Penalized G-estimation for effect modifier selection in a structural nested mean model for repeated outcomes.

Effect modification occurs when the impact of the treatment on an outcome varies based on the levels of other covariates known as effect modifiers. Modeling these effect differences is important for etiological goals and for purposes of optimizing treatment. Structural nested mean models (SNMMs) are useful causal models for estimating the potentially heterogeneous effect of a time-varying exposure on the mean of an outcome in the presence of time-varying confounding.

Site-specific sulfations regulate the physicochemical properties of papillomavirus-heparan sulfate interactions for entry.

Certain human papillomaviruses (HPVs) are etiological agents for several anogenital and oropharyngeal cancers. During initial infection, HPV16, the most prevalent cancer-causing type, specifically interacts with heparan sulfates (HSs), not only enabling initial cell attachment but also triggering a crucial conformational change in viral capsids termed structural activation. It is unknown, whether these HPV16-HS interactions depend on HS sulfation patterns.

Accumulation of liposomes in metastatic tumor sites is not necessary for anti-cancer drug efficacy.

Background: The tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes.

Assessing the impact of transitioning to 11th revision of the International Classification of Diseases (ICD-11) on comorbidity indices.

Objectives: This study aimed to support the implementation of the 11th Revision of the International Classification of Diseases (ICD-11). We used common comorbidity indices as a case study for proactively assessing the impact of transitioning to ICD-11 for mortality and morbidity statistics (ICD-11-MMS) on real-world data analyses.

Materials And Methods: Using the MIMIC IV database and a table of mappings between the clinical modification of previous versions of ICD and ICD-11-MMS, we assembled a population whose diagnosis can be represented in ICD-11-MMS.

Investigating the outcomes of a threatened gorgonian in situ transplantation: Survival and microbiome diversity in Paramuricea clavata (Risso, 1827).

Gorgonian octocorals are threatened by global and local stressors that can act synergistically to affect their health. In recent years, mass mortality events triggered by marine heatwaves have caused demographic declines in Mediterranean gorgonian populations that may lead to their collapse. Potential changes in microbiome composition under stressful conditions may further increase the susceptibility of the gorgonian holobiont to disease.

Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells.

Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models.

Induced Vascular Normalization-Can One Force Tumors to Surrender to a Better Microenvironment?

Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics.

Structure and Role of O-Linked Glycans in Viral Envelope Proteins.

N- and O-glycans are both important constituents of viral envelope glycoproteins. O-linked glycosylation can be initiated by any of 20 different human polypeptide O-acetylgalactosaminyl transferases, resulting in an important functional O-glycan heterogeneity. O-glycans are organized as solitary glycans or in clusters of multiple glycans forming mucin-like domains.

Simultaneous membrane and RNA binding by tick-borne encephalitis virus capsid protein.

Tick-borne encephalitis virus is an enveloped, pathogenic, RNA virus in the family Flaviviridae, genus Flavivirus. Viral particles are formed when the nucleocapsid, consisting of an RNA genome and multiple copies of the capsid protein, buds through the endoplasmic reticulum membrane and acquires the viral envelope and the associated proteins. The coordination of the nucleocapsid components to the sites of assembly and budding are poorly understood.

Spatial characterization of redox processes and speciation of Ru(III) anticancer complexes by F magnetic resonance imaging.

The application of CF-labeled Ru(III) anticancer complexes to magnetic resonance (MR) imaging of tumour tissues is demonstrated. By combining anatomical chemical-shift selective (CHESS) imaging with F chemical-shift imaging (CSI) MR methods, we show that oxidation states and ligand-exchange processes of the complexes can be spatially encoded. Measurements on different tissue models, including a human breast adenocarcinoma tumour, validate the application of these complexes as MR theranostics for the sensing and targeting of hypoxia.

PEG Conjugated Zein Nanoparticles for In Vivo Use.

Zein can be utilized to form nanoscale particles for drug delivery applications. Despite the ease of synthesis, these particles often aggregate when exposed to physiologically relevant conditions (e.g.

Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility.

The diffusion of viruses at the cell membrane is essential to reach a suitable entry site and initiate subsequent internalization. Although many viruses take advantage of glycosaminoglycans (GAG) to bind to the cell surface, little is known about the dynamics of the virus-GAG interactions. Here, single-particle tracking of the initial interaction of individual herpes simplex virus 1 (HSV-1) virions reveals a heterogeneous diffusive behavior, regulated by cell-surface GAGs with two main diffusion types: confined and normal free.

Ferrocene-appended anthraquinone and coumarin as redox-active cytotoxins.

Appending of ferrocene (Fc) to biologically-active organic backbones can generate novel multi-functional species for targeting bacteria and cancer. In this work Fc was linked to coumarin and anthraquinone with the goal of harnessing the redox-active Fc centre to generate new compounds that exhibit cytoxicity through the generation of toxic reactive oxygen species (ROS). A Cu(I)-catalyzed azide-alkyne cycloaddition "click" reaction was used to connect the organic and Fc components a triazole linker.

Membrane insertion mechanism of the caveola coat protein Cavin1.

Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades, and lipid sorting. The caveola coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking.

Structural characteristics, cation distribution, and elastic properties of Cr substituted stoichiometric and non-stoichiometric cobalt ferrites.

Structural, elastic and cation distribution properties have been investigated on stoichiometric and non-stoichiometric cobalt ferrites. Crystal structure, formation of spinel type ferrite, chemical bonding, cation distribution, and thermal properties of two series of Cr substituted stoichiometric and non-stoichiometric various cobalt ferrites with general formula Co Cr FeO (S1), and Co Cr Fe O (S2) were reported. Samples are synthesized by the solid-state reaction technique planetary ball milling.

DMPC/Chol liposomal copper CX5461 is therapeutically superior to a DSPC/Chol formulation.

CX5461, a compound initially identified as an RNA polymerase inhibitor and more recently as a G-quadruplex binder, binds copper to form a complex. Our previous publication showed that the complexation reaction can be leveraged to formulate copper-CX5461 inside liposomes, improving the apparent solubility of CX5461 by over 500-fold and reducing the elimination of CX5461 from the plasma compartment following intravenous administration. In mouse models of acute myeloid leukemia, the resulting formulation was more effective than the free drug solution of CX5461 (pH 3.

Monolignol export by diffusion down a polymerization-induced concentration gradient.

Lignin, the second most abundant biopolymer, is a promising renewable energy source and chemical feedstock. A key element of lignin biosynthesis is unknown: how do lignin precursors (monolignols) get from inside the cell out to the cell wall where they are polymerized? Modeling indicates that monolignols can passively diffuse through lipid bilayers, but this has not been tested experimentally. We demonstrate significant monolignol diffusion occurs when laccases, which consume monolignols, are present on one side of the membrane.

Dissimilar Deformation of Fluid- and Gel-Phase Liposomes upon Multivalent Interaction with Cell Membrane Mimics Revealed Using Dual-Wavelength Surface Plasmon Resonance.

The mechanical properties of biological nanoparticles play a crucial role in their interaction with the cellular membrane, in particular for cellular uptake. This has significant implications for the design of pharmaceutical carrier particles. In this context, liposomes have become increasingly popular, among other reasons due to their customizability and easily varied physicochemical properties.

Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from .

The α-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. We demonstrate a remarkable, hitherto unknown mechanism by an α-PFT protein from . As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs.

A tripartite cytolytic toxin formed by proteins with flagellum-facilitated secretion.

The protein MakA was discovered as a motility-associated secreted toxin from Here, we show that MakA is part of a gene cluster encoding four additional proteins: MakB, MakC, MakD, and MakE. MakA, MakB, and MakE were readily detected in culture supernatants of wild-type , whereas secretion was very much reduced from a flagellum-deficient mutant. Crystal structures of MakA, MakB, and MakE revealed a structural relationship to a superfamily of bacterial pore-forming toxins.

Gold-Protein Composite Nanoparticles for Enhanced X-ray Interactions: A Potential Formulation for Triggered Release.

Drug-delivery vehicles have been used extensively to modulate the biodistribution of drugs for the purpose of maximizing their therapeutic effects while minimizing systemic toxicity. The release characteristics of the vehicle must be balanced with its encapsulation properties to achieve optimal delivery of the drug. An alternative approach is to design a delivery vehicle that preferentially releases its contents under specific endogenous (e.

Physicochemical tools for studying virus interactions with targeted cell membranes in a molecular and spatiotemporally resolved context.

The objective of this critical review is to provide an overview of how emerging bioanalytical techniques are expanding our understanding of the complex physicochemical nature of virus interactions with host cell surfaces. Herein, selected model viruses representing both non-enveloped (simian virus 40 and human norovirus) and enveloped (influenza A virus, human herpes simplex virus, and human immunodeficiency virus type 1) viruses are highlighted. The technologies covered utilize a wide range of cell membrane mimics, from supported lipid bilayers (SLBs) containing a single purified host membrane component to SLBs derived from the plasma membrane of a target cell, which can be compared with live-cell experiments to better understand the role of individual interaction pairs in virus attachment and entry.

The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry.

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood.

Modular Lipid Nanoparticle Platform Technology for siRNA and Lipophilic Prodrug Delivery.

Successfully employing small interfering RNA (siRNA) therapeutics requires the use of nanotechnology for efficient intracellular delivery. Lipid nanoparticles (LNPs) have enabled the approval of various nucleic acid therapeutics. A major advantage of LNPs is the interchangeability of its building blocks and RNA payload, which allow it to be a highly modular system.

Inter-Metastatic Heterogeneity of Tumor Marker Expression and Microenvironment Architecture in a Preclinical Cancer Model.

Background: Preclinical drug development studies rarely consider the impact of a candidate drug on established metastatic disease. This may explain why agents that are successful in subcutaneous and even orthotopic preclinical models often fail to demonstrate efficacy in clinical trials. It is reasonable to anticipate that sites of metastasis will be phenotypically unique, as each tumor will have evolved heterogeneously with respect to gene expression as well as the associated phenotypic outcome of that expression.