Oral formulations for highly lipophilic drugs: Impact of surface decoration on the efficacy of self-emulsifying drug delivery systems.

AIM: To evaluate the impact of the surface decoration of cannabidiol (CBD) loaded self-emulsifying drug delivery systems (SEDDS) on the efficacy of the formulations to cross the various barriers faced by orally administered drugs. METHODS: Polyethylene glycol (PEG)-free polyglycerol (PG)-based SEDDS, mixed zwitterionic phosphatidyl choline (PC)/PEG-containing SEDDS and PEG-based SEDDS were compared regarding stability against lipid degrading enzymes, surface properties, permeation across porcine mucus, cellular uptake and cytocompatibility. RESULTS: SEDDS with a size of about 200 nm with narrow size distributions were developed and loaded with 20-21 % of CBD. For PG containing PEG-free SEDDS increased degradation by lipid degrading enzymes was observed compared to PEG-containing formulations. The surface hydrophobicity of placebo SEDDS increased in the order of PG-based to mixed PC/PEG-based to PEG-based SEDDS. The influence of this surface hydrophobicity was also observed on the ability of the SEDDS to cross the mucus gel layer where highest mucus permeation was achieved for most hydrophobic PEG-based SEDDS. Highest cellular internalization was observed for PEG-based Lumogen Yellow (LY) loaded SEDDS with 92 % in Caco-2 cells compared to only 30 % for mixed PC/PEG-based SEDDS and 1 % for PG-based SEDDS, leading to a 100-fold improvement in cellular uptake for SEDDS having highest surface hydrophobicity. For cytocompatibility all developed placebo SEDDS showed similar results with a cell survival of above 75 % for concentrations below 0.05 % on Caco-2 cells. CONCLUSION: Higher surface hydrophobicity of SEDDS to orally deliver lipophilic drugs as CBD seems to be a promising approach to increase the intracellular drug concentration by an enhanced permeation through the mucus layer and cellular internalization.

Biomedical applications of functional hydrogels: Innovative developments, relevant clinical trials and advanced products.

Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.

A Serological Multiplexed Immunoassay (MIA) Detects Antibody Reactivity to SARS-CoV-2 and Other Viral Pathogens in Liberia and Is Configurable as a Multiplexed Inhibition Test (MINT).

The SARS-CoV-2 pandemic ignited global efforts to rapidly develop testing, therapeutics, and vaccines. However, the rewards of these efforts were slow to reach many low- to middle-income countries (LMIC) across the African continent and globally. Therefore, two bead-based multiplexed serological assays were developed to determine SARS-CoV-2 exposure across four counties in Liberia. This study was conducted during the summer of 2021 on 189 samples collected throughout Grand Bassa, Bong, Margibi, and Montserrado counties. Our multiplexed immunoassay (MIA) detected elevated exposure to SARS-CoV-2 and multiple variant antigens. Additionally, we detected evidence of exposure to Dengue virus serotype 2, Chikungunya virus, and the seasonal coronavirus NL63. Our multiplexed inhibition test (MINT) was developed from the MIA to observe antibody-mediated inhibition of SARS-CoV-2 spike protein binding to its cognate cellular receptor ACE-2. We detected inhibitory antibodies in the tested Liberian samples, which were collectively consistent with a convalescent serological profile. These complementary assays serve to supplement existing serological testing needs and may enhance the technical capacity of scientifically underrepresented regions globally.

Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3.

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2H34, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

Inhibition of Ribosome Biogenesis in vivo Causes p53-Dependent Death and p53-Independent Dysfunction.

Ribosomes are critical for cell function; their synthesis (known as ribosome biogenesis; "RiBi") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in vivo in adult tissue. Here, we generated mice with conditional deletion of Nat10 , an essential gene for RiBi and translation, to investigate effects of RiBi blockade in vivo. We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion of Trp53 could rescue acinar cells from apoptotic cell death; however, Nat10 Δ / Δ ; Trp53 Δ / Δ acinar cells remained morphologically and functionally abnormal. Moreover, the deletion of Trp53 did not rescue the lethality of inducible, globally deleted Nat10 in adult mice nor did it rescue embryonic lethality of global Nat10 deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion of Nat10 in acinar cells blocked Kras -oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translation in vivo .

A Flexible Artificial Spiking Photoreceptor Enabled by a Single VO2 Mott Memristor for the Spike-Based Electronic Retina.

The neuromorphic vision system that utilizes spikes as information carriers is crucial for the formation of spiking neural networks. Here, we present a bioinspired flexible artificial spiking photoreceptor (ASP), which is realized by using a single VO2 Mott memristor that can simultaneously sense and encode the stimulus light into spikes. The ASP has high spike-encoded photosensitivity and ultrawide photosensing range (405-808 nm) with good endurance (>7 × 107) and high flexibility (bending radius ∼5 mm). Then, we put forward an all-spike electronic retina architecture that comprises one layer of ASPs and one layer of artificial optical nerves (AONs) to process the spike information. Each AON consists of a single Mott memristor connected in series with a neuro-transistor that is a multiple-input floating-gate MOS transistor. Simulation results demonstrate that the all-spike electronic retina can successfully segment images with high Shannon entropy, thus laying the foundation for the development of a spike-based neuromorphic vision system.

Charge-converting nanocarriers: Phosphorylated polysaccharide coatings for overcoming intestinal barriers.

For the design of charge-converting nanocarriers (NCs), cationic lipid-based NCs containing curcumin as model drug were coated with phosphorylated starch (NC-SP) and phosphorylated dextran (NC-DP). NCs showed a drug encapsulation efficiency of 94 % and had a mean size of 175 to 180 nm. The recorded zeta potential of the core NC (cNC) was +8.3 mV, whereas it reversed to -10.6 mV and -7.4 mV after decorating with SP and DP, respectively. Furthermore, a 3-fold higher amount of curcumin having been incorporated in these NCs remained stable within 2 h of UV exposure indicating a photoprotective effect of this delivery system. Charge-converting properties were confirmed by cleavage with intestinal alkaline phosphatase (IAP) and resulted in a zeta potential shift of Δ15.4 mV for NC-SP and Δ11.2 mV for NC-DP. NC-SP and NC-DP showed enhanced mucus permeating properties compared to cNC, that were additionally confirmed by an up to 2.2-fold improved cellular uptake on mucus secreting Caco-2/HT29-MTX cells. According to these results, NC-SP and NC-DP coatings hold promise as a viable and efficient strategy for charge-converting NCs.

Mandibular Implant-Supported Overdentures Using Telescopic Crowns and Immediate Loading Protocol: A 2-Year Prospective Follow-up Study.

PURPOSE: Implant-supported overdentures have been an effective treatment method for edentulous mandibles. However, the loading time after implant placement is still controversial. The purpose of this study was to evaluate the outcome of implant-supported overdentures using telescopic crowns for the treatment of edentulous patients with immediate loading protocol. MATERIALS AND METHODS: This study was conducted on 22 edentulous mandibular patients visiting the Department of High Technique, National Hospital of Odonto - Stomatology, Ho Chi Minh City, Vietnam for prosthodontic rehabilitation. Each patient received four interforaminal implants. Immediate loading protocol was applied, and Ankylos Syncone copings systems was used to connect the prosthesis and the implants. The survival rate of implants and prostheses, as the primary outcome, were evaluated at 6 months, 01 year, and 02 years post-surgery. Peri-implant tissue condition, peri-implant bone loss, and patient satisfaction were the secondary outcomes. RESULTS: The implant survival rate was 98.9% with 01 failed implant. The peri-implant bone loss changes after 6 months, 01 year, and 02 years were 0.07 ± 0.22 mm, 0.12 ± 0.3 mm, and 0.15 ± 0.2 mm, respectively. No gingival hyperplasia was recorded. The prosthesis survival rate was 86.4% with 1 fractured overdenture, 1 overdenture relining and 1 abutment fracture. CONCLUSIONS: Mandibular rehabilitation using implant-supported overdenture with telescopic crowns and immediate loading protocol showed high survival rates of both implant and prosthesis in 2-year follow-up.

A 1,2-Aryl Migration Reaction in Visible-Light-Mediated Synthesis of Quinoxaline Derivatives: Mechanistic Studies.

The synthesis of quinoxaline derivatives holds critical importance in various fields ranging from pharmaceuticals to material science. In this study, we introduce a practical light-mediated method for the efficient synthesis of quinoxaline derivatives. This approach enabled the sequential two-step, one-pot synthesis of 1,2-dihydro-2,2-diaryl-substituted quinoxalines from quinones, alkynes, and diamines. By adjusting the stoichiometric ratios and reaction conditions, the method was shifted to yield 2,3-diaryl-substituted quinoxalines exclusively, demonstrating remarkable versatility and efficiency. This switch in reaction outcomes was revealed to involve an oxidative 1,2-aryl migration through a combination of thorough experimental and computational mechanistic studies.

The histone demethylase JMJ27 acts during the UV-induced modulation of H3K9me2 landscape and facilitates photodamage repair.

Plants have evolved sophisticated DNA repair mechanisms to cope with the deleterious effects of ultraviolet (UV)-induced DNA damage. Indeed, DNA repair pathways cooperate with epigenetic-related processes to efficiently maintain genome integrity. However, it remains to be deciphered how photodamages are recognized within different chromatin landscapes, especially in compacted genomic regions such as constitutive heterochromatin. Here we combined cytogenetics and epigenomics to identify that UV-C irradiation induces modulation of the main epigenetic mark found in constitutive heterochromatin, H3K9me2. We demonstrated that the histone demethylase, Jumonji27 (JMJ27), contributes to the UV-induced reduction of H3K9me2 content at chromocentres. In addition, we identified that JMJ27 forms a complex with the photodamage recognition factor, DNA Damage Binding protein 2 (DDB2), and that the fine-tuning of H3K9me2 contents orchestrates DDB2 dynamics on chromatin in response to UV-C exposure. Hence, this study uncovers the unexpected existence of an interplay between photodamage repair and H3K9me2 homeostasis.

Alzheimer's Disease Linkage to Real-World Evidence (AD-LINE) Study: Linking Claims Data to Phase 3 GRADUATE Study of Gantenerumab.

BACKGROUND: Linking data from clinical trials and real-world claims may improve the robustness of trial data and provide information on the health, economic, and societal impacts of a disease. OBJECTIVE: To report on the feasibility of linking trial data to Medicare claims data in early symptomatic Alzheimer's disease (AD) in the US. DESIGN AND SETTING: Alzheimer's Disease Linkage to Real-World Evidence (AD-LINE) was a noninterventional cohort study that included participants recruited from the GRADUATE program whose trial data were linked to their Medicare claims. PARTICIPANTS: AD-LINE participants were 66 years and older with early symptomatic AD (ie, mild cognitive impairment [MCI] due to AD or mild AD dementia) and were enrolled in the GRADUATE program and a Medicare fee-for-service or Medicare Advantage plan. MEASUREMENTS: The Centers for Medicare and Medicaid Services linked participants' clinical trial identifiers to their Medicare beneficiary identifiers using a deterministic, exact matching process. Demographics and clinical characteristics of the AD-LINE cohort at baseline were collected. Outcomes measured in this study included healthcare resource utilization derived from Medicare claims data. RESULTS: In total, 147 participants across 21 US sites were invited to participate and 111 provided informed consent. Of those, 61 patients had linkable data (ie, Medicare beneficiary identifier), Medicare Parts A/B enrollment, and no health maintenance organization (HMO) enrollment in the year before trial entry. Of the 61 participants whose data were analyzed in this study, 30 had MCI due to AD and 31 had mild AD dementia. Participants in the MCI due to AD group had more healthcare resource utilization on average in the baseline period than those in the mild AD dementia group (29.9 [SD, 20.9] vs 24.5 claims [SD, 12.3]). In an ad hoc analysis, a relatively high concordance (85.3%) was seen between the rates of clinically confirmed AD diagnosis and evidence of AD diagnosis in claims data. CONCLUSION: This linkage process may serve as a proof of concept for researchers interested in linking clinical trial and real-world claims data. The lessons learned from AD-LINE and innovation of data linkage approaches may encourage key stakeholders to link data in the future.

Stacking based ensemble learning framework for identification of nitrotyrosine sites.

Protein nitrotyrosine is an essential post-translational modification that results from the nitration of tyrosine amino acid residues. This modification is known to be associated with the regulation and characterization of several biological functions and diseases. Therefore, accurate identification of nitrotyrosine sites plays a significant role in the elucidating progress of associated biological signs. In this regard, we reported an accurate computational tool known as iNTyro-Stack for the identification of protein nitrotyrosine sites. iNTyro-Stack is a machine-learning model based on a stacking algorithm. The base classifiers in stacking are selected based on the highest performance. The feature map employed is a linear combination of the amino composition encoding schemes, including the composition of k-spaced amino acid pairs and tri-peptide composition. The recursive feature elimination technique is used for significant feature selection. The performance of the proposed method is evaluated using k-fold cross-validation and independent testing approaches. iNTyro-Stack achieved an accuracy of 86.3% and a Matthews correlation coefficient (MCC) of 72.6% in cross-validation. Its generalization capability was further validated on an imbalanced independent test set, where it attained an accuracy of 69.32%. iNTyro-Stack outperforms existing state-of-the-art methods across both evaluation techniques. The github repository is create to reproduce the method and results of iNTyro-Stack, accessible on: https://github.com/waleed551/iNTyro-Stack/.

A Total Internal Reflection Microscopy (TIRM)-Based Approach for Direct Characterization of Polymer Brush Conformational Change in Aqueous Solution.

This study presents a novel approach utilizing total internal reflection microscopy (TIRM) to effectively characterize the swelling and collapse of polymer brushes in aqueous solutions. Zwitterionic poly(carboxybetaine methacrylate) (PCBMA) and nonionic poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) brushes are chosen as model systems. By investigation of an intriguing theory-experiment discrepancy observed during the measurement of near-wall hindered diffusion, valuable insights into the compressibility of polymer brushes are obtained, revealing their conformational information in aqueous solution. The results demonstrate that zwitterionic PCBMA brushes exhibit minimal antipolyelectrolyte effects in 0.1-10 mM NaCl solution but undergo significant swelling with increasing pH. On the other hand, nonionic POEGMA brushes exhibit similar responses to ionic strength as weak polyelectrolyte brushes. These unexpected findings enhance our understanding of polymer brushes beyond classical theories. The TIRM-based approach proves to be effective for characterizing polymer brushes and other soft nanomaterials.

Risk Factors and Profiles of Falls Among Inpatients in Vietnam: A Multicenter Nested Case-Control Study.

Purpose: Falls among inpatients represent a significant global health concern and are among the leading causes of accidental death. However, hospital falls are context- and population dependent. This study aimed to investigate the risk factors contributing to falls and the fall profiles among Vietnamese inpatients. Methods: A nested case-control study was conducted at nine public hospitals in Ho Chi Minh City. For every fall identified through the medical fall incident reporting system, four controls (ie, nonfall patients) were also selected from medical records within the same department and timeframe. Medical records were extracted, which included detailed information about the falls. Results: Among 101 fall cases and 404 nonfall controls, several risk factors for falls were found, including reduced strength and mobility (OR=3.08, 95% 1.30-7.30), nocturia (OR=9.08, 95% CI 4.04-20.45), having more than two diseases (OR=2.76, 95% CI 1.53-4.98), using walking aids (OR=23.26, 95% CI 10.20-53.03), using medical devices (OR=3.44, 95% CI 1.92-6.15) and using antiepileptics (OR=3.94, 95% CI 1.22-12.77). About 19.8% of the falls occurred within the first 24 hours from admission and the most common time of falls was from 0:00 am to 5:59 am (44.6%). The patient bed and bathroom were the most frequent locations for falls, accounting for 44.55% and 37.62% of the cases, respectively. More than 40% of the falls occurred when the patients were with their personal caregivers. Conclusion: Although intervention programs can use these risk factors to target those who have a high risk of falling, to optimize resources, such programs should consider the fall patterns found in our study.

Antibiotic-Polyphosphate Nanocomplexes: A Promising System for Effective Biofilm Eradication.

Purpose: The eradication of bacterial biofilms poses an enormous challenge owing to the inherently low antibiotic susceptibility of the resident microbiota. The complexation of antibiotics with polyphosphate can substantially improve antimicrobial performance. Methods: Nanoparticular complexes of the model drug colistin and polyphosphate (CP-NPs) were developed and characterized in terms of their particle size and morphology, polydispersity index (PDI), zeta potential, and cytotoxicity. Enzyme-triggered monophosphate and colistin release from the CP-NPs was evaluated in the presence of alkaline phosphatase (AP). Subsequently, antimicrobial efficacy was assessed by inhibition experiments on planktonic cultures, as well as time-kill assays on biofilms formed by the model organism Micrococcus luteus. Results: The CP-NPs exhibited a spherical morphology with particle sizes <200 nm, PDI <0.25, and negative zeta potential. They showed reduced cytotoxicity toward two human cell lines and significantly decreased hemotoxicity compared with native colistin. Release experiments with AP verified the enzymatic cleavage of polyphosphate and subsequent release of monophosphate and colistin from CP-NPs. Although CP-NPs were ineffective against planktonic M. luteus cultures, they showed major activity against bacterial biofilms, outperforming native colistin treatment. Strongly elevated AP levels in the biofilm state were identified as a potential key factor for the observed findings. Conclusion: Accordingly, polyphosphate-based nanocomplexes represent a promising tool to tackle bacterial biofilm.

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics.

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

Dinuclear Cyclometalated Pincer Nickel(II) Complexes with Metal-Metal-to-Ligand Charge Transfer Excited States and Near-Infrared Emission.

Facile non-radiative decay of low-lying metal-centered (MC) d-d excited states has been well documented to pose a significant obstacle to the development of phosphorescent NiII complexes due to substantial structural distortions between the d-d excited state and the ground state. Herein, we prepared a series of dinuclear Ni2II,II complexes by using strong σ-donors, carbene-phenyl-carbene (CNHC^Cphenyl^CNHC) pincer ligands, and prepared their dinuclear Pt2II,II and Pd2II,II analogues. Dinuclear Ni2II,II complexes bridged by formamidinate/α-carbolinato ligand exhibit short Ni-Ni distances of 2.947-3.054 Å and singlet metal-metal-to-ligand charge transfer (1MMLCT) transitions at 500-550 nm. Their 1MMLCT absorption energies are red-shifted relative to the Pt2II,II and Pd2II,II analogues at ~450 nm and ≤420 nm respectively. One-electron oxidation of these Ni2II,II complexes produces valence-trapped dinuclear Ni2II,III species, which are characterized by EPR spectroscopy. Upon photoexcitation, these Ni2II,II complexes display phosphorescence (τ=2.6-8.6 µs) in the NIR (800-1400nm) spectral region in 2-MeTHF and in solid state at 77 K, which is insensitive to π-conjugation of the coordinated [CNHC^Cphenyl^CNHC] ligand. Combined with DFT calculations, the NIR emission is assigned to originate from the 3dd excited state. Studies have found that the dinuclear Ni2II,II complex can sensitize the formation of singlet oxygen and catalyze the oxidation of cyclo-dienes under light irradiation.