Maximum Activity Research Articles

A Randomized, Double-blind, Placebo-controlled, Short-term Monotherapy Study of MK-6186, an HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), in Treatment-Naïve HIV-Infected Participants.

To assess the antiviral activity, pharmacokinetics, and safety of MK-6186 in NNRTI-naïve, HIV-1-infected male participants. Double-blind, randomized, two-panel study. In 2 sequential panels, 18 participants received MK-6186 (40 mg [Panel A] or 150 mg [Panel B]) or matching placebo once daily for 7 days. Plasma samples were collected for measurement of HIV-1 RNA levels and MK-6186 pharmacokinetics. For the mean change from baseline in HIV-1 RNA (log10 copies/mL) at 24 hours post Day 7 dose, the mean difference (90% confidence interval) between MK-6186 and placebo was 1.54 (-1.73, -1.34) in the 40-mg group and -1.28 (-1.81, -0.75) in the 150-mg group. One participant in the 150-mg group had viral rebound at 24 hours after Day 6 dosing (Day 7 predose) associated with outgrowth of the V106A minority variant. Ultra-deep sequencing confirmed expansion of this predose minority variant from 0.26% to 63.67%. No outgrowth and rebound was seen in another participant in whom a V106A minority variant was also detected. MK-6186 was generally well tolerated. MK-6186 was rapidly absorbed with peak concentrations at 2 hours followed by a biphasic decline. The effective t½ of MK-6186 was 43.9 to 48.7 hrs. Steady state was not achieved. Daily monotherapy with MK-6186 demonstrated robust antiviral activity with maximal antiviral activity at a dose of 40 mg. One participant in the 150-mg group exhibited viral rebound with outgrowth of the resistant V106A minority variant, demonstrating a risk of resistance development typical of NNRTIs. The reason for this outgrowth remains unclear as no outgrowth occurred in a participant in the 40-mg group in whom the V106A minority variant was also detected. MK-6186 may be an alternative next-generation NNRTI in combination therapy, in that combination antiretroviral therapy could prevent outgrowth of resistant minority variants.

Synthesis and evaluation of in vitro antioxidant, anticancer, and antibacterial properties of new benzylideneiminophenylthiazole analogues

A series of new benzylideneiminophenylthiazole analogues were designed and synthesized. Common spectroscopic methods, such as FT-IR, 1H-, 13C-NMR, and MASS spectra, and elemental analysis, were used to confirm the molecular structures. Then, the antioxidant, cytotoxicity, and anti-bacterial effects of synthesized analogues were assessed against 2,2-diphenyl-1-picrylhydrazyl (DPPH), three cancer cell lines, and two bacterial strains, respectively. Among the analogues, 7f was detected as the most potent compound for antioxidant activity. Moreover, the compounds 7b, 7f, and 7 g exhibited the maximum cytotoxicity activity against MCF-7, HepG-2, and A549 cell lines, respectively. Finally, 7e showed the highest anti-bacterial activity against both S. aureus and E. coli strains. It was concluded from the antioxidant, cytotoxicity, and anti-bacterial effects that the benzylideneiminophenylthiazoles might serve as candidate molecules for the development of small molecules with medicinal potential.

Wild chamomile essential oils bioactivity at different locations in sulaimani region, Iraq

This study was conducted to evaluate the bioactivity of wild chamomile (Matricaria chamomile L.), in response to different elevations flower samples at full blooming. The analysis of chamomile flower essential oils (EOs) through GC-MS identified the predominant abundance of terpenoids including Bisabolol oxides, farnesene, and Azulen, constituting 61.765% of the identified compounds across various locations. The highest concentration was 74.554% out of the total components observed at Kanipanka, while it was the minimum (16.414%) at the Qaradagh location. Oppositely the highest concentration of Farnasene was observed at the Qaradagh location, while the lowest concentration occurred with the essential oil of Kanipanka.α-Bisabolol oxide A% dominates, except in the Qara Dagh location. The best antioxidant concentration was found in Sharbazher essential oil. The essential oil in Sharbazher significantly shows the highest inhibition capacity (IC%). The stronger IC50% value was 64.645 µg mL-1, recorded at the Qara Dagh location. The disc diffusion assay revealed that the activity of chamomile essential oil at various locations significantly affected the death of most bacterial strains (Gram-negative and Gram-positive). Chamomile EOs from the Kanipanka location recorded maximum antibacterial activity on Pseudomonas aeruginosaPenjween EOs observed the maximum antibacterial activity against Staphylococcus haemolyticus, while a high level inhibition zone (IZ) against Enterococcus faecalis was observed in Bakrajo. The finding revealed that the highest MIC and MBC against Pseudomonas aeruginosa were achieved with the concentration of 2.5 µg mL-1 of Kanipanka EOs.

Characterization of a marine endolysin LysVPB against Vibrio parahaemolyticus

Currently, there is an urgent to develop safe and environmentally friendly alternatives to antibiotics for combating Vibrio parahaemolyticus. Endolysins are considered promising antibacterial agents due to their desirable range of action and ability to deal with antibiotic-resistant bacteria. While numerous Vibrio phages have been identified, the research on their endolysins is still in its infancy. In this study, a novel endolysin called LysVPB was cloned and expressed in Pichia pastoris. Phylogenetic analysis revealed that LysVPB bears little resemblance to other known endolysins, highlighting its unique nature. Homology modeling identified a putative calcium-binding site in LysVPB. The recombinant LysVPB achieved a lytic activity of 64.8 U/mL and had a molecular weight of approximately 17 kDa. LysVPB exhibited enhanced efficacy at pH 9.0, with 60 % of its maximum activity observed within the broad pH range of 6.0–10.0. The catalytic efficiency of LysVPB peaked at 30 °C but significantly declined beyond 50 °C. Ba2+, Co2+, and Cu2+ showed inhibitory effects on the activity of LysVPB, while Ca2+ can boost it to 126.8 %. Furthermore, LysVPB exhibited satisfactory efficacy against strains of V. parahaemolyticus. LysVPB is an innovative phage lysin with good characteristics that are specific to certain hosts. The modular nature of LysVPB allows for efficient domain exchange with alternative lysins as antimicrobial components and fusion with antimicrobial peptides. This opens up possibilities for engineering chimeric lysins in a broader range of target hosts with high antimicrobial effectiveness and strong activity under physiological conditions.

Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine.

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

101 5-HT4 receptor-mediated vasorelaxation occurs through a cyclic mononucleotide-dependent mechanism in the isolated bovine lateral saphenous vein

Abstract Serotonin (5-HT)-mediated vasorelaxation of the isolated bovine lateral saphenous vein occurs primarily through 5-HT4 receptor activation. Vasorelaxation responses mediated through 5-HT4 have only been documented to occur in cattle and sheep and thus, may represent a novel vasorelaxation mechanism that is specific to ruminants. In tissues from other species, the 5-HT4 receptor and its associated G protein couple with adenylate cyclase. However, the mechanisms contributing to 5-HT4-mediated vasorelaxation in vascular tissue remain undefined. To better understand the mechanisms of 5-HT4-mediated vasorelaxation, lateral saphenous veins from cattle (n = 4) were collected and assessed for vasoactivity in response to increasing concentrations of a selective 5-HT4 receptor agonist (BIMU-8) in the absence and presence of selective inhibitors of downstream proteins involved with cyclic mononucleotide-mediated signaling. Isolated vessel segments were suspended in chambers of a multi-myograph containing 5 mL of continuously oxygenated Krebs-Henseleit buffer and equilibrated to 1 g tension for 90 min. After the equilibration period, vessels were exposed to dimethyl sulfoxide (DMSO; vehicle control) or selective inhibitors of downstream protein targets dissolved in DMSO (1×10-5 M) for 5 min. Vessels were pre-contracted with 1×10-4 M phenylephrine for 10 min to achieve a sustained increase in tension. After the 10-min pre-contraction period, vessels were exposed to increasing concentrations (1×10-9 to 1×10-4) of BIMU-8 non-cumulatively. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. In the absence of selective inhibitors (control), BIMU-8 induced (P < 0.01) dose-dependent relaxations (mean -log EC50 = 6.30 M) with a 112% increase in maximal vasorelaxation activity occurring at 1×10-4 M. In the presence of the selective inhibitors for adenylate cyclase (NKY80) or guanylate cyclase (NS2028), 66% and 86% of the vasorelaxation responses to BIMU-8 were attenuated (P < 0.01), respectively. In the presence of the selective inhibitors for protein kinase A [protein kinase A inhibitor fragment (6-22) amide] or protein kinase G (Rp-8-bromo-PET-Cyclic GMPS), 66% and 97% of the maximal vasorelaxation responses to BIMU-8 were attenuated (P < 0.01), respectively. In the presence of non-selective inhibitors for Ca2+ channels and K+ channels, vasorelaxation responses to BIMU-8 were attenuated (P < 0.01). In the presence of selective inhibitors for the protein phosphatase 1 and 2A subunits of myosin light chain (calyculin A) and heat shock protein synthesis (quercetin), vasorelaxation responses to BIMU-8 were attenuated (P < 0.01). The findings of the current study demonstrate that 5-HT4-receptor mediated vasorelaxation occurs through a cyclic mononucleotide-dependent mechanism involving cross-activation of protein kinase A and G signaling. Downstream proteins involved in the signaling cascade leading to vasorelaxation include Ca2+ channels, K+ channels, myosin light chain phosphatase, and heat shock proteins. More research is needed to fully describe the cellular and molecular mechanisms responsible for 5-HT4 receptor-mediated vasorelaxation.

Fc-FcγR interactions during infections: From neutralizing antibodies to antibody-dependent enhancement.

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fcγ receptors (FcγRs) on effector leukocytes. Fc-FcγR interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific FcγR pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease.

Monte Carlo simulation of shielding materials in storage drums for 241Am-Be disused sealed radioactive sources

Disused Sealed Radioactive Sources (DSRS) containing neutron sources such as 241Am-Be require careful management due to neutron radiation. However, finding readily available and effective combination layer shielding materials for practical use to safely contain 241Am-Be can be challenging. The main objective of this study is to investigate the configuration of shielding materials and determine the maximum activity of 241Am-Be sources that can be safely stored in a 200-L drum. A three-layer shielding approach using a 200-L drum as a storage container, with sequential layers of lead (Pb), polyethylene (PE), and ordinary Portland concrete (OPC), achieves the lowest dose rates compared to other combination sequences, as shown by Monte Carlo simulations. With a fixed lead thickness and varying polyethylene and ordinary Portland concrete thicknesses, Monte Carlo simulations using the Particle and Heavy Ion Transport code System (PHITS) demonstrate that this drum design can safely accommodate activities ranging from 22.01 Ci to 72.92 Ci of 241Am-Be. The fitted model equation determines the required polyethylene thickness for any activity within this range. Additionally, case-based simulation results indicate that Indonesia's total inventory of 241Am-Be DSRS can be stored in three 200-L drums with a polyethylene thickness of 15 cm. This configuration meets international standards, ensuring the dose rate does not exceed 2 mSv/h at the surface and 0.1 mSv/h at 1 m from the drum's surface.

Structural, magnetic and electrical properties of gadolinium doped cobalt ferrite nanoparticles: Role of Gd doping level

In this communication, effect of Gd doping for CoFe2–xGdxO4 (CFGO) nanoparticles has been investigated for structural, magnetic and electrical properties. X–ray diffraction (XRD) patterns reveal the presence of matrix like CFGO phase fraction with coexisting GdFeO3 (GFO) smaller crystallites and α–Fe2O3 (FO) phase fraction. Variation in crystallite size (D) for all three phases has been explored from the analysis on XRD patterns. Magnetic nature has been understood on the basis of lattice disorder, magnetic linkages between different ions of CFGO lattices that conduces magnetic characteristic of three different phases coexist within the CFGO nanoparticle lattices. Influence of frequency, temperature and Gd doping level on different electrical behaviors has been understood on the bases of various relaxation processes, charge conduction mechanism, correlated barrier hopping (CBH) mechanism, maximum barrier height, activation energy and structure–property correlations.

Does the response of Rubisco and photosynthesis to elevated [CO2] change with unfavourable environmental conditions?

Climate change due to anthropogenic CO2 emissions affects plant performance globally. To improve crop resilience, we need to understand the effects of elevated CO2 concentration (e[CO2]) on CO2 assimilation and Rubisco biochemistry. However, the interactive effects of e[CO2] and abiotic stress are especially unclear. This study analyses the CO2 effect on photosynthetic capacity under different water availability and temperature conditions in 42 different crop species, varying in functional group, photosynthetic pathway and phenological stage. We analysed close to 3000 data points extracted from 120 published manuscripts. For C3 species, e[CO2] increases net photosynthesis and intercellular [CO2], while reducing stomatal conductance and transpiration. Vmaxc, Rubisco in vitro extractable maximal activity and content also decrease with e[CO2] in C3 species, while C4 crops are less responsive to e[CO2]. The interaction with drought and/or heat stress does not significantly alter these photosynthetic responses, indicating that the photosynthetic capacity of stressed plants responds to e[CO2]. Moreover, e[CO2] has strong effect on the photosynthetic capacity of grasses mainly in the final stages of development. This study provides insight into the intricate interactions within the plant photosynthetic apparatus under the influence of climate change, enhancing the understanding of mechanisms governing plant responses to environmental parameters.

Influence of stimulation parameters on torque development during the combined application of electrical nerve stimulation and muscle lengthening.

This study investigated the influence of stimulation parameters on torque production when combining a brief muscle lengthening with electrical stimulation. Fifteen volunteers participated in one experimental session where two distinct stimulation modalities were compared: wide-pulse high-frequency (WPHF, pulse duration: 1ms, frequency: 100Hz), favouring afferent pathways activation, and narrow-pulse low-frequency (NPLF, pulse duration: 0.05ms, frequency: 20Hz), favouring activation of the efferent pathway. Both stimulation modalities, were applied to evoke 5-10% of maximal voluntary contraction either in isometric conditions (WPHF and NPLF) or in combination with a muscle lengthening (lengthening condition: WPHF+LEN and NPLF+LEN). The torque-time integral (TTI) during the stimulation trains and the muscle activity after the cessation of the stimulation trains (sustained EMG activity, normalized to the maximal EMG activity) were assessed and compared between the stimulation modalities and the conditions (two-way ANOVA). An interaction effect was obtained, revealing significant differences in TTI and sustained EMG activity between the WPHF+LEN and the other tested conditions (P=0.048 and P=0.044, respectively). TTI and sustained EMG activity were higher for WPHF+LEN (228.4±105.3 Nm.s and 0.085±0.070, respectively) compared to WPHF (168.4±72.9 Nm.s; 0.052±0.026), NPLF+LEN (136.4±38.9 Nm.s; 0.031±0.016) and NPLF (125.2±36.1 Nm.s; 0.028±0.015). The increased TTI during the WPHF+LEN condition suggests that the contribution of afferent pathways to the evoked torque can be enhanced with the muscle lengthening superimposition. They highlight the importance of using WPHF stimulation that already solicits Ia afferents to benefit from the cumulative afferent activation induced by the muscle lengthening to further increase torque production.

Chnoospora minima: a Robust Candidate for Hyperglycemia Management, Unveiling Potent Inhibitory Compounds and Their Therapeutic Potential.

The present study aimed to isolate a bioactive compound from Sri Lankan edible marine brown algae, Chnoospora minima, to manage diabetes. The de-polysaccharide crude methanolic extract was partitioned using hexane, chloroform, and ethyl acetate with increased polarity. The samples were subjected to determine the quantitative phytochemical analysis, antioxidants, and antidiabetic potentials. Further, the potent antidiabetic fraction was selected to isolate an active compound using bioactivity-guided fractionation. From the selected extract, the chloroform fraction exhibited comparatively high TPC (59.01 ± 1.86mg GAE/g), TFC (5.14 ± 0.43mg QE/g) and alkaloid content (2.79 ± 0.31 PE/g of extract). Crude methanol extract exhibited a potent DPPH activity (IC50: 0.48 ± 0.01mg/mL) whereas the ethyl acetate fraction elicited a maximum ABTS activity (IC50: 0.064 ± 0.001mg/mL) and a ferrous iron-chelating capacity (IC50: 0.019mg/mL). Similarly, the chloroform fraction exhibited the highest FRAP (20.34 ± 1.72mg TE/g) and ORAC (19.72 ± 2.92mg TE/g) capacities. The potent inhibitory activity of α-amylase (IC50:3.17 ± 0.02µg/mL) and α-glucosidase (IC50: 1.99 ± 0.01µg/mL) enzymes and glucose diffusion was observed in the chloroform fraction. Similarly, the chloroform extract exhibited a potent BSA-glucose (IC50: 202.43 ± 5.71µg/mL), BSA-MGO (IC50: 124.30 ± 2.85µg/mL) antiglycation model and reversing activities (EC50BSAglucose: 98.99 ± 0.35µg/mL; EC50BSA-MGO: 118.89 ± 1.58µg/mL). Depending on the hypoglycemic activity, fucoxanthin was isolated as the active compound which showed a notable change in the functional group. Molecular docking studies were conducted on the compound, and binding energy was observed to be - 6.56kcal/mol and - 4.83kcal/mol for α-amylase and α-glucosidase enzymes, respectively, which confirmed the hypoglycemic effect of the isolated compounds. However, more studies are required to understand the mechanistic insights of these observations.

Characterization of the extracellular proteases from Bacillus inaquosorum strain E1-8 and its application in the preparation of hydrolysates from plant and animal proteins with antioxidant, antifreeze and anti-browning properties.

Bacillus inaquosorum strains is widely recognized for their plant-growth-promoting and biocontrol capabilities, yet their roles in protease production remain unclear. The present study aimed to comprehensively assess the protease-producing performance of B. inaquosorum strain E1-8, at the same time as exploring the novel application of agricultural Bacillus proteases in the preparation of protein hydrolysates for fresh-cut fruits preservation. First, genomic sequencing revealed the diversity of E1-8 proteases, indicating 15 putative extracellular proteases. Subsequently, the fermentation conditions for E1-8 protease production were optimized, with sweet potato powder and soybean meal identified as the most suitable carbon and nitrogen sources, respectively, resulting in a maximum protease activity of 321.48 U mL-1. Upon culturing the strain under these optimized conditions, only an S8 family serine protease and an M48 family metalloprotease were revealed by secretomic analysis and protease inhibitor assays. Additionally, the optimal protease conditions for generating protein hydrolysates from soy, pea, fish and porcine proteins were determined. The molecular weight of the hydrolysates primarily ranged from 2000 to 180 Da, with a total of 17 amino acids identified. The application of these hydrolysates demonstrated a 2,2-diphenyl-1-picrylhydrazyl (i.e. DPPH) scavenging activity ranging from 58.64% to 84.12%, significantly reducing of the melting peaks and the freezing points. Furthermore, the browning index of apple slices stored at 4 °C decreased by 14.81% to 22.15% on the second day, and similar effects were observed in fresh-cut banana stored at 4 °C for 7 days. The protein hydrolysates obtained exhibit remarkable antioxidant, antifreeze and anti-browning properties for fresh-cut fruits. © 2024 Society of Chemical Industry.

Saturated dissolved oxygen-driven high-rate and ultrastable partial nitrification in municipal wastewater

Achieving stable and high-rate partial nitrification (PN) remains a worldwide technical conundrum in low-strength mainstream conditions. This study successfully achieved ultrarapid mainstream PN within 8 days under a saturated dissolved oxygen (DO) supply strategy, reaching a record-breaking PN rate of over 1.0 kg N m−3 d−1 treating municipal wastewater. Stable PN was maintained for over 200 days with an ultrahigh nitrite accumulation ratio of 98.5 ± 0.9 %, resilient to seasonal fluctuations in temperature (16.0–25.6 °C) and load (NH4+-N, 40–80 mg N/L). Kinetics revealed a remarkable 159.1-fold increase in the maximum activity ratio of ammonia-oxidizing bacteria (AOB) to nitrite-oxidizing bacteria (NOB). The faster response of AOB to saturated DO stimulated its highest activity difference with NOB, contributing to the AOB (Nitrosomonas oligotropha) boom and the elimination of NOB groups (−99.9 %). Our results highlight the importance of promoting AOB rather than solely focusing on NOB suppression for initiating and stabilizing high-rate mainstream PN.

Effect of ammonium polyphosphate on flame retardancy of bio-based rigid polyurethane foams

Rigid polyurethane foam (RPUF) has attracted a lot of attention as a multifunctional material. However, the use of fossil fuels in various fields is limited due to their flammability and excessive consumption in the preparation process. In order to solve this problem, a sustainable bio-based RPUF was prepared by ammonium polyphosphate (APP) and lignin-based polyol flame-retardant modification. The impact of APP on the smoke characteristics, flame retardancy, and thermal behavior of lignin-based polyol RPUFs was examined. The modified RPUF (RPUF-20) with 20 wt.% APP had the greatest starting temperature and residual rate. The maximum activation energy (E) and best thermal stability were found in the pyrolysis kinetics calculation utilizing the thermogravimetric trajectory compared with other specimens. Cone showed that when RPUF-20 was compared with RPUF-0, the peak heat release rate was lowered by 79.43%, 72.79%, and 67.91%, and the total heat release was reduced by 50.59%, 56.29%, and 37.14%, respectively. In addition, RPUF-20 had the lowest smoke density, according to the statistics. The current results showed that RPUF-20 had low smoke toxicity and outstanding flame retardancy, which gave rise to a novel notion for RPUFs following flame-retardant modification using biomass.

The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity.

The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC-mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly neutralizing antibodies and even showed activity against HIV-1-infected monocyte-derived macrophages. Thus, combining CD4i antibodies with different specificities achieves maximal ADCC activity, which may be of utility in HIV cure strategies.IMPORTANCEThe elimination of HIV-1-infected cells remains an important medical goal. Although current antiretroviral therapy decreases viral loads below detection levels, it does not eliminate latently infected cells that form the viral reservoir. Here, we developed a cocktail of non-neutralizing antibodies targeting highly conserved Env regions and combined it with a potent indoline CD4mc. This combination exhibited potent ADCC activity against HIV-1-infected primary CD4 + T cells as well as monocyte-derived macrophages, suggesting its potential utility in decreasing the size of the viral reservoir.

Study on the Preparation and Performance of Lightweight Wallboards from MSWIBA Foam Concrete.

To reduce land use and avoid further pollution, incineration for power generation has become the main method for municipal solid waste treatment. This research focused on the potential for transforming Municipal Solid Waste Incineration Bottom Ash (MSWIBA) into a finely ground powder. The impact of the powder's fineness and the amount of water used on its effectiveness was analyzed using a method called grey theory. MSWIBA was used as a partial substitute for cement in making MSWIBA foam concrete and lightweight wall panels. By modifying the fineness and water utilization of the recycled micro-powder, its maximum activity index can be increased to 90.1. This study determined the influence of factors including apparent dry density, water-cement ratio, foaming agent dilution ratio, and admixture dosage on the strength of the recycled foam concrete, and established the optimal mix ratio. This study employed a combination of physical experiments and numerical simulations to elucidate the impact of panel material, core layer thickness, and layer sequence on sound insulation performance. The simulation results were in close agreement with the experimental findings.

Synergistic performance of microwave-activated coal gangue with limestone in low-carbon cement

This study aims to apply microwave-activated coal gangue (MCG) to develop limestone calcined clay cement (LC3). The impact of microwave activation schemes (microwave temperature and holding time) on the pozzolanic activity of coal gangue were explored. After that, LC3 cements were prepared by replacing cement clinker with limestone powder (LS) and MCG at different ratios. The uniaxial compressive strength, phase composition, microstructure, and pore structure of the MCG-based LC3 cements were analyzed. The results indicate that the maximum volcanic ash activity index is achieved when the material is microwave-activated at 800 °C with a holding time of 20 min. The MCG based LC3 cements achieve the highest strength at an MCG content of 20 % with an MCG:LS ratio of 2. Then, the response surface methodology was employed to predict the optimal mixture proportions for achieving the best strength of the material. The life cycle analysis shows that the carbon emission of the MCG-based LC3 material is 30 % lower than that of Ordinary Portland Cement. This study develops a new high-performance material with low carbon emission for construction industry.

In vitro antibacterial, antioxidant, in silico molecular docking and ADEMT analysis of chemical constituents from the roots of Acokanthera schimperi and Rhus glutinosa

Acokanthera schimperi is a medicinal plant traditionally used for the treatment of wounds, scabies, and malaria. Rhus glutinosa has been also utilized for the management of ectoparasites and hemorrhoids. Silica gel column chromatography separation of CH2Cl2/MeOH (1:1) extract root of A. schimperi afforded oleic acid (1), lupeol (2), dihydroferulic acid (3), acovenosigenin A- 3-O-α-L-rhamnopyranoside (4) and sucrose (5) whereas CH2Cl2/ MeOH (1:1) and MeOH roots extracts of R. glutinosa afforded β-sitosterol (6), (E)-5-(heptadec-14-en-1-yl)-4,5-dihydroxycyclohex-2-enone (7), methyl gallate (8), and gallic acid (9). The structures of the compounds were established using spectroscopic (1D and 2D NMR) and FT-IR techniques. Disc diffusin and DPPH assay were used, respectively, to evaluate the antibacterial and antioxidant potential of the extracts and isolated compounds. MeOH extract root of A. schimperi showed a modest antibacterial effect against E.coli with an inhibition zone (ZI) of 16 ± 0.0 mm compared to ciprofloxacin (ZI of 27.0 ± 0.0 mm). CH2Cl2/MeOH (1:1) and MeOH root extracts of R. glutinosa showed maximum activity against S. aureus with ZI of 17.3 ± 0.04 and 18.0 ± 0.0 mm, respectively. At 5 mg/mL, the highest activity was noted against S. aureus by 8 with ZI of 18.6 ± 0.08 mm. Dihydroferulic acid (3), methyl gallate (8), and gallic acid (9) displayed potent scavenging of DPPH radical with respective IC50 of 10.66, 7.48, and 6.08 µg/mL, compared with ascorbic acid (IC50 of 5.83 µg/mL). Molecular docking results showed that lupeol (2) exhibited strong binding energy of -7.7 and − 10 kcal/mol towards PDB ID: 4F86 and PDB ID: 3T07, respectively, compared to ciprofloxacin (-6.5 and − 7.2 kcal/mole). Towards PDB ID: 1DNU receptor, compounds 3, 8, and 9 showed minimum binding energy of -5.1, -4.8, and − 4.9 kcal/mol, respectively, compared to ascorbic acid (-5.7 kcal/mol). The Swiss ADME prediction results indicated that compounds 2, 3, 8, and 9 obeyed the Lipinksi rule of five and Veber rule with 0 violations. The in vitro antibacterial and antioxidant results supported by in silico analysis indicated that compounds 2, 3, 8, and 9 can potentially be lead candidates for the treatment of pathogenic and free radical-induced disorders.

Stimulation of cytochrome c oxidase activity by detergents

Cytochrome c oxidase (CytcO) is an integral membrane protein, which catalyzes four-electron reduction of oxygen linked to proton uptake and pumping. Amphipathic molecules bind in sites near the so-called K proton pathway of CytcO to reversibly modulate its activity. However, purification of CytcO for mechanistic studies typically involves the use of detergents, which may interfere with binding of these regulatory molecules. Here, we investigated the CytcO enzymatic activity as well as intramolecular electron transfer linked to proton transfer upon addition of different detergents to bovine heart mitoplasts. The CytcO activity increased upon addition of alkyl glucosides (DDM and DM) and the steroid analog GDN. The maximum stimulating effect was observed for DDM and DM, and the half-stimulating effect correlated with their CMC values. With GDN the stimulation effect was smaller and occurred at a concentration higher than CMC. A kinetic analysis suggests that the stimulation of activity is due to removal of a ligand bound near the K proton pathway, which indicates that in the native membrane this site is occupied to yield a lower than maximal possible CytcO activity. Possible functional consequences are discussed.