Synthesis of a multivalent α-1,2-mannobiose ligand for targeting C-type lectins.

The importance of lectins in biological processes such as pathogen recognition, cell adhesion, and cell recognition is well documented. C-Type lectins, which require calcium for binding, play an important role in the innate immune response by engaging carbohydrates presented as part of the human and pathogen glycocalyx. For example, lectins such as MBL, Dectin-2, langerin and DC-SIGN selectively recognize mannose rich (high-mannose) structures presented as part of the glycocalyx.

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.

EMS injury cause codes more accurate than emergency department visit ICD-10-CM codes for firearm injury intent in North Carolina.

Background: The timeliness, accuracy, and completeness of data for firearm injury surveillance is crucial for public health surveillance efforts and informing injury prevention measures. While emergency department (ED) visit data can provide near real-time information on firearms injuries, there are concerns surrounding the accuracy of intent coding in these data. We examined whether emergency medical service (EMS) data provide more accurate firearm injury intent coding in comparison to ED data.

GalNAc- or Mannose-PEG-Functionalized Polyplexes Enable Effective Lectin-Mediated DNA Delivery.

A cationic, dendrimer-like oligo(aminoamide) carrier with four-arm topology based on succinoyl tetraethylene pentamine and histidines, cysteines, and -terminal azido-lysines was screened for plasmid DNA delivery on various cell lines. The incorporated azides allow modification with various shielding agents of different polyethylene glycol (PEG) lengths and/or different ligands by copper-free click reaction, either before or after polyplex formation. Prefunctionalization was found to be advantageous over postfunctionalization in terms of nanoparticle formation, stability, and efficacy.

An Electronic Health Record Alert for Inpatient Coronavirus Disease 2019 Vaccinations Increases Vaccination Ordering and Uncovers Workflow Inefficiencies.

Background:  Despite mortality benefits, only 19.9% of U.S.

Molecular Recognition of Glycan-Bearing Glycomacromolecules Presented at Membrane Surfaces by Lectins: An NMR View.

Lectin-glycan interactions are at the heart of a multitude of biological events. Glycans are usually presented in a multivalent manner on the cell surface as part of the so-called glycocalyx, where they interact with other entities. This multivalent presentation allows us to overcome the typical low affinities found for individual glycan-lectin interactions.

Glycopolymers against pathogen infection.

Pathogens including viruses, bacteria, fungi, and parasites continue to shape our lives in profound ways every day. As we have learned to live in parallel with pathogens, we have gained a better understanding of the rules of engagement for how they bind, adhere, and invade host cells. One such mechanism involves the exploitation of host cell surface glycans for attachment/adhesion, one of the first steps of infection.

Polymers Inspired by Heparin and Heparan Sulfate for Viral Targeting.

Heparin (HP) and heparan sulfate (HS) are linear, anionically charged polysaccharides well-known for their diverse biological activities. While HP is generally localized in mast cells and in connective tissues, HS is part of the glycocalyx and involved in the attachment of viruses to host cells, constituting the first step of an infection. HP and HS also exhibit antiviral activity by blocking viral receptors, thereby inhibiting viruses from engaging with host cells.

Glycosaminoglycan Mimetic Precision Glycomacromolecules with Sequence-Defined Sulfation and Rigidity Patterns.

Sulfated glycosaminoglycans (sGAGs) such as heparan sulfate (HS) are structurally diverse linear polysaccharides that are involved in many biological processes and have gained interest as antiviral compounds. Their recognition is driven by a complex orchestra of structural parameters that are still under intense investigation. One distinct characteristic is the incorporation of sulfation patterns including highly sulfated and non-sulfated sequences that provide variations in flexibility and conformation, which in turn impact the biological function of sGAGs.

Synthesis and evaluation of porphyrin glycoconjugates varying in linker length: preliminary effects on the photodynamic inactivation of .

Porphyrins have served as common photosensitizing agents in photomedicine due to their unique properties and broad therapeutic potential. While photodynamic therapy (PDT) offers a promising avenue for novel drug development, limitations in application due to selectivity, and the inherent hydrophobicity and poor solubility of porphyrins and other organic photosensitizers has been noted. Porphyrin glycoconjugates have recently gained attention for their potential to overcome these limitations.

Acetylcholine signaling genes are required for cocaine-stimulated egg laying in Caenorhabditis elegans.

The toxicity and addictive liability associated with cocaine abuse are well-known. However, its mode of action is not completely understood, and effective pharmacotherapeutic interventions remain elusive. The cholinergic effects of cocaine on acetylcholine receptors, synthetic enzymes, and degradative enzymes have been the focus of relatively little empirical investigation.

Synthesis of Porphyrin and Bacteriochlorin Glycoconjugates through CuAAC Reaction Tuning.

Rapid and reproducible access to a series of unique porphyrin and bacteriochlorin glycoconjugates, including meso-glycosylated porphyrins and bacteriochlorins, and beta-glycosylated porphyrins, via copper catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) is reported for the first time. The work presented highlights the system-dependent reaction conditions required for glycosylation to porphyrins and bacteriochlorins based on the unique electronic properties of each ring system. Attenuated reaction conditions were used to synthesize fifteen new glycosylated porphyrin and bacteriochlorin analogs in 74 - 99% yield, and were extended to solid support to produce the first oligo(amidoamine)-based porphyrin glycoconjugate.

Sequence-Defined Heteromultivalent Precision Glycomacromolecules Bearing Sulfonated/Sulfated Nonglycosidic Moieties Preferentially Bind Galectin-3 and Delay Wound Healing of a Galectin-3 Positive Tumor Cell Line in an In Vitro Wound Scratch Assay.

Within this work, a new class of sequence-defined heteromultivalent glycomacromolecules bearing lactose residues and nonglycosidic motifs for probing glycoconjugate recognition in carbohydrate recognition domain (CRD) of galectin-3 is presented. Galectins, a family of β-galactoside-binding proteins, are known to play crucial roles in different signaling pathways involved in tumor biology. Thus, research has focused on the design and synthesis of galectin-targeting ligands for use as diagnostic markers or potential therapeutics.

Prophylactic Antiviral Activity of Sulfated Glycomimetic Oligomers and Polymers.

In this work, we investigate the potential of highly sulfated synthetic glycomimetics to act as inhibitors of viral binding/infection. Our results indicate that both long-chain glycopolymers and short-chain glycooligomers are capable of preventing viral infection. Notably, glycopolymers efficiently inhibit Human Papillomavirus (HPV16) infection in vitro and maintain their antiviral activity in vivo, while the glycooligomers exert their inhibitory function post attachment of viruses to cells.

Recovery, Purification, and Reusability of Building Blocks for Solid Phase Synthesis.

Solid phase synthesis (SPS) is well established for the synthesis of biomacromolecules such as peptides, oligonucelotides, and oligosaccharides, and today is also used for the synthesis of synthetic macromolecules and polymers. The key feature of this approach is the stepwise assembly of building blocks on solid support, enabling monodispersity and monomer sequence control. However, in order to achieve such control, a high excess of building blocks is required during the reaction.

Effects of linker and liposome anchoring on lactose-functionalized glycomacromolecules as multivalent ligands for binding galectin-3.

In this work, we present a bottom-up approach for the synthesis of lactose-functionalized glycomacromolecules and glycofunctionalized liposomes and apply these compounds to investigate their effects of multivalent presentation on binding to galectin-3. Step-wise assembly of tailor-made building blocks on solid supports was used to synthesize a series of oligo(amidoamine) scaffolds that were further conjugated to lactose copper catalyzed 1,3-dipolar cycloaddition. Binding studies with galectin-3 revealed affinities in the micromolar range that increased with increasing carbohydrate valency, and decreased with increasing size and linker flexibility.

Heteromultivalent Glycooligomers as Mimetics of Blood Group Antigens.

Precision glycomacromolecules have proven to be important tools for the investigation of multivalent carbohydrate-lectin interactions by presenting multiple glycan epitopes on a highly-defined synthetic scaffold. Herein, we present a new strategy for the versatile assembly of heteromultivalent glycomacromolecules that contain different carbohydrate motifs in proximity within the side chains. A new building block suitable for the solid-phase polymer synthesis of precision glycomacromolecules was developed with a branching point in the side chain that bears a free alkyne and a TIPS-protected alkyne moiety, which enables the subsequent attachment of different carbohydrate motifs by on-resin copper-mediated azide-alkyne cycloaddition reactions.

Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.

Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process.

NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis.

Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process.

Toward Orthogonal Preparation of Sequence-Defined Monodisperse Heteromultivalent Glycomacromolecules on Solid Support Using Staudinger Ligation and Copper-Catalyzed Click Reactions.

The investigation of heteromultivalent interactions of complex glycoligands and proteins is critical for understanding important biological processes and developing carbohydrate-based pharmaceutics. Synthetic glycomimetics, derived by mimicking complex glycoligands on a variety of scaffolds, have become important tools for studying the role of carbohydrates in chemistry and biology. In this paper, we report on a new synthetic strategy for the preparation of monodisperse, sequence-defined glycooligomers or so-called precision glycomacromolecules based on solid phase oligomer synthesis and the Staudinger ligation.

Programmed evolution for optimization of orthogonal metabolic output in bacteria.

Current use of microbes for metabolic engineering suffers from loss of metabolic output due to natural selection. Rather than combat the evolution of bacterial populations, we chose to embrace what makes biological engineering unique among engineering fields - evolving materials. We harnessed bacteria to compute solutions to the biological problem of metabolic pathway optimization.

Use of epigenetic drugs in disease: an overview.

Epigenetic changes such as DNA methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulating, downregulating, or silencing genes completely. Dysregulation of epigenetic events can be pathological, leading to cardiovascular disease, neurological disorders, metabolic disorders, and cancer development. Therefore, identifying drugs that inhibit these epigenetic changes are of great clinical interest.

Drug resistance in cancer: an overview.

Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies.