Different Mechanisms Of Action Research Articles

Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies.

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural-functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.

Development of silver-doped copper oxide and chitosan nanocomposites for enhanced antimicrobial activities.

Antimicrobial resistance (AMR) has emerged as a significant and pressing public health concern, posing serious challenges to effectively preventing and treating persistent diseases. Despite various efforts made in recent years to address this problem, the global trends of AMR continue to escalate without any indication of decline. As AMR is well-known for antibiotics, developing new materials such as metal containing compounds with different mechanisms of action is crucial to effectively address this challenge. Copper, silver, and chitosan in various forms have demonstrated significant biological activities and hold promise for applications in medicine and biotechnology. Exploring the biological properties of these nanoparticles is essential for innovative therapeutic approaches in treating bacterial and fungal infections, cancer, and other diseases. To this end, the present study aimed to synthesize silver@copper oxide (Ag@CuO) nanoparticles and its chitosan nanocomposite (Chi-Ag@CuO) to investigate their antimicrobial efficacy. Various established spectroscopic and microscopic methods were employed for characterization purposes, encompassing scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Subsequently, the antimicrobial activity of the nanoparticles was assessed through MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration), and well-disk diffusion assays against Pseudomonas aeruginosa, Acinetobacter baumannii Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. The size of the CuO-NPs, Ag@CuO, and Chi-Ag@CuO NPs was found to be 70-120 nm with a spherical shape and an almost uniform distribution. The nanocomposites were found to possess a minimum inhibitory concentration (MIC) of 5 μg/mL and a minimum bactericidal concentration (MBC) of 250 μg/mL. Moreover, these nanocomposites generated varying clear inhibition zones, with diameters ranging from a minimum of 9±0.5 mm to a maximum of 25±0.5 mm. Consequently, it is evident that the amalgamation of copper-silver-chitosan nanoparticles has exhibited noteworthy antimicrobial properties in the controlled laboratory environment, surpassing the performance of other types of nanoparticles.

Methods of increasing the seed productivity of the new variety of sage medicinal Fioletovy Aromat

Relevance. Salvia officinalis L. is an important essential oilseed crop with anti-inflammatory, antimicrobial and antioxidant properties. Providing the pharmaceutical industry with raw materials of Salvia in full is possible due to the expansion of production areas and the availability of the maximum amount of highquality seed material of new promising varieties.Methods. In 2019-2022 in the conditions of the North Caucasus branch of VILAR on a new variety of Salvia Fioletovy aromat II year of vegetation by staging small-scale experiments were conducted to study the systematic application of organomineral fertilizer – EcoFus and growth regulators of different mechanism of action – Zircon, Epin-extra, retardant Hardy to increase seed productivity and seed quality. The area of the experimental plots was 12 m2. Treatment with EcoFus was carried out at the beginning of regrowth, and with bioregulators – during the budding phase. The consumption of the working solution is 300 l/ha. Control variants of medicinal crops were treated with water.Results. Application of EcoFus in the phase of regrowth contributed to the activation of the intensity of photosynthesis and increase in the accumulation of plastic substances, which allowed plants to enter the generative phase earlier, the budding phase came 2-3 days earlier than in the control. Subsequent treatment of budding plants with growth regulators led to earlier and more friendly flowering, the time of seed ripening was reduced by 3-4 days. The highest efficiency was observed in the variants of joint application of EcoFus with Zircon or Hardy, where the number of inflorescences on plants increased, seed setting and seed productivity increased by 37-42%, seed quality also improved – weight of 1000 seeds increased by 9-10% and germination by 6-7%.

#313 Enhanced urinary phosphorous reduction: comparative study of oxylanthanum carbonate and tenapanor in rat

Abstract Background and Aims End-stage renal disease (ESRD) affects >7 M people worldwide and ∼70% of patients with ESRD have hyperphosphatemia. Oxylanthanum carbonate (OLC) is a novel nanotechnology product that combines lanthanum, which has the highest binding capacity vs other phosphate (P) binders, with a smaller pill size that is swallowed with water vs chewed. Tenapanor is a sodium hydrogen exchanger inhibitor used to reduce serum P in adults with chronic kidney disease (CKD) on dialysis. A previous study conducted by King et al found that when administered together, tenapanor and sevelamer decreased urinary p excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. Employing an identical study design and dosing regimen, the objective of our study was to evaluate the effects of tenapanor and OLC on P excretion. Method In our study, we utilized the study design and dosage regimen from King et al involving sevelamer and tenapanor. 64 male Sprague Dawley rats were fed standard chow 1 week prior to study start. On study day −1, animals were randomized into 3 study groups (n = 8): 1) vehicle, 2) tenapanor 0.15 mg/kg, 3) Vehicle + OLC 0.75%, 4) Vehicle + OLC 1.5%, 5) Vehicle + OLC 3%, 6) tenapanor 0.15 mg/kg + OLC 0.75%, 7) tenapanor 0.15 mg/kg + OLC 1.5%, and 8) tenapanor 0.15 mg/kg + OLC 3%. Vehicle and tenapanor were dosed PO twice/day whereas OLC was incorporated into the diets. 24-hour urine samples were collected using metabolic cages on day 9, 10, and 11 for urinary P measurements. Results Compared to vehicle alone (group 1), P reduction of tenapanor (group 2) was 8.5 mg/day (not significant), while P reduction of OLC (group 5) was 25.3 mg/day (significant). OLC had 16.8 mg/day more P reduction than tenapanor (Fig. 1). Conclusion OLC demonstrated 3x more effective urine P reduction vs tenapanor. Subsequent analyses will focus on examining the combination of tenapanor and OLC. Combining OLC and tenapanor utilizes 2 different mechanisms of action to manage P levels while having a low pill burden, which may lead to synergistic effects to be investigated in future studies.

The Synergistic Enhancement of Anti-Metabolic Diseases Function of Morus alba with the Combination of Cha [Camellia sinensis

Background: Functional foods play an important role in the prevention and ameliora-tion of metabolic syndromes leading to type 2 diabetes. Plant resources that have anti-metabolic syndromes activity, such as Morus alba L. and Cha [Camellia sinensis L.], have been used in functional foods against diabetes. Since Morus and Cha have different mechanisms of action against metabolic syndromes, such as prevention of sugar uptake and lipidosis, respectively, and the combination of both resources will be a reliable approach for developing more efficient functional food against type 2 diabetes because certain synergism is expected in their functions. Methods: Male Wister Rats were fed the high fat-high sucrose [HFHS] diet for 12 weeks, with and without supplementation of Morus and Cha alone and their combination, and the effect of their supplementation on the markers of the metabolic syndrome such as obesity, lipidosis, and fatty liver formation, were examined. Results: Several metabolic syndrome markers, including body weight gain, lipid deposit, and fatty liver formation, were more significantly prevented by the diet supplemented with Morus and Cha combination compared to Morus or Cha given separately . Conclusion: Appropriate formulation of food resources with different functional mechanisms is a promising strategy for developing effective dietary treatment of type 2 diabetes that is a typical Mibyou.

Case report: CBD: THC medical cannabis in the treatment of neuropathic pain

Chronic neuropathic pain affects millions of adults worldwide, creating a direct impact on quality of life. The control of neuropathic pain is a challenge in daily clinical practice. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of this pathology. The use of cannabis and cannabinoid products is a growing area of research for the treatment of different pathologies including neuropathic pain. The studies developed so far and what is observed in the clinical practice, demonstrate the importance of this medication in a pathology of such complexity and difficult control, besides of that, more randomized controlled studies are needed to confirm medical cannabis an adjunct medication in the treatment of neuropathic pain. This case report aims to demonstrate the validity of joining GMP cannabis products as an adjuvant therapy for an effective with low profile side effects treatment leading to an improvement in quality of life.

Silkworm model of bacterial infection facilitates the identification of lysocin E, a potent, ultra-rapid bactericidal antibiotic.

The development of novel antimicrobial agents is required to solve the problem of antimicrobial resistance. We established a quantitative method for evaluating the therapeutic efficacy of antimicrobial agents in a silkworm bacterial infection model. Pharmacokinetic factors are present in the silkworm as well as in mice, and evaluating the therapeutic efficacy of antimicrobial agents is possible in a silkworm infection model, comparable to that in a mammalian model. This silkworm model was used to screen for novel antimicrobial agents with therapeutic efficacy as an indicator. As a result, a new antibiotic, lysocin E, was discovered. Lysocin E has a completely different mechanism of action from existing antimicrobial agents, and its potent bactericidal activity leads to remarkable therapeutic efficacy in a mouse model. In this review, I describe the features of the silkworm model that have contributed to the discovery of lysocin E and its mechanisms of action.

MORPHOLOGICAL CHANGES IN RAT SKIN AFTER THERMAL BURNS

Every day around the world, children and adults suffer from burn injuries. Burn injury is one of the global health problems due to its high prevalence and mortality. The skin is the largest multifunctional human organ. The area of the entire skin is on average 1.7-1.9 square meters. The skin has a wide variety of functions from protective to energy-saving and tactile. Burns have a long history, but new methods of study are needed, this is due to the increase in the frequency of burns in everyday life, production, as well as the complexity of the pathogenesis and treatment of burn disease. Pathological changes that occur in the body of burned animals lead to the fact that in the first hours with extensive burn injury, circulatory disorders occur in parenchymal organs, especially in the liver, lungs and adrenal glands. In the future, with severe intoxication, severe dystrophic processes occur in the muscles of the heart and other internal organs. Recently, the main areas of research into the pathogenesis of inflammation have become immunological, at the morphological level it has not been sufficiently studied. The article shows the morphological features of the study in thermal burns of the skin of rats during treatment with a different mechanism of action. Rats in the amount of 15 pieces were divided into 3 groups: the first control group with a burn without treatment, the second group with a thermal burn, to which levomekol gel was applied to the burn area, the third group was treated with powder from the medicinal plant yarrow Achillea millefolium L. On the 3rd, 7th, 14th, and 21st days, the rats were taken out of the experiment, after which the skin pieces were fixed in 10% formalin for further histological examination.

Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study.

To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric. Using the 2011-2020 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the 1st-line urate-lowering treatment (ULT). The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models with a 5:1 ratio propensity-score matching on > 80 variables. Subgroup analyses were done by age, sex, thiazide use, and cardiovascular (CV) risk. 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). ∼44% of urinary stones required intervention with a HR of 0.61 (95% CI 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high CV risk subgroup (p for interaction = 0.02). This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high CV risk. This finding provides important safety information for clinicians' decision-making on ULTs of different mechanisms of action.

Using wavelet phase coherence of heart rate variability and blood flow oscillations to compare mechanisms of action between Tai Chi mind-body exercise and brisk walking aerobic exercise

Tai Chi exercise has been demonstrated to be beneficial for health and quality of life. However, the mind–body effect of Tai Chi on modulating interactions of the cardiovascular components has not been investigated. This study aimed to differentiate the effect of Tai Chi (mind–body exercise) and brisk walking (aerobic exercise) on modulating skin blood flow oscillations (BFO) of the upper and lower limbs and heart rate variability (HRV). Bafa Wubu of Tai Chi for 15 min and brisk walking for 15 min were performed by 30 adults in two different days. Wavelet phase coherence was employed to assess the coordination between HRV and BFO before and after exercise. Two indices were proposed to quantify the coherence, i.e., the area (Aϕ) and maximal difference (dmax) between the coherence function and the threshold obtained by surrogate test. The results demonstrated that Tai Chi resulted in a significant decrease in phase coherence between HRV and BFO of the upper limb in the frequency interval 0.05–0.15 Hz (Aϕ baseline 0.1600 ± 0.0288, post-exercise 0.0486 ± 0.0220, p < 0.001; dmax baseline 0.3222 ± 0.0220, post-exercise 0.2578 ± 0.0219, p < 0.005), but not between HRV and BFO of the lower limb. Brisk walking resulted in a significant increase in phase coherence between HRV and BFO of the lower limb in the frequency interval 0.05–0.15 Hz (Aϕ baseline 0.0455 ± 0.0251, post-exercise 0.1190 ± 0.0241, p < 0.05; dmax baseline 0.2191 ± 0.0225, post-exercise 0.3103 ± 0.0208, p < 0.05) but not between HRV and BFO of the upper limb. Our finding indicates that mind–body exercise and aerobic exercise modulate cardiovascular regulations through different mechanisms of action.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. ClinicalTrials.gov Identifier: NCT04738123.

A sirtuin 6 activator in the pipeline: New perspectives in depressive disorder treatment

Major Depressive Disorder (MDD) is among the most prevalent mental illnesses worldwide. Its symptoms include persistent feelings of sadness, loss of interest in previously enjoyed activities, and a lack of motivation for daily tasks. While FDA-approved medications are available, they often come with side effects, especially those targeting monoamine neurotransmitters like SSRIs and SNRIs. Thus, there is a need for innovative medications with different mechanisms of action. Sp-624, a derivative of griseofulvin, is currently undergoing clinical trials for MDD treatment. It acts as a sirtuin 6 (SIRT6) activator, offering a novel approach to treating this disorder. This article discusses the biochemical aspects related to the mechanism of action of sp-624, provides a brief overview of related patents, and highlights ongoing clinical trials involving this substance.

Anesthesiological provision in hip and knee joint replacement (a scientific literature review)

Effective pain management during hip and knee replacement ensures the efficient and fast recovery of patients. Joint replacement surgery is typically accompanied by the use of general anesthesia or spinal anesthesia. Spinal anesthesia, despite certain risks, demonstrates better effectiveness compared to general anesthesia in hip and knee replacements. In other words, spinal anesthesia entails fewer perioperative complications. The addition of sedation and anesthesia monitoring during joint replacements using spinal anesthesia is of particular importance. After a successful surgical procedure of joint replacement, achieving adequate pain relief in the postoperative period is crucial. This is achieved through intravenous patient-controlled analgesia or epidural analgesia. A multimodal analgesia strategy combines analgesics with different mechanisms of action to enhance pain management. Intraoperative periarticular administration of multimodal agents is one of the most important procedures in the perioperative pain control during total hip arthroplasty. Peripheral nerve blocks have emerged recently as an alternative analgesic approach. During hip and knee replacements, various nerve blocks are utilized, including lumbar plexus block, fascia iliaca block, femoral and sciatic nerve block, adductor canal block, quadratus lumborum block, erector spinae plane block. Given the entire perioperative process, the use of preventive and multimodal therapy along with peripheral nerve blocks can help reduce the intensity of postoperative pain, thereby improving the functional status and quality of life for patients.

Iron-Based Nanoparticles Synthesis, Characterization, and Antimicrobial Effectiveness

Background: Antimicrobial resistance (AMR) has emerged as a significant and pressing public health concern, posing serious challenges to effectively preventing and treating persistent diseases. Developing new antibiotics with different mechanisms of action is crucial to effectively address challenges in treating infections. A lot of work has already been done on mono-metallic nanoparticles to address the issue.Methods: This study aimed to synthesize multi-metallic iron, silver, and chitosan-embedded nanoparticles using a green approach. Iron, silver, chitosan nanoparticles, and a composite of iron–silver–chitosan was also synthesized. The synthesized nanoparticles and composites were characterized through X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and Fourier Transform Infrared Spectroscopy (FTIR) to evaluate their structural parameters. Their antimicrobial efficacy was investigated through MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration), and well-disk diffusion assays against Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans.Results: The size of the Cu-NPs, Cu-Ag NPs, and Cu-Ag-CS NPs were found to be in the range of 32-40 nm size with a spherical shape. The nanocomposites' MIC and MBC were calculated to be 125 μg/mL and 500 μg/mL, respectively. The nanocomposites exhibited a range of clear inhibition zones, with a minimum diameter of 12 ± 0.5 mm and a maximum diameter of 22 ± 0.5 mm. Conclusion: The iron–silver–chitosan nanocomposite has been shown to have significant antimicrobial effects in the laboratory environment compared to other nanoparticles hence can be applied as potential biomedical/biological candidates in future.Keywords: Antibacterial; Antifungal Agents; Iron; Silver; Chitosan; Nanoparticles

Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.

Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.

High Consistency Silicone Rubber Foams.

Silicone elastomers are high-performance plastics. In the extrusion process, only high-consistency silicone rubbers were used. In order to reduce the cost and weight, silicone rubbers can be foamed during processing. In this study, high-consistency silicone rubber is processed with different physical and chemical blowing agents. The resulting reaction kinetics, as well as the mechanical and morphological properties, had been investigated and compared with each other. This showed that the chemical blowing agent significantly influenced the crosslinking reaction compared to the microspheres and the water/silica mixture tested, but it also achieved the lowest density compared to the physical blowing agents. When evaluating the foam morphology, it became clear that the largest number of pores was achieved with the microspheres and the largest pores when using the water/silica mixture. Furthermore, it has been shown that the different mechanisms of action of the blowing agents have a major influence on the mechanical properties, such as the micro shore hardness and the foam morphology.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Improving the power of drug toxicity measurements by quantitative nuclei imaging

Imaging-based anticancer drug screens are becoming more prevalent due to development of automated fluorescent microscopes and imaging stations, as well as rapid advancements in image processing software. Automated cell imaging provides many benefits such as their ability to provide high-content data, modularity, dynamics recording and the fact that imaging is the most direct way to access cell viability and cell proliferation. However, currently most publicly available large-scale anticancer drugs screens, such as GDSC, CTRP and NCI-60, provide cell viability data measured by assays based on colorimetric or luminometric measurements of NADH or ATP levels. Although such datasets provide valuable data, it is unclear how well drug toxicity measurements can be integrated with imaging data. Here we explored the relations between drug toxicity data obtained by XTT assay, two quantitative nuclei imaging methods and trypan blue dye exclusion assay using a set of four cancer cell lines with different morphologies and 30 drugs with different mechanisms of action. We show that imaging-based approaches provide high accuracy and the differences between results obtained by different methods highly depend on drug mechanism of action. Selecting AUC metrics over IC50 or comparing data where significantly drugs reduced cell numbers noticeably improves consistency between methods. Using automated cell segmentation protocols we analyzed mitochondria activity in more than 11 thousand drug-treated cells and showed that XTT assay produces unreliable data for CDK4/6, Aurora A, VEGFR and PARP inhibitors due induced cell size growth and increase in individual mitochondria activity. We also explored several benefits of image-based analysis such as ability to monitor cell number dynamics, dissect changes in total and individual mitochondria activity from cell proliferation, and ability to identify chromatin remodeling drugs. Finally, we provide a web tool that allows comparing results obtained by different methods.

Prenatal exposure to acid suppressor medications and development of ductus arteriosus in term newborn.

The ductus arteriosus normally closes after birth. Histamine2 Receptor Antagonist (H2RA) has been associated with patent ductus arteriosus (PDA). We aimed to study the characteristics of term infants with PDA and their possible association with prenatal exposure to antacids - Proton Pump Inhibitors (PPI) and H2RA. Population-based matched case-control study of mothers registered at "Clalit" Health Maintenance Organization (HMO) and their infants born at "Soroka" University Medical Center (SUMC) between 2001-2018. Cases are defined as term infants born with PDA diagnosed by echocardiography and registered in the post-delivery discharge form. Each case was matched with four term newborns without PDA diagnosis. Exposure window was defined by the timing of first purchase of H2RA or PPI during pregnancy and based on information from a computerized medication database (Clalit HMO, SUMC) Results. PDA was diagnosed in 1,884 term infants (4.9%). Characteristics included a significantly higher percentage of lack of prenatal care, cesarean section, in vitro fertilization, polyhydramnios, oligohydramnios, Apgar 1 minute <5, and prenatal exposure to H2RA (OR4.18) and PPIs (OR3.50) (all p<0.001). PDA association with exposure window was similar in each trimester (1.5-2%) for both H2RA and PPI. PDA Incidence in term infants in our population was greater than previously reported. PPI and H2RA are both anti-acids with different mechanisms of action. The similar OR for exposure to one as well as the other, and the lack of influence of the initial exposure period, are compatible with bias.

DNA-targeting short Argonautes complex with effector proteins for collateral nuclease activity and bacterial population immunity.

Two prokaryotic defence systems, prokaryotic Argonautes (pAgos) and CRISPR-Cas, detect and cleave invader nucleic acids using complementary guides and the nuclease activities of pAgo or Cas proteins. However, not all pAgos are active nucleases. A large clade of short pAgos bind nucleic acid guides but lack nuclease activity, suggesting a different mechanism of action. Here we investigate short pAgos associated with a putative effector nuclease, NbaAgo from Novosphingopyxis baekryungensis and CmeAgo from Cupriavidus metallidurans. We show that these pAgos form a heterodimeric complex with co-encoded effector nucleases (short prokaryotic Argonaute, DNase and RNase associated (SPARDA)). RNA-guided target DNA recognition unleashes the nuclease activity of SPARDA leading to indiscriminate collateral cleavage of DNA and RNA. Activation of SPARDA by plasmids or phages results in degradation of cellular DNA and cell death or dormancy, conferring target-specific population protection and expanding the range of known prokaryotic immune systems.