Multitarget action of Benzothiazole-piperazine small hybrid molecule against Alzheimer's disease: In silico, In vitro, and In vivo investigation.

A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aß1-42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) -18.64± 0.16 and -16.10 ± 0.18 kcal/mol against AChE and Aß1-42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42 µM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aß, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.

Efficacy of Bacillus Calmette-Guérin in Cancer Prevention and Its Putative Mechanisms.

Bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis. Although it was developed as a prophylactic vaccine against tuberculosis (TB), researchers have also evaluated it for preventing cancer development or progression. These studies were inspired by the available data regarding the protective effects of microbial infection against cancers and an inverse relationship between TB and cancer mortality. Initial studies demonstrated the efficacy of BCG in preventing leukemia, melanoma and a few other cancers. However, mixed results were observed in later studies. Importantly, these studies have led to the successful use of BCG in the tertiary prevention of non-muscle invasive bladder cancer, wherein BCG therapy has been found to be more effective than chemotherapy. Moreover, in a recently published 60-year follow-up study, childhood BCG vaccination has been found to significantly prevent lung cancer development. In the present manuscript, we reviewed the studies evaluating the efficacy of BCG in cancer prevention and discussed its putative mechanisms. Also, we sought to explain the mixed results of BCG efficacy in preventing different cancers.

A Cross-Sectional Study of the Relationship Between Perceived Stress and Thyroid Function Among Apparently Normal Women in the Reproductive Age.

BACKGROUND: A substantial majority of women in India report experiencing stress frequently, with a significant number indicating a lack of time for relaxation. Women within a central productive age bracket often report higher stress levels. Chronic stress can lead to the development of autoimmune disorders affecting the thyroid gland. OBJECTIVE: To evaluate the relationship between perceived stress and thyroid function among apparently normal women of reproductive age. MATERIALS AND METHODS: The present study was conducted at the Vijayanagar Institute of Medical Sciences (VIMS) after obtaining clearance from the Institutional Ethical Committee and informed written consent from the participants. One hundred and fourteen working women aged 20-49 who consented to the study and had no personal or family history of medical illness or thyroid disease were randomly selected. Stress levels were measured using a Perceived Stress Scale (PSS), and thyroid parameters (total triiodothyronine [T3], total thyroxine [T4], and thyroid-stimulating hormone [TSH]) in blood samples were assessed by the electrochemical luminescence immunoassay method. Anthropometric parameters such as age and body mass index (BMI), as well as vital parameters like pulse rate and blood pressure, were measured for all participants. A detailed history was also recorded, including marital status, duration of married life, education, number of children, type of family, per capita income, phase of menstrual cycle, and dietary habits. RESULTS: The Statistical Package for the Social Sciences (SPSS) software version 22.0 was used for statistical analysis. The analysis used Pearson's chi-square test, Student's t-test, and binary logistic regression. A positive correlation was observed between PSS and TSH (correlation coefficient "r" value = 0.060) without a significant p-value. Participants were divided into two groups based on TSH values: those with normal thyroid function (TSH <4.2 international units [IU]) and those with subclinical hypothyroidism (SCH) (TSH >4.2 IU). Both groups had total T3 and T4 levels within the normal reference range. A highly significant difference was observed for age, BMI, TSH, marital status, and duration of married life between women with normal thyroid function and those with SCH. No significant difference was found between the two groups for PSS. DISCUSSION: Both acute and chronic stress affect thyroid function through the hypothalamus-pituitary-thyroid (HPT) axis and the hypothalamus-pituitary-adrenal (HPA) axis. Psychological and physiological stressors induce immune modulations that can lead to autoimmune thyroid diseases, resulting in hypothyroidism. CONCLUSION: The study examined the link between stress and thyroid health in women of childbearing age, revealing a trend where higher stress levels corresponded with increased TSH levels, though not significantly. It also found that older age, higher BMI, and longer duration of marriage were linked to a greater occurrence of SCH. These findings underscore the potential influence of lifestyle factors and stress on thyroid function, suggesting that stress management and demographic factors should be considered in managing thyroid health. For women of reproductive age under high stress, routine monitoring of thyroid function could be beneficial for overall health maintenance.

Fast current-induced skyrmion motion in synthetic antiferromagnets.

Magnetic skyrmions are topological magnetic textures that hold great promise as nanoscale bits of information in memory and logic devices. Although room-temperature ferromagnetic skyrmions and their current-induced manipulation have been demonstrated, their velocity has been limited to about 100 meters per second. In addition, their dynamics are perturbed by the skyrmion Hall effect, a motion transverse to the current direction caused by the skyrmion topological charge. Here, we show that skyrmions in compensated synthetic antiferromagnets can be moved by current along the current direction at velocities of up to 900 meters per second. This can be explained by the cancellation of the net topological charge leading to a vanishing skyrmion Hall effect. Our results open an important path toward the realization of logic and memory devices based on the fast manipulation of skyrmions in tracks.

Agrobacterium-Mediated Transient Gene Expression Optimized for the Bioenergy Crop Camelina sativa.

Camelina sativa, a Brassicaceae family crop, is used for fodder, human food, and biofuels. Its relatively high resistance to abiotic and biotic stresses, as well as being a climate-resilient oilseed crop, has contributed to its popularity. Camelina's seed yield and oil contents have been improved using various technologies like RNAi and CRISPR/Cas9 genome editing. A stable transformation system for protein localization and other cell autonomous investigations, on the other hand, is tedious and time consuming. This study describes a transient gene expression protocol for Camelina sativa cultivar DH55 leaves using Agrobacterium strain C58C1. The method is suitable for subcellular protein localization and colocalization studies and can be used with both constitutive and chemically induced genes. We report the subcellular localization of the N-terminal ER membrane signal anchor region (1-32 aa) of the At3G28580 gene-encoded protein from Arabidopsis in intact leaves and the expression and localization of other known organelle markers. This method offers a fast and convenient way to study proteins in the commercially important Camelina crop system. Key features • This method is based on the approach of Zhang et al. [1] and has been optimized for bioenergy crop Camelina species. • A constitutive and inducible transient gene expression in the hexaploid species Camelina sativa cultivar DH55. • Requires only 16-18 days to complete with high efficacy. Graphical overview.

Interface engineering for facile switching of bulk-strong polarization in Si-compatible vertical superlattices.

Ferroelectric thin films incorporating different compositional layers have emerged as a promising approach for enhancing properties and performance of electronic devices. In recent years, superlattices utilizing various interactions between their constituent layers have been used to reveal unusual properties, such as improper ferroelectricity, charged domain walls, and negative capacitance in conventional ferroelectrics. Herein, we report a symmetry scheme based on the interface engineering in which the inherent cell-doubling symmetry allowed atomic distortions (phonons) in any vertically aligned superlattice activate novel interface couplings among atomic distortions of different symmetries and fundamentally improve the ferroelectric properties. In a materialized case, the ionic size difference between Hf4+ and Ce4+ in the HfO2/CeO2 (HCO) ferroelectric/paraelectric superlattice leads to these couplings. These couplings mitigate the phase boundary between polar and non-polar phases, and facilitate polarization switching with a remarkably low coercive field ( E c ) while preserving the original magnitude of the bulk HfO2 polarization and its scale-free ferroelectric characteristics. We show that the cell-doubled distortions present in any vertical superlattice have unique implications for designing low-voltage ferroelectric switching while retaining bulk-strong charge storing capacities in Si-compatible memory candidates.

Molecular docking analysis of marine phytochemicals with BACE-1.

Alzheimer's disease (AD), a debilitating neurodegenerative condition, is characterized by progressive cognitive decline brought about by the deposition of amyloid beta (Aß) plaques in the brain initiates downstream neuronal dysfunction and death in AD pathogenesis. The ß-secretase (BACE-1) enzyme plays a crucial role in generating Aß from amyloid precursor protein (APP). Hence, we report the virtual screening of marine phytochemicals as BACE-1 inhibitors. 2583 compounds, retrieved from Comprehensive Marine Natural Product Database (CMNPD), were primarily screened for drug-likeliness and blood-brain barrier permeability using admetSAR 2.0 and in-house BBBper tool and resulted in a total of 635 phytochemicals, selected for further docking studies using BACE-1 as target receptor and Atabecestat as standard BACE-1 inhibitor. Seven of 635 compounds docked against BACE-1, showed better binding affinities than Atabecestat, with the red algal metabolite lactodehydrothyrsiferol showing lowest binding energy of -10.83 kcal/mol. These compounds are worth investigating further to assess their neuroprotective efficacy and pharmacokinetic properties. The study also provides a rational framework to uncover novel pharmacophores from marine sources for AD therapy acting through BACE-1 inhibition.

Harnessing the Synergetic Effects of Ag, Mn Dopants in Eco-Friendly Ultraviolet Selective Quantum Dots for Luminescent Solar Concentrators.

Quantum dots (QDs) are promising building blocks for luminescent solar concentrators (LSCs), yet most QD-based LSCs suffer from toxic metal composition and color tinting. UV-selective harvesting QDs can enable visible transparency, but their development is restricted by large reabsorption losses and low photoluminescence quantum yield (PLQY). The developed here Ag, Mn: ZnInS2/ZnS QDs show a high PLQY of 53% due to the passivating effect of ZnS shell. These QDs selectively absorb UV light and emit orange-red light with a large Stokes shift of 180 nm. A LSC of 5 × 5 × 0.2 cm3, fabricated using a poly(lauryl methacrylate) (PLMA) as a matrix, maintains 87% of integrated PL after 7 h of UV exposure. The QD-PLMA achieved 90.7% average visible transparency (AVT) and a color rendering index (CRI) of 95.8, which is close to plain PLMA (AVT = 90.8%; CRI = 99.5), yielding excellent visible light transparency. Incorporating Si-PVs at LSC edges, the Ag, Mn: ZIS/ZnS QD-LSC achieved an optical efficiency of 1.42%, ranking competitively among high-performing UV-harvesting LSCs.

Computational insights into dynamics and conformational stability of N-acetylmannosamine kinase mutations.

The activity of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) is essential for the biosynthesis of sialic acid, which is involved in cellular processes in health and diseases. GNE contains an N-terminal epimerase domain and a C-terminal kinase domain (N-acetylmannosamine kinase, MNK). Mutations of the GNE protein led to hypoactivity of the enzyme and cause sialurea or autosomal recessive inclusion body myopathy/Nonaka myopathy. Here, we used all-atom molecular dynamics (MD) simulations to comprehend the folding, dynamics and conformational stability of MNK variants, including the wild type (WT) and three mutants (H677R, V696M and H677R/V696M). The deleterious and destabilizing nature of MNK mutants were predicted using different prediction tools. Results predicted that mutations modulate the stability, flexibility and function of MNK. The effect of mutations on the conformational stability and dynamics of MNK was next studied through the free-energy landscape (FEL), hydrogen-bonds and secondary structure changes. The FEL results show that the mutations interfere with various conformational transitions in both WT and mutants, exposing the structural underpinnings of protein destabilization and unfolding brought on by mutation. We discover that, when compared to the other two mutations, V696M and H677R/V696M, H677R has the most harmful effects. These findings have a strong correlation with published experimental studies that demonstrate how these mutations disrupt MNK activity. Hence, this computational study describes the structural details to unravel the mutant effects at the atomistic resolution and has implications for understanding the GNE's physiological and pathological role.Communicated by Ramaswamy H. Sarma.

Comparison of efficacy of daily and alternate day maintenance treatment of GERD with Vonoprazan 10-mg using Gastroesophageal Reflux Disease Symptom Assessment Scale.

Objectives: To compare efficacy of 10-mg of vonoprazan daily & on alternate days by Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS). Method: This prospective interventional cohort was done at Department of Medicine/Gastroenterology Dow Medical College, Karachi, Pakistan during the period August 2022 & January 2023. Potential participants fulfilling inclusion and exclusion criteria were asked to fill out GSAS questionnaires after their written consent. Patients were allocated in to two groups using random tables. Group-A was given Tab Vonoprazan 10-mg daily for two weeks. Group-B was given Tab Vonoprazan 10-mg on alternate day. GSAS was scored by totaling scores across symptoms and then they are divided by the total number of non-missing symptom scores. Both groups were assessed week-0 & week-2. Results: Only 90 proformas that were completely filled were included, Group-A had 30 males and 15 females while Group-B had 29 males and 16 females. No significant difference in score was found in GSAS score at week-0 except that in item 'gurgling' while at week two there was no significant difference between any of the items. Total GSAS score were significantly lower at Week-2 than at week-0 (p = <.001). Conclusions: Vonoprazan of 10-mg on alternate day is equally effective as 10-mg daily in maintenance of GERD patients at two weeks.

Alopecia areata: review of epidemiology, pathophysiology, current treatments and nanoparticulate delivery system.

Alopecia areata (AA) is a kind of alopecia that affects hair follicles and nails. It typically comes with round patches and is a type of nonscarring hair loss. Various therapies are accessible for the management and treatment of AA, including topical, systemic and injectable modalities. It is a very complex type of autoimmune disease and is identified as round patches of hair loss and may occur at any age. This review paper highlights the epidemiology, clinical features, pathogenesis and new treatment options for AA, with a specific emphasis on nanoparticulate drug-delivery systems. By exploring these innovative treatment approaches, researchers aim to enhance the effectiveness and targeted delivery of therapeutic agents, ultimately improving outcomes for individuals living with AA.

Fused Deposition Modeling 3D-Printed Scaffolds for Bone Tissue Engineering Applications: A Review.

The emergence of bone tissue engineering as a trend in regenerative medicine is forcing scientists to create highly functional materials and scaffold construction techniques. Bone tissue engineering uses 3D bio-printed scaffolds that allow and stimulate the attachment and proliferation of osteoinductive cells on their surfaces. Bone grafting is necessary to expedite the patient's condition because the natural healing process of bones is slow. Fused deposition modeling (FDM) is therefore suggested as a technique for the production process due to its simplicity, ability to create intricate components and movable forms, and low running costs. 3D-printed scaffolds can repair bone defects in vivo and in vitro. For 3D printing, various materials including metals, polymers, and ceramics are often employed but polymeric biofilaments are promising candidates for replacing non-biodegradable materials due to their adaptability and environment friendliness. This review paper majorly focuses on the fused deposition modeling approach for the fabrication of 3D scaffolds. In addition, it also provides information on biofilaments used in FDM 3D printing, applications, and commercial aspects of scaffolds in bone tissue engineering.

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.

IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.

Current Insights on the Photoprotective Mechanism of the Macular Carotenoids, Lutein and Zeaxanthin: Safety, Efficacy and Bio-Delivery.

Ocular health has emerged as one of the major issues of global health concern with a decline in quality of life in an aging population, in particular and rise in the number of associated morbidities and mortalities. One of the chief reasons for vision impairment is oxidative damage inflicted to photoreceptors in rods and cone cells by blue light as well as UV radiation. The scenario has been aggravated by unprecedented rise in screen-time during the COVID and post-COVID era. Lutein and Zeaxanthin are oxygenated carotenoids with proven roles in augmentation of ocular health largely by virtue of their antioxidant properties and protective effects against photobleaching of retinal pigments, age-linked macular degeneration, cataract, and retinitis pigmentosa. These molecules are characterized by their characteristic yellow-orange colored pigmentation and are found in significant amounts in vegetables such as corn, spinach, broccoli, carrots as well as fish and eggs. Unique structural signatures including tetraterpenoid skeleton with extensive conjugation and the presence of hydroxyl groups at the end rings have made these molecules evolutionarily adapted to localize in the membrane of the photoreceptor cells and prevent their free radical induced peroxidation. Apart from the benefits imparted to ocular health, lutein and zeaxanthin are also known to improve cognitive function, cardiovascular physiology, and arrest the development of malignancy. Although abundant in many natural sources, bioavailability of these compounds is low owing to their long aliphatic backbones. Under the circumstances, there has been a concerted effort to develop vegetable oil-based carriers such as lipid nano-emulsions for therapeutic administration of carotenoids. This review presents a comprehensive update of the therapeutic potential of the carotenoids along with the challenges in achieving an optimized delivery tool for maximizing their effectiveness inside the body.

Lutein and zeaxanthin are the two most abundant natural xanthophylls (oxygenated carotenoids) with a linear C40 tetraterpene/isoprenoid lycopene-based backbone.Presence of extensive conjugation (more than 10 double bonds) enable these molecules to act as accessory light harvesting pigments apart from chlorophyll.More importantly, the xanthophylls prevent photobleaching of the pigments and proteins in the Light Harvesting Complex (LHC) by sequestering the excess unutilized blue light and preventing triplet chlorophyll associated formation of Reactive Oxygen Species.In human eye, lutein, zeaxanthin along with mesozeaxanthin constitute the three macular pigments forming the so called "yellow spot" of the macula and are implicated in maintaining the redox balance, homeostasis and normal physiology of the eyes.However, unlike plants, xanthophylls must be acquired from dietary sources such as colored leafy vegetables and egg yolk.Increase in the number of eye diseases in the aging population coupled with insufficient bioavailability of xanthophylls has mandated the industrial production of supplements enriched in xanthophylls.The bioavailability and delivery of xanthophylls can be significantly enhanced by suspension in a blend of extra-virgin olive oil and other vegetable oils.

Highlights in Interface of Wastewater Treatment by Utilizing Metal Organic Frameworks: Purification and Adsorption Kinetics.

Polluted water has become a concern for the scientific community as it causes many severe threats to living beings. Detection or removal of contaminants present in wastewater and attaining purity of water that can be used for various purposes are a primary responsibility. Different treatment methods have already been used for the purification of sewage. There is a need for low-cost, highly selective, and reusable materials that can efficiently remove pollutants or purify contaminated water. In this regard, MOFs have shown significant potential for applications such as supercapacitors, drug delivery, gas storage, pollutant adsorption, etc. The outstanding structural diversity, substantial surface areas, and adjustable pore sizes of MOFs make them superior candidates for wastewater treatment. This Review provides an overview of the interaction science and engineering (kinetic and thermodynamic aspects with interactions) underpinning MOFs for water purification. First, fundamental strategies for the synthesis methods of MOFs, different categories, and their applicability in wastewater treatment are summarized, followed by a detailed explanation of various interaction mechanisms. Finally, current challenges and future outlooks for research on MOF materials toward the adsorption of hazardous components are discussed. A new avenue for modifying their structural characteristics for the adsorption and separation of hazardous materials, which will undoubtedly direct future work, is also summarized.

The emergence and implications of SARS-CoV-2 omicron subvariant BA.2.86 on global health.

The SARS-CoV-2 subvariant BA.2.86 "Pirola", first identified in Denmark in August 2023, has manifested with a significantly mutated spike protein profile, suggesting a heightened ability to evade vaccine- and infection-induced antibodies. This article outlines the epidemiological spread, immune response implications, and global responses to BA.2.86. Preliminary observations indicate community transmissions of the subvariant, even among those previously infected or vaccinated. Notably, the BA.2.86 infection has shown potential to amplify antibody responses. The variant's emergence has evoked memories of the Omicron variant's rise in late 2021, though global immunity levels might modulate BA.2.86's impact differently. Continuous genomic surveillance, coupled with integrated diagnostic and epidemiological strategies, proves crucial in early detection and management. The emergence of BA.2.86 reaffirms the unpredictable nature of the COVID-19 pandemic, emphasizing the need for ongoing research, adaptability, and global collaboration.

Clinical Evaluation of a Novel, Patented Green Coffee Bean Extract (GCB70®), Enriched in 70% Chlorogenic Acid, in Overweight Individuals.

OBJECTIVE: Obesity and overweight are challenging health problems of the millennium that lead to diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Green coffee bean exhibited significant promise in healthy weight management, potentiating glucose-insulin sensitization and supporting liver health. The safety and efficacy of a novel, patented water-soluble green coffee bean extract (GCB70® enriched in 70% total chlorogenic acid and <1% caffeine) was investigated in 105 participants for 12 consecutive weeks. An institutional review board and Drugs Controller General (India) (DCGI) approvals were obtained, and the study was registered at ClinicalTrials.gov. METHOD: Body weight, body mass index (BMI), waist circumference, lipid profile, plasma leptin, glycosylated hemoglobin (HbA1c), and total blood chemistry were assessed over a period of 12 weeks of treatment. Safety was affirmed. RESULTS: GCB70 (500 mg BID) supplementation significantly reduced body weight (approximately 6%; p = 0.000**) in approximately 97% of the study population. About a 5.65% statistically significant reduction (p = 0.000**) in BMI was observed in 96% of the study volunteers. Waist circumference was significantly reduced by 6.77% and 6.62% in 98% of the male and female participants, respectively. Plasma leptin levels decreased by 13.6% in 99% of the study population as compared to the baseline value. Upon completion of 12 weeks' treatment, fasting glucose levels decreased by 13.05% (p = 0.000**) in 79% of the study population. There was a statistically significant decrease in HbA1c levels in both male and female participants (p = 0.000**), while 86.7% of the study participants showed a statistically significant decrease in thyroid-stimulating hormone (TSH) levels (p = 0.000**). The mean decrease in TSH levels on completion of the treatment was 14.07% in the study population as compared to baseline levels. Total blood chemistry analysis exhibited broad-spectrum safety. CONCLUSIONS: This investigation demonstrated that GCB70 is safe and efficacious in healthy weight management.