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Elderly and individuals with disabilities can greatly benefit from human activity recognition (HAR) systems, which have recently advanced significantly due to the integration of the Internet of Things (IoT) and artificial intelligence (AI). The blending of IoT and AI methodologies into HAR systems has the potential to enable these populations to lead more autonomous and comfortable lives. HAR systems are equipped with various sensors, including motion capture sensors, microcontrollers, and transceivers, which supply data to assorted AI and machine learning (ML) algorithms for subsequent analyses. Despite the substantial advantages of this integration, current frameworks encounter significant challenges related to computational overhead, which arises from the complexity of AI and ML algorithms. This article introduces a novel ensemble of gated recurrent networks (GRN) and deep extreme feedforward neural networks (DEFNN), with hyperparameters optimized through the artificial water drop optimization (AWDO) algorithm. This framework leverages GRN for effective feature extraction, subsequently utilized by DEFNN for accurately classifying HAR data. Additionally, AWDO is employed within DEFNN to adjust hyperparameters, thereby mitigating computational overhead and enhancing detection efficiency. Extensive experiments were conducted to verify the proposed methodology using real-time datasets gathered from IoT testbeds, which employ NodeMCU units interfaced with Wi-Fi transceivers. The framework's efficiency was assessed using several metrics: accuracy at 99.5%, precision at 98%, recall at 97%, specificity at 98%, and F1-score of 98.2%. These results then were benchmarked against other contemporary deep learning (DL)-based HAR systems. The experimental outcomes indicate that our model achieves near-perfect accuracy, surpassing alternative learning-based HAR systems. Moreover, our model demonstrates reduced computational demands compared to preceding algorithms, suggesting that the proposed framework may offer superior efficacy and compatibility for deployment in HAR systems designed for elderly or individuals with disabilities.

Diabetic Retinopathy (DR) is a serious eye condition that occurs due to high blood sugar levels in patients with Diabetes Mellitus. If left untreated, DR can potentially result in blindness. Using automated neural network-based methods to grade DR shows potential for early detection. However, the uneven and non-quadrilateral forms of DR lesions provide difficulties for traditional Convolutional Neural Network (CNN)-based architectures. To address this challenge and explore a novel algorithm architecture, this work delves into the usage of contrasting cluster assignments in retinal fundus images with the Swapping Assignments between multiple Views (SwAV) algorithm for DR grading. An ablation study was made where SwAV outperformed other CNN and Transformer-based models, independently and in ensemble configurations with an accuracy of 87.00% despite having fewer parameters and layers. The proposed approach outperforms existing state-of-the-art models regarding classification metrics, complexity, and prediction time. The findings offer great potential for medical practitioners, allowing for more accurate diagnosis of DR and earlier treatments to avoid visual loss.

A novel technique for electronic control unit (ECU) identification is proposed in this study to address security vulnerabilities of the controller area network (CAN) protocol. The reliable ECU identification has the potential to prevent spoofing attacks launched over the CAN due to the lack of message authentication. In this regard, we model the ECU-specific random distortion caused by the imperfections in the digital-to-analog converter and semiconductor impurities in the transmitting ECU for fingerprinting. Afterward, a 4-layered artificial neural network (ANN) is trained on the feature set to identify the transmitting ECU and the corresponding ECU pin. The ECU-pin identification is also a novel contribution of this study and can be used to prevent voltage-based attacks. We have evaluated our method using ANNs over a dataset generated from 7 ECUs with 6 pins, each having 185 records, and 40 records for each pin. The performance evaluation against state-of-the-art methods revealed that the proposed method achieved 99.4% accuracy for ECU identification and 96.7% accuracy for pin identification, which signifies the reliability of the proposed approach.

Human proteins repurposed as biologics for clinical use have been engineered through in vitro techniques that improve the affinity of the biologics for their ligands. However, the techniques do not select against properties, such as protease sensitivity or self-reactivity, that impair the biologics' clinical efficacy. Here we show that the B-cell receptors of primary murine B cells can be engineered to affinity mature in vivo the human CD4 domains of the HIV-1-entry inhibitor CD4 immunoadhesin (CD4-Ig). Specifically, we introduced genes encoding the CD4 domains 1 and 2 (D1D2) of a half-life-enhanced form of CD4-Ig (CD4-Ig-v0) into the heavy-chain loci of murine B cells and adoptively transferred these cells into wild-type mice. After immunization, the B cells proliferated, class switched, affinity matured and produced D1D2-presenting antibodies. Somatic hypermutations in the D1D2-encoding region of the engrafted cells improved the binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein and the inhibitor's ability to neutralize a panel of HIV-1 isolates without impairing its pharmacokinetic properties. In vivo affinity maturation of non-antibody protein biologics may guide the development of more effective therapeutics., Competing Interests: Competing interests: A.P., W.H., T.O., Y.Y. and M.F. are inventors of a patent describing the in vivo affinity maturation of antibodies and biologics. C.C.B., M.D.A. and M.F. have equity stakes in Emmune, Inc., which developed CD4-Ig-v0. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Spinal cord injury (SCI) poses significant challenges to regenerative medicine due to its limited self-repair capabilities. In this study, we engineered a biomimetic injectable hydrogel using modified chitosan and alginate biopolymers encapsulating selenium-folic acid nanoparticles (Se-FA NPs) to facilitate SCI regeneration. The hydrogel exhibited a unique porous structure attributed to the incorporation of nanofiber fragments, enhancing its biocompatibility and bioactivity. Through a series of in vitro evaluations, including cell viability assays, proliferation studies, gene expression analysis, we assessed the hydrogel's cytocompatibility and its potential for supporting neural cell growth. Our results demonstrate the promising efficacy of the hydrogel in providing a conducive microenvironment for neural tissue regeneration. Moreover, the sustained release of Se-FA NPs from the hydrogel system offers neuroprotective, antioxidative, and anti-inflammatory benefits crucial for SCI therapy. Overall, our biomimetic hydrogel biocomposites hold great potential as a therapeutic strategy for promoting spinal cord regeneration, highlighting their significance in advancing the field of regenerative medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The chronic inflammatory condition known as multiple sclerosis (MS) causes inflammation and demyelination in the central nervous system (CNS). The activation of multiple cell types, including the CNS's resident immune cells called microglia, is a component of the immunological response in MS. Recently, the triggering receptor expressed on myeloid cells (TREM) family has emerged as a crucial player in modulating microglial function and subsequent neuroinflammation. Understanding the role of TREM receptors in MS pathogenesis could provide insightful information on how to develop new therapeutic approaches., Main Body: The TREM family consists of several receptors, including TREM-1 and TREM-2, which can be expressed on both immune cells, such as myeloid cells and microglia, and non-immune cells. These receptors interact with their respective ligands and regulate signaling pathways, ultimately leading to the control of microglial activation and inflammatory reactions. TREM-2, in particular, has garnered significant interest because of its connection with MS and other neurodegenerative diseases. The activation of microglia through TREM receptors in MS is thought to influence the equilibrium between helpful and detrimental inflammatory responses. TREM receptors can promote the phagocytosis of myelin debris and remove apoptotic cells, thus contributing to tissue repair and regeneration. However, excessive or dysregulated activation of microglia mediated by TREM receptors can lead to the release of pro-inflammatory cytokines and neurotoxic factors, exacerbating neuroinflammation and neurodegeneration in MS., Conclusion: The emerging role of the TREM family in demyelinating diseases highlights the importance of microglia in disease pathogenesis. Understanding the mechanisms by which TREM receptors modulate microglial function can provide valuable insights into the development of targeted therapies for these disorders. By selectively targeting TREM receptors, it may be possible to harness their beneficial effects on tissue repair while dampening their detrimental pro-inflammatory responses. Further research is warranted to elucidate the precise signaling pathways and ligand interactions involved in TREM-mediated microglial activation, which could uncover novel therapeutic avenues for treating MS and other neuroinflammatory disorders., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Elderly and individuals with disabilities can greatly benefit from human activity recognition (HAR) systems, which have recently advanced significantly due to the integration of the Internet of Things (IoT) and artificial intelligence (AI). The blending of IoT and AI methodologies into HAR systems has the potential to enable these populations to lead more autonomous and comfortable lives. HAR systems are equipped with various sensors, including motion capture sensors, microcontrollers, and transceivers, which supply data to assorted AI and machine learning (ML) algorithms for subsequent analyses. Despite the substantial advantages of this integration, current frameworks encounter significant challenges related to computational overhead, which arises from the complexity of AI and ML algorithms. This article introduces a novel ensemble of gated recurrent networks (GRN) and deep extreme feedforward neural networks (DEFNN), with hyperparameters optimized through the artificial water drop optimization (AWDO) algorithm. This framework leverages GRN for effective feature extraction, subsequently utilized by DEFNN for accurately classifying HAR data. Additionally, AWDO is employed within DEFNN to adjust hyperparameters, thereby mitigating computational overhead and enhancing detection efficiency. Extensive experiments were conducted to verify the proposed methodology using real-time datasets gathered from IoT testbeds, which employ NodeMCU units interfaced with Wi-Fi transceivers. The framework's efficiency was assessed using several metrics: accuracy at 99.5%, precision at 98%, recall at 97%, specificity at 98%, and F1-score of 98.2%. These results then were benchmarked against other contemporary deep learning (DL)-based HAR systems. The experimental outcomes indicate that our model achieves near-perfect accuracy, surpassing alternative learning-based HAR systems. Moreover, our model demonstrates reduced computational demands compared to preceding algorithms, suggesting that the proposed framework may offer superior efficacy and compatibility for deployment in HAR systems designed for elderly or individuals with disabilities. [ABSTRACT FROM AUTHOR]

Skin injuries resulting from physical trauma pose significant health risks, necessitating advanced wound care solutions. This investigation introduces an innovative bilayer wound dressing composed of 3D-printed propolis-coated polycaprolactone (PCL/PP) and an electrospun composite of polyvinyl alcohol, chitosan, polycaprolactone, and diltiazem (PVA/CTS/PCL/DTZ). SEM analysis revealed a bilayer structure with 89.23 ± 51.47 % porosity and uniformly distributed nanofibers. The scaffold tensile strength, with pore sizes of 100, 300, and 500 μm, was comparable to native skin. However, smaller pore sizes reduced water vapor transmission from 4211.59 ± 168.53 to 2358.49 ± 203.63 g/m 2 . The incorporation of DTZ lowered the contact angle to 35.23 ± 3.65°, while the addition of PCL reduced the degradation rate and modulated the release of DTZ by approximately 50 %. Moreover, lower pH increased the degradation rate and decreased swelling. The inclusion of propolis enhanced antibacterial activity, and 10 % DTZ promoted the viability, proliferation, and migration of fibroblasts and adipose-derived stem cells. However, increasing DTZ concentration to 12 % reduced cell viability. In vivo tests on rats demonstrated effective wound healing and anti-inflammatory properties of the bilayer samples. Regarding the aforementioned results, the PCL/PP-PVA/CTS/PCL/DTZ (10 % w/w) bilayer wound dressing is a promising candidate for wound healing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic Retinopathy (DR) is a serious eye condition that occurs due to high blood sugar levels in patients with Diabetes Mellitus. If left untreated, DR can potentially result in blindness. Using automated neural network-based methods to grade DR shows potential for early detection. However, the uneven and non-quadrilateral forms of DR lesions provide difficulties for traditional Convolutional Neural Network (CNN)-based architectures. To address this challenge and explore a novel algorithm architecture, this work delves into the usage of contrasting cluster assignments in retinal fundus images with the Swapping Assignments between multiple Views (SwAV) algorithm for DR grading. An ablation study was made where SwAV outperformed other CNN and Transformer-based models, independently and in ensemble configurations with an accuracy of 87.00% despite having fewer parameters and layers. The proposed approach outperforms existing state-of-the-art models regarding classification metrics, complexity, and prediction time. The findings offer great potential for medical practitioners, allowing for more accurate diagnosis of DR and earlier treatments to avoid visual loss. [ABSTRACT FROM AUTHOR]

eCD4-immunoglobulin (Ig) is an HIV entry inhibitor that mimics the engagement of both CD4 and CCR5 with the HIV envelope (Env) protein, a property that imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in SHIV-AD8 EO -infected rhesus macaques (RMs) treated with adeno-associated virus vectors encoding eCD4-Ig. In one RM, setpoint viremia plateaued at 1,000 vRNA copies/mL, despite concomitant serum concentrations of eCD4-Ig in the 60-110 μg/mL range, implying that the virus had gained partial eCD4-Ig resistance. Env mutations occurring prominently in this animal were cloned and further characterized. Three of these mutations (R315G, A436T, and G471E) were sufficient to confer substantial resistance to eCD4-Ig-mediated neutralization onto the parental Env, accompanied by a marked loss of viral fitness. This resistance was not driven by decreased CD4 affinity, subverted sulfopeptide mimicry, changes to co-receptor tropism, or by a gain of CD4 independence. Rather, our data argue that the Env evolving in this animal attained eCD4-Ig resistance by decreasing triggerability, stabilizing the triggered state, and changing the nature of its relationship to the host CD4., Competing Interests: Declaration of interests M.A.M., M.D.A., M.R.G., and M.F. have significant financial interests in Emmune, Inc., a company that is developing HIV immunotherapies based on the immunoadhesin eCD4-Ig, and each serve in a consulting capacity for the company. These potential conflicts of interest are being managed by the authors’ respective institutions. None of the other authors or their immediate family members have any conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fampridine is the only drug approved by the US Food and Drug Administration (FDA) for people with multiple sclerosis (MS) to improve their movement and has exhibited a clinically significant improvement in gait function in a subset of MS patients with Expanded Disability Status Scale (ESDSS) from 4 to 7. Nevertheless, this drug has been reported to possess some adverse effects (AEs) like seizure because of its pharmacological features. The aim of this study was to evaluate the incidence rate of post-medication side effects (SEs) of fampridine in MS patients., Methods: This prospective cohort study includes MS patients aged between 18 and 65 years, referred to the neurology clinic of Kashani Hospital from April 2022 to October 2022, all with administration of fampridine (10 mg tablet twice daily according to the product specifications). Safety in these patients was monitored through monthly SEs checklist questions during 6 months of screening. SPSS version 18 was used to analyze the data of this study., Results: From 319 participants screened at baseline, 254 patients with MS, including 127 relapsing-remitting multiple sclerosis (RRMS), 101 secondary progressive multiple sclerosis (SPMS), and 26 primary progressive multiple sclerosis (PPMS), were included in the study. The most observed AEs in SPMS and RRMS patients were dry mouth (13.9% vs. 15%) and insomnia (12.9% vs. 11%), respectively. Urinary tract infection (UTI) (11.5%) and stomachache (11.5%) were the most common SEs in PPMS patients. The most severe complication of the patients was back pain, while digestive complications were less severe. Also, insomnia and UTI were the patients' most persistent SEs., Conclusions: The drug seems to be safe and well tolerated, as the SEs were mild and transient and they were consistent with most of the previous studies focusing on this medication., Competing Interests: There are no conflicts of interest., (Copyright: © 2025 International Journal of Preventive Medicine.)

This paper summarizes the information technology-related research findings after 5 years with the INTROducing Mental health through Adaptive Technology project. The aim was to improve mental healthcare by introducing new technologies for adaptive interventions in mental healthcare through interdisciplinary research and development. We focus on the challenges related to internet-delivered psychological treatments, emphasising artificial intelligence, human-computer interaction, and software engineering. We present the main research findings, the developed artefacts, and lessons learned from the project before outlining directions for future research. The main findings from this project are encapsulated in a reference architecture that is used for establishing an infrastructure for adaptive internet-delivered psychological treatment systems in clinical contexts. The infrastructure is developed by introducing an interdisciplinary design and development process inspired by domain-driven design, user-centred design, and the person based approach for intervention design. The process aligns the software development with the intervention design and illustrates their mutual dependencies. Finally, we present software artefacts produced within the project and discuss how they are related to the proposed reference architecture. Our results indicate that the proposed development process, the reference architecture and the produced software can be practical means of designing adaptive mental health care treatments in correspondence with the patients’ needs and preferences. In summary, we have created the initial version of an information technology infrastructure to support the development and deployment of Internet-delivered mental health interventions with inherent support for data sharing, data analysis, reusability of treatment content, and adaptation of intervention based on user needs and preferences.

Sinapic acid (SA) is a phenylpropanoid derivative found in various natural sources that exhibits remarkable versatile properties, including antioxidant, anti-inflammatory, and metal-chelating capabilities, establishing itself as a promising candidate for the prevention and treatment of conditions affecting the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and other neurological disorders. These effects also include neuroprotection in epilepsy models, as evidenced by a reduction in seizure-like behavior, cell death in specific hippocampal regions, and lowered neuroinflammatory markers. In AD, SA treatment enhances memory, reverses cognitive deficits, and attenuates astrocyte activation. SA also has positive effects on cognition by improving memory and lowering oxidative stress. This is shown by lower levels of oxidative stress markers, higher levels of antioxidant enzyme activity, and better memory retention. Additionally, in ischemic stroke and PD models, SA provides microglial protection and exerts anti-inflammatory effects. This review emphasizes SA's multifaceted neuroprotective properties and its potential role in the prevention and treatment of various brain disorders. Despite the need for further research to fully understand its mechanisms of action and clinical applicability, SA stands out as a valuable bioactive compound in the ongoing quest to combat neurodegenerative diseases and enhance the quality of life for affected individuals.

Cognitive deficits are the main outcome of neurological disorders whose occurrence has risen over the past three decades. Although there are some pharmacologic approaches approved for managing neurological disorders, it remains largely ineffective. Hence, exploring novel nature-based nutraceuticals is a pressing need to alleviate the results of neurodegenerative diseases, such as Alzheimer's disease (AD) and other neurodegenerative disorders. Some triterpenoids and their derivates can be considered potential therapeutics against neurological disorders due to their neuroprotective and cognitive-improving effects. Betulin (B), betulinic acid (BA), and ursolic acid (UA) are pentacyclic triterpenoid compounds with a variety of biological activities, including antioxidative, neuroprotective and anti-inflammatory properties. This review focuses on the therapeutic efficacy and probable molecular mechanisms of triterpenoids in damage prevention to neurons and restoring cognition in neurodegenerative diseases. Considering few studies on this concept, the precise mechanisms that mediate the effect of these compounds in neurodegenerative disorders have remained unknown. The findings can provide sufficient information about the advantages of these compounds against neurodegenerative diseases.

Emerging highly pathogenic viruses can pose profound impacts on global health, the economy, and society. To meet that challenge, the National Institute of Allergy and Infectious Diseases (NIAID) established nine Antiviral Drug Discovery (AViDD) centers for early-stage identification and validation of novel antiviral drug candidates against viruses with pandemic potential. As part of this initiative, we established paired entry assays that simultaneously screen for inhibitors specifically targeting SARS-CoV-2 (SARS2), Lassa virus (LASV) and Machupo virus (MACV) entry. To do so we employed a dual pseudotyped virus (PV) infection system allowing us to screen ∼650,000 compounds efficiently and cost-effectively. Adaptation of these paired assays into 1536 well-plate format for ultra-high throughput screening (uHTS) resulted in the largest screening ever conducted in our facility, with over 2.4 million wells completed. The paired infection system allowed us to detect two PV infections simultaneously: LASV + MACV, MACV + SARS2, and SARS2 + LASV. Each PV contains a different luciferase reporter gene which enabled us to measure the infection of each PV exclusively, albeit in the same well. Each PV was screened at least twice utilizing different reporters, which allowed us to select the inhibitors specific to a particular PV and to exclude those that hit off targets, including cellular components or the reporter proteins. All assays were robust with an average Z' value ranging from 0.5 to 0.8. The primary screening of ∼650,000 compounds resulted in 1812, 1506, and 2586 unique hits for LASV, MACV, and SARS2, respectively. The confirmation screening narrowed this list further to 60, 40, and 90 compounds that are unique to LASV, MACV, and SARS2, respectively. Of these compounds, 8, 35, and 50 compounds showed IC 50 value < 10 μM, some of which have much greater potency and excellent antiviral activity profiles specific to LASV, MACV, and SARS2, and none are cytotoxic. These selected compounds are currently being studied for their mechanism of action and to improve their specificity and potency through chemical modification., Competing Interests: Declaration of competing interest The are no conflicts of interest amongst any of the authors and the work pertained in this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Chronic wounds, such as diabetic ulcers and pressure sores, pose significant challenges in modern healthcare due to their prolonged healing times and susceptibility to infections. This study aims to engineer a bilayered wound dressing (BLWD) composed of soy protein isolate/collagen with the ability to release Cinnamaldehyde, Artemisia absinthium (AA), and oxygen. Cinnamaldehyde, magnesium peroxide (MgO 2 ), and AA extract were encapsulated. Nanoparticles were evaluated using scanning electron microscopy (SEM), dynamic light scattering, and ZETA potential tests. Swelling, degradation, water vapor penetration, tensile, MTT, SEM, oxygen release, AA extract release, and antibacterial properties were performed. An in vivo study was carried out to assess the final wound dressing under Hematoxiline&Eosin and Masson trichrome staining analysis and compared to a commercial product. According to the results, the synthesized nanoparticles had an average diameter of about 20 nm with a zeta potential in the range of -20 to -30 mV. The layers had uniform and dense surfaces. The maximum swelling and degradation of the dressing was about 130 and 13% respectively. Generally, better mechanical properties were observed in BLWD than in the single-layer case. More than 90% biocompatibility for the wound dressing was reported. The BLWD could inhibit the growth of Gram-positive and Gram-negative microorganisms. Histopathological analysis showed an acceptable wound-healing property. To sum up, the engineered wound dressing can be a good candidate for more clinical trials.

Background: Current therapeutic strategies for multiple sclerosis (MS) aim to suppress the immune response and reduce relapse rates. As alternative treatments, mesenchymal stem cells (MSCs) are being explored. MSCs show promise in repairing nerve tissue and reducing autoimmune responses in people with MS (pwMS)., Objective: This review delves into the literature on the efficacy and safety of MSC therapy for pwMS., Methods: A comprehensive search strategy was employed to identify relevant articles from five databases until January 2024. The inclusion criteria encompassed interventional studies. Efficacy and safety data concerning MSC therapy in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) groups were extracted and analyzed., Results: A comprehensive analysis encompassing 30 studies revealed that individuals who underwent intrathecal (IT) protocol-based transplantation of MSCs experienced a noteworthy improvement in their expanded disability status scale (EDSS) compared to the placebo group. Weighted mean difference (WMD) was -0.28; 95 % CI -0.53 to -0.03, I 2 = 0 %, p-value = 0.028); however, the intravenous (IV) group did not show significant changes in EDSS scores. The annualized relapse rate (ARR) did not significantly decrease among pwMS (WMD = -0.34; 95 % CI -1.05 to 0.38, I 2 = 98 %, p-value = 0.357). Favorable results were observed in magnetic resonance imaging (MRI), with only 19.11 % of pwMS showing contrast-enhanced lesions (CEL) in the short term and no long-term MRI activity. The most common complications in both short-term and long-term follow-ups were infection, back pain, and gastrointestinal symptoms., Conclusions: The study highlights the safety potential of MSC therapy for pwMS. While MRI-based neural regeneration shows significant treatment potential, the effectiveness of MSC therapy remains uncertain due to study limitations and ineffective outcome measures. Further research is needed to establish efficacy and optimize evaluation methods for MSC therapy on pwMS., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: On May 7, 2022, WHO reported a new monkeypox case. By May 2023 over 80,000 cases had been reported worldwide outside previously endemic nations. (This primarily affected the men who have sex with men (MSM) community in rich nations). The present research aims to develop a multi-epitope vaccine for the monkeypox virus (MPXV) using structural and cell surface proteins., Methods: The first part of the research involved retrieving protein sequences. The Immune Epitope Database (IEDB) was then used to analyze the B and T lymphocyte epitopes. After analyzing the sensitizing properties, toxicity, antigenicity, and molecular binding, appropriate linkers were utilizedto connect selected epitopes to adjuvants, and the structure of the vaccine was formulated. Algorithms from the field of immunoinformatics predicted the secondary and tertiary structures of vaccines. The physical, chemical, and structural properties were refined and validated to achieve maximum stability. Molecular docking and molecular dynamic simulations were subsequently employed to assess the vaccine's efficacy. Afterward, the ability of the vaccine to interact with toll-like receptors 3 and 4 (TLR3 and TLR4) was evaluated. Finally, the optimized sequence was then introduced into the Escherichia coli (E. coli) PET30A + vector., Results: An immunoinformatics evaluation suggested that such a vaccine might be safe revealed that this vaccine is safe, hydrophilic, temperature- and condition-stable, and can stimulate innate immunity by binding to TLR3 and TLR4., Conclusion: Our findings suggest that the first step in MPXV pathogenesis is structural and cell surface epitopes. In this study, the most effective and promising epitopes were selected and designed throughprecision servers. Furthermore,through the utilization of multi-epitope structures and a combination of two established adjuvants, this research has the potential to be a landmarkin developing an antiviralvaccine against MPXV. However, additional in vitro and in vivo tests are required to confirm these results., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Mice adoptively transferred with mouse B cells edited via CRISPR to express human antibody variable chains could help evaluate candidate vaccines and develop better antibody therapies. However, current editing strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that these key B-cell functions can be preserved by directly and simultaneously replacing recombined mouse heavy and kappa chains with those of human antibodies, using a single Cas12a-mediated cut at each locus and 5' homology arms complementary to distal V segments. Cells edited in this way to express the human immunodeficiency virus type 1 (HIV-1) broadly neutralizing antibody 10-1074 or VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated mice. The 10-1074 variants isolated from the mice neutralized a global panel of HIV-1 isolates more efficiently than wild-type 10-1074 while maintaining its low polyreactivity and long half-life. We also used the approach to improve the potency of anti-SARS-CoV-2 antibodies against recent Omicron strains. In vivo affinity maturation of B cells edited at their native loci may facilitate the development of broad, potent and bioavailable antibodies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Wound infection is still an important challenge in healing of different types of skin injuries. This highlights the need for new and improved antibacterial agents with novel and different mechanisms of action. In this study, by electrospinning process Tanacetum polycephalum essential oil (EO), as a natural antibacterial and anti-inflammatory agent, along with Amoxicillin (AMX) as an antibiotic are incorporated into PVA/gelatin-based nanofiber mats individually and in combination to fabricate a novel wound dressing. Briefly, we fabricated PVA/gelatin loaded by Amoxicillin as first layer for direct contact with wound surface to protects the wound from exogenous bacteria, and then built a PVA/gelatin/Tanacetum polycephalum essential oil layer on the first layer to help cleanses the wound from infection and accelerates wound closure. Finally, PVA/gelatin layer as third layer fabricated on middle layer to guarantee desirable mechanical properties. For each layer, the electrospinning parameters were adjusted to form bead-free fibers. The morphology of fabricated nanofiber scaffolds was characterized by Fourier-transform infrared (FTIR) and scanning electron microscopy (SEM). Microscopic images demonstrated the smooth bead-free microstructures fabrication of every layer of nanofiber with a uniform fiber size of 126.888 to 136.833 nm. While, EO and AMX increased the diameter of nanofibers but there was no change in physical structure of nanofiber. The water contact angle test demonstrated hydrophilicity of nanofibers with 47.35°. Although EO and AMX had little effect on reducing hydrophilicity but nanofibers with contact angle between 51.4° until 65.4° are still hydrophilic. Multilayer nanofibers loaded by EO and AMX killed 99.99 % of both gram-negative and gram-positive bacteria in comparison with control and PVA/gelatin nanofiber. Also, in addition to confirming the non-toxicity of nanofibers, MTT results also showed the acceleration of cell proliferation. In vivo wound evaluation in mouse models showed that designed nanofibrous scaffolds could be an appropriate option for wound treatment due to their positive effect on angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound closure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ab initio quantum mechanical models can characterize and predict intermolecular binding, but only recently have models including more than a few hundred atoms gained traction. Here, we simulate the electronic structure for approximately 13 000 atoms to predict and characterize binding of SARS-CoV-2 spike variants to the human ACE2 (hACE2) receptor using the quantum mechanics complexity reduction (QM-CR) approach. We compare four spike variants in our analysis: Wuhan, Omicron, and two Omicron-based variants. To assess binding, we mechanistically characterize the energetic contribution of each amino acid involved, and predict the effect of select single amino acid mutations. We validate our computational predictions experimentally by comparing the efficacy of spike variants binding to cells expressing hACE2. At the time we performed our simulations (December 2021), the mutation A484K which our model predicted to be highly beneficial to ACE2 binding had not been identified in epidemiological surveys; only recently (August 2023) has it appeared in variant BA.2.86. We argue that our computational model, QM-CR, can identify mutations critical for intermolecular interactions and inform the engineering of high-specificity interactors.

Compounds derived from herbs exhibit a range of biological properties, including anti-inflammatory, antioxidant, and neuroprotective properties. However, the exact mechanism of action of these compounds in various neurological disorders is not fully discovered yet. Herein, the present work detected the effect of Vanillic acid (VA), a widely-used flavoring agent derived from vanillin, on autistic-like behaviors to assess the probable underlying mechanisms that mediate behavioral, electrophysiological, molecular, and histopathological alterations in the rat model of maternal separation (MS) stress. Maternal separated rats were treated with VA (25, 50, and 100 mg/kg interperitoneally for 14 days). In addition, anxiety-like, autistic-like behaviors, and learning and memory impairment were evaluated using various behavioral tests. Hippocampus samples were assessed histopathologically by H&E staining. Levels of malondialdehyde (MDA) and antioxidant capacity (by the FRAP method), as well as nitrite levels, were measured in brain tissue. Moreover, gene expression of inflammatory markers (IL-1β, TLR-4, TNF-α, and NLRP3) was evaluated in the hippocampus. Electrophysiological alterations were also estimated in the hippocampus by long-term potentiation (LTP) assessments. Results showed that VA reversed the negative effects of MS on behavior. VA increased the diameter and decreased the percentage of dark neurons in the CA3 area. Accordingly, VA decreased MDA and nitrite levels and increased the antioxidant capacity in brain samples and decreased the expression of all inflammatory genes. VA treated rats showed significant improvements in all LTP parameters. This study provided evidence suggesting a possible role for VA in preventing autism spectrum disorder (ASD) by regulating immune signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that recombined murine heavy- and kappa-variable genes can be directly and simultaneously overwritten, using Cas12a-mediated cuts at their 3'-most J segments and 5' homology arms complementary to distal V segments. Cells edited in this way to express the HIV-1 broadly neutralizing antibodies 10-1074 or VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated recipient mice. 10-1074 variants isolated from these mice bound and neutralized HIV-1 envelope glycoprotein more efficiently than wild-type 10-1074 while maintaining or improving its already low polyreactivity and long in vivo half-life. We further validated this approach by generating substantially broader and more potent variants of the anti-SARS-CoV-2 antibodies ZCB11 and S309. Thus, B cells edited at their native loci affinity mature, facilitating development of broad, potent, and bioavailable antibodies and expanding the potential applications of engineered B cells., Competing Interests: Competing interests Y.Y., W.H., T.O., and M.F. are inventors on a pending patent application describing methods for editing B cells. The other authors declare no competing interests.

During the COVID-19 pandemic, Pfizer-BioNTech and Moderna successfully developed nucleoside-modified mRNA lipid nanoparticle (LNP) vaccines. SARS-CoV-2 spike protein expressed by those vaccines are identical in amino acid sequence, but several key components are distinct. Here, we compared the effect of ionizable lipids, untranslated regions (UTRs), and nucleotide composition of the two vaccines, focusing on mRNA delivery, antibody generation, and long-term stability. We found that the ionizable lipid, SM-102, in Moderna's vaccine performs better than ALC-0315 in Pfizer-BioNTech's vaccine for intramuscular delivery of mRNA and antibody production in mice and long-term stability at 4 °C. Moreover, Pfizer-BioNTech's 5' UTR and Moderna's 3' UTR outperform their counterparts in their contribution to transgene expression in mice. We further found that varying N1-methylpseudouridine content at the wobble position of mRNA has little effect on vaccine efficacy. These findings may contribute to the further improvement of nucleoside-modified mRNA-LNP vaccines and therapeutics., (© 2023. Springer Nature Limited.)

V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach., Competing Interests: Declaration of interests W.H., T.O., Y.Y., and M.F. are inventors on a pending patent application describing methods for editing B cells., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A number of studies have suggested that multiple sclerosis (MS) can be associated with serious vascular complications, for which pulmonary thromboembolism (PTE) is a potentially lethal complication. The purpose of this study is to establish a current literature-based estimate of the incidence of venous thromboembolism (VTE), deep vein thrombosis (DVT), and PTE in patients with MS (pwMS) due to the lack of systematic reviews and meta-analyses on this topic. In this systematic review and meta-analysis, studies were assessed regarding the association between MS and the incidence of VTE. The studies were identified through a systematic search of major electronic databases spanning the period from 1950 to February 2022. A random-effects analysis was conducted to calculate the pooled effect size (ES) and 95% confidence intervals (CI) using STATA software. Nine out of 4605 studies were included in the meta-analysis, with an overall sample size of 158,546 individuals. Meta-analysis revealed that the pooled incidence of VTE was 1.8% (95% CI 1.4-2.3) among pwMS. Also, there was an incidence of 0.9% (95% CI 0.4-1.4) and 1.5% (95% CI 1-2.2) for PTE and DVT, respectively in pwMS. Analysis showed MS would be significantly associated with a twofold increased risk of VTE [risk ratios (RR) = 2.12 (95% CI 1.53-2.93)]. Although MS is not typically considered a major risk factor for VTE, the meta-analysis of cohort studies shows that MS has a relative association with an increased incidence of VTE. Future research should focus on the investigation of the effects of MS and its treatments on VTE risk, and also a full range of confounding adjustments will be needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer has been become threatening the health and life of humans. Therefore, attempt to discovery more effective anticancer agents continue. Thiadiazole derivatives have been shown remarkable effects among chemotherapeutic agents. In this study, hybrid molecules containing thiadiazole amide derivatives -aromatic amines (anthranilic acid and 2, 5 dichloro aniline) were synthesized in multi-step reactions including Namidation and S-alkylation of thiadiazole. Synthesized compounds were assayed by MTT test against three cell lines. Molecular docking was performed on Src tyrosine kinases. Compounds 5a, 5b and 8 rendered remarkable cytotoxic properties on HeLa with IC50‹ 60 µM. Compound 5b showed significant cytotoxic effect on both cancer cell lines compared to other tested derivatives. Compound 5a with ΔG = -8.05kcal/mol was the best compound among docked compounds.The results revealed that the quiddity of the amide substitution has a definitive role in the cytotoxic activity. [ABSTRACT FROM AUTHOR]

Introduction: Subacute thyroiditis (SAT) is an inflammatory disease that has different trigger factors. Recent studies show the possible role of COVID-19 vaccine-induced thyroiditis in its initiation. Herein we report the first case of post-Sputnik V vaccination SAT., Case Presentation: A 42-year-old man without any specific disease was admitted due to tremors, palpation and sweating, and neck tenderness on the thyroid gland. Laboratory markers and radiologic assessments highlighted thyroiditis for him, and his symptoms were relieved by administering NSAIDs and corticosteroids., Discussion: There are several hypotheses for the etiology of post-COVID-19 immunization SAT; among them, immunologic reactions like the interactivity of human proteome with viral components and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are more probable than other discussed possibilities. We suggest further studies to discover the exact SAT pathophysiology to prevent the underlying causes among future vaccine candidates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)-the cellular receptor of SARS-CoV-2-into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses., (© 2023. Springer Nature Limited.)

Porous materials are ubiquitous and exhibit properties suitable for depositing therapeutic compounds. Drug loading in porous materials can protect the drug, control its release rate, and improve its solubility. However, to achieve such outcomes from porous delivery systems, effective incorporation of the drug in the internal porosity of the carrier must be guaranteed. Mechanistic knowledge of the factors influencing drug loading and release from porous carriers allows rational design of formulations by selecting a suitable carrier for each application. Much of this knowledge exists in research areas other than drug delivery. Thus, a comprehensive overview of this topic from the drug delivery aspect is warranted. This review aims to identify the loading processes and carrier characteristics influencing the drug delivery outcome with porous materials. Additionally, the kinetics of drug release from porous materials are elucidated, and the common approaches to mathematical modeling of these processes are outlined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Rare diseases are a new global health priority, requiring evidence-based estimates of the global prevalence of diseases to inform public policymakers and provide a serious challenge to the healthcare system that must not be ignored. The purpose of this study is to investigate Iranian future healthcare professionals' knowledge and opinions about rare diseases., Results: A total of 6838 students responded to the questionnaire. Nursing and medical students had the highest participation. Almost 85% of participants rated their knowledge about rare diseases as poor or insufficient. While nearly 70 percent of participants took courses about rare diseases at university. Finally, 72.7% of future healthcare professionals did not feel ready to take care of a patient with a rare disease., Conclusion: The present study has indicated a gap in Iranian medical students' knowledge of rare diseases. The researchers believe that health science policymakers should make a joint effort to improve knowledge about rare diseases. Including courses with regard to rare diseases would be of benefit to future healthcare professionals., (© 2022. The Author(s).)

Echium amoenum is an annual herb native to the northern mountains of Iran which has medicinal application. Petals of Echium amoenum (Gole-Gavzaban) is one of the most valuable medicinal plants in Iranian folk medicine. The dry petals of E. amoenum have long been used as a sedative, tonic, anxiolytic and as a treatment for sore throat, cough and inflammation. Previous studies have shown that petals of E. amoenum contain four toxic pyrrolizidine alkaloids but conflicting results have been acquired in experimental studies investigating the hepatotoxicy of E. amoenum. However, the direct effect of E. amoenum on liver cells and the complete mechanisms of its possible cytotoxic effects toward these cells remain to be defined. The main aim of this study was to assay the mechanisms underlying the toxic effects of E. amoenum toward hepG2 cells. E. amoenum extract was obtained by infusion of dried petals in hot water (90 centigrade) for 15 or 30 min. Cell viability and mechanistic parameters were determined following 12 h incubation of hepG2 with E. amoenum extract that was obtained after 15 or 30 min infusion. The results indicated that E. amoenum extract exerts cytotoxic effects on hepG2 cells, probably through mitochondrial and lysosomal damage induced by glutathione depletion and oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Use of adeno-associated virus (AAV) vectors is complicated by host immune responses that can limit transgene expression. Recent clinical trials using AAV vectors to deliver HIV broadly neutralizing antibodies (bNAbs) by intramuscular administration resulted in poor expression with anti-drug antibodies (ADA) responses against the bNAb., Methods: Here we compared the expression of, and ADA responses against, an anti-SIV antibody ITS01 when delivered by five different AAV capsids. We first evaluated ITS01 expression from AAV vectors three different 2A peptides. Rhesus macaques were selected for the study based on preexisiting neutralizing antibodies by evaluating serum samples in a neutralization assay against the five capsids used in the study. Macaques were intramuscularly administered AAV vectors at a 2.5x10^12 vg/kg over eight administration sites. ITS01 concentrations and anti-drug antibodies (ADA) were measured by ELISA and a neutralization assay was conducted to confirm ex vivo antibody potency., Results: We observed that ITS01 expressed three-fold more efficiently in mice from AAV vectors in which heavy and light-chain genes were separated by a P2A ribosomal skipping peptide, compared with those bearing F2A or T2A peptides. We then measured the preexisting neutralizing antibody responses against three traditional AAV capsids in 360 rhesus macaques and observed that 8%, 16%, and 42% were seronegative for AAV1, AAV8, and AAV9, respectively. Finally, we compared ITS01 expression in seronegative macaques intramuscularly transduced with AAV1, AAV8, or AAV9, or with the synthetic capsids AAV-NP22 or AAV-KP1. We observed at 30 weeks after administration that AAV9- and AAV1-delivered vectors expressed the highest concentrations of ITS01 (224 µg/mL, n=5, and 216 µg/mL, n=3, respectively). The remaining groups expressed an average of 35-73 µg/mL. Notably, ADA responses against ITS01 were observed in six of the 19 animals. Lastly, we demonstrated that the expressed ITS01 retained its neutralizing activity with nearly the same potency of purified recombinant protein., Discussion: Overall, these data suggest that the AAV9 capsid is a suitable choice for intramuscular expression of antibodies in nonhuman primates., Competing Interests: MG and MF are co-founders and consultants for Emmune, Inc. MG and MF are inventors on patents with potential royalties licensed to Emmune, Inc. KP and MK are named on patent applications for AAV variants used in this paper. MK has equity interests in LogicBio Therapeutics. GG is a co-founder of Voyager Therapeutics and Aspa Therapeutics and holds equity in both companies. GG is an inventor on patents with potential royalties licensed to Voyager Therapeutics, Aspa Therapeutics, and other biopharmaceutical companies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Davis-Gardner, Weber, Xie, Pekrun, Alexander, Weisgrau, Furlott, Rakasz, Kay, Gao, Farzan and Gardner.)

The SARS coronavirus 2 (SARS-CoV-2) pandemic remains a major problem in many parts of the world and infection rates remain at extremely high levels. This high prevalence drives the continued emergence of new variants, and possibly ones that are more vaccine-resistant and that can drive infections even in highly vaccinated populations. The high rate of variant evolution makes clear the need for new therapeutics that can be clinically applied to minimize or eliminate the effects of COVID-19. With a hurdle of 10 years, on average, for first in class small molecule therapeutics to achieve FDA approval, the fastest way to identify therapeutics is by drug repurposing. To this end, we developed a high throughput cell-based screen that incorporates the essential viral 3C-like protease and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or FDA-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Medicinal chemistry efforts to optimize the hits identified Tranilast as a potential lead. Here, we report the rapid screening and identification of potentially relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral 3C-like protease., Competing Interests: Declaration of Competing Interest The authors declared no potential conflict of interest with respect to the research, authorship and or publication of this article., (Copyright © 2023. Published by Elsevier Inc.)

Barriers to effective gene therapy for many diseases include the number of modified target cells required to achieve therapeutic outcomes and host immune responses to expressed therapeutic proteins. As long-lived cells specialized for protein secretion, antibody-secreting B cells are an attractive target for foreign protein expression in blood and tissue. To neutralize HIV-1, we developed a lentiviral vector (LV) gene therapy platform for delivery of the anti-HIV-1 immunoadhesin, eCD4-Ig, to B cells. The EμB29 enhancer/promoter in the LV limited gene expression in non-B cell lineages. By engineering a knob-in-hole-reversed (KiHR) modification in the CH3-Fc eCD4-Ig domain, we reduced interactions between eCD4-Ig and endogenous B cell immunoglobulin G proteins, which improved HIV-1 neutralization potency. Unlike previous approaches in non-lymphoid cells, eCD4-Ig-KiHR produced in B cells promoted HIV-1 neutralizing protection without requiring exogenous TPST2, a tyrosine sulfation enzyme required for eCD4-Ig-KiHR function. This finding indicated that B cell machinery is well suited to produce therapeutic proteins. Lastly, to overcome the inefficient transduction efficiency associated with VSV-G LV delivery to primary B cells, an optimized measles pseudotyped LV packaging methodology achieved up to 75% transduction efficiency. Overall, our findings support the utility of B cell gene therapy platforms for therapeutic protein delivery., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Viscosity behavior of liquid oligonucleotide therapeutics and its dependence on formulation properties has been poorly studied to date. We observed a high increase in viscosity and solidification of therapeutic oligonucleotide formulations with increasing oligonucleotide concentration creating challenges during drug product manufacturing. In this study, we characterized the viscosity behavior of three different single strand DNA oligonucleotides based on oligonucleotide concentration and formulation composition. We subsequently studied the underlying mechanism for increased viscosity at higher oligonucleotide concentrations by dynamic light scattering (DLS), 1H nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and polarized light microscopy. Viscosity was highly dependent on formulation composition, oligonucleotide sequence, and concentration, and especially dependent on the presence and combination of different individual ions, such as the presence of sodium chloride in the formulation. In samples with elevated viscosity, the viscosity behavior was characterized by non-Newtonian, shear-thinning flow behavior. We further studied these samples by DLS and 1H NMR, which revealed the presence of supra-molecular assemblies, and further characterization by polarized light and DSC characterized these assemblies as liquid crystals in the formulation. The present study links the macroscopic viscosity behavior of oligonucleotide formulations to the formation of supra-molecular assemblies and to the presence of liquid crystals, and highlights the importance of formulation composition selection for these therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

We employ a recently developed complexity-reduction quantum mechanical (QM-CR) approach, based on complexity reduction of density functional theory calculations, to characterize the interactions of the SARS-CoV-2 spike receptor binding domain (RBD) with ACE2 host receptors and antibodies. QM-CR operates via ab initio identification of individual amino acid residue's contributions to chemical binding and leads to the identification of the impact of point mutations. Here, we especially focus on the E484K mutation of the viral spike protein. We find that spike residue 484 hinders the spike's binding to the human ACE2 receptor (hACE2). In contrast, the same residue is beneficial in binding to the bat receptor Rhinolophus macrotis ACE2 (macACE2). In agreement with empirical evidence, QM-CR shows that the E484K mutation allows the spike to evade categories of neutralizing antibodies like C121 and C144. The simulation also shows how the Delta variant spike binds more strongly to hACE2 compared to the original Wuhan strain, and predicts that a E484K mutation can further improve its binding. Broad agreement between the QM-CR predictions and experimental evidence supports the notion that ab initio modeling has now reached the maturity required to handle large intermolecular interactions central to biological processes., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

Interferon-induced transmembrane protein 3 (IFITM3) is implicated in the pathogenesis of Alzheimer's Disease (AD) by regulating γ-secretase activity and subsequent amyloid β (Aβ) generation. However, the regulation of IFITM3 gene expression and the underlying mechanisms remain exclusive. In this study, we aimed to investigate the regulation of the IFITM3 and its role in amyloidogenesis. The functional active promoter of the IFITM3 gene was identified within the 1047 bp of 5'-flanking regions by luciferase assays. Through chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA), we successfully identified a specific Krüppel-like factor 9 (KLF9) binding site within the promoter region. Moreover, KLF9 overexpression significantly upregulates IFITM3 expression in vitro and in vivo, which promotes Aβ generation in the hippocampus of mice. Consistently, reduced IFITM3 expression results in a notable decrease of Aβ production. Together, we demonstrate that KLF9 plays a critical role in regulating IFITM3 expression and subsequent Aβ production. It highly suggests that inhibiting KLF9-mediated IFITM3 expression may have therapeutic potential for AD by reducing Aβ production., (© 2025 Federation of American Societies for Experimental Biology.)

Background and Aims: Protein tyrosine sulfation (PTS) is a common posttranslational modification that regulates a variety of physiological and pathological processes. However, the role of PTS in cancer remains poorly understood. The goal of this study was to determine whether and how PTS plays a role in HCC progression., Approach and Results: By mass spectrometry and bioinformatics analysis, we identified SAV1 as a novel substrate of PTS in HCC. Oxidative stress upregulates the transcription of SLC35B2, a Golgi-resident transporter of sulfate donor 3'-phosphoadenosine 5'-phosphosulfate, leading to increased sulfation of SAV1. Sulfation of SAV1 disrupts the formation of the SAV1-MST1 complex, resulting in a decrease of MST1 phosphorylation and subsequent inactivation of Hippo signaling. These molecular events ultimately foster the growth of HCC cells both in vivo and in vitro. Moreover, SLC35B2 is a novel transcription target gene of the Hippo pathway, constituting a positive feedback loop that facilitates HCC progression under oxidative stress., Conclusions: Our findings reveal a regulatory mechanism of the SLC35B2/SAV1 sulfation axis in response to oxidative stress, highlighting its potential as a promising therapeutic target for HCC., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Growing evidence suggests that plant compounds are emerging as a tremendous source for slowing the onset and progression of Alzheimer's disease (AD). Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid with some hypoglycemic, anticancer, and antiinflammatory activities. However, the pharmacological effects of UNA on AD are still unknown. In the present experiments, the effects and mechanisms of UNA on AD were firstly explored by H 2 O 2 -induced PC12 cells and Aβ 1-42 -induced AD model of Caenorhabditis elegans (C. elegans). The results showed that UNA increased the cell viability and the level of mitochondrial membrane potential and reversed apoptosis in H 2 O 2 -induced PC12 cells, and Nrf2 and HO-1 were involved in this process. UNA also decreased the phosphorylation of related proteins in the MAPK signaling pathway. Meanwhile, we found that UNA upregulated cellular catalase levels and decreased ROS production. Besides, UNA could activate the Nrf2 /HO-1 signaling pathway and upregulate its protein expression under oxidative stress conditions, whereas Nrf2 and HO-1 inhibitors partially eliminated the protective ability of UNA. The results of in vivo experiments showed that UNA prolonged the lifespan and enhanced the health parameters of AD C. elegans and reduced Aβ 1-42 -induced neurotoxicity and ROS levels. Moreover, UNA increased GFP-tagged LGG-1 puncta in DA2123 C. elegans. Further mechanistic studies suggested that the protection of UNA on AD C. elegans may be through modulation of the MAPKs/Nrf2/HO-1 pathway. These results highlight the neuroprotective potential of UNA and suggest that UNA may be an effective therapeutic agent for alleviating AD., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an exceptionally rare inflammatory disorder affecting choroid and retinal pigment epithelial (RPE) cells. Although recent studies suggest an immune-driven nature, the underlying etiology of APMPPE remains elusive. In this study, we conducted a comprehensive investigation on the peripheral blood mononuclear cells (PBMCs) profile of an APMPPE patient using single-cell RNA sequencing. Our analysis revealed striking transcriptional alterations in monocytes within the PBMCs, identifying five distinct subpopulations: S100A12, CD16, pro-inflammatory, megakaryocyte-like, and NK-like monocyte subsets. Employing pseudotime inference, we observed a shift in APMPPE monocytes towards differentiation into inflammation-associated pro-inflammatory monocytes and a CD16 monocyte trajectory. Furthermore, we identified IFITM3 as a key player in the immune response driving the pathogenesis of APMPPE. Notably, two disease-relevant subgroups of monocytes, pro-inflammatory and CD16 monocytes, were implicated in APMPPE. CD16 monocytes, in particular, were involved in melanogenesis, suggesting that the abnormal expression of melanin in monocytes might result from autoimmune responses against pigment-enriched RPE cells. This study provided a comprehensive view of immune landscape in APMPPE, shedding light on the previously unrecognized contributions of pro-inflammatory and CD16 monocytes to this autoimmune condition., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

This study evaluates the protective effects of sinapic acid (SA), a polyphenolic compound with diverse biological activities, against ethanol-induced gastric ulcers in rats. A gastric ulcer model was established using ethanol (ETH), and the experimental groups received either omeprazole (OMEP, 20 mg/kg) or SA at doses of 20 mg/kg and 40 mg/kg via oral gavage for 14 days. Biochemical markers, including total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), malondialdehyde (MDA), and myeloperoxidase (MPO) activity, were assessed alongside proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6) using ELISA. Histopathological and immunohistochemical analyses were conducted to evaluate tissue integrity and apoptosis. Statistical analysis was performed using one-way ANOVA, followed by Tukey's HSD test for post hoc comparisons. For non-parametric data, the Kruskal-Wallis test and Mann-Whitney U test were used. A p-value < 0.05 was considered statistically significant. Results revealed that SA significantly enhanced antioxidant defenses, as evidenced by elevated TAS levels and reductions in TOS, OSI, MPO activity, and MDA levels (p < 0.05). Additionally, SA treatment mitigated inflammation and apoptosis by decreasing TNF-α, IL-1β, IL-6, and Bax expression (p < 0.05). These effects were comparable to those observed with OMEP, a widely used clinical agent. Notably, the findings underscore SA's potential as a novel therapeutic agent for managing ethanol-induced gastric ulcers. By targeting oxidative stress and inflammatory pathways, SA could complement or serve as an alternative to current treatment strategies. Future research should focus on exploring SA's molecular mechanisms, dose optimization, and long-term efficacy in clinical settings, paving the way for its integration into therapeutic regimens for gastric mucosal injuries., Competing Interests: Declarations. Ethics approval: This study was approved by Atatürk University Animal Experiments Local Ethics Committee (approval number: 113, approval date April 27, 2018) and is in compliance with the existing protocols of the ethics committee and the Helsinki Declaration of the World Medical Association recommendations on animal studies. Consent to participate: Not required. Human ethics: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)