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Intracellular Delivery of Oxaliplatin Conjugate via Cell Penetrating Peptide for the Treatment of Colorectal Carcinoma in vitro and in vivo.

Int J Pharm 2021 Jul 19:120904. Epub 2021 Jul 19.

Department of Electronic Materials and Devices Engineering, Soonchunhyang University, Asan 31538, Republic of Korea; Department of Chemical Engineering, Soonchunhyang University, Asan 31538, Republic of Korea. Electronic address:

Pt-based drugs are one of the main active agents in colorectal cancer treatment. However, drug resistance and dose-dependent side effects are the main barriers that restrict their clinical applications. As an alternative approach to these issues, we designed and synthesized a cell penetrating peptide (CPP) octaarginine-oxaliplatin conjugate that quickly and successfully delivered oxaliplatin into colon cancer cells. Read More

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PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer.

Sci Rep 2021 Jul 21;11(1):14841. Epub 2021 Jul 21.

NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. Read More

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Tight electrostatic regulation of the OH production rate from the photolysis of hydrogen peroxide adsorbed on surfaces.

Proc Natl Acad Sci U S A 2021 Jul;118(30)

Departament de Química Biològica, Institut de Química Avançada de Catalunya, Consejo Superior de Investigaciones Científicas, E-08034 Barcelona, Spain

Recently, experimental and theoretical works have reported evidence indicating that photochemical processes may significantly be accelerated at heterogeneous interfaces, although a complete understanding of the phenomenon is still lacking. We have carried out a theoretical study of interface and surface effects on the photochemistry of hydrogen peroxide (HO) using high-level ab initio methods and a variety of models. Hydrogen peroxide is an important oxidant that decomposes in the presence of light, forming two OH radicals. Read More

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Propane-Trapping Ultramicroporous Metal-Organic Framework in the Low-Pressure Area toward the Purification of Propylene.

ACS Appl Mater Interfaces 2021 Jul 21. Epub 2021 Jul 21.

School of Materials Science and Engineering, National Institute for Advanced Materials, Nankai University, Tianjin 300350, China.

The propane (CH)-trapping adsorption behavior is considered as a potential performance to directly produce high-purity propylene (CH). Herein, we report an ultramicroporous Mn-based metal-organic framework () with a reverse CH-selective behavior in the low-pressure area. The pore structure of this material possesses more electronegative aromatic benzene rings for the stronger binding affinity to CH, and the material shows outstanding reverse ideal adsorbed solution theory (IAST) selectivity values. Read More

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Photocrosslinking O-GlcNAcylated Proteins to Neighboring Biomolecules.

Curr Protoc 2021 Jul;1(7):e201

Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas.

This protocol enables identification of the interaction partners of O-GlcNAcylated proteins. The method involves the introduction of the diazirine photocrosslinker onto the O-GlcNAc modification within living cells. The photocrosslinker is activated by UV light to yield covalent crosslinking between O-GlcNAcylated proteins and neighboring molecules. Read More

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Toward conditional control of Smac mimetic activity by RNA-templated reduction of azidopeptides on PNA or 2'-OMe-RNA.

Biopolymers 2021 Jul 19:e23466. Epub 2021 Jul 19.

Department of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany.

Oligonucleotide templated reactions can be used to control the activity of functional molecules based on the presence of a specific trigger sequence. We report an RNA-controlled reaction system to conditionally restore the N-terminal amino group and thus binding affinity of azide-modified Smac mimetic compounds (SMCs) for their target protein X-linked Inhibitor of Apoptosis Protein (XIAP). Two templated reactions were compared: Staudinger reduction with phosphines and a photocatalytic reaction with Ru(bpy) (mcbpy). Read More

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Weak Binding of Epigallocatechin to α-Lactalbumin Greatly Improves Its Stability and Uptake by Caco-2 Cells.

J Agric Food Chem 2021 Jul 21. Epub 2021 Jul 21.

College of Food Science and Nutritional Engineering, China Agricultural University, Beijing Key Laboratory of Functional Food from Plant Resources, Beijing 100083, China.

Improving the stability and bioavailability of catechins is of great importance. Epigallocatechin (EGC), the major catechin in green tea, is a potent antioxidant with numerous attributed health benefits. However, the low permeability and stability limit its enrichment in the diet for preventive medicine. Read More

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Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into "early"- and "late"-phases.

Authors:
Siddhartha Kundu

Heliyon 2021 Jul 5;7(7):e07466. Epub 2021 Jul 5.

Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India.

The peptide loading complex (PLC) is a multi-protein complex of the endoplasmic reticulum (ER) which optimizes major histocompatibility I (MHC1)-mediated export of intracellular high-affinity peptides. Whilst, the molecular biology of MHC1-mediated export is well supported by empirical data, the stoichiometry, kinetics and spatio-temporal profile of the participating molecular entities are a matter of considerable debate. Here, a low-affinity peptide-driven (LAPD)-model of MHC1-mediated high-affinity peptide export is formulated, implemented, analyzed and simulated. Read More

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Could Function as a Prognostic Marker and Correlate with Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

Biomed Res Int 2021 5;2021:8874578. Epub 2021 Jul 5.

Department of Oncology, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fujian 350001, China.

Objective: We aim to investigate the correlation between mRNA level and prognosis of head and neck squamous cancer (HNSC) in public databases. In addition, we investigated the correlation between expression and clinicopathological characteristics and tumor-infiltrating immune cells in HNSC patients.

Methods: mRNA expression in multiple cancers was analyzed based on Gene Expression Profiling Interactive Analysis. Read More

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Response to substrate limitation by a marine sulfate-reducing bacterium.

ISME J 2021 Jul 20. Epub 2021 Jul 20.

Section for Microbiology, Department of Biology, Aarhus University, Aarhus, Denmark.

Sulfate-reducing microorganisms (SRM) in subsurface sediments live under constant substrate and energy limitation, yet little is known about how they adapt to this mode of life. We combined controlled chemostat cultivation and transcriptomics to examine how the marine sulfate reducer, Desulfobacterium autotrophicum, copes with substrate (sulfate or lactate) limitation. The half-saturation uptake constant (K) for lactate was 1. Read More

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Termite gas emissions select for hydrogenotrophic microbial communities in termite mounds.

Proc Natl Acad Sci U S A 2021 Jul;118(30)

Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;

Organoheterotrophs are the dominant bacteria in most soils worldwide. While many of these bacteria can subsist on atmospheric hydrogen (H), levels of this gas are generally insufficient to sustain hydrogenotrophic growth. In contrast, bacteria residing within soil-derived termite mounds are exposed to high fluxes of H due to fermentative production within termite guts. Read More

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A scalable and reproducible preparation for the antitumor protein TLC, a human-derived telomerase inhibitor.

Protein Expr Purif 2021 Jul 17;187:105942. Epub 2021 Jul 17.

Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, 313000, China; School of Medicine, Huzhou University, Huzhou, 313000, China. Electronic address:

Telomerase, which is overexpressed in approximately 90% of liver cancer cells, is an ideal target for anti-liver cancer therapy. LPTS, a putative liver tumor suppressor, is the only human-derived protein that can bind telomerase directly and inhibit the extension of telomere activity. Our previous studies demonstrated that TAT-LPTS-LC (TLC), a recombinant protein fused by the C-terminal 133-328 fragment of LPTS and TAT peptides, could be delivered into cells to inhibit telomerase-positive hepatoma cell growth in vitro and in vivo with very low toxicity. Read More

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Effect of PEGylation on Host Defense Peptide Complexation with Bacterial Lipopolysaccharide.

Bioconjug Chem 2021 Jul 20. Epub 2021 Jul 20.

Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.

Conjugation with poly(ethylene glycol) ("PEGylation") is a widely used approach for improving the therapeutic propensities of peptide and protein drugs through prolonging bloodstream circulation, reducing toxicity and immunogenicity, and improving proteolytic stability. In the present study, we investigate how PEGylation affects the interaction of host defense peptides (HDPs) with bacterial lipopolysaccharide (LPS) as well as HDP suppression of LPS-induced cell activation. In particular, we investigate the effects of PEGylation site for KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), a peptide displaying potent anti-inflammatory effects, primarily provided by its N-terminal part. Read More

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Organic Cation Transporters in Psychiatric Disorders.

Authors:
Lynette C Daws

Handb Exp Pharmacol 2021 Jul 20. Epub 2021 Jul 20.

Departments of Cellular and Integrative Physiology, and Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for psychiatric disorders, yet they leave the majority of patients without full symptom relief. Therefore, a major research challenge is to identify novel targets for the improved treatment of these disorders. SSRIs act by blocking the serotonin transporter (SERT), the high-affinity, low-capacity, uptake-1 transporter for serotonin. Read More

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An artificial membrane binding protein-polymer surfactant nanocomplex facilitates stem cell adhesion to the cartilage extracellular matrix.

Biomaterials 2021 Jun 28;276:120996. Epub 2021 Jun 28.

School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD, UK; BrisSynBio Synthetic Biology Research Centre, University of Bristol, BS8 1TQ, UK. Electronic address:

One of the major challenges within the emerging field of injectable stem cell therapies for articular cartilage (AC) repair is the retention of sufficient viable cell numbers at the site of injury. Even when delivered via intra-articular injection, the number of stem cells retained at the target is often low and declines rapidly over time. To address this challenge, an artificial plasma membrane binding nanocomplex was rationally designed to provide human mesenchymal stem cells (hMSCs) with increased adhesion to articular cartilage tissue. Read More

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New method for the protection and restoration of calcareous cultural heritage stones by polyelectrolytes and hydroxyapatite nanocrystals.

J Colloid Interface Sci 2021 Jul 6;604:604-615. Epub 2021 Jul 6.

Climate and Atmosphere Research Center, The Cyprus Institute, Nicosia 2121, Cyprus; Faculty of Civil Engineering and Geosciences, Delft University of Technology, Delft 2628 CN, the Netherlands.

We have investigated the feasibility of a new two-step protocol for the restoration of marbles. The process employs a polyelectrolyte multilayer film that enhances the chemical affinity between the treated stone and restorative material (hydroxyapatite nanocrystals), through functionalization, while at the same time it attributes an acid resistant property to the resulting system. Surface functionalization and material deposition is achieved through spraying; a simple and versatile application method suitable for objects of various sizes and geometries. Read More

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Candida albicans exhibit two classes of cell surface binding sites for serum albumin defined by their affinity, abundance and prospective role in interkingdom signalling.

PLoS One 2021 19;16(7):e0254593. Epub 2021 Jul 19.

Faculty of Health & Medicine, Lancaster University, Lancaster, England, United Kingdom.

Serum albumin binding to the yeast form of Candida albicans is described. Two populations of binding site are identified using two complementary spectroscopic techniques: an extrinsic fluorescent probe, 3-hexa-decanoyl-7-hydrocoumarin ([HEXCO) added to the C. albicans yeast cell surface that records the electrostatic surface potential and so responds to the surface binding of serum albumin and secondly a light scattering technique that reveals how albumin modulates aggregation of the yeast population. Read More

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Interaction of Ammonia with Nafion and Electrolyte in Electrocatalytic Nitrogen Reduction Study.

J Phys Chem Lett 2021 Jul 19:6861-6866. Epub 2021 Jul 19.

Institute of Fuel Cells, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.

Ammonia synthesis by electrochemical nitrogen reduction reaction (NRR) is a promising alternative to the Haber-Bosch process. Accurate measurement of produced ammonia requires rigorous criteria, which rely on a deeper understanding of ammonia characteristics. Herein, we systematically investigated the interaction of ammonia with Nafion membrane and electrolyte to reveal factors that may induce deviation in ammonia measurements. Read More

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A tailored LNA clamping design principle: efficient, economized, specific and ultrasensitive for the detection of point mutations.

Biotechnol J 2021 Jul 18:e2100233. Epub 2021 Jul 18.

School of Biomedical Engineering/Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, PR China.

In the development of personalized medicine, the ultrasensitive detection of point mutations that correlate with diseases is important to improve the efficacy of treatment and guide clinical medication. In this study, locked nucleic acid (LNA) was introduced as an amplification suppressor of a massive number of wild-type alleles in an amplification refractory mutation system (ARMS) to achieve the detection of low-abundance mutations with high specificity and sensitivity of at least 0.1%. Read More

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Peptide Based Inhibitors of Protein Binding to the Mitogen-Activated Protein Kinase Docking Groove.

Front Mol Biosci 2021 1;8:690429. Epub 2021 Jul 1.

Department of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary.

Mitogen-activated protein kinases (MAPK) are important regulatory units in cells and they take part in the regulation of many cellular functions such as cell division, differentiation or apoptosis. All MAPKs have a shallow docking groove that interacts with linear binding motifs of their substrate proteins and their regulatory proteins such as kinases, phosphatases, scaffolds. Inhibition of these protein-protein interactions may reduce or abolish the activity of the targeted kinase. Read More

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Antibodies induced by oral immunization of mice with a recombinant protein produced in tobacco plants harboring epitopes.

Plant Cell Tissue Organ Cult 2021 Jul 10:1-12. Epub 2021 Jul 10.

División de Biología Molecular, IPICYT, Camino a la Presa San José 2055, 78216 San Luis Potosí, S.L.P. México.

causes whooping cough or pertussis, disease that has not been eradicated and is reemerging despite the availability and massive application for decades of vaccines, such as Boostrix® which is an acellular vaccine harboring two regions of S1 subunit of the pertussis toxin, one region of filamentous hemagglutinin and one region of pertactin. In 2008, the World Health Organization estimated 16 million new cases and 95% occurred in developing countries with 195,000 children's deaths. We attempt to improve the vaccine against whooping cough and reduce its production costs by obtaining plants and bacteria expressing a heterologous protein harboring pertactin, pertussis toxin, and filamentous hemagglutinin epitopes from and assessing its immunogenicity after oral administration to mice. Read More

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Injectable Supramolecular Hydrogel for Locoregional Immune Checkpoint Blockade and Enhanced Cancer Chemo-Immunotherapy.

ACS Appl Mater Interfaces 2021 Jul 19. Epub 2021 Jul 19.

School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, P. R. China.

Immunotherapy has revolutionized the therapeutic modalities of cancer treatment but is severely limited by a low objective response rate and the risk of immune-related side effects. Herein, an injectable supramolecular hydrogel is developed for local delivery of the PPA-1 peptide (a d-peptide antagonist with a high binding affinity to programmed cell death-ligand 1 (PD-L1)) and doxorubicin (DOX). On the one hand, DOX could kill tumor cells directly and also induce immunogenic cell death to provoke the antitumor immune response. Read More

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Current noise of a protein-selective biological nanopore.

Proteomics 2021 Jul 18:e2100077. Epub 2021 Jul 18.

Department of Physics, Syracuse University, 201 Physics Building, Syracuse, New York, 13244-1130, USA.

1/f current noise is ubiquitous in protein pores, porins, and channels. We have previously shown that a protein-selective biological nanopore with an external protein receptor can function as a 1/f noise generator when a high-affinity protein ligand is reversibly captured by the receptor. Here, we demonstrate that the binding affinity and concentration of the ligand are key determinants for the nature of current noise. Read More

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Flexible microtubule anchoring modulates the bi-directional motility of the kinesin-5 Cin8.

Cell Mol Life Sci 2021 Jul 17. Epub 2021 Jul 17.

Department of Chemistry, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel.

Two modes of motility have been reported for bi-directional kinesin-5 motors: (a) context-dependent directionality reversal, a mode in which motors undergo persistent minus-end directed motility at the single-molecule level and switch to plus-end directed motility in different assays or under different conditions, such as during MT gliding or antiparallel sliding or as a function of motor clustering; and (b) bi-directional motility, defined as movement in two directions in the same assay, without persistent unidirectional motility. Here, we examine how modulation of motor-microtubule (MT) interactions affects these two modes of motility for the bi-directional kinesin-5, Cin8. We report that the large insert in loop 8 (L8) within the motor domain of Cin8 increases the MT affinity of Cin8 in vivo and in vitro and is required for Cin8 intracellular functions. Read More

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Sustained nitrogen loss in a symbiotic association of Comammox Nitrospira and Anammox bacteria.

Water Res 2021 Jul 11;202:117426. Epub 2021 Jul 11.

Civil and Environmental Engineering, University of Washington, Seattle, WA 98165, United States.

The discovery of anaerobic ammonia-oxidizing bacteria (Anammox) and, more recently, aerobic bacteria common in many natural and engineered systems that oxidize ammonia completely to nitrate (Comammox) have significantly altered our understanding of the global nitrogen cycle. A high affinity for ammonia (K ≈ 63nM) and oxygen place Comammox Nitrospira inopinata, the first described isolate, in the same trophic category as organisms such as some ammonia-oxidizing archaea. However, N. Read More

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Fed-batch production assessment of a tetravalent bispecific antibody: A case study on piggyBac stably transfected HEK293 cells.

N Biotechnol 2021 Jul 15;65:9-19. Epub 2021 Jul 15.

Department of Pharmaceutical Biosciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address:

The transition from preclinical biological drug development into clinical trials requires an efficient upscaling process. In this context, bispecific antibody drugs are particularly challenging due to their propensity to form aggregates and generally produce low titers. Here, the upscaling process for a tetravalent bispecific antibody expressed by a piggyBac transposon-mediated stable HEK293 cell pool has been evaluated. Read More

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Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma.

J Immunother Cancer 2021 Jul;9(7)

Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA

Background: Phase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy. Read More

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Structural basis for potassium transport in prokaryotes by KdpFABC.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016;

KdpFABC is an oligomeric K transport complex in prokaryotes that maintains ionic homeostasis under stress conditions. The complex comprises a channel-like subunit (KdpA) from the superfamily of K transporters and a pump-like subunit (KdpB) from the superfamily of P-type ATPases. Recent structural work has defined the architecture and generated contradictory hypotheses for the transport mechanism. Read More

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Purification of active human vacuolar ATPase in native lipid-containing nanodiscs.

J Biol Chem 2021 Jul 13:100964. Epub 2021 Jul 13.

Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Electronic address:

Vacuolar H-ATPases (V-ATPases) are large, multisubunit proton pumps that acidify the lumen of organelles in virtually every eukaryotic cell and in specialized acid-secreting animal cells, the enzyme pumps protons into the extracellular space. In higher organisms, most of the subunits are expressed as multiple isoforms, with some enriched in specific compartments or tissues and others expressed ubiquitously. In mammals, subunit a is expressed as four isoforms (a1-4) that target the enzyme to distinct biological membranes. Read More

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Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies.

PLoS One 2021 16;16(7):e0253364. Epub 2021 Jul 16.

MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.

Of the 16 non-structural proteins (Nsps) encoded by SARS CoV-2, Nsp3 is the largest and plays important roles in the viral life cycle. Being a large, multidomain, transmembrane protein, Nsp3 has been the most challenging Nsp to characterize. Encoded within Nsp3 is the papain-like protease domain (PLpro) that cleaves not only the viral polypeptide but also K48-linked polyubiquitin and the ubiquitin-like modifier, ISG15, from host cell proteins. Read More

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