Activity Profile Research Articles

Alloreactive-free CAR-VST therapy: a step forward in long-term tumor control in viral context

CAR-T cell therapy has revolutionized immunotherapy but its allogeneic application, using various strategies, faces significant challenges including graft-versus-host disease and graft rejection. Recent advances using Virus Specific T cells to generate CAR-VST have demonstrated potential for enhanced persistence and antitumor efficacy, positioning CAR-VSTs as a promising alternative to conventional CAR-T cells in an allogeneic setting. This review provides a comprehensive overview of CAR-VST development, emphasizing strategies to mitigate immunogenicity, such as using a specialized TCR, and approaches to improve therapeutic persistence against host immune responses. In this review, we discuss the production methods of CAR-VSTs and explore optimization strategies to enhance their functionality, activation profiles, memory persistence, and exhaustion resistance. Emphasis is placed on their unique dual specificity for both antitumor and antiviral responses, along with an in-depth examination of preclinical and clinical outcomes. We highlight how these advances contribute to the efficacy and durability of CAR-VSTs in therapeutic settings, offering new perspectives for broad clinical applications. By focusing on the key mechanisms that enable CAR-VSTs to address autologous CAR-T cell challenges, this review highlights their potential as a promising strategy for developing effective allogeneic CAR-T therapies.

Single-cell analysis identifies the CNP/GC-B/cGMP axis as marker and regulator of modulated VSMCs in atherosclerosis

A balanced activity of cGMP signaling contributes to the maintenance of cardiovascular homeostasis. Vascular smooth muscle cells (VSMCs) can generate cGMP via three ligand-activated guanylyl cyclases, the NO-sensitive guanylyl cyclase, the atrial natriuretic peptide (ANP)-activated GC-A, and the C-type natriuretic peptide (CNP)-stimulated GC-B. Here, we study natriuretic peptide signaling in murine VSMCs and atherosclerotic lesions. Correlative profiling of pathway activity and VSMC phenotype at the single-cell level shows that phenotypic modulation of contractile VSMCs to chondrocyte-like plaque cells during atherogenesis is associated with a switch from ANP/GC‑A to CNP/GC‑B signaling. Silencing of the CNP/GC-B axis in VSMCs results in an increase of chondrocyte-like plaque cells. These findings indicate that the CNP/GC-B/cGMP pathway is a marker and atheroprotective regulator of modulated VSMCs, limiting their transition to chondrocyte-like cells. Overall, this study highlights the plasticity of cGMP signaling in VSMCs and suggests analogies between CNP-dependent remodeling of bone and blood vessels.

Scientometric tools in strategising the development of scientific periodicals: the case of the journal Digital Models and Solutions

The present study is dedicated to the development of scientometric tools for the strategic advancement of a scientific periodical, exemplified by the journal of the Ural State University of Economics, “Digital Models and Solutions”. The research involved a compre hensive analysis of the publication activity and thematic profile of this journal, as well as a general statistical examination of Russian academic journals indexed in the Russian Science Citation Index (RSCI) that pertain to the upper echelon of the State Rubricator of Scientific and Technical Information category “Informatics”. Primary data collection was conducted using the platforms elibrary.ru, CyberLeninka and CrossRef. The data analysis and visuali zation were performed utilizing the R programming language. The construction of thematic networks was carried out using the VOSviewer software, while additional visualization of certain results was executed using Scimago Graphica. The findings of the study identify the current positioning of the journal “Digital Models and Solutions” among scientific publi cations in informatics, define target scientometric indicators for its prospective growth, and propose specific recommendations for the strategic development of the journal, aimed at enhancing its competitiveness and scholarly impact.

BDNF levels in serum and CSF are associated with clinicoradiological characteristics of aggressive disease in MS patients

BackgroundBDNF has increasingly gained attention as a key molecule controlling remyelination with a prominent role in neuroplasticity and neuroprotection. Still, it remains unclear how BDNF relates to clinicoradiological characteristics particularly at the early stage of the disease where precise prognosis for the further MS course is crucial.MethodsBDNF, NfL and GFAP concentrations in serum and CSF were assessed in 106 treatment naïve patients with MS (pwMS) as well as 73 patients with other inflammatory/non-inflammatory neurological or somatoform disorders using a single molecule array HD-1 analyser. PwMS were evaluated for highly active profiles by applying the aggressive disease course criteria proposed by ECTRIMS. Serum/CSF values were logarithmically transformed and compared across groups using one-way ANOVA, while correlations were calculated using Pearson’s correlations. ROC analysis and AUC comparisons for diagnostic performance of the three biomarkers were computed in an explorative analysis.ResultsSerum BDNF (sBDNF) concentrations were higher in treatment naïve pwMS with disease onset after the age of 40 years (p = 0.029), in pwMS with ≥2 gadolinium-enhancing lesions (p = 0.009) and with motor, cerebellar, cognitive or sphincter symptoms at onset (p = 0.036). BDNF correlated positively with NfL (r = 0.198, p = 0.014) and GFAP (r = 0.253, p = 0.002) in serum, but not in CSF. Neurological patients with an acute inflammatory relapse showed significantly higher sBDNF levels (p = 0.03) compared to somatoform controls, while patients without acute relapse did not differ from somatoform controls (p = 0.4). Better diagnostic performance was found for sBDNF than sNfL and sGFAP in differentiating between patients with vs. without 2 or more gadolinium-enhancing lesions (p < 0.05) and for sBDNF as compared to sNfL for separating patients with disease onset after vs. before age of 40 years.ConclusionIn pwMS, BDNF serum levels differ depending on disease-related characteristics, suggesting that not only inflammatory activity but also remyelination capacities may vary with disease severity. BDNF is increased when other biomarkers of neuroaxonal damage and neurodegeneration, such as NfL and GFAP, are elevated, possibly as a compensatory mechanism, and reflect possibly further pathophysiological aspects in MS beyond NfL and GFAP, probably including an apoptotic role for BDNF in neuroinflammation.

Specific immune response to M. tuberculosis and ability to in vitro control mycobacterial replication are not impaired in subjects with immune-mediated inflammatory disease and tuberculosis infection

BackgroundSubjects with immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis, with tuberculosis infection (TBI), have a high probability of progressing to tuberculosis disease (TB). We aim to characterize the impact of IMID on the immune response to M. tuberculosis (Mtb) in patients with TBI and TB disease.MethodsWe enrolled TBI and TB patients with and without IMID. Peripheral blood mononuclear cells (PBMCs) were stimulated with Mtb-derived epitopes (MTB300). By flow-cytometry, we identified the Mtb-specific CD4+ T cells as cytokine-producing T cells or as CD25+ CD134+ CD4+ T cells. Memory and activation status of Mtb-specific T cells were assessed by evaluating: CD153, HLA-DR, CD45RA, CD27. Mycobacterial growth inhibition assay (MGIA) was used to evaluate the ability of PBMCs to inhibit mycobacteria growth. A long-term stimulation assay was used to detect a memory response.ResultsThe IMID status and therapy did not affect the magnitude of response to Mtb-antigen stimulation and the number of responders. TBI-IMID showed a cytokine profile like TBI and TB patients. The Mtb response of TBI-IMID patients was characterized by an effector memory and central memory phenotype as in TBI and TB groups. This memory phenotype allowed the increased IFN-γ production after 6 days of MTB300-stimulation. HLA-DR expression on Mtb-specific T cells was associated with TB, whereas CD153 was associated with TBI status. Finally, the TBI-IMID had an MGIA response like TBI and TB patients.ConclusionIMID condition does not affect key aspects of the immune response to Mtb, such as the cytokine response, memory and activation profile, and the ability to contain the mycobacteria replication. The immunological characterization of the fragile population of TBI-IMID patients is fundamental to understanding the correlation between protection and disease.

Characterization, Bioactive Profiling and Evaluation of the Pharmacological Activities of Ethanol Extract of Lannea welwitschii (Hiern) Engl.

Introduction: Lannea welwitschii is a medicinal plant used in traditional medicine to treat various infectious diseases due to its plethora of bioactive compounds that possess various pharmacological activities. This study aimed to characterize and determine the phytochemical profile and the bioactive compounds responsible for their pharmacological activities. Methods: Phytochemical screening and Gas-Chromatography Mass Spectrometry (GC-MS) analysis were carried out on the ethanolic extract of L. welwitschii to determine the volatile compounds present. Characterization of the crude extract was carried out using Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM), X-ray diffraction (XRD) and Energy Dispersive X-ray spectroscopy (EDX). The antioxidant potential of the extract was evaluated using methods such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric-reducing antioxidant Potential (FRAP). The antibacterial activities were determined using the macro-broth dilution technique. Results: Secondary metabolites such as saponins, tannins, alkaloids, reducing sugars, and cardiac glycoside were identified. The GC-MS analysis showed the presence of 48 bioactive compounds, out of which 12 had peak area percentages ≥ 1%. Some of the bioactive compounds identified include 2-butoxy-ethanol, Dodecanoic acid, Stigmasterol, Isopropenyl, and n-hexadecanoic acid, which have been reported with different biological activities. FTIR analysis revealed the presence of various functional groups which showed major compounds in the plant extract. The morphological features showed the spherical shape of the plant extract with several aggregates, while the EDX analysis identified elements such as silicon, oxygen, and silver. The extract demonstrated inhibitory potential against some of the bacterial isolates. However, Bacillus pumilus, Klebsiella quasipneumoniae, Klebsiella aerogenes, and Staphylococcus aureus are more susceptible with MIC of 0.313 and 0.625 mg/ml respectively. Conclusion: The presence of secondary metabolites and bioactive compounds revealed by the characterization and phytochemical analysis provided enough evidence for the usage of the plant in the treatment of infectious diseases and thus might be considered a therapeutic agent.

Comparative evaluation of PD-L1 expression and tumor immune microenvironment in molecular subtypes of muscle-invasive bladder cancer and its correlation with survival outcomes.

Immune checkpoint inhibitors have revolutionized treatment of platinum-refractory advanced bladder cancer, offering hope where options are limited. Response varies, however, influenced by factors such as the tumor's immune microenvironment and prior therapy. Muscle-invasive bladder cancer (MIBC) is stratified into molecular subtypes, with distinct clinicopathologic features affecting prognosis and treatment. This study assessed the expression of programmed cell death 1 ligand 1 (PD-L1) and other immune markers in MIBC, categorized by molecular phenotype. Using GATA3 and CK5/6 immunohistochemistry, 90 neoadjuvant chemotherapy-naive MIBC cases were classified into luminal andnon-luminalsubtypes. The immune microenvironment was characterized through immunostaining for PD-L1, CD4, and CD8. We applied PD-L1 positivity thresholds of 1% or greater for tumor cells and 5% or greater for immune cells. Tumors were examined for PD-L1 expression, histologic subtypes, and immune cell infiltration. Varied expression of PD-L1 and T-cell subtype densities were observed among MIBC subtypes. The double-negative subtype displayed the highest PD-L1 immune cell expression and stromal CD4 and CD8 T-cell densities, indicating an active immune profile. The basal subtype exhibited the highest PD-L1 positivity in tumor cells. In contrast, the luminal type showed the lowest PD-L1 tumor and immune cell expression, with high intratumoral CD4 T-cell density. Although PD-L1 expression in tumor or immune cells did not independently affect survival, patients with basal and double-negative tumors had poorer overall survival. This study highlighted the immune diversity of MIBC in the context of molecular subtypes. Distinct molecular and immune profiles could guide the development of predictive signatures for enhanced immunotherapy response in advanced bladder cancer.

Spiny mice (Acomys) have evolved cellular features to support regenerative healing.

Spiny mice (Acomys spp.) are warm-blooded (homeothermic) vertebrates whose ability to restore missing tissue through regenerative healing has coincided with the evolution of unique cellular and physiological adaptations across different tissue types. This review seeks to explore how these bizarre rodents deploy unique or altered injury response mechanisms to either enhance tissue repair or fully regenerate excised tissue compared to closely related, scar-forming mammals. First, we examine overall trends in healing Acomys tissues, including the cellular stress response, the ability to activate and maintain cell cycle progression, and the expression of certain features in reproductive adults that are normally associated with embryos. Second, we focus on specific cell types that exhibit precisely regulated proliferation to restore missing tissue. While Acomys utilize many of the same cell types involved in scar formation, these cells exhibit divergent activation profiles during regenerative healing. Considered together, current lines of evidence support sustained deployment of proregenerative pathways in conjunction with transient activation of fibrotic pathways to facilitate regeneration and improve tissue repair in Acomys.

Physicochemical Properties, Antioxidant Activity, and Flavor Profile of Strawberry Fruit-Based Novel Drinking Jelly Made with Gracilaria fisheri Seaweed as a Gelling Agent at Varying Concentrations

Physicochemical Properties, Antioxidant Activity, and Flavor Profile of Strawberry Fruit-Based Novel Drinking Jelly Made with Gracilaria fisheri Seaweed as a Gelling Agent at Varying Concentrations

PrivacyGuard: Exploring Hidden Cross-App Privacy Leakage Threats In IoT Apps

The increasing use of the Internet of Things (IoT) technology has made our lives convenient, however, it also poses new security and privacy threats. In this work, we study a new type of privacy threat enabled by cross-app chains built among multiple seemingly benign IoT apps. We find that interactions among apps could leak privacy-sensitive information, e.g., users' identification, location and tracking, activity patterns, etc. To tackle this challenge, we introduce PrivacyGuard, which extracts cross-app chains in the form of trigger-condition-action rules and identifies the corresponding privacy leakage risk with an inference probability. PrivacyGuard supports a fine-grained categorization of privacy threats to generate detailed alerts about privacy leakages. We evaluated PrivacyGuard on a dataset with 2,101 SmartApps, 2,788 IFTTT rules, and 2,086 OpenHAB rules, respectively. The results show that PrivacyGuard could uncover hidden privacy leaks that existing studies fail to detect. For example, 7.67% chains constructed by two seemingly benign IoT apps could leak at least one type of privacy information, while over 80% of the leaks involved privacy information regarding Localization &amp; Tracking and Activity Profiling.

Phase Ib Study of BI 836880 (VEGF/Ang2 nanobody) in Combination With Ezabenlimab (anti–PD-1 antibody) in Patients With Advanced or Metastatic Solid Tumors

PURPOSE This phase Ib study investigated the safety and antitumor activity of BI 836880, a bispecific nanobody targeting vascular endothelial growth factor and angiopoietin-2, and ezabenlimab, an anti–PD-1 antibody, in patients with advanced or metastatic solid tumors. METHODS This was an open-label, multinational study (ClinicalTrials.gov identifier: NCT03468426 ) conducted in two parts. Part 1 was a dose-escalation phase to determine the recommended phase II dose (RP2D) of BI 836880 in combination with ezabenlimab in patients with metastatic non–small cell lung cancer (mNSCLC). Part 2 was an expansion phase investigating the efficacy and safety of the combination at the RP2D in eight cohorts, on the basis of tumor type. The primary end point of part 2 was objective response rate (ORR). RESULTS Overall, 14 patients were recruited in part 1 and 238 in part 2. In part 1, the maximum tolerated dose of the combination was not reached; the RP2D was BI 836880 720 mg plus ezabenlimab 240 mg every 3 weeks. In part 2, the ORR was 18.9% across all cohorts. In the mNSCLC cohorts, ORRs were 16.7% (after checkpoint inhibitor [CPI] monotherapy) and 7.5% (after chemotherapy + CPI). Notably higher rates were seen in patients with glioblastoma (GBM; 22.6%); hepatocellular carcinoma (HCC) who had previously received sorafenib or lenvatinib (40.0%); and previously untreated HCC (25.8%). The combination was well tolerated; the most common adverse events in part 2 were asthenia (27.3%), hypertension (21.4%), and diarrhea (20.2%). CONCLUSION BI 836880 combined with ezabenlimab had a positive benefit-risk ratio, with a manageable safety profile and signs of antitumor activity across a wide range of tumor types, with particularly promising activity in patients with HCC and GBM.

SARS-CoV-2 Activated Peripheral Blood Mononuclear Cells (PBMCs) Do Not Provoke Adverse Effects in Trophoblast Spheroids.

Although it is still uncertain whether Severe Acute Respiratory Coronavirus (SARS-CoV-2) placental infection and vertical transmission occur, inflammation during early pregnancy can have devastating consequences for gestation itself and the growing fetus. If and how SARS-CoV-2-specific immune cells negatively affect placenta functionality is still unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from women of reproductive age with SARS-CoV-2 peptides and cocultured them with trophoblast spheroids (HTR-8/SVneo and JEG-3) to dissect if SARS-CoV-2-activated immune cells can interfere with trophoblast functionality. The activation and cytokine profile of the PBMCs were determined using multicolor flow cytometry. The functionality of trophoblast spheroids was assessed using microscopy, enzyme-linked immunosorbent assay (ELISA), and RT-qPCR. SARS-CoV-2 S and M peptides significantly activated PBMCs (monocytes, NK cells, and T cells with memory subsets) and induced the upregulation of proinflammatory cytokines, such as IFNγ. The activated PBMCs did not impact the viability, growth rate, and invasion capabilities of trophoblast spheroids. Furthermore, the hormonal production of hCG by JEG-3 spheroids was not compromised upon coculture with the activated PBMCs. mRNA transcript levels of genes involved in trophoblast spheroid functional pathways were also not dysregulated after coculture. Together, the findings of our in vitro coculture model, although not fully representative of in vivo conditions, strongly support the claim that the interaction of SARS-CoV-2-activated peripheral blood immune cells with trophoblast cells at the fetal-maternal interface does not negatively affect trophoblast functionality. This goes in hand with the recommendation of vaccinating pregnant women in their first trimester.

Immunoregulatory programs in anti-N-methyl-D-aspartate receptor encephalitis identified by single-cell multi-omics analysis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti-NMDARE remain elusive. This study aimed to characterize immune cell interactionsand dysregulation in anti-NMDARE by leveraging single-cell multi-omics sequencing technologies. Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti-NMDARE and healthy controls were sequenced using single-cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell-cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single-cell B cell receptor sequencing (scBCR-seq) and repertoire analysis were conducted to assess antigen-driven clonal expansion within the B cell population. The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti-NMDARE patients. The novel finding of type I interferon (IFN-I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll-like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor-alpha (TNF-α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation. This study presents a comprehensive single-cell multi-omics characterization of immune dysregulation in anti-NMDARE, highlighting the expansion of B cell and the activation of the IFN-I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti-NMDARE and offer promising targets for future therapeutic intervention. Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition. IFN-I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation. TLR2 pathway activation in myeloid cells contributes to TNF-α secretion and could influence adaptive immune responses.

Ravulizumab and Efgartigimod in Myasthenia Gravis: A Real-World Study.

Biologics that target pathogenic antibodies (Abs) and their effector functions such as the complement inhibitor ravulizumab and the neonatal Fc receptor agonist efgartigimod have recently been approved for the treatment of acetylcholine receptor (AChR)-Ab-positive myasthenia gravis (MG), but comparative studies are lacking. In a prospective, exploratory real-world study, we assessed clinical efficacy, safety, and biological effects of ravulizumab and efgartigimod treatment initiation. Myasthenia Gravis-Activities of Daily Living and Quantitative Myasthenia Gravis scores were used as clinical endpoints. Ab effector functions were determined by AChR-Ab-dependent complement activation and phagocytosis assays and systemic complement activation profiling. We observed similar moderate short-term efficacy of ravulizumab and efgartigimod in achieving clinical improvement. Ravulizumab reduced systemic terminal complement activation, but neither treatment showed significant effects on complement pathways proximal to C5 or functional capacities of AChR-Abs. Both treatment modalities were well tolerated with no serious adverse events reported. Clinical benefits obtained with ravulizumab and efgartigimod can be remarkably heterogeneous in daily clinical practice. Neither treatment relevantly changed effector functions of pathogenic AChR-Abs, supporting the concept that durable disease control in MG requires continuous administration of both fast-acting agents. This study provides Class III evidence that in AChR-Ab-positive patients with generalized MG, ravulizumab and efgartigimod provide comparable modest improvement in MG functional scales.

Complement Activation Profiles Predict Clinical Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

The role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD. Multicentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples. A panel of CFs were measured by multiplex ELISA, and the levels were compared between the 3 conditions. Univariable and multivariable analyses were performed to evaluate the association between levels of CFs and relapse and disability outcomes in MOGAD patients. Ninety-four patients (MOGAD, n = 60; MS, n = 18; AQP4-NMOSD, n = 16) were included. Mean (SD) age at sampling was 39.4 (16.7), 40.7 (7.0), and 43.3 (21.0), respectively. Female were predominant, especially in AQP4-NMOSD (88%). Combination of the serum levels of C3a, C4a, and C3a/C3 ratio showed excellent potential to discriminate MOGAD from patients with MS (area under the curve [AUC] [95% CI] 0.95 [0.90-0.99]) and from AQP4-NMOSD (AUC 0.88 [0.76-1.00]). In patients with MOGAD, CSF levels of CFs of the classical/lectin pathway influenced relapse-related outcomes, and lower C4 levels were associated with higher number of relapses during follow-up (incidence rate ratio [95% CI] 0.88 [0.78-0.99]; p = 0.04 in multivariable analysis), and a high C4a/C4 ratio was associated with increased risk of second relapse during the first year (hazard ratio [95% CI] 3.68 [1.26-10.78]; p = 0.02 in multivariable analysis). Time to second relapse was shorter in patients with MOGAD with a high CSF C4a/C4 ratio (log-rank p = 0.01). CSF levels of the membrane attack complex SC5b9 influenced disability-related outcomes, and baseline CSF SC5b9 levels were higher in patients who reached the final Expanded Disability Status Scale (EDSS) ≥ 3.0 (p = 0.002), and elevated SC5b9 levels were associated with increased risk of reaching EDSS ≥ 3.0 (odds ratio [95% CI] 1.79 [1.16-3.67]; p = 0.04 in multivariable analyses). Our results suggest that serum and CSF levels of CFs have diagnostic and prognostic value respectively in patients with MOGAD. These findings support the use of complement inhibitors as a therapeutic approach in these patients.

Screening of native wild Salvia nemorosa populations for chemical compositions, antioxidant activity and UHPLC-HRMS profiling

Screening of native wild Salvia nemorosa populations for chemical compositions, antioxidant activity and UHPLC-HRMS profiling

Investigating risk profiles of smartphone activities and psychosocial factors in adolescents during the COVID‐19 pandemic

AbstractAssociations of adolescents' smartphone use and well‐being have been contradictory. The present study investigates patterns of smartphone use and psychosocial risk / protective factors in US adolescents during COVID‐19 and examines their associations with depression symptom trajectories from 5 yearly waves beginning prior to the COVID‐19 pandemic. Latent profile analyses revealed three risk profiles, including a high risk profile (18.9% adolescents) characterized by elevated social media use, high levels of psychosocial risk, and low levels of protective variables. Latent growth mixture modeling identified three depression trajectories; stable low, moderate‐increasing, and high‐severely increasing depression. Both the moderate‐increasing and high‐severely increasing depression trajectories were associated with membership in the high risk profile. Results highlight the impacts of type of smartphone activity rather than use per se and can inform targeted intervention strategies.

You Win Some, You Lose Some: Modifying the Molecular Periphery of Nitrofuran-Tagged Diazaspirooctane Reshapes Its Antibacterial Activity Profile.

The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124-0.0441 μg/mL against MTb multiresistant strains. Several series of structural analogues have been synthesized, including variations in the periphery and simplifications of their scaffolds. All synthesized compounds were tested against the MTb H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of 1 did not lead to the development of more active compounds which can work against MTb, but to substances with high activity against S. aureus. Induced-fit docking and MM-GBSA calculations determined a change in the likely biotarget from deazaflavin-dependent nitroreductase to azoreductases. The privileged nature of the scaffold was demonstrated by the detection of a different type of activity.

Active Site Studies to Explain Kinetics of Lipases in Organic Solvents Using Molecular Dynamics Simulations.

This study investigates the intricate dynamics underlying lipase performance in organic solvents using comprehensive molecular dynamics (MD) simulations, supported by enzyme kinetics data. The study reveals that a single criterion can neither predict nor explain lipase activity in organic solvents, indicating the need for a comprehensive approach. Three lipases were included in this study: Candida antarctica lipase B (CALB), Rhizomucor miehei lipase (RML), and Thermomyces lanuginosus lipase (TLL). The lipases were investigated in acetonitrile, methyl tert-butyl ether, and hexane with increasing water activity. Computational investigations reveal that CALB's activity is negatively correlated to water cluster formations on its surface. In contrast, TLL's and RML's activity profiles show no negative effects of high water activity. However, TLL's and RML's activities are highly correlated to the conformation and stability of their active site regions. This study may pave the way for tailored applications of lipases, highlighting some of the factors that should be considered when lipase-catalyzed reactions are designed.

A comprehensive profiling of phenolic compounds and antioxidant activities of 24 varieties of red raspberry cultivated in Northeast China.

Red raspberries, valued for their nutrients and bioactive compounds, have broad uses in processing and healthy products. However, limited comprehensive research focused on the comparison of phenolic compounds of red raspberry, especially species cultivated in Northeast China, has been reported. This study aimed to conduct a thorough investigation of 24 red raspberry varieties in Northeast China for the first time, evaluating their phenolic compounds and antioxidant capacities. The results showed that 'DNS1' had the highest total phenolic content (TPC), 'Willamette' had the highest total flavonoid content (TFC), and 'Boyne' had the highest total anthocyanin content (TAC). Phenolic compounds in red raspberries were predominantly found in esterified form, while glycosylated phenolics should not be overlooked. Chlorogenic acid, cryptochlorogenic acid, ellagic acid, and arbutin were the main phenolic compounds, and the distribution of their contents varied between varieties. The antioxidant activity in the red raspberry had a close association with the content of phenolic compounds. Principal component analysis (PCA) showed that phenolic compounds and antioxidant activities were higher in samples from 'DNS1', 'Boyne', 'Beijing10', 'DNS5', and 'Willamette' varieties. These varieties should be given priority in breeding programs that aim to boost the utility and bioactive profile of red raspberries. PRACTICAL APPLICATION: Red raspberry is becoming a desirable commercially grown fruit species and is viewed as a new functional food. In this context, this research offers strong support for confirming the quality of 24 varieties of red raspberry and plays a critical role in the food industry. It also indicates the potential sources of superior varieties of red raspberry, which are advantageous for growers and consumers in search of high-quality red raspberry varieties.