrastudy reproducibility, with mean values in the upper range of previous meta-analyses. In the future, automated border-detection algorithms may be able to generate highly reproducible normal values. Furthermore, the study showed atrial S/SR as an additional indicator of elevated NT-proBNP levels in the general population, demonstrating the incremental value of both ATS and PACS in addition to conventional and ventricular strain echocardiography. Thus, the LA S/SR may be regarded as an important addition to the multiparametric approach used for evaluating LV filling.

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High-affinity and specific agents are widely applied in various areas, including diagnostics, scientific research, and disease therapy (as drugs and drug delivery systems). It takes significant time to develop them. For this reason, development of high-affinity agents extensively utilizes computer methods at various stages for the analysis and modeling of these molecules. The review describes the main affinity and specific agents, such as monoclonal antibodies and their fragments, antibody mimetics, aptamers, and molecularly imprinted polymers. The methods of their obtaining as well as their main advantages and disadvantages are briefly described, with special attention focused on the molecular modeling methods used for their analysis and development.

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INTRODUCTION: The primary analysis (median follow-up 34.9 months across all arms) of the phase 3 POSEIDON study demonstrated a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR/ALK-wild-type metastatic NSCLC (mNSCLC). D+CT showed a trend for OS improvement versus CT that did not reach statistical significance. This paper reports prespecified OS analyses after longer-term follow-up (median >5 years). METHODS: 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell (TC) PD-L1 expression (≥50% vs <50%), disease stage (IVA vs IVB), and histology (squamous vs nonsquamous). Serious adverse events were collected during follow-up. RESULTS: After median follow-up of 63.4 months across all arms, T+D+CT showed sustained OS benefit versus CT (hazard ratio [HR] 0.76, 95% CI: 0.64-0.89; 5-year OS: 15.7% vs 6.8%). OS improvement with D+CT versus CT (HR 0.84, 95% CI: 0.72-1.00; 5-year OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR 0.69, 95% CI: 0.56-0.85) versus squamous (HR 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 TC <1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. CONCLUSIONS: After median follow-up of >5 years, T+D+CT showed durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

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Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.

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Providencia alcalifaciens is a Gram-negative bacterium found in various water and land environments and organisms, including insects and mammals. Some P. alcalifaciens strains encode gene homologs of virulence factors found in pathogenic Enterobacterales members, such as Salmonella enterica serovar Typhimurium and Shigella flexneri. Whether these genes are pathogenic determinants in P. alcalifaciens is not known. In this study, we investigated P. alcalifaciens-host interactions at the cellular level, focusing on the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS1b is widespread in Providencia spp. and encoded on the chromosome. A large plasmid that is present in a subset of P. alcalifaciens strains, primarily isolated from diarrheal patients, encodes for T3SS1a. We show that P. alcalifaciens 205/92 is internalized into eukaryotic cells, lyses its internalization vacuole, and proliferates in the cytosol. This triggers caspase-4-dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS1a in entry, vacuole lysis, and cytosolic proliferation is host cell type-specific, playing a more prominent role in intestinal epithelial cells than in macrophages or insect cells. In a bovine ligated intestinal loop model, P. alcalifaciens colonizes the intestinal mucosa and induces mild epithelial damage with negligible fluid accumulation in a T3SS1a- and T3SS1b-independent manner. However, T3SS1b was required for the rapid killing of Drosophila melanogaster. We propose that the acquisition of two T3SS has allowed P. alcalifaciens to diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.