Engineering the Mechanical Stability of a Therapeutic Complex between Affibody and Programmed Death-Ligand 1 by Anchor Point Selection.

Protein-protein complexes can vary in mechanical stability depending on the direction from which force is applied. Here, we investigated the mechanical stability of a complex between a binding scaffold called Affibody and an immune checkpoint protein Programmed Death-Ligand 1 (PD-L1). We used AFM single-molecule force spectroscopy with bioorthogonal clickable peptide handles, shear stress bead adhesion assays, molecular modeling, and steered molecular dynamics (SMD) to understand the pulling point dependency of the mechanostability of the Affibody:(PD-L1) complex.

In vitro evaluation against Leishmania amazonensis and Leishmania chagasi of medicinal plant species of interest to the Unified Health System.

Leishmaniasis is a disease of public health relevance that demands new therapeutic alternatives due to the toxicity of conventional treatments. In this study, 27 plants of interest to the Unified Health System (SUS) were evaluated for cytotoxicity in macrophages, leishmanicidal activity and production of nitric oxide (NO). None of the species demonstrated cytotoxicity to macrophages (CC50 >100 μg/mL).

Engineering the Mechanical Stability of a Therapeutic Affibody/PD-L1 Complex by Anchor Point Selection.

Protein-protein complexes can vary in mechanical stability depending on the direction from which force is applied. Here we investigated the anisotropic mechanical stability of a molecular complex between a therapeutic non-immunoglobulin scaffold called Affibody and the extracellular domain of the immune checkpoint protein PD-L1. We used a combination of single-molecule AFM force spectroscopy (AFM-SMFS) with bioorthogonal clickable peptide handles, shear stress bead adhesion assays, molecular modeling, and steered molecular dynamics (SMD) simulations to understand the pulling point dependency of mechanostability of the Affibody:(PD-L1) complex.

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data.

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without knowledge, will vastly enhance the understanding of microorganisms' role in ecology and human health.

Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear.

Nanostructures for Solar Energy Harvesting.

Renewable energy sources are becoming more and more essential to energy production as societies evolve toward a fossil-fuel-free world. Solar energy is one of the most abundant sources of green energy. Nanoantennas can be used to improve and enhance the absorption of light into a photovoltaic cell in order to generate more current.

Titrating Avidity of Yeast-Displayed Proteins Using a Transcriptional Regulator.

Yeast surface display is a valuable tool for protein engineering and directed evolution; however, significant variability in the copy number (i.e., avidity) of displayed variants on the yeast cell wall complicates screening and selection campaigns.

Monoclonal Gammopathy of Renal Significance and Thrombotic Microangiopathy: A Case Report.

Monoclonal gammopathy of renal significance (MGRS) is a group of pathologies that includes all kidney disorders related to a monoclonal protein in patients without diagnostic criteria for B-cell malignancies. There are multiple MGRS-associated kidney disorders, and more are still being discovered, which makes this diagnosis challenging. The relationship between monoclonal gammopathies and thrombotic microangiopathy (TMA) is of growing interest in literature.

MOG analogues to explore the MCT2 pharmacophore, α-ketoglutarate biology and cellular effects of N-oxalylglycine.

α-ketoglutarate (αKG) is a central metabolic node with a broad influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyl-oxalylglycine (DMOG) have been extensively used as tools to study prolyl hydroxylases (PHDs) and other αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, which enters cells through monocarboxylate transporter MCT2, leading to intracellular NOG concentrations that are sufficiently high to inhibit glutaminolysis enzymes and cause cytotoxicity.

A Case of Paraganglioma-Induced Adrenergic Shock.

Paragangliomas (PGLs) are rare neuroendocrine tumors that, when functional, can release excessive catecholamines, causing health conditions ranging from asymptomatic arterial hypertension to life-threatening arrhythmias and cardiogenic shock. Early diagnosis of functional PGLs is extremely important as timely treatment can be curative and prevent vascular sequelae. We describe the clinical case of a 30-year-old woman with arterial hypertension under study, who was presented to the emergency department with a hypertensive crisis that progressed to adrenergic shock, in the context of a functional PGL.

The Importance of Eculizumab in the Treatment of Atypical Hemolytic Uremic Syndrome.

In most cases, the atypical hemolytic uremic syndrome (aHUS) is a genetic disease resulting from defects in the regulation of the complement cascade, which conditions the development of thrombotic microangiopathy. Clinically, aHUS presents with acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia, with frequent renal and extrarenal thrombotic phenomena. Early diagnosis and treatment are essential.

Correlating single-molecule rupture mechanics with cell population adhesion by yeast display.

Here, we present a method based on yeast surface display that allows for direct comparison between population-level cell adhesion strength and single-molecule receptor-ligand rupture mechanics. We developed a high-throughput yeast adhesion assay in which yeasts displaying monomeric streptavidin (mSA) or enhanced mutant mSA were adhered to a biotinylated coverglass submerged in fluid. After exposure to shear stress (20-1000 dyn/cm) by rapid spinning of the coverglass, cells were imaged to quantify the midpoint detachment shear stress for the cell population.

Nestin and Neuron-glial antigen 2 transgenes unveil progenitor units in murine salivary glands.

Objective: Undifferentiated cells play pivotal roles in sustaining tissue homeostasis during physiological turnovers and after tissue impairment. Nestin and Neuron-glial antigen 2 (NG2) are markers frequently deployed to distinguish progenitor populations. In the salivary gland scenario, these markers remain largely unknown.

Metabolic turnover and dynamics of modified ribonucleosides by C labeling.

Tandem mass spectrometry (MS/MS) is an accurate tool to assess modified ribonucleosides and their dynamics in mammalian cells. However, MS/MS quantification of lowly abundant modifications in non-ribosomal RNAs is unreliable, and the dynamic features of various modifications are poorly understood. Here, we developed a C labeling approach, called C-dynamods, to quantify the turnover of base modifications in newly transcribed RNA.

Leismanicidal Activity of Propolis Collected in the Semiarid Region of Brazil.

The aim of the current study is to investigate the chemical composition, cytotoxic effect, and leishmanicidal activity of propolis collected in the semi-arid region of Bahia, Brazil. EtOH extract, hexane, EtOAc and MeOH fractions from propolis were analyzed by ultra-performance liquid chromatography coupled with diode array detector and quadrupole time-of-flight mass spectrometry. The identification was based on the exact mass, general fragmentation behaviors and UV absorption of the flavonoids.

SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD).

Synthesis, Antileishmanial Activity and Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Amastigotes.

Background: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used in an urgent need.

SARS-CoV-2 recruits a haem metabolite to evade antibody immunity.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD).

Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells.

Circadian clocks coordinate mammalian behavior and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms.

Photodynamic therapry with curcumin in the reduction of enterococcus faecalis biofilm in bone cavity: rMicrobiological and spectral fluorescense analysis.

Background: Antimicrobial photodynamic therapy (PDT) has emerged as a therapeutic strategy to conventional procedures using antibiotics.

Objective: To evaluate the antimicrobial effectiveness of PDT using blue light emitting diode (LED) associated with curcumin on biofilms of Enterococcus faecalis in bovine bone cavities and also to analyze the presence of these biofilms through spectral fluorescence.

Materials And Methods: Standardized suspensions of E.

Compatibility of with Pesticides Used for Treatment of Maize Seeds.

Seed treatment with chemical pesticides is commonly used as an initial plant protection procedure against pests and diseases. However, the use of such chemicals may impair the survival and performance of beneficial microorganisms introduced via inoculants, such as the plant growth-promoting bacterium . We assessed the compatibility between the most common pesticide used in Brazil for the treatment of maize seeds, composed of two fungicides, and one insecticide, with the commercial strains Ab-V5 and Ab-V6 of , and evaluated the impacts on initial plant development.

Developmental Exposure to the Flame Retardant Mixture Firemaster 550 Compromises Adult Bone Integrity in Male but not Female Rats.

Flame retardants (FRs) are used in a variety of common items from furniture to carpet to electronics to reduce flammability and combustion, but the potential toxicity of these compounds is raising health concerns globally. Organophosphate FRs (OPFRs) are becoming more prevalent as older, brominated FRs are phased out, but the toxicity of these compounds, and the FR mixtures that contain them, is poorly understood. Work in a variety of in vitro model systems has suggested that FRs may induce metabolic reprogramming such that bone density is compromised at the expense of increasing adiposity.

The 'Digital Twin' to enable the vision of precision cardiology.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions.