Structure Characterization of a Disordered Peptide Using In-Droplet Hydrogen/Deuterium Exchange Mass Spectrometry and Molecular Dynamics.

In-droplet hydrogen/deuterium exchange (HDX)-mass spectrometry (MS) experiments have been conducted for peptides of highly varied conformational type. A new model is presented that combines the use of protection factors (PF) from molecular dynamics (MD) simulations with intrinsic HDX rates ( ) to obtain a structure-to-reactivity calibration curve. Using the model, the relationship of peptide structural flexibility and HDX reactivity for different peptides is elucidated.

Independent aggregation in the nordic day-ahead market: What is the welfare impact of socializing supplier compensation payments?

This paper addresses the participation of independent aggregators (IAs) for demand response (DR) in European electricity markets. An IA is an aggregator trading the flexibility of consumers of which it is not the electricity supplier. Particularly, we focus on the controversial issue of a compensation payment from the IA to the supplier for energy sourcing.

Anthracyclines disaggregate and restore mutant p63 function: a potential therapeutic approach for AEC syndrome.

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome is a rare genetic disorder caused by mutations in the TP63 gene, which encodes a transcription factor essential for epidermal gene expression. A key feature of AEC syndrome is chronic skin erosion, for which no effective treatment currently exists. Our previous studies demonstrated that mutations associated with AEC syndrome lead to p63 protein misfolding and aggregation, exerting a dominant-negative effect.

Viral Transcript and Tumor Immune Microenvironment-Based Transcriptomic Profiling of HPV-Associated Head and Neck Squamous Cell Carcinoma Identifies Subtypes Associated with Prognosis.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed five distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal).

Like, share, and spike: Glioblastoma progenitors influence neuronal excitability at the glioma-neural interface.

Writing in Neuron, Zhang et al. identify a subpopulation of glioblastoma cells from patient tumor samples with progenitor-like features that expresses the potassium ion channel KCND2. In mouse and organoid models, these cells enhance neural activity at the glioma-neural interface.

Epstein-Barr virus BALF0/1 subverts the Caveolin and ERAD pathways to target B cell receptor complexes for degradation.

Epstein-Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane (PM) B cell receptor (BCR) complexes, composed of immunoglobulin and the CD79A and CD79B signaling chains.

Hypoxia as a medicine.

Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude physiology, clinical medicine, and sports technology.

Automated Flow Synthesis of Artificial Heme Enzymes for Enantiodivergent Biocatalysis.

The remarkable efficiency with which enzymes catalyze small-molecule reactions has driven their widespread application in organic chemistry. Here, we employ automated fast-flow solid-phase synthesis to access catalytically active full-length enzymes without restrictions on the number and structure of noncanonical amino acids incorporated. We demonstrate the total syntheses of iron-dependent myoglobin (BsMb) and sperm whale myoglobin (SwMb).

19S proteasome loss causes monopolar spindles through ubiquitin-independent KIF11 degradation.

To direct regulated protein degradation, the 26S proteasome recognizes ubiquitinated substrates through its 19S particle and then degrades them in the 20S enzymatic core. Despite this close interdependency between proteasome subunits, we demonstrate that knockouts from different proteasome subcomplexes result in distinct highly cellular phenotypes. In particular, depletion of 19S PSMD lid proteins, but not that of other proteasome subunits, prevents bipolar spindle assembly during mitosis, resulting in a mitotic arrest.

Unusual Phospholipids from Linked to Depression.

A multifactorial association study detected a probable causal connection between the prevalence of in the gut microbiome and the incidence of major depressive disorder (MDD) in the human host. A bioassay-guided fractionation approach identified bacterially produced metabolites that induced pro-inflammatory immune responses. The metabolites are unusual phospholipids that resemble conventional cardiolipins, in which diethanolamine (DEA) replaces the central glycerol.

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.

Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo.

Synthesis of Sulfonated Peptides Using a Trifluoromethyltoluene-Protected Amino Acid.

A scalable, seven step synthesis is reported for a trifluoromethyl toluene protected sulfonated phenylalanine building block whose utility was demonstrated in the synthesis of four CXCR4-derived sulfonopeptides. When compared to a conventional trichloroethyl protected building block, overall yield was improved by up to 4-fold. We believe this building block will prove to be of significant value for the synthesis of a variety of peptide targets containing phenylalanine sulfonate, a bioisostere of tyrosine sulfate, enabling orthogonal protection strategies and improving synthetic efficiency and yield.

Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions.

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of -anhydrides.

Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicases and .

The Y-linked gene and its X-linked homolog survived the evolution of the human sex chromosomes from ordinary autosomes. encodes a multifunctional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs, is extraordinarily dosage sensitive.

Oncogenic IDH1 drives robust loss of histone acetylation and increases chromatin heterogeneity.

Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype.

3D-Printable Elastomers for Real-Time Autonomous Self-Healing in Soft Devices.

Photocurable self-healing elastomers are promising candidates for producing complex soft devices that can mend damage. However, the practicality of these materials is limited by reliance on external stimuli, custom synthesis, manual realignment, and multihour healing cycles. This paper introduces a tough 3D-printable hybrid acrylate/thiol-ene elastomer (prepared with commercially available precursors) that exhibits nearly instantaneous damage repair in the absence of external stimuli.

Underscoring long-term host-microbiome interactions in a physiologically relevant gingival tissue model.

The human body houses many distinct and interconnecting microbial populations with long-lasting systemic effects, where the oral cavity serves as a pathogens' reservoir. The correlation of different disease states strongly supports the need to understand the interplay between the oral tissue niche and microbiome. Despite efforts, the recapitulation of gingival architecture and physiological characteristics of the periodontal niche has yet to be accomplished by traditional cultural strategies.

A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury.

Hyperammonemia is characterized by the accumulation of ammonia within the bloodstream upon liver injury. Left untreated, hyperammonemia contributes to conditions such as hepatic encephalopathy that have high rates of patient morbidity and mortality. Previous studies have identified gut bacterial urease, an enzyme that converts urea into ammonia, as a major contributor to systemic ammonia levels.

Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon.

LINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity is unclear. Here, we apply whole-genome sequencing to experimental models of L1 expression to comprehensively define the spectrum of genomic changes caused by L1.

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.

Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available.

Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator.

Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library.

Rational engineering of minimally immunogenic nucleases for gene therapy.

Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically relevant nucleases, SaCas9 and AsCas12a.

Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.

Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions.

Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.

Mechanisms of tandem duplication in the cancer genome.

Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.