Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature.

Toward a Radically Simple Multi-Modal Nasal Spray for Preventing Respiratory Infections.

Nasal sprays for pre-exposure prophylaxis against respiratory infections show limited protection (20-70%), largely due to their single mechanism of action-either neutralizing pathogens or blocking their entry at the nasal lining, and a failure to maximize the capture of respiratory droplets, allowing them to potentially rebound and reach deeper airways. This report introduces the Pathogen Capture and Neutralizing Spray (PCANS), which utilizes a multi-modal approach to enhance efficacy. PCANS coats the nasal cavity, capturing large respiratory droplets from the air, and serving as a physical barrier against a broad spectrum of viruses and bacteria, while rapidly neutralizing them with over 99.

Non-invasive Analysis of Fiber Type Composition in Lower Limb Skeletal Muscles Using Reduced Interference Rihaczek Distribution.

Fiber composition is an important factor influencing force generation and endurance of different skeletal muscles. The analysis of the heterogeneous composition of muscles has gained importance in the field of sports biomechanics and biomedicine. In this work, an attempt is made to analyze the fiber composition of Rectus femoris (type II dominant) and Soleus (type I dominant) muscles using surface electromyography.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP).

Exploring intermixed magnetic nanoparticles: insights from atomistic spin dynamics simulations.

Binary nanoparticles, composed of both rare-earth elements with substantial magnetic properties and transition metals known for their high magnetic ordering temperatures, hold great promise as innovative materials for novel magnetic applications. In this study, we employ an atomistic spin dynamics framework to investigate how the magnetic properties change at finite temperatures in mixed NiGd nanoparticles. We specifically examine parameters such as saturation magnetization and spin-reorientation in relation to the nanoparticle's size, which ranges from 4 nm to 16 nm, and composition.

Engineering Improved CAR T Cell Products with A Multi-Cytokine Particle Platform for Hematologic and Solid Tumors.

Despite the remarkable clinical efficacy of chimeric antigen receptor (CAR) T cells in hematological malignancies, only a subset of patients achieves a durable complete response (dCR). DCR has been correlated with CAR T cell products enriched with T cells memory phenotypes. Therefore, reagents that consistently promote memory phenotypes during the manufacturing of CAR T cells have the potential to significantly improve clinical outcomes.

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.

Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity.

The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the US Food and Drug Administration-approved bortezomib (BTZ) and carfilzomib (CFZ), are frequently used for the treatment of patients with MM. Nevertheless, a significant proportion of patients with MM are refractory or develop resistance to this class of inhibitors, which represents a significant challenge in the clinic.

Practices for running a research-oriented shared cryo-EM facility.

The Harvard Cryo-Electron Microscopy Center for Structural Biology, which was formed as a consortium between Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital, serves both academic and commercial users in the greater Harvard community. The facility strives to optimize research productivity while training users to become expert electron microscopists. These two tasks may be at odds and require careful balance to keep research projects moving forward while still allowing trainees to develop independence and expertise.

Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy.

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatment-refractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood.

Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma.

The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs).

The Peptide Methionine Sulfoxide Reductase (MsrAB) of Repairs Oxidatively Damaged Outer Membrane and Periplasmic Proteins Involved in Nutrient Acquisition and Virulence.

Sulfoxide-damage repair mechanisms are emerging as essential for the virulence of bacterial pathogens, and in the human respiratory pathogen the periplasmic MsrAB peptide methionine sulfoxide reductase is necessary for resistance to reactive chlorine species such as hypochlorite. Additionally, this enzyme has a role in modulating the host immune response to infection. Here, we have analysed the enzymatic properties of MsrAB, which revealed that both domains of the protein are catalytically active, with the turnover number of the MsrA domain being 50% greater than that for the MsrB domain.

Measuring Gene Expression via mRNA Abundance in Candida auris.

The recently emerged human pathogenic yeast Candida auris has become a major global threat. As compared to other Candida species, C. auris often displays a high level of resistance to commonly used antifungals and poses additional therapeutic challenges.

Stretchable nanofibers of polyvinylidenefluoride (PVDF)/thermoplastic polyurethane (TPU) nanocomposite to support piezoelectric response via mechanical elasticity.

Interest in piezoelectric nanocomposites has been vastly growing in the energy harvesting field. They are applied in wearable electronics, mechanical actuators, and electromechanical membranes. In this research work, nanocomposite membranes of different blend ratios from PVDF and TPU have been synthesized.

Caltech Conte Center, a multimodal data resource for exploring social cognition and decision-making.

This data release of 117 healthy community-dwelling adults provides multimodal high-quality neuroimaging and behavioral data for the investigation of brain-behavior relationships. We provide structural MRI, resting-state functional MRI, movie functional MRI, together with questionnaire-based and task-based psychological variables; many of the participants have multiple datasets from retesting over the course of several years. Our dataset is distinguished by utilizing open-source data formats and processing tools (BIDS, FreeSurfer, fMRIPrep, MRIQC), providing data that is thoroughly quality checked, preprocessed to various extents and available in multiple anatomical spaces.

Erratum: Generation and analysis of innovative genomically humanized knockin , (TDP-43), and mouse models.

[This corrects the article DOI: 10.1016/j.isci.

Use of biomass-derived biochar in wastewater treatment and power production: A promising solution for a sustainable environment.

Over the past few years, we are witnessing the advent of a revolutionary bioengineering technology in biochar production and its application in waste treatment and an important component in power generation devices. Biochar is a solid product, highly rich in carbon, whose adsorption properties are ideal for wastewater decontamination. Due to its high specific surface area to volume ratio, it can be utilized for many environmental applications.

Generation and analysis of innovative genomically humanized knockin , (TDP-43), and mouse models.

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation knockin mouse models, by replacing the mouse genomic region of , (TDP-43), and , with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing.

Sizing, stabilising, and cloning repeat-expansions for gene targeting constructs.

Aberrant microsatellite repeat-expansions at specific loci within the human genome cause several distinct, heritable, and predominantly neurological, disorders. Creating models for these diseases poses a challenge, due to the instability of such repeats in bacterial vectors, especially with large repeat expansions. Designing constructs for more precise genome engineering projects, such as engineering knock-in mice, proves a greater challenge still, since these unstable repeats require numerous cloning steps in order to introduce homology arms or selection cassettes.

Acoustic Energy Harvesting and Sensing via Electrospun PVDF Nanofiber Membrane.

This paper introduces a new usage of piezoelectric poly (vinylidene fluoride) (PVDF) electrospun nanofiber (NF) membrane as a sensing unit for acoustic signals. In this work, an NF mat has been used as a transducer to convert acoustic signals into electric voltage outcomes. The detected voltage has been analyzed as a function of both frequency and amplitude of the excitation acoustic signal.

Erratum: Fundamental Physics Implications for Higher-Curvature Theories from Binary Black Hole Signals in the LIGO-Virgo Catalog GWTC-1 [Phys. Rev. Lett. 123, 191101 (2019)].

This corrects the article DOI: 10.1103/PhysRevLett.123.