Highly-efficient low-cost polarization-sensitive organic photodetectors based on laminated self-assembly planar and bulk heterojunctions.

To overcome the severe problems arising from the insufficient light absorption of ultrathin self-assembly active layers and the high cost use of ALD-grown low-leakage-current transport layers, we successfully developed a low-cost, simple and facile strategy of floating-film transfer and multilayer lamination (FFTML) for constructing highly-efficient ALD-free broadband polarization-sensitive organic photodetectors (OPDs) with the two commonly used structures of donor/acceptor planar heterojunction (PHJ) and donor:acceptor multilayer bulk heterojunction (BHJ). It was found that the PHJ-based polarization-sensitive OPD by FFTML possesses a low dark current due to the high carrier injection barrier, indicating it is more suitable to be applied in low polarized light detection scenarios. In contrast, the BHJ-based device by FFTML has a higher spectral responsivity in the whole wavelength due to more photo-excitons transferred to the donor:acceptor interface and dissociated into photoexcited carrirers. Furthermore, the film thickness, which is tuned by increasing lamination number of BHJ layers, has a big effect on the polarization-sensitive photodetection performance. The polarization-sensitive 4-BHJ OPD by FFTML finally achieved a high specific detectivity of 8.33 × 1010 Jones, which was much higher than 2.72 × 1010 Jones for the 2-BHJ device at 0 V. This work demonstrates that layer-by-layer lamination of self-assembly films can effectively improve the polarized-light detection performance, contributing significantly to the rapid development of the field.

Results of a 12-Week Open-Label, Non-Interventional Study of the Efficacy and Safety of Olokizumab Therapy in Patients with Rheumatoid Arthritis after Switching from Anti-B-Cell Therapy during the SARS-CoV-2 Pandemic.

ABSTTACT: -The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is primarily due to the negative impact of a number of basic disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (biological DMARDs, or biologics) on the course and outcomes of a new coronavirus infection. A number of studies have shown that anti-B-cell therapy (rituximab) gave a statistically significant increase in the risk of severe COVID-19 and an increase in mortality. At the same time, the analysis of real clinical practice data dictated the need to establish a number of restrictions on the use of certain classes of biologics and to search for alternative therapy programs to maintain control over disease activity. PURPOSE OF THE STUDY: The purpose of the study was to evaluate the efficacy and safety of the drug Artlegia® (olokizumab), solution for subcutaneous injection, 160 mg/ml-0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheumatoid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic. MATERIALS AND METHODS: The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000-500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. On weeks 0, 4, 8, and 12 after the switch, the severity of pain was assessed on the VAS scale, the number of tender and swollen joints (TJC28 and SJC28), the level of acute-phase inflammation markers, the DAS28 (disease activity score), ESR, CRP, CDAI (clinical activity index), and the functional state index HAQ (Health Assessment Questionnaire) were determined, as well as the safety profile of therapy was assessed. RESULTS: Data analysis was performed using median values (Me) were used for data analysis. A significant decrease in TJC28 was detected after 8 and 12 weeks of treatment with olokizumab (Artlegia®) (Me baseline = 10, Me 8 weeks = 4, Me 12 weeks = 4, p < 0.05) and a decrease in TSC28 was detected after 4, 8, and 12 weeks of treatment (Me baseline = 9, Me 4 weeks = 3.5, Me 8 weeks = 2.5, Me 12 weeks = 2.0, p < 0.05). Laboratory markers of inflammation showed a decrease in CRP and ESR levels after 4 weeks of treatment (CRP: Me4 weeks = 21, Me4 weeks = 1, p < 0.05, ESR: Mesno = 31, Me4 weeks = 7, p < 0.05). Positive dynamics persisted on 8 and 12 weeks (CRP: Me 8 weeks = 1, Me 12 weeks = 0; ESR: Me 8 weeks = 4, Me 12 weeks = 5). The level of CRP by week 4 became within the normal range, regardless of the initial values. All activity indices improved from week 4 in each evaluation period compared to baseline: DAS28-ESR: Me baseline = 5.52, Me 4 weeks = 3.59, Me 8 weeks = 3.33, Me 12 weeks = 3.22, p < 0.05; DAS28CRP: Me baseline = 5.39, Me 4 weeks = 3.71, Me 8 weeks = 3.35, Me 12 weeks = 3.45, p < 0.05; CDAI: Me baseline = 28.5, Me 4 weeks = 18.0, Me 8 weeks = 16.5, Me 12 weeks = 16.0, p < 0.05. All patients showed a reduction in pain (VAS scale) by week 8. The functional status of patients, according to the HAQ index, showed a significant decrease only by week 12 of the study: Me baseline = 1.62, Me 12 weeks = 1.31, p < 0.05. CONCLUSIONS: The study found that switching from rituximab to olokizumab was effective and safe during the COVID-19 pandemic.

Population genetic structure of Schistosoma bovis and S. curassoni collected from cattle in Mali.

Schistosomiasis is of medical and veterinary importance. Despite the critical situation of schistosomiasis in sub-Saharan Africa, few molecular epidemiological studies have been carried out to determine the role of animals in its transmission. In Mali, it has been over three decades since the last molecular study of animal schistosomes was carried out. It is now urgent to identify circulating strains of the parasite because of potential interactions with other schistosome species, which could complicate disease control. The aim of our work was to study the composition and genetic structure of schistosome populations collected from cattle. The prevalence of schistosome was 23.9%, with the prevalences of Schistosoma bovis (Sb) and S. curassoni (Sc) estimated at 12.6% and 9.8%, respectively. No hybrid strains or S. haematobium were found. The parasites displayed distinct geographical distribution with Sb dominant in Bamako (78.8% and 98% in Central Bamako Slaughterhouse and Sabalibougou Slaughterhouses, respectively) and Sc dominant in Kayes (95.3%). Of the 476 parasites with a complete genetic profile, 60.4% were pure Sc, and were mainly from Kayes. We identified two clusters at the site level (Fst of 0.057 and 0.042 for Sb and Sc, respectively). Cluster 1 was predominantly composed of pure Sb parasites and cluster 2 was mainly composed of pure Sc parasites, from Bamako and Kayes, respectively. Our study shows that cattle schistosomiasis remains endemic in Mali with S. bovis and S. curassoni. A robust genetic structure between the different schistosome populations was identified, which included two clusters based on the geographical distribution of the parasites.

Title: Structure génétique des populations de Schistosoma bovis et S. curassoni collectées chez des bovins au Mali. Abstract: La schistosomiase revêt une grande importance médicale et vétérinaire. Malgré la situation critique de la schistosomiase en Afrique subsaharienne, peu d'études épidémiologiques moléculaires ont été réalisées pour déterminer le rôle des animaux dans sa transmission. Au Mali, cela fait plus de trois décennies que la dernière étude moléculaire des schistosomes animaux a été réalisée. Il est désormais urgent d'identifier les souches circulantes du parasite en raison des interactions potentielles avec d'autres espèces de schistosomes, ce qui pourrait compliquer la lutte contre la maladie. Le but de notre travail était d'étudier la composition et la structure génétique des populations de schistosomes collectées chez des bovins. La prévalence des schistosomes était de 23,9 %, celles de Schistosoma bovis (Sb) et de S. curassoni (Sc) étant respectivement estimées à 12,6 % et 9,8 %. Aucune souche hybride ni S. haematobium n'ont été trouvés. Les parasites présentaient une répartition géographique distincte avec Sb dominant à Bamako (respectivement 78,8 % et 98 % aux Abattoirs Centraux de Bamako et aux Abattoirs de Sabalibougou) et Sc dominant à Kayes (95,3 %). Sur les 476 parasites ayant un profil génétique complet, 60,4 % étaient des Sc purs, et provenaient principalement de Kayes. Nous avons identifié deux clusters au niveau du site (Fst de 0,057 et 0,042 pour Sb et Sc, respectivement). Le groupe 1 était principalement composé de parasites Sb purs et le groupe 2 était principalement composé de parasites Sc purs, provenant respectivement de Bamako et de Kayes. Notre étude montre que la schistosomiase bovine reste endémique au Mali, avec S. bovis and S. curassoni. Une structure génétique robuste entre les différentes populations de schistosomes a été identifiée, comprenant deux groupes basés sur la répartition géographique des parasites.

Long-term musculoskeletal function after Open Pelvic ring fractures in Children (OPEC); a multicentre, retrospective case series with follow-up measurement.

Background: The proportion of Open Pelvic fractures in the paediatric population is relatively high. While operative fixation is the primary approach for managing Open Pelvic fractures in adults, there is limited literature on treatment outcomes in Children, particularly regarding long-term musculoskeletal, neurological, and urogenital function. Methods: This multicentre case series included paediatric patients (<18 years old) with Open Pelvic ring fractures treated at one of two major trauma centres in the Netherlands between January 1, 2001 and December 31, 2021. Data collection involved clinical records and long-term assessments, including musculoskeletal function, growth disorders, urogenital function, sexual dysfunction, and sensory motor function. Results: A total of 11 patients were included, primarily females (73 %), with a median age at trauma of 12 years (P25-P75 7-14). Most patients had unstable Pelvic ring fractures resulting from high-energy trauma. Surgical interventions were common, with external fixation as the main initial surgical approach (n = 7, 70 %). Complications were observed in eight (73 %) patients. Musculoskeletal function revealed a range of issues in the lower extremity, daily activities, and mental and emotional domain. Long-term radiologic follow-up showed high rates of Pelvic malunion (n = 7, 64 %). Neurological function assessment showed motor and sensory function impairment in a subset of patients. Urogenital function was moderately affected, and sexual dysfunction was limited with most respondents reporting no issues. Conclusion: Paediatric Open Pelvic fractures are challenging injuries associated with significant short-term complications and long-term musculoskeletal and urogenital issues. Further research is needed to develop tailored treatment strategies and improve outcomes of these patients.

Analysis of the Diversity and Functional Potential of Bacterial Communities in Tuberculomas.

The dynamics of lung microbiota in tuberculosis remains poorly understood. Sequencing of variable regions of the 16S rRNA gene from surgically excised tuberculosis foci and biopsy specimens of normal lung tissue allowed characterization of the diversity and predictive potential of bacterial communities. Taxonomic diversity indices attested to differences in the structure of microbial communities between "healthy" lungs and tuberculomas. The microbial composition of "healthy" lungs varied in taxonomic diversity and was presented by both gram-positive and gram-negative bacteria with sufficiently similar metabolic potential. The microbiota of the examined tuberculomas consisted of Mycobacterium tuberculosis in 99.9% of cases. A significant part of the metabolic pathways predicted by PICRUSt2 included cholesterol catabolism, sulfate assimilation, and various pathways for the biosynthesis of cell wall components.

Cellular Uptake of Upconversion Nanoparticles Based on Surface Polymer Coatings and Protein Corona.

Upconversion nanoparticles (UCNPs) are materials that provide unique advantages for biomedical applications. There are constantly emerging customized UCNPs with varying compositions, coatings, and upconversion mechanisms. Cellular uptake is a key parameter for the biological application of UCNPs. Uptake experiments have yielded highly varying results, and correlating trends between cellular uptake with different types of UCNP coatings remains challenging. In this report, the impact of surface polymer coatings on the formation of protein coronas and subsequent cellular uptake of UCNPs by macrophages and cancer cells was investigated. Luminescence confocal microscopy and elemental analysis techniques were used to evaluate the different coatings for internalization within cells. Pathway inhibitors were used to unravel the specific internalization mechanisms of polymer-coated UCNPs. Coatings were chosen as the most promising for colloidal stability, conjugation chemistry, and biomedical applications. PIMA-PEG (poly(isobutylene-alt-maleic) anhydride with polyethylene glycol)-coated UCNPs were found to have low cytotoxicity, low uptake by macrophages (when compared with PEI, poly(ethylenimine)), and sufficient uptake by tumor cells for surface-loaded drug delivery applications. Inductively coupled plasma-optical emission spectroscopy (ICP-OES) studies revealed that PIMA-coated NPs were preferentially internalized by the clathrin- and caveolar-independent pathways, with a preference for clathrin-mediated uptake at longer time points. PMAO-PEG (poly(maleic anhydride-alt-1-octadecene) with polyethylene glycol)-coated UCNPs were internalized by energy-dependent pathways, while PAA- (poly(acrylic acid)) and PEI-coated NPs were internalized by multifactorial mechanisms of internalization. The results indicate that copolymers of PIMA-PEG coatings on UCNPs were well suited for the next-generation of biomedical applications.

[Three-component tear substitute as preoperative support in glaucoma surgery]. / Primenenie trekhkomponentnogo slezozamenitelya v meditsinskom soprovozhdenii khirurgii glaukomy.

PURPOSE: This study investigates the effect of preoperative preparation with the three-component tear substitute Stillavit on the outcomes of glaucoma surgery in patients on long-term topical glaucoma therapy. MATERIAL AND METHODS: The study included 63 patients (63 eyes) with glaucoma, among them 30 (30 eyes) were women and 33 (33 eyes) were men. Group 1 consisted of 33 patients (33 eyes) receiving long-term topical antihypertensive therapy with preservatives and tear substitute Stillavit 3 times a day for 1 month as preoperative preparation. Group 2 included 30 patients (30 eyes) receiving similar antihypertensive therapy who were not prescribed preoperative medications. All patients underwent a comprehensive ophthalmological examination and computer tomography of the filtering blebs (FB) on Visante system (Carl Zeiss Meditec, Germany) before surgery, as well as 1 week, 1, 3, and 6 months after surgery. RESULTS: Mean intraocular pressure (IOP) elevation at 6 months postoperatively was significantly higher in the group that did not undergo preoperative preparation with a tear substitute, compared to the group of patients who received the tear substitute Stillavit preoperatively. According to anterior segment optical coherence tomography, a greater number of favorable diffuse FB were noted in the group that received the tear substitute Stillavit in preparation for surgery - 87.9%, while in group 2 (without preparation) - 66.7%. Odds ratio calculation between the two groups revealed that preoperative preparation with the tear substitute Stillavit reduced the odds of IOP elevation to 20 mm Hg or higher at 3 months postoperatively by more than 10 times. CONCLUSION: The use of tear substitute Stillavit in preparation for anti-glaucoma surgery reduces the chances of IOP elevation in the early postoperative period by more than 10 times, which may indicate a reduction in the rate of FB scarring due to the beneficial effect of the drug's components on the precorneal tear film.

Evaluation of plant-derived biomaterials for the development of tissue-engineered corneal substitutes.

Corneal blindness affects over 10 million patients worldwide. Due to the limited supply of donor corneas and frequent graft failure, bioengineered alternatives are crucial. To overcome drawbacks associated with corneal substitutes from synthetic biomaterials, fabrication from plant-derived biomaterials is a potential alternative. Herein, soy protein and glutenin in combination with different crosslinkers were evaluated for fabrication of corneal substitutes. Optical, mechanical, and biochemical properties of fabricated constructs and control rabbit corneas were evaluated in vitro. Soy protein crosslinked with peroxidase/H202 possessed transparency and mechanical properties comparable to controls, although their water content and biocompatibility were inferior. In contrast, soy protein crosslinked with tannic acid showed similar water content, tensile strength, and biocompatibility as rabbit corneas; however, these constructs displayed significantly lower transparency and higher strain to failure. Finally, glutenin cross-linked using formaldehyde showed excellent transparency, strain to failure, and biocompatibility, however; they exhibited significantly lower water content and tensile strength than controls. This study is the first to establish CIELAB color values for the rabbit cornea, allowing quantitative optical evaluation of tissue-engineered substitutes. Thus, a crosslinking strategy utilizing plant-derived proteins for fabrication of constructs with properties comparable to rabbit corneas is a promising direction for development of tissue-engineered corneal substitutes.

Impact of graft width and chondrolabral junction preservation on labral suction seal integrity in bovine hip models.

OBJECTIVE: This study investigates the biomechanical effects of graft width and chondrolabral junction (CLJ) preservation on the labral suction seal in a bovine hip model and aims to validate this model as a practical alternative for hip biomechanical research by comparing it with human cadaver studies. MATERIALS AND METHODS: Twenty hips from two-year-old male bovines were divided into two main groups: CLJ preserved (CLJ+) and CLJ excised (CLJ-). These groups were further divided into eight subgroups: Group 1 with an intact labrum; Group 2 with labrum excision preserving CLJ; Groups 3 and 4 with labral reconstruction on preserved CLJ using 4.5 mm and 9 mm grafts, respectively; Group 5 with a labral tear at 12 to 3 o'clock position without CLJ preservation; Group 6 with complete labrum excision without CLJ preservation; and Groups 7 and 8 with labral reconstruction on excised CLJ using 4.5 mm and 9 mm grafts. Mechanical tests measuring compression and distraction forces were conducted, recording force-displacement values. RESULTS: Both CLJ+ and CLJ- groups showed that labrum excision resulted in the lowest distraction forces, emphasizing labral integrity. Notably, reconstruction with 9 mm grafts improved distraction forces more than 4.5 mm grafts (p<0.001). The change in distraction forces from intact to excised stages was nearly significant between CLJ+ and CLJ- groups (Δ Intact-excised: CLJ+ vs. CLJ-: 92 N vs. 105 N, p=0.08). Distraction forces were measured at 206±27 Newtons in the CLJ preserved group and 186±24 Newtons in the resected group. CONCLUSIONS: This study demonstrates that increasing the width of the graft, despite being approximately half and a quarter of the native labrum's size, significantly enhances the distraction force in labral reconstruction within a bovine hip model. This improvement is more pronounced than the effects of preserving the CLJ, highlighting the critical role of graft size in maintaining the biomechanical integrity of the labral suction seal.

Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I-Bioequivalence of Acyclovir Topical Creams.

PURPOSE: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

Bevacizumab-IRDye800CW for tumor detection in fluorescence-guided meningioma surgery (LUMINA trial): a single-center phase I study.

OBJECTIVE: Meningiomas are one of the most frequently occurring brain tumors and can be curatively treated with gross-total resection. A subtotal resection increases the chances of recurrence. The intraoperative identification of invisible tumor remnants by using a fluorescent tracer targeting an upregulated biomarker could help to optimize meningioma resection. This is called molecular fluorescence-guided surgery (MFGS). Vascular endothelial growth factor α (VEGFα) has been identified as a suitable meningioma biomarker and can be targeted with bevacizumab-IRDye800CW. METHODS: The aim of this prospective phase I trial was to determine the safety and feasibility of bevacizumab-IRDye800CW for MFGS for intracranial meningiomas by administering 4.5, 10, or 25 mg of the tracer 2-4 days prior to surgery. Fluorescence was verified during the operation with the standard neurosurgical microscope, and tissue specimens were postoperatively analyzed with fluorescence imaging systems (Pearl and Odyssey CLx) and spectroscopy to determine the optimal dose. Uptake was compared in several tissue types and correlated with VEGFα expression. RESULTS: No adverse events related to the use of bevacizumab-IRDye800CW occurred. After two interim analyses, 10 mg was the optimal dose based on ex vivo tumor-to-background ratio. Although the standard intraoperative imaging revealed no fluorescence, postoperative analyses with tailored imaging systems showed high fluorescence uptake in tumor compared with unaffected dura mater and brain. Additionally, tumor invasion of the dura mater (dural tail) and invasion of bone could be distinguished using fluorescence imaging. Fluorescence intensity showed a good correlation with VEGFα expression. CONCLUSIONS: Bevacizumab-IRDye800CW can be safely used in patients with meningioma; 10 mg bevacizumab-IRDye800CW provided an adequate tumor-to-background ratio. Adjustments of the currently available neurosurgical microscopes are needed to achieve visualization of targeted IRDye800CW intraoperatively. A phase II/III trial is needed to methodically investigate the benefit of MFGS with bevacizumab-IRDye800CW for meningioma surgery in a larger cohort of patients.

Synthesis, insecticidal Activity, and molecular docking analysis of some benzo[h]quinoline derivatives against Culex pipiens L. Larvae.

Some heterocycles bearing a benzo[h]quinoline moiety were synthesized through treating a 3-((2-chlorobenzo[h]quinolin-3-yl)methylene)-5-(p-tolyl)furan-2(3H)-one with four nitrogen nucleophiles comprising ammonium acetate, benzylamine, dodecan-1-amine, and 1,2-diaminoethane. Also, thiation reactions of furanone and pyrrolinone derivatives were investigated. The insecticidal activity of these compounds against mosquito larvae (Culex pipiens L.) was evaluated. All tested compounds exhibited significant larvicidal activity, surpassing that of the conventional insecticide chlorpyrifos. In silico docking analysis revealed that these compounds may act as acetyl cholinesterase (AChE) inhibitors, potentially explaining their larvicidal effect. Additionally, interactions with other neuroreceptors, such as nicotinic acetylcholine receptor and sodium channel voltage-gated alpha subunit were also predicted. The results obtained from this study reflected the potential of benzo[h]quinoline derivatives as promising candidates for developing more effective and sustainable mosquito control strategies. The ADME (absorption, distribution, metabolism, and excretion) analyses displayed their desirable drug-likeness and oral bioavailability properties.

Trimethoprim-Based multicomponent solid Systems: Mechanochemical Screening, characterization and antibacterial activity assessment.

In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and -negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin.. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug.

Synthesis and in silico studies of certain benzo[f]quinoline-based heterocycles as antitumor agents.

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,ß-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were - 6.6320 kcal/mol (with RMSD of 0.9477 Å) and - 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties.

Quantum-inspired modeling of distributed intelligence systems with artificial intelligent agents self-organization.

Distributed intelligence systems (DIS) containing natural and artificial intelligence agents (NIA and AIA) for decision making (DM) belong to promising interdisciplinary studies aimed at digitalization of routine processes in industry, economy, management, and everyday life. In this work, we suggest a novel quantum-inspired approach to investigate the crucial features of DIS consisting of NIAs (users) and AIAs (digital assistants, or avatars). We suppose that N users and their avatars are located in N nodes of a complex avatar - avatar network. The avatars can receive information from and transmit it to each other within this network, while the users obtain information from the outside. The users are associated with their digital assistants and cannot communicate with each other directly. Depending on the meaningfulness/uselessness of the information presented by avatars, users show their attitude making emotional binary "like"/"dislike" responses. To characterize NIA cognitive abilities in a simple DM process, we propose a mapping procedure for the Russell's valence-arousal circumplex model onto an effective quantum-like two-level system. The DIS aims to maximize the average satisfaction of users via AIAs long-term adaptation to their users. In this regard, we examine the opinion formation and social impact as a result of the collective emotional state evolution occurring in the DIS. We show that generalized cooperativity parameters G i , i = 1 , ⋯ , N introduced in this work play a significant role in DIS features reflecting the users activity in possible cooperation and responses to their avatar suggestions. These parameters reveal how frequently AIAs and NIAs communicate with each other accounting the cognitive abilities of NIAs and information losses within the network. We demonstrate that conditions for opinion formation and social impact in the DIS are relevant to the second-order non-equilibrium phase transition. The transition establishes a non-vanishing average information field inherent to information diffusion and long-term avatar adaptation to their users. It occurs above the phase transition threshold, i.e. at G i > 1 , which implies small (residual) social polarization of the NIAs community. Below the threshold, at weak AIA-NIA coupling ( G i ≤ 1 ), many uncertainties in the DIS inhibit opinion formation and social impact for the DM agents due to the information diffusion suppression; the AIAs self-organization within the avatar-avatar network is elucidated in this limit. To increase the users' impact, we suggest an adaptive approach by establishing a network-dependent coupling rate with their digital assistants. In this case, the mechanism of AIA control helps resolve the DM process in the presence of some uncertainties resulting from the variety of users' preferences. Our findings open new perspectives in different areas where AIAs become effective teammates for humans to solve common routine problems in network organizations.

An exploration of frontline health professional's current understanding of non-fatal strangulation.

AIM: To explore frontline health professionals' current understanding of non-fatal strangulation and their need for and support for a comprehensive education and screening package to support health delivery. DESIGN: A descriptive mixed-method approach was chosen to analyse responses to an anonymous, online survey consisting of ten Likert scale, open-ended and five demographic questions. 103 frontline health professionals (nurses, doctors, paramedics, midwives) participated in this study. METHODS: Content analysis of the Likert scale and open-ended questions describing the subjective experiences and perceptions of the participants was undertaken along with percentage and frequency counts of the rated Likert responses. RESULTS: The findings identified that 51.1% of health professionals do not ask about strangulation routinely and that 59% of health professionals reported receiving no formal education or professional development on NFS to enhance their knowledge or inform clinical practice. No health professionals identified mild traumatic brain injury as a consequence or sign of strangulation, nor did they identify an understanding that 50% of people may have no visible injuries after being strangled. Health professionals also do not routinely document the different agencies referred to or involved in supporting the person who experienced NFS. CONCLUSION: Findings suggest that frontline health professionals lack the confidence, skills and education needed to meet medical obligations to their patients and to fulfil their duty to 'do no harm'. Frontline health professionals would welcome a comprehensive education and screening package to guide recognition and response to non-fatal strangulation in their clinical settings. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: The purpose of the study was to understand and explore health professionals' knowledge about non-fatal strangulation so that improved education around better screening, and management of trauma-focused care to people who have been subjected to non-fatal strangulation could occur. NO PATIENT OR PUBLIC CONTRIBUTION: This review contains no patient or public contribution since it examines health professionals' knowledge of identifying non-fatal strangulation and the screening and assessment tools used in clinical practice.

Lake Baikal amphipods and their genomes, great and small.

Endemic amphipods (Crustacea: Amphipoda) of Lake Baikal represent an outstanding example of large species flocks occupying a wide range of ecological niches and originating from a handful of ancestor species. Their development took place at a restricted territory and is thus open for comprehensive research. Such examples provide unique opportunities for studying behavioral, anatomic, or physiological adaptations in multiple combinations of environmental conditions and thus attract considerable attention. The existing taxonomies of this group list over 350 species and subspecies, which, according to the molecular phylogenetic studies of marker genes, full transcriptomes and mitochondrial genomes, originated from at least two introductions into the lake. The studies of allozymes and marker genes have revealed a significant cryptic diversity in Baikal amphipods, as well as a large variance in genetic diversity within some morphological species. Crossing experiments conducted so far for two morphological species suggest that the differences in the mitochondrial marker (cytochrome c oxidase subunit I gene) can potentially be applied for making predictions about reproductive isolation. For about one-tenth of the Baikal amphipod species, nuclear genome sizes and chromosome numbers are known. While genome sizes vary within one order of magnitude, the karyotypes are relatively stable (2n = 52 for most species studied). Moreover, analysis of the diversity of repeated sequences in nuclear genomes showed significant between-species differences. Studies of mitochondrial genomes revealed some unusual features, such as variation in length and gene order, as well as duplications of tRNA genes, some of which also underwent remolding (change in anticodon specificity due to point mutations). The next important steps should be (i) the assembly of whole genomes for different species of Baikal amphipods, which is at the moment hampered by complicated genome structures with high repeat content, and (ii) updating species taxonomy taking into account all the data.

Combined effects of matrix stiffness and obesity-associated signaling directs progressive phenotype in PANC-1 pancreatic cancer cells in vitro.

Obesity is a leading risk factor of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor disease prognosis and outcomes. Retrospective studies have identified this link, but interactions surrounding obesity and PDAC are still unclear. Research has shifted to contributions of fibrosis (desmoplasia) on malignancy, which involves increased deposition of collagens and other extracellular matrix (ECM) molecules and increased ECM crosslinking, all of which contribute to increased tissue stiffening. However, fibrotic stiffening is underrepresented as a model feature in current PDAC models. Fibrosis is shared between PDAC and obesity, and can be leveraged for in vitro model design, as current animal obesity models of PDAC are limited in their ability to isolate individual components of fibrosis to study cell behavior. In the current study, methacrylated type I collagen (PhotoCol®) was photo-crosslinked to pathological stiffness levels to recapitulate fibrotic ECM stiffening. PANC-1 cells were encapsulated within PhotoCol®, and the tumor-tissue constructs were prepared to represent normal (healthy) (~600 Pa) and pathological (~2000 Pa) tissues. Separately, human mesenchymal stem cells were differentiated into adipocytes representing lean (2D differentiation) and obese fat tissue (3D collagen matrix differentiation), and conditioned media was applied to PANC-1 tumor-tissue constructs. Conditioned media from obese adipocytes showed increased vimentin expression, a hallmark of invasiveness and progression, that was not seen after exposure to media from lean adipocytes or control media. Characterization of the obese adipocyte secretome suggested that some PANC-1 differences may arise from increased interleukin-8 and -10 compared to lean adipocytes. Additionally, high matrix stiffness associated induced an amoeboid morphology in PANC-1 cells that was not present at low stiffness. Amoeboid morphology is an accessory to epithelial-to-mesenchymal transition and is used to navigate complex ECM environments. This plasticity has greater implications for treatment efficacy of metastatic cancers. Overall, this work 1) highlights the importance of investigating PDAC-obesity interactions to study the effects on disease progression and persistence, 2) establishes PhotoCol® as a matrix material that can be leveraged to study amoeboid morphology and invasion in PDAC, and 3) emphasizes the importance of integrating both biophysical and biochemical interactions associated within both pathologies for in vitro PDAC models.

Myo-inositol Levels in the Dorsal Anterior Cingulate Cortex Predicts Anxiety-to-Eat in Anorexia Nervosa.

Background: Anorexia nervosa (AN) is a mental and behavioral health condition characterized by an intense fear of weight or fat gain, severe restriction of food intake resulting in low body weight, and distorted self-perception of body shape or weight. While substantial research has focused on general anxiety in AN, less is known about eating-related anxiety and its underlying neural mechanisms. Therefore, we sought to characterize anxiety-to-eat in AN and examine the neurometabolic profile within the dorsal anterior cingulate cortex (dACC), a brain region putatively involved in magnifying the threat response. Methods: Women seeking inpatient treatment for AN and women of healthy weight without a lifetime history of an eating disorder (healthy controls; HC) completed a computer-based behavioral task assessing anxiety-to-eat in response to images of higher (HED) and lower (LED) energy density foods. Participants also underwent magnetic resonance spectroscopy of the dACC in a 3 Tesla scanner. Results: The AN group reported greater anxiety to eat HED and LED foods relative to the HC group. Both groups reported greater anxiety to eat HED foods relative to LED foods. The neurometabolite myo-inositol (mI) was lower in the dACC in AN relative to HC, and mI levels negatively predicted anxiety to eat HED but not LED foods in the AN group only. mI levels in the dACC were independent of body weight, body mass, and general anxiety. Conclusions: These findings provide critical new insight into the clinically challenging feature and underlying neural mechanisms of eating-related anxiety and indicate mI levels in the dACC could serve as a novel biomarker of illness severity that is independent of body weight to identify individuals vulnerable to disordered eating or eating pathology as well as a potential therapeutic target.

Ten Years of Quality Monitoring of Abdominal Organ Procurement in the Netherlands and Its Impact on Transplant Outcome.

In this study, 10 years of procurement quality monitoring data were analyzed to identify potential risk factors associated with procurement-related injury and their association with long-term graft survival. All deceased kidney, liver, and pancreas donors from 2012 to 2022 and their corresponding recipients in the Netherlands were retrospectively included. The incidence of procurement-related injuries and potential risk factors were analyzed. Of all abdominal organs procured, 23% exhibited procurement-related injuries, with a discard rate of 4.0%. In kidneys and livers, 23% of the grafts had procurement-related injury, with 2.5% and 4% of organs with procurement-related injury being discarded, respectively. In pancreas procurement, this was 27%, with a discard rate of 24%. Male donor gender and donor BMI >25 were significant risk factors for procurement-related injury in all three abdominal organs, whereas aberrant vascularization was significant only for the kidney and liver. In the multivariable Cox regression analyses, procurement-related injury was not a significant predictor for graft failure (kidney; HR 0.99, 95% CI 0.75-1.33, p = 0.99, liver; HR 0.92, 95% CI 0.66-1.28, p = 0.61, pancreas: HR 1.16; 95% CI 0.16-8.68, p = 0.88). The findings of this study suggest that transplant surgeons exhibited good decision-making skills in determining the acceptability and repairability of procurement-related injuries.