Killing Properties Research Articles

Comparative Properties of Helical and Linear Amphipathicity of Peptides Composed of Arginine, Tryptophan, and Valine.

The persistence of antibiotic resistance has incited a strong interest in the discovery of agents with novel antimicrobial mechanisms. The direct killing of multidrug-resistant bacteria by cationic antimicrobial peptides (AMPs) underscores their importance in the fight against infections associated with antibiotic resistance. Despite a vast body of AMP literature demonstrating a plurality in structural classes, AMP engineering has been largely skewed toward peptides with idealized amphipathic helices (H-amphipathic). In contrast to helical amphipathicity, we designed a series of peptides that display the amphipathic motifs in the primary structure. We previously developed a rational framework for designing AMP libraries of H-amphipathic peptides consisting of Arg, Trp, and Val (H-RWV, with a confirmed helicity up to 88% in the presence of membrane lipids) tested against the most common MDR organisms. In this study, we re-engineered one of the series of the H-RWV peptides (8, 10, 12, 14, and 16 residues in length) to display the amphipathicity in the primary structure by side-by-side (linear) alignment of the cationic and hydrophobic residues into the 2 separate linear amphipathic (L-amphipathic) motifs. We compared the 2 series of peptides for antibacterial activity, red blood cell (RBC) lysis, killing and membrane-perturbation properties. The L-RWV peptides achieved the highest antibacterial activity at a minimum length of 12 residues (L-RWV12, minimum optimal length or MOL) with the lowest mean MIC of 3-4 µM, whereas the MOL for the H-RWV series was reached at 16 residues (H-RWV16). Overall, H-RWV16 displayed the lowest mean MIC at 2 µM but higher levels of RBC lysis (25-30%), while the L-RWV series displayed minor RBC lytic effects at the test concentrations. Interestingly, when the S. aureus strain SA719 was chosen because of its susceptibility to most of the peptides, none of the L-RWV peptides demonstrated a high level of membrane perturbation determined by propidium iodide incorporation measured by flow cytometry, with <50% PI incorporation for the L-RWV peptides. By contrast, most H-RWV peptides displayed almost up to 100% PI incorporation. The results suggest that membrane perturbation is not the primary killing mechanism of the L-amphipathic RWV peptides, in contrast to the H-RWV peptides. Taken together, the data indicate that both types of amphipathicity may provide different ideal pharmacological properties that deserve further investigation.

Quaternary Ammonium Salts-Based Materials: A Review on Environmental Toxicity, Anti-Fouling Mechanisms and Applications in Marine and Water Treatment Industries.

The adherence of pathogenic microorganisms to surfaces and their association to form antibiotic-resistant biofilms threatens public health and affects several industrial sectors with significant economic losses. For this reason, the medical, pharmaceutical and materials science communities are exploring more effective anti-fouling approaches. This review focuses on the anti-fouling properties, structure-activity relationships and environmental toxicity of quaternary ammonium salts (QAS) and, as a subclass, ionic liquid compounds. Greener alternatives such as QAS-based antimicrobial polymers with biocide release, non-fouling (i.e., PEG, zwitterions), fouling release (i.e., poly(dimethylsiloxanes), fluorocarbon) and contact killing properties are highlighted. We also report on dual-functional polymers and stimuli-responsive materials. Given the economic and environmental impacts of biofilms in submerged surfaces, we emphasize the importance of less explored QAS-based anti-fouling approaches in the marine industry and in developing efficient membranes for water treatment systems.

Local delivery of accutox® synergises with immune-checkpoint inhibitors at disrupting tumor growth

BackgroundThe Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule.MethodsA series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI).ResultsIn total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model.ConclusionsAccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.Graphical

Harnessing natural killer cells engineering for cancer immunotherapy

The use of genetically modified immune cells for cancer therapy is one of the most significant achievements in biotechnology in recent years. Although currently approved cell therapies are dominated by CAR-T cells, natural killer (NK) cells, with their unique cancer killing properties and safety of use, set the stage for the development of more convenient allogeneic therapies. Herein, we reviewed the challenges and strategies in harnessing NK cells for cancer immunotherapy. Various sources for NK cell acquisition are discussed, and genetic engineering methods, including retroviral vectors, lentiviral vectors, adeno-associated virus (AAV) vectors, and non-viral transfection, are explored. NK cells have the potential to address limitations associated with CAR-T therapy, and the paper addresses the need for innovative solutions to overcome technical hurdles associated with NK cell immunotherapy.

Withanone as an Emerging Anticancer Agent and Understanding Its Molecular Mechanisms: Experimental and Computational Evidence.

Despite decades of research and effort, treating cancer is still a challenging task. Current conventional treatments are still unsatisfactory to fully eliminate and prevent re-emergence or relapses, and targeted or personalised therapy, which are more effective in managing cancer, may be unattainable or inaccessible for some. In the past, research in natural products have yielded some of the most commonly used cancer treatment drugs known today. Hence it is possible more are awaiting to be discovered. Withanone, a common withanolide found in the Ayurvedic herb Withania somnifera, has been claimed to possess multiple benefits capable of treating cancer. This review focuses on the potential of withanone as a safe cancer treatment drug based on the pharmacokinetic profile and molecular mechanisms of actions of withanone. Through these in silico and in vitro studies discussed in this review, withanone showspotent anticancer activities and interactions with molecular targets involved in cancer progression. Furthermore, some evidences also show the selective killing property of withanone, which highlights the safety and specificity of withanone in targeting cancer cell. By compiling these evidences, this review hopes to spark interest for future research to be conducted in more extensive studies involving withanone to generate more data, especially involving in vivo experiments and toxicity evaluation of withanone.

S-Nitroso-N-acetylpenicillamine impregnated latex: A new class of barrier contraception for the prevention of intercourse-associated UTIs.

Urinary tract infections (UTIs) are some of the most common infections seen in humans, affecting over half of the female population. Though easily and quickly treatable, if gone untreated for too long, UTIs can lead to narrowing of the urethra as well as bladder and kidney infections. Due to the disease potential, it is crucial to mitigate the development of UTIs throughout healthcare. Unfortunately, sexual activity and the use of condoms have been identified as common risk factors for the development of sexually acquired UTIs. Therefore, this study outlines a potential alteration to existing condom technology to decrease the risk of developing sexually acquired UTIs using S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor. Herein, varying concentrations of SNAP are integrated into commercialized condoms through a facile solvent swelling method. Physical characterization studies showed that 72%-100% of the ultimate tensile strength was maintained with lower SNAP concentrations, validating the modified condom's mechanical integrity. Additionally, the evaluation of room-temperature storage stability via NO release analysis outlined a lack of special storage conditions needed compared to commercial products. Moreover, these samples exhibited >90% relative cell viability and >96% bacterial killing, proving biocompatibility and antimicrobial properties. SNAP-Latex maintains the desired condom durability while demonstrating excellent potential as an effective new contraceptive technology to mitigate the occurrence of sexually acquired UTIs.

Robust and Multifunctional Therapeutic Nanoparticles against Peritonitis-Induced Sepsis.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Customized A-D-A type molecule to construct a nitric oxide nanogenerator with enhanced antibacterial activity for infected wound healing.

Bacterial infections pose an increasingly serious threat to global health due to the development of drug-resistant strains. Developing a method to efficiently kill bacteria and promote tissue repair is imperative to decrease the damage from bacterial infection, especially infected wounds. Herein, a biofriendly and light-controlled nitric oxide (NO) generator HFB with simultaneous bacterial killing and wound repair properties is reported based on a tailored light-responsive molecule F(EIBC)2. HFB demonstrates an appropriate photothermal conversion efficiency of 33.4% and type I reactive oxygen species (˙OH and H2O2) generation capability to simultaneously trigger NO generation and potently kill bacteria. Furthermore, HFB can effectively eradicate mature bacterial biofilms with the aid of favorable permeability of NO. Additionally, HFB effectively eradicates Staphylococcus aureus in infected wounds of living mice and accelerates healing via NO-induced angiogenesis and collagen deposition. Owing to the encapsulated human serum albumin (HSA), heavy metal-free feature, and synergistic killing mechanism, HFB exhibits good biosafety to surrounding tissue and major organs. This work provides a novel dual-functional photo-responsive molecule and a potential light-controlled release platform for the treatment of bacterial infections.

Self-Assembled Multilayered Coatings with Multiple Cyclic Self-Healing Capability, Bacteria Killing, Osteogenesis, and Angiogenesis Properties on Magnesium Alloys.

Self-healing coatings improve the durability of magnesium (Mg) implants, but rapid corrosion still poses a challenge in the healing stage. Moreover, Mg-based materials with acceptable bacteria killing, osteogenic and angiogenic properties are challenging in biomedical applications. Herein, the self-healing polymeric coatings are fabricated on Mg alloys using the spin-assisted layer-by-layer (SLbL) assembly of hyaluronic acid (HA) and branched polyethyleneimine (bPEI) followed by chemical crosslinking treatment. The self-healing coatings show excellent adhesion strength and structure stability. The corrosion resistance is improved due to the physical barrier of polymer coatings, which also promotes the formation of hydroxyapatite (HAp) during degradation for further protection of Mg substrate. Owing to the dynamic reversible hydrogen bonds existing between HA and bPEI, the crosslinked multilayered coatings possess fast, substantial, and cyclic self-healing capabilities leading to restoration of the original structure and functions. Invitro investigations reveal that the self-healing coatings have multiple functionalities pertaining to bacteria killing, cytocompatibility, osteogenesis, as well as angiogenesis. In addition, the self-healing coatings stimulate alkaline phosphatase activity (ALP), extracellular matrix (ECM) mineralization, and the expression of osteogenesis-related genes of mBMSCs and HUVECs. This study reveals a feasible strategy to design and prepare versatile self-healing coatings on Mg implants for biomedical applications.

Incorporating pH/NIR responsive nanocontainers into a smart self-healing coating for a magnesium alloy with controlled drug release, bacteria killing and osteogenesis properties

Magnesium (Mg)-based orthopedic implant materials can potentially be protected from deterioration using a protective polymer coating. However, this coating is susceptible to excessive corrosion and accidental scratches. Moreover, the inadequate bone integration and infections associated with bone implants present additional challenges that hinder their effective use. In this work, a spin-spray layer-by-layer (SSLbL) assembly technique was employed to develop a smart self-healing coating for Mg alloy WE43. This coating was based on paeonol-encapsulated nanocontainers (PMP) that were modified with a stimuli-responsive polydopamine (PDA). The leached paeonol could form a compact chelating layer when complexed with Mg2+ ions. Dynamic reversible hydrogen bonds were formed between assembly units, which ensured that the hybrid coating possessed rapid and cyclic self-healing properties. Under 808 nm near-infrared (NIR) laser irradiation, the self-healing coating exhibited antibacterial properties due to the synergistic effects of hyperthermia, reactive oxygen species (ROS), and paeonol. In addition, the incorporation of nanoparticles into the hybrid coating led to improvements in the cytocompatibility and osteogenic properties of the implant material. The smart coating enhanced alkaline phosphatase activity, extracellular matrix (ECM) mineralization, and the expression of osteogenic genes. This study presents a promising opportunity to explore the application of a smart self-healing coating for a Mg alloy. Statement of significanceHerein, we report a self-healing coating comprised of polyethyleneimine and nanocontainer-crosslinked hyaluronic acid to achieve drug-controlled release, antimicrobial activity, and osteogenesis performance. The formation of hydrogen bonds between HA and PEI facilitated the self-assembly process, thereby improving the coating's corrosion resistance and adhesion strength. The hybrid coating exhibited a rapid and cyclic self-healing activity due to paeonol and dynamic reversible bonds. The release of paeonol was controlled by pH and NIR stimuli owing to polydopamine modification. In vitro testing revealed that the hybrid coating achieved effective bacteria eradication through synergistic effects of hyperthermia, reactive oxygen species, and paeonol. Moreover, the smart coating was found to enhance alkaline phosphatase activity, extracellular matrix mineralization, and the expression of osteogenic genes.

Preparation and Application of High-Efficiency, Antibacterial, and Antiviral PET-PTHP Fibers.

Transmission through the respiratory tract is one of the most important ways for bacteria and viruses to infect the human body; the use of high-performance antibacterial and antiviral protective equipment is the most effective way to prevent the spread of respiratory diseases. However, at present, most personal protective equipment lacks the ability to kill pathogens. In this paper, a kind of polytetrahydropyrimidine-polyethylene terephthalate functional fiber (PET-PTHP fibers) with highly sustained antibacterial and antiviral properties was prepared. The inactivation rate of the fibers against Staphylococcus aureus and Escherichia coli was as high as 99.99%, and the antibacterial time was more than 72 h. The fibers have an obvious destructive effect on lentiviruses and can reduce the infection rate of lentiviruses in BxPC-3 cells from 25.4 to 9.7%. The cytotoxicity test, cell live/dead staining test, and cell proliferation test all confirmed that PET-PTHP fibers have no obvious cytotoxicity and good cytocompatibility. By applying the functional fibers to the inner layer of the masks, a new type of mask with adsorption, filtration, and killing properties against pathogens was prepared. The filtration efficiency of the new masks was 99.3%, and the pressure drop was 104 Pa. The new masks have excellent air permeability and filtration effect, meet the practical application conditions, and are of grade A; therefore, these masks provide medical protection as well as kill pathogens at the same time, further reducing the risk of human infection.

Novel mesothelin-targeted chimeric antigen receptor-modified UNKT cells are highly effective in inhibiting tumor progression

The design of chimeric antigen receptors (CAR) significantly enhances the antitumor efficacy of T cells. Although some CAR-T products have been approved by FDA in treating hematological tumors, adoptive immune therapy still faces many difficulties and challenges in the treatment of solid tumors. In this study, we reported a new strategy to treat solid tumors using a natural killer-like T (NKT) cell line which showed strong cytotoxicity to lyse 15 cancer cell lines, safe to normal cells and had low or no Graft-versus-host activity. We thus named it as universal NKT (UNKT). In both direct and indirect 3D tumor-like organ model, UNKT showed efficient tumor-killing properties, indicating that it could penetrate the microenvironment of solid tumors. In mesothelin (MSLN)-positive tumor cells (SKOV-3 and MCF-7), MSLN targeting CAR modified-UNKT cells had enhanced killing potential against MSLN positive ovarian cancer compared with the wild type UNKT, as well as MSLN-CAR-T cells. Compared with CAR-T, Single-cell microarray 32-plex proteomics revealed CAR-UNKT cells express more effector cytokines, such as perforin and granzyme B, and less interleukin-6 after activation. Moreover, our CAR-UNKT cells featured in more multifunctionality than CAR-T cells. CAR-UNKT cells also demonstrated strong antitumor activity in mouse models of ovarian cancer, with the ability to migrate and infiltrate the tumor without inducing immune memory. The fast-in and -out, enhanced and prolonged tumor killing properties of CAR-UNKT suggested a novel cure option of cellular immunotherapy in the treatment of MSLN-positive solid tumors.

Bacterial ghost cell based bivalent candidate vaccine against Salmonella Typhi and Salmonella Paratyphi A: A prophylactic study in BALB/c mice

Typhoid and emerging paratyphoid fever are a severe enteric disease worldwide with high morbidity and mortality. Licensed typhoid vaccines are in the market, but no paratyphoid vaccine is currently available. In the present study we developed a bivalent vaccine against Salmonella Typhi and Paratyphi A using a bacterial ghost platform. Bacterial ghost cells (BGs) are bacteria-derived cell membranes without cytoplasmic contents that retain their cellular morphology, including all cell surface features. Furthermore, BGs have inherent adjuvant properties that promote an enhanced humoral and cellular immune reaction to the target antigen. Sodium hydroxide was used to prepare ghost cells of Salmonella Typhi and Paratyphi A. The bacterial ghost cells were characterised using electron microscopy. Then BALB/c mice were immunized three times (0th, 14th and 28th day) with the bivalent typhoidal bacterial ghost cells. Haematological study of adult mice throughout immunization period reflected that the immunogen was safe to administer and does not affect the animals’ health. After complete immunization, we found significant serum antibody titter against whole cell lysate, outer membrane protein and lipopolysaccharide of both bacteria, and cell-mediated immunity was observed in an ex-vivo experiment. CD4+, CD8a+ and CD19+ splenic cell populations were increased in immunized animals. Bivalent Typhoidal ghost cell immunized mice showed better survival, less bacterial colonization in systemic organs, and less inflammation and/or destruction of tissue in histopathological analysis than non-immunized control mice.Serum antibodies of immunized animals can significantly inhibit bacterial motility and mucin penetration ability with better killing properties against Salmonella Typhi and Paratyphi A. Furthermore, significant passive protection was observed through the adoptive transfer of serum antibody and lymphocytes of immunized animals to naïve animals after bacterial infection. In summary, Bivalent Typhoidal Bacterial Ghost cells (BTBGs) enhances immunogenic properties and serves as a safe and effective prevention strategy against Salmonella Typhi and Paratyphi A.

Novel anti-CD30/CD3 bispecific antibodies activate human T cells and mediate potent anti-tumor activity.

CD30 is expressed on Hodgkin lymphomas (HL), many non-Hodgkin lymphomas (NHLs), and non-lymphoid malignancies in children and adults. Tumor expression, combined with restricted expression in healthy tissues, identifies CD30 as a promising immunotherapy target. An anti-CD30 antibody-drug conjugate (ADC) has been approved by the FDA for HL. While anti-CD30 ADCs and chimeric antigen receptors (CARs) have shown promise, their shortcomings and toxicities suggest that alternative treatments are needed. We developed novel anti-CD30 x anti-CD3 bispecific antibodies (biAbs) to coat activated patient T cells (ATCs) ex vivo prior to autologous re-infusions. Our goal is to harness the dual specificity of the biAb, the power of cellular therapy, and the safety of non-genetically modified autologous T cell infusions. We present a comprehensive characterization of the CD30 binding and tumor cell killing properties of these biAbs. Five unique murine monoclonal antibodies (mAbs) were generated against the extracellular domain of human CD30. Resultant anti-CD30 mAbs were purified and screened for binding specificity, affinity, and epitope recognition. Two lead mAb candidates with unique sequences and CD30 binding clusters that differ from the ADC in clinical use were identified. These mAbs were chemically conjugated with OKT3 (an anti-CD3 mAb). ATCs were armed and evaluated in vitro for binding, cytokine production, and cytotoxicity against tumor lines and then in vivo for tumor cell killing. Our lead mAb was subcloned to make a Master Cell Bank (MCB) and screened for binding against a library of human cell surface proteins. Only huCD30 was bound. These studies support a clinical trial in development employing ex vivo-loading of autologous T cells with this novel biAb.

(1→3)-α-d-Glucooligosaccharides Increase the Killing Capacity of NK Cells against Selected Human Colon Cancer Cells.

Despite the progress of medicine, colorectal cancer has occupied one of the highest positions in the rankings of cancer morbidity and mortality for many years. Thus, alternative methods of its treatment are sought. One of the newer therapeutic strategies is immunotherapy based on NK cells (natural killers), which are the body's first line of defense against cancer. The aim of the study was to verify the possibility of using (1→3)-α-d-glucooligosaccharides (GOSs) obtained via acid hydrolysis of (1→3)-α-d-glucan from the fruiting body of Laetiporus sulphureus to improve the anticancer effect of NK-92 cells, with proven clinical utility, against selected human colon adenocarcinoma cell lines LS180 and HT-29. The study revealed that the investigated oligosaccharides significantly enhanced the ability of NK-92 cells to eliminate the examined colon cancer cells, mostly by an increase in their cytotoxic activity. The most significant effect was observed in LS180 and HT-29 cells exposed to a two-times higher quantity of NK cells activated by 500 µg/mL GOS, wherein NK-92 killing properties increased for 20.5% (p < 0.001) and 24.8% (p < 0.001), respectively. The beneficial impact of (1→3)-α-d-glucooligosaccharides on the anticancer properties of NK-92 suggests their use in colon cancer immunotherapy as adjuvants; however, the obtained data require further investigation and confirmation.

Analysis of sequence diversity in Plasmodium falciparum glutamic acid-rich protein (PfGARP), an asexual blood stage vaccine candidate

Glutamic acid-rich protein of Plasmodium falciparum (PfGARP) binds to erythrocyte band 3 and may enhance cytoadherence of infected erythrocytes. Naturally acquired anti-PfGARP antibodies could confer protection against high parasitemia and severe symptoms. While whole genome sequencing analysis has suggested high conservation in this locus, little is known about repeat polymorphism in this vaccine candidate antigen. Direct sequencing was performed from the PCR-amplified complete PfGARP gene of 80 clinical isolates from four malaria endemic provinces in Thailand and an isolate from a Guinean patient. Publicly available complete coding sequences of this locus were included for comparative analysis. Six complex repeat (RI-RVI) and two homopolymeric glutamic acid repeat (E1 and E2) domains were identified in PfGARP. The erythrocyte band 3-binding ligand in domain RIV and the epitope for mAB7899 antibody eliciting in vitro parasite killing property were perfectly conserved across isolates. Repeat lengths in domains RIII and E1-RVI-E2 seemed to be correlated with parasite density of the patients. Sequence variation in PfGARP exhibited genetic differentiation across most endemic areas of Thailand. Phylogenetic tree inferred from this locus has shown that most Thai isolates formed closely related lineages, suggesting local expansion/contractions of repeat-encoding regions. Positive selection was observed in non-repeat region preceding domain RII which corresponded to a helper T cell epitope predicted to be recognized by a common HLA class II among Thai population. Predicted linear B cell epitopes were identified in both repeat and non-repeat domains. Besides length variation in some repeat domains, sequence conservation in non-repeat regions and almost all predicted immunogenic epitopes have suggested that PfGARP-derived vaccine may largely elicit strain-transcending immunity.

High performance polyvinylidene fluoride membrane functionalized with poly(ionic liquid) brushes for dual resistance to organic and biological fouling

The balance between antifouling properties and permeability is an inevitable problem for the application of ultrafiltration membranes. Herein, hydrophilic poly(ionic liquid) (PIL)-functionalized PVDF membranes with organic foulant resistance and bacterial killing properties were developed via atom transfer radical polymerization (ATRP). PILs with different anions bromide ([Br]-), tetrafluoroborate ([BF4]-) and hexafluorophosphate ([PF6]-) were functionalized onto the membrane surface, which all showed microbial inactivation ability. By optimizing PIL anions and ATRP conditions, a C4BF4-M membrane with favorable antibacterial and hydrophilic surface properties was obtained, which showed dual resistance to organic and biological fouling. With bovine serum albumin (BSA) and E. coli as model foulants, dynamic filtration tests further confirmed that PIL-M membranes have favorable anti-organic and anti-biological fouling abilities. Compared with the pristine PVDF membrane, the stable water flux of the C4BF4-M membrane increased up to 56% and 32%, respectively, during the anti-organic and anti-biological fouling experiments. The surface plasmon resonance confirmed that very loose binding can be formed between BSA and PIL brushes, leading to the excellent anti-organic fouling performance of the C4BF4-M membrane. We further evaluated the practical application and substantially reduced the fouling potential of the PIL-M membrane by wastewater effluent filtration tests. The results confirm that the surface grafting of PIL brushes is a promising method for membrane fouling control.

Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments

The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.

Efficacy of biopesticides in management of potato tuber moth, Phthorimaea operculella (Zeller), in potato under storage

Pest infestation causes heavy loss to farmers; both in fields and in stores. This study evaluated the efficacy of biopesticides in management of potato tuber moths (PTM) under storage condition. The potato cultivars Khumal Seto-1, Janak Dev and MS-42.3 and biopesticides Bacillus thuringiensis , Acorus calamus , Azadirachta indica , Artemisia vulgaris were used at the rate of 5 g l −1 , 2 g kg −1 , 4 g kg −1 and 20 g kg −1 of potato tubers respectively; also, a control was set to compare the treatment effects. Tubers were coated with solution for Bacillus thuringiensis while for the remaining biopesticidial powder was dusted on tubers. The cv. Janak Dev had the lowest infestation points per tuber (8.13), emergence of PTM adults (19.77%), physiological loss in weight (26.03%), decay loss (17.89%) and tuber damage score (2.74). The biopesticide Acorus calamus had the least infestation points per tuber (2.56), infested eyes per tuber (0.17), emergence of PTM adults (1%), tuber damage index (2.24), physiological loss in weight (12.11%), decay loss (4%) and tuber damage score (1.36). Acorus calamus had reduced larval mining by 88% and eventually had reduced decay loss by 93% as compared to control. The parameters relating to damage indicated that the cv. Janak Dev was least susceptible among the tested cultivars and Acorus calamus provided the best protection against damage caused by potato tuber moth. • Natural plant products with insecticidal properties are effective against potato tuber moth. • Against potato tuber moth infestations, Acorus calamus has both deterrent and killing properties. • Acorus calamus can serve to minimize the infestation, cut down physiological weight loss as well as decay loss. • Acorus calamus can be incorporated along with other integrated pest management options for more effective management.

Bio-based polybenzoxazines coatings for efficient marine antifouling

It is a subject of great practical significance and challenge to endow marine coatings with both excellent bacterial killing and antifouling properties. In this work, a series of bio-based organic coatings demonstrating high antibacterial rate, strong algae-killing ability and satisfied real-sea fouling resistance were reported. The main-chain type benzoxazine (MCBZ) resins were prepared from the renewable daidzein and furfurylamine, together with polyetheramine, long aliphatic chain primary amines, and paraformaldehyde. By adjusting the amines, the overall performance of synthesized MCBZs could be manipulated. Results indicated that the low surface energy of obtained MCBZ could prevent fouling adhesion, and the synergistic effect of long alkyl chains and daidzein led to the efficient anti-fouling. Notably, besides the low curing temperature of 200 °C, excellent processing property and good substrate adhesion (5.02 MPa), poly (12-fu-MCBZ) also possessed 94.5 % antibacterial rate, 100 % algae-killing ability and excellent real-sea antifouling performance. This work provides us a new strategy to solve the marine biological pollution using renewable raw materials.