Structured protein domains enter the spotlight: modulators of biomolecular condensate form and function.

Biomolecular condensates are membraneless organelles that concentrate proteins and nucleic acids. One of the primary components of condensates is multidomain proteins, whose domains can be broadly classified as structured and disordered. While structured protein domains are ubiquitous within biomolecular condensates, the physical ramifications of their unique properties have been relatively underexplored.

Biomolecular condensates control and are defined by RNA-RNA interactions that arise in viral replication.

Cells must limit RNA-RNA interactions to avoid irreversible RNA entanglement. Cells may prevent deleterious RNA-RNA interactions by genome organization to avoid complementarity however, RNA viruses generate long, perfectly complementary antisense RNA during replication. How do viral RNAs avoid irreversible entanglement? One possibility is RNA sequestration into biomolecular condensates.

Accelerated Simulations Reveal Physicochemical Factors Governing Stability and Composition of RNA Clusters.

Under certain conditions, RNA repeat sequences phase separate, yielding protein-free biomolecular condensates. Importantly, RNA repeat sequences have also been implicated in neurological disorders, such as Huntington's disease. Thus, mapping repeat sequences to their phase behavior, functions, and dysfunctions is an active area of research.

Antibiotic De-Escalation Practices in the Intensive Care Unit: A Multicenter Observational Study.

Background: There is little known about antibiotic de-escalation (ADE) practices in the intensive care unit (ICU).

Objective: The objective was to determine the proportion of patients who received ADE within 24 hours of actionable cultures and identify predictors of timely ADE.

Methods: Multicenter cohort study in ICUs of 15 hospitals in Australia and New Zealand.

Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation.

Pyomyositis in an Immunocompetent Patient Following Gardening Activity.

Nocardia pyomyositis in immunocompetent patients is a rare occurrence. The diagnosis may be missed or delayed with the risk of progressive infection and suboptimal or inappropriate treatment. We present the case of a 48-year-old immunocompetent firefighter diagnosed with pyomyositis caused by acquired by direct skin inoculation from gardening activity.

Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.

Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation.

Total Intravenous Anesthesia with Propofol Reduces Discharge Times Compared with Inhaled General Anesthesia in Shoulder Arthroscopy: A Randomized Controlled Trial.

Background: Shoulder arthroscopy is commonly performed at ambulatory surgical centers (ASCs) with use of an interscalene block and inhaled general anesthesia (IGA). However, an alternative option known as total intravenous anesthesia with propofol (TIVA-P) has shown promising results in reducing recovery time for other surgeries. The objective of this study was to assess whether there is a clinically meaningful difference in post-anesthesia care unit phase-I (PACU-I) time following shoulder arthroscopy between patients receiving an interscalene block with IGA and those receiving an interscalene block with TIVA-P.

Integrated Place-Based Primary Interventions: Levers and Tensions Related to Multilevel Governance for Community Integrated Pathways, A Multiple Case Study.

Integrated Place-Based Primary Interventions (IPPIs) are considered an innovative response to the challenges and complex issues faced in disadvantaged areas where traditional institutional services have difficulty reaching people in vulnerable situations. IPPIs are an innovative approach to the delivery of in services, conceived as an original community-based local care and service pathways. However, these intervention practices require adaptive modes of governance.

Cenicriviroc prevents dysregulation of astrocyte/endothelial cross talk induced by ischemia and HIV-1 via inhibiting the NLRP3 inflammasome and pyroptosis.

Blood-brain barrier (BBB) breakdown is one of the pathophysiological characteristics of ischemic stroke, which may contribute to the progression of brain tissue damage and subsequent neurological impairment. Human immunodeficiency virus (HIV)-infected individuals are at greater risk for ischemic stroke due to diminished immune function and HIV-associated vasculopathy. Studies have shown that astrocytes are involved in maintaining BBB integrity and facilitating HIV-1 infection in the brain.

Neurocysticercosis mimicking craniopharyngioma: A case report.

Key Clinical Message: In patients with appropriate epidemiological risk factors, neurocysticecosis should be considered as part of the differential diagnosis of suprasellar or parasellar mass lesions. As neuroimaging findings can be nonspecific, serology may be helpful, but when still in doubt, brain biopsy, and histopathology may be necessary to make the correct diagnosis.

Abstract: Neurocysticercosis (NCC) is a well-documented central nervous system helminth infection that is, frequently observed in developing countries.

Energy landscapes and heat capacity signatures for peptides correlate with phase separation propensity.

Phase separation plays an important role in the formation of membraneless compartments within the cell and intrinsically disordered proteins with low-complexity sequences can drive this compartmentalisation. Various intermolecular forces, such as aromatic-aromatic and cation-aromatic interactions, promote phase separation. However, little is known about how the ability of proteins to phase separate under physiological conditions is encoded in their energy landscapes and this is the focus of the present investigation.

Macroscopic modeling of the growth and substrate consumption of wild type and genetically modified Pichia pastoris.

Pichia pastoris is a popular yeast platform to generate several industrially relevant products which have applications in a wide range of sectors. The complexities in the processes due to the addition of a foreign gene are not widely explored. Since these complexities can be dependent on the strain characteristics, promoter, and type of protein produced, it is vital to investigate the growth and substrate consumption patterns of the host to facilitate customized process optimization.

Aromatic and arginine content drives multiphasic condensation of protein-RNA mixtures.

Multiphasic architectures are found ubiquitously in biomolecular condensates and are thought to have important implications for the organization of multiple chemical reactions within the same compartment. Many of these multiphasic condensates contain RNA in addition to proteins. Here, we investigate the importance of different interactions in multiphasic condensates comprising two different proteins and RNA using computer simulations with a residue-resolution coarse-grained model of proteins and RNA.

"Common-Precursor" Protein Mimetic Approach to Rescue Aβ Aggregation-Mediated Alzheimer's Phenotypes.

Abberent protein-protein interactions (aPPIs) are associated with an array of pathological conditions, which make them important therapeutic targets. The aPPIs are mediated via specific chemical interactions that spread over a large and hydrophobic surface. Therefore, ligands that can complement the surface topography and chemical fingerprints could manipulate aPPIs.

The NLRP3 inflammasome and gut dysbiosis as a putative link between HIV-1 infection and ischemic stroke.

HIV-associated comorbidities, such as ischemic stroke, are prevalent in people with HIV (PWH). Several studies both in animal models and humans have revealed an association between activation of the inflammasome in HIV-1 infection and stroke. The gut microbiota is an important component in controlling neuroinflammation in the CNS.

Thermodynamic origins of two-component multiphase condensates of proteins.

Intracellular condensates are highly multi-component systems in which complex phase behaviour can ensue, including the formation of architectures comprising multiple immiscible condensed phases. Relying solely on physical intuition to manipulate such condensates is difficult because of the complexity of their composition, and systematically learning the underlying rules experimentally would be extremely costly. We address this challenge by developing a computational approach to design pairs of protein sequences that result in well-separated multilayered condensates and elucidate the molecular origins of these compartments.

The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus.

The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro.

Processing Method for the Quantification of Methanol and Ethanol from Bioreactor Samples Using Gas Chromatography-Flame Ionization Detection.

Methanol, a simple polar solvent, has been widely identified as an attractive carbon source to produce chemicals and fuels in bioprocesses. Specifically, to achieve recombinant protein production from methylotrophic yeasts, such as , this organic solvent can be used as a sole carbon source for growth and maintenance as well as an inducer for protein expression. However, if methanol feeding is not controlled well in such a fermentation process, accumulation of the solvent in the growth media will have a detrimental effect on the cells.

Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy.

Various physics- and data-driven sequence-dependent protein coarse-grained models have been developed to study biomolecular phase separation and elucidate the dominant physicochemical driving forces. Here, we present Mpipi, a multiscale coarse-grained model that describes almost quantitatively the change in protein critical temperatures as a function of amino-acid sequence. The model is parameterised from both atomistic simulations and bioinformatics data and accounts for the dominant role of - and hybrid cation-/- interactions and the much stronger attractive contacts established by arginines than lysines.

Aging can transform single-component protein condensates into multiphase architectures.

Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multicomponent mixtures of biomolecules (e.g.

Effects of Temperature and pH on Recombinant Thaumatin II Production by .

The sweet protein thaumatin is emerging as a promising sugar replacer in the market today, especially in the food and beverage sector. Rising demand for its production necessitates the large-scale extraction of this protein from its natural plant source, which can be limited in terms of raw material availability and production costs. Using a recombinant production technique via a yeast platform, specifically, , is more promising to achieve the product economically while maintaining batch-to-batch consistency.

Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly.

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation.