Browse Articles

Increased antioxidative defense and reduced advanced glycation end-product formation by metabolic adaptation in non-small-cell-lung-cancer patients

Abstract Reactive oxygen species can oxidatively modify enzymes to reroute metabolism according to tumor needs, rendering identification of oxidized proteins important for understanding neoplastic survival mechanisms. Thiol groups are most susceptible to oxidative modifications but challenging to analyze in clinical settings. We here describe the protein and small-molecular thiol oxidation landscape of 70 human lung tumors (and their paired healthy counter parts) and demonstrate that cancer adapts metabolism to increase glutathione synthesis to counteract oxidative stress. Glyoxalases, the key enzymes in the detoxification of methylglyoxal, a byproduct of glycolysis and precursor of advanced glycation end-products, are compromised by oxidation and downregulation. Despite decreased methylglyoxal detoxification capacity, cancers do not accumulate advanced glycation end-products. Since in vitro downregulation or inhibition of GAPDH upregulates glyoxalases, we propose that tumors reduce methylglyoxal by activating GAPDH.

Diversity and bioprospecting activities of endophytic Fungi associated with different Egyptian medicinal plants

Abstract The use of medicinal plants in marginal communities was for the treatment of various ailments for centuries. Nevertheless, the potential of endophytic fungi (EF) associated with bioprospecting medicinal plants remains understudied. Research on the diversity of EF associated with various Egyptian medicinal plants remains limited. Therefore, our study conducted an analysis and comparison of the colonization frequency (CF), richness, and diversity indices of EF communities that inhabit nine different medicinal plants located in two different areas: the Protected Area of Wadi Degla in Maadi and the Natural Cultivated Area in Helwan, Egypt. These plants were Agathophora alopecuroides, Anabasis setifera, Atriplex halimus, Halocnemum strobitaceum, Lantana camara, Mesembryanthemum forsskaollii, Raphanus raphanistrum, Suaeda vermiculata, and Zygophyllum coccineum. Also, the antimicrobial and antioxidant potential of isolated EF has been investigated. A total of 39 morphospecies EF were isolated and identified, belonging to fifteen genera. Aspergillus spp. and Penicillium spp. were the dominant genera identified in the selected plants. A. setifera and S. vermiculata plants had the highest numbers of EF isolates, followed by M. forsskaollii and R. raphanistrum. Furthermore, these plants had a significant diversity index and species richness compared to other plants investigated. The most predominant EF was Aspergillus sp.3, which had the highest occurrence rate. Among all EF ethyl acetate extracts (EAEs), Aspergillus sp.3 demonstrated the highest antimicrobial activities against different human pathogenic bacteria, yeasts, and fungi. Furthermore, it showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity. Therefore, this isolate was reidentified molecularly as Aspergillus terreus AUMC16223 with accession number PP491988. Moreover, EAE of A. terreus endophyte showed cytotoxicity potential activity with the significant IC50 value of 41.75 ± 1.83 µg/mL for the human lung carcinoma cell line (A549) and a nontoxic effect on the normal cell line (WI 38) with the significant CC50 value of 196.2 ± 3.74 µg/mL. Our results indicated diverse EF communities associated with different Egyptian medicinal plants, showing A. terreus endophyte extract as the most significant antimicrobial, antioxidant, and cytotoxic agent.

Rhomboid-mediated cleavage of the immune receptor XA21 protects grain set and male fertility in rice

To maintain growth and to successfully reproduce, organisms must protect key functions in specific tissues, particularly when countering pathogen invasion using internal defensive proteins that may disrupt their own developmental processes. The rice immune receptor XA21 confers race-specific resistance against Xanthomonas oryzae pv. oryzae , which causes the deadly disease bacterial leaf blight. Here, we demonstrate that XA21 is cleaved by the rhomboid-like protease OsRBL3b, likely within its transmembrane domain. OsRBL3b mRNA transcripts are preferentially expressed in rice spikelets. Rice plants expressing Xa21 but lacking a functional OsRBL3b displayed impaired anther dehiscence and pollen viability, resulting in male sterility and yield reduction with high levels of XA21 protein present in spikelets during anthesis. In leaves, osrbl3b mutants expressing XA21 had normal levels of this resistance protein and disease immunity. This balance between reproduction and disease resistance through the specific expression of a rhomboid protease may be key to limiting the detrimental effects of an active immune response and may be useful in future for genetic improvement of crops.

Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis

Abstract In adult mammals, hematopoietic stem/progenitor cells reside in the bone marrow, in a specialized microenvironment called a “niche”, which is composed of different cell types, including nerves. Although it is established that sympathetic nerves regulate hematopoiesis, little is known about the role of neural serotonin in bone marrow. The Drosophila hematopoietic organ, the lymph gland, is aligned along the aorta, which corresponds to the vascular niche. Here, we report that serotonin signaling in the vascular niche regulates the hematopoietic response to an immune challenge. The serotonin receptor 1B expressed in vascular niche cells, together with serotonin produced by neurons regulate the degradation of the extracellular matrix of the lymph gland and prevent its premature dispersal after an immune challenge. Serotonin signaling in aorta cells acts via JAK/STAT pathway activation. Our results provide novel insights into how vascular niche cells integrate neural information to regulate lymph gland immune stress hematopoiesis.

Development and validation of a risk prediction model for kinesiophobia in postoperative lung cancer patients: an interpretable machine learning algorithm study

Label-free high-throughput live-cell sorting of genome-wide random mutagenesis libraries for metabolic traits by Raman flow cytometry

A full spontaneous single-cell Raman spectrum captures the metabolic phenome in a label-free and noninvasive manner. However, Raman-activated cell sorting (RACS) of rare target cells from highly heterogeneous systems has remained largely conceptual. Here, we present a positive dielectrophoresis-induced deterministic lateral displacement (pDEP-DLD)-based RACS (pDEP-DLD-RACS), in which a modulated pDEP-DLD force is applied to focus, trap, and functionally sort fast-moving single cells in a wide channel. For pigment- and oil-producing yeasts, pDEP-DLD-RACS shows high sorting accuracy (>90%), high throughput (~600 events min −1 ), high yield (>85%), and long stable running time (~10 h), and can sort rare cells while preserving full cellular vitality. Moreover, label-free sorting directly from a genome-wide random mutagenesis library with >10 5 Aurantiochytrium sp. Mutants, based on intracellular docosahexaenoic acid (DHA) content, produces mutant cells with 58% higher DHA productivity in just two RACS runs over two days, representing two-orders-of-magnitude higher time- and cost-efficiency than conventional approaches. This superior trait arises from global remolding of transcriptomes, including enhanced carbon metabolism, reduced intracellular NADPH synthesis rates, and increased triacylglycerol (TAG) synthesis. By enabling direct screening of metabolic traits from genome-wide mutagenesis libraries, pDEP-DLD-RACS is a powerful platform for synthetic biology.

Sex-specific lipidomic signatures in aortic valve disease reflect differential fibro-calcific progression

Abstract Fibro-calcific aortic valve disease (FCAVD) is the most common valvular heart disease manifesting in pathological remodeling of the aortic valve (AV) leaflets, ultimately leading to aortic stenosis. Although dyslipidemia is a driver of FCAVD pathogenesis, the precise lipidome-wide changes underlying AV fibrosis and calcification remain largely unknown. Here, we performed deep quantitative lipidomics to profile the metabolic trajectories in human tricuspid and bicuspid AVs, and found stage-dependent extrinsic and intrinsic lipid trends. Furthermore, lipids derived from infiltrating lipoproteins are further metabolized within the AV. Intrinsic lipid remodeling suggested tissue degeneration with a loss of phosphatidylserines. Surprisingly, male and female patients showed markedly different lipid signatures of FCAVD progression, with female patients accumulating significantly higher levels of sphingomyelins and ceramides. The high extent of sexual dimorphism in the valve lipidome strongly suggests that tailored approaches should be undertaken to enhance mechanistic insight and to facilitate pharmacological intervention for FCAVD.

The relationship between physical activity and college students’ sense of security: the chain-mediated role of self-esteem and psychological capital

Transcription-templated assembly of the nucleolus in the <i>Caenorhabditis elegans</i> embryo

The nucleolus is a multicomponent structure made of RNA and proteins that serves as the site of ribosome biogenesis within the nucleus. It has been extensively studied as a prototype of a biomolecular condensate whose assembly is driven by phase separation. While the steady-state size of the nucleolus is quantitatively accounted for by the thermodynamics of phase separation, we show that experimental measurements of the assembly dynamics are inconsistent with a simple model of a phase-separating system relaxing to its equilibrium state. Instead, we show that the dynamics are well described by a model in which the transcription of ribosomal RNA actively drives nucleolar assembly. We find that our model of active transcription-templated assembly quantitatively accounts for the rapid kinetics observed in early embryos at different developmental stages, and for different RNA interference (RNAi) perturbations of embryo size. Our model predicts a scaling of the time to assembly with the volume of the nucleus to the one-third power, which is confirmed by experimental data. Our study highlights the role of active processes such as transcription in controlling the placement and timing of assembly of membraneless organelles.

Brillouin-induced Kerr frequency comb in normal dispersion fiber Fabry Perot resonators

Optimizing shared decision-making for risk-reducing mastectomy in women with Li–Fraumeni syndrome using patient-reported outcome measures

Proofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation

T cells display the remarkable ability to detect single foreign peptides displayed on target cells, while ignoring highly abundant self-peptides. This selectivity has been explained by kinetic proofreading in the T cell receptor (TCR) signaling pathway, which prevents responses to short-lived binding events regardless of their abundance. However, the biochemical mechanisms that drive kinetic proofreading have remained unclear. Here, using computational modeling, we show that these key signaling properties of the TCR pathway can emerge from the dynamics of linker for activation of T cells (LAT) phosphorylation, diffusion, and condensation following TCR–peptide major histocompatibility complex (pMHC) binding. In this model, time delays in LAT condensate nucleation underlie kinetic proofreading, enabling selective signaling responses to high-affinity pMHC ligands. The cooperativity in the nucleation and growth of LAT condensates also provides a mechanism to amplify weak signals from single high-affinity peptides and for condensates to grow with increasing antigen numbers. In contrast to other models, condensate-nucleation proofreading predicts a dependence of signal strength on pMHC spacing at fixed number, a prediction we validated experimentally using a protein scaffold to present pMHCs at defined intervals. Our results suggest that nucleation-condensation proofreading underlies the remarkable antigen detection capabilities of the TCR signaling pathway.

Observations of the seiche that shook the world

Abstract On September 16th, 2023, an anomalous 10.88 mHz seismic signal was observed globally, persisting for 9 days. One month later an identical signal appeared, lasting for another week. Several studies have theorized that these signals were produced by seiches which formed after two landslide-generated mega-tsunamis in an East Greenland fjord. This theory is supported by seismic inversions, and analytical and numerical modeling, but no direct observations have been made. Here, we present primary observations of this phenomenon using data from the Surface Water Ocean Topography mission. By ruling out other oceanographic processes, we validate the seiche theory of previous authors and independently estimate its initial amplitude at 7.9 m using Bayesian machine learning and seismic data. This study demonstrates the value of satellite altimetry for studying fast oceanic processes and extreme events, while also highlighting the need for specialized methods to address the altimetric data’s limitations, namely temporal sparsity. These data and approaches will help in understanding future unseen extremes driven by climate change.

Chromosome-scale genome assembly and annotation of two geographically distinct strains of malaria vector Anopheles albimanus

Abstract Anopheles albimanus is one of the principal malaria vectors in the Americas and exhibits phenotypic variation across its geographic distribution. High-quality reference genomes from geographically distant populations are essential to deepen our understanding of the biology, evolution, and genetic variation of this important malaria vector. In this study, we applied long-read PacBio and short-read Illumina sequencing technologies to assemble the complete genomes of two reference strains of An. albimanus, Stecla (originating from El Salvador), and Cartagena (originating from Colombia); and investigated the structural features of these genomes, including gene content, transposable elements (TEs), genetic variation, and structural rearrangements. Our hybrid assembly approach generated reference-quality genomes for each strain and recovered ~ 96% of the expected genome size. The genome assemblies of Stecla and Cartagena consisted of 109 and 149 scaffolds, with estimated genome sizes of 167.5 Mbp (N50 = 88 Mbp) and 167.1 Mbp (N50 = 87 Mbp), respectively. They exhibited a high level of completeness and contained a smaller number of gaps and ambiguous bases than either of the two previously published reference genomes for this species, suggesting a considerable improvement in the quality and completeness of the assemblies. A total of 12,082 and 12,120 protein-coding genes were predicted in Stecla and Cartagena, respectively. TE analyses indicated more repetitive content was captured in the long read assemblies. The assembled genomes shared 98.12% pairwise identity and synteny analyses suggested that gene position was conserved between both strains. These newly assembled genomes will serve as an important resource for future research in comparative genomics, proteomics, epigenetics, transcriptomics, and functional analysis of this important malaria vector.

Phage-induced protection against lethal bacterial reinfection

Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, providing almost complete protection against a second lethal infection for animals treated with phage therapy. The activity also reduced infection burden an astounding billion-fold over the control. Reinfection protection requires phage lytic killing of its target bacterium but is independent of additional phage therapy. The effect is not driven by phage alone, lingering phage resistors, or a sublethal inoculum. In vitro phage-lysed bacteria provide partial protection, suggesting a combination of phage-induced lytic activity and immune stimulation by phage treatment is responsible for the effect. These observations imply certain phages may induce host adaptive responses following the lysis of the infecting bacteria. This work suggests phage therapy may contain a dual-action effect, an initial treatment efficacy followed by a long-term protection against reoccurring infection, a therapeutic-vaccination mechanism of action.

High resolution assessment of air quality and health in Europe under different climate mitigation scenarios

Experimental study of folded metal mesh for efficient fog harvesting

Three dimensional multiscalar neurovascular nephron connectivity map of the human kidney across the lifespan

Forage maize type influences on methane emissions, nutrient degradation, and fermentation profiles in ruminants

Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency

Bispecific T cell engagers (TcEs) link T cell receptors to tumor-associated antigens on cancer cells, forming cytotoxic immunological synapses (IS). Close membrane-to-membrane contact (≤13 nm) has been proposed as a key mechanism of TcE function. To investigate this and identify potential additional mechanisms, we compared four immunoglobulin G1-based (IgG1) TcE Formats (A–D) targeting CD3ε and Her2, designed to create varying intermembrane distances (A &lt; B &lt; C &lt; D). Small-angle X-ray scattering (SAXS) and modeling of the conformational states of isolated TcEs and TcE–antigen complexes predicted close contacts (≤13 nm) for Formats A and B and far contacts (≥18 nm) for Formats C and D. In supported lipid bilayer (SLB) model interfaces, Formats A and B recruited, whereas Formats C and D repelled, CD2–CD58 interactions. Formats A and B also excluded bulky Quantum dots more effectively. SAXS also revealed that TcE–antigen complexes formed by Formats A and C were less flexible than complexes formed by Formats B and D. Functional data with Her2-expressing tumor cells showed cytotoxicity, surface marker expression, and cytokine release following the order A &gt; B = C &gt; D. In a minimal system for IS formation on SLBs, TcE performance followed the trend A = B = C &gt; D. Addition of close contact requiring CD58 costimulation revealed phospholipase C-γ activation matching cytotoxicity with A &gt; B = C &gt; D. Our findings suggest that when adhesion is equivalent, TcE potency is determined by two parameters: contact distance and flexibility. Both the close/far-contact formation axis and the low/high flexibility axis significantly impact TcE potency, explaining the similar potency of Format B (close contact/high flexibility) and C (far contact/low flexibility).