To the Editor A recent article on PICS provided an excellent synthesis of the cognitive and emotional difficulties experienced by ICU survivors.
Science Journals
Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP, and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS, and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to the Kelch domain and allosterically regulated three specific regions of KEAP1: L342-L355, D394-G423, and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin-coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo. Our hypothesis was further verified our hypothesis in Nrf2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g., aging, cancer, neurodegenerative, and cardiovascular diseases.
<p>by Hiroki Oishi, Vladimir K. Berezovskii, Margaret S. Livingstone, Kevin S. Weiner, Michael J. Arcaro</p>
Neural activity depends on energy metabolism, yet the extent to which regional variation in cortical metabolic architecture reflects the functional and perceptual demands of visual processing remains unclear. In the primate visual system, retinotopic eccentricity, the topographic mapping of visual space relative to gaze, provides a large-scale organizational axis along which spatial resolution and selectivity for behaviorally relevant visual categories vary systematically. Here, we tested whether cortical metabolic architecture reflects this axis by aligning in vivo fMRI maps of eccentricity and visual category selectivity with <i>ex vivo</i> cytochrome oxidase (CO) histology, a marker of oxidative metabolism, in macaque visual cortex. We found that the middle lateral (ML) face-selective region, which is biased toward central vision, exhibited higher CO intensity than the lateral place patch (LPP), a scene-selective region biased toward peripheral vision. More broadly, CO intensity covaried with eccentricity within both ML and LPP and across occipitotemporal visual cortex, though eccentricity only partially accounted for the elevated CO in ML. These findings reveal a close correspondence between cortical metabolic architecture and retinotopic organization, suggesting that the distribution of cortical metabolic resources is shaped by both visual field organization and the processing demands of perceptual specialization.
<p>by Marc de Manuel, Molly Przeworski, Natanael Spisak, Anastasia Stolyarova</p>
Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation burdens at the end of lifespans are comparable across mammals. These observations point to a key role for natural selection in shaping mutation rates. This Essay summarizes the patterns identified to date and outlines existing theories for how selection pressures might shape mutation rates in animal germline and soma. An understanding of what sets the mutation rate of a given cell type in a species requires better integration of genetics and development with population processes of selection and genetic drift.
The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions, including spatial attention. When it comes to oculomotor areas, such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while two rhesus macaque monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with pupil size and simultaneously recorded data in the prefrontal cortex (PFC), consistent with slow changes in the monkeys’ arousal levels while they were performing the task. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.
Animals respond to tactile stimulations of the body with location-appropriate behavior, such as aimed grooming. These responses are mediated by mechanosensory neurons distributed across the body, whose axons project into somatotopically organized brain regions corresponding to body location. How mechanosensory neurons interface with brain circuits to transform mechanical stimulations into location-appropriate behavior is unclear. We previously described the somatotopic organization of bristle mechanosensory neurons (BMNs) around the <i>Drosophila</i> head that elicit a sequence of location-aimed grooming movements (Eichler et al., 2024). Here, we use a serial section electron microscopy reconstruction of a full adult fly brain to identify nearly all of BMN pre- and postsynaptic partners uncovering circuit pathways that control head grooming. Postsynaptic partners dominate the connectome and are both excitatory and inhibitory. We identified an excitatory cholinergic hemilineage (hemilineage 23b), a developmentally related group of neurons that elicits aimed head grooming and exhibits differential connectivity with BMNs from distinct head locations, revealing a lineage-based somatotopically organized parallel circuit architecture. Presynaptic partners provide extensive BMN presynaptic inhibition, consistent with models of sensory gain control as a mechanism of suppressing grooming movements and controlling the sequence. This work provides the first comprehensive map of a somatotopically organized connectome, and reveals how this organization could shape grooming. It also reveals the mechanosensory interface with the brain, illuminating fundamental features of mechanosensory processing, including feedforward excitation and inhibition, feedback inhibition, somatotopic circuit organization, and developmental origins.
Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode <i>Caenorhabditis elegans</i> both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine-coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and <i>gar-3</i> mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.
With the continuous rise in antibiotic resistance, novel methods that can reveal currently unknown antibiotic resistance mechanisms are essential to prepare and inform health responses and novel antibiotic discovery campaigns. Here, we built a library of species representative of the genus <i>Mycobacterium</i> and determined their antibiotic resistance profiles, allowing for the first time systematic multispecies comparisons. Analyzing antibiotic resistance in the context of other closely related yet diverse organisms revealed species with truly exceptional traits as well as general principles underpinning antibiotic resistance. Among these, we reveal that intrabacterial accumulation of antibiotics does not correlate with their potency at the species level. Our data also reveals that rifamycin resistance in mycobacteria is dominantly caused by antibiotic modification, contrary to what has been observed in <i>Mycobacterium tuberculosis</i>. Our data provides a solid starting point for the exploration of novel determinants of antibiotic resistance. We illustrate the utility of this species-level approach to discovery of novel traits by characterizing a previously unrecognized rifamycin-inactivating enzyme group that is present in a wide range of bacterial genera.
Insulin degrading enzyme (IDE) is a dimeric M16A zinc metalloprotease that degrades amyloidogenic peptides diverse in shape and sequence, including insulin and amyloid-β, to prevent toxic amyloid fibril formation. IDE has a hollow catalytic chamber formed by two ~55 kDa N- and C- domains (IDE-N and IDE-C, respectively), in which peptides bind, unfold, and are repositioned for proteolysis. IDE is known to transition between a closed state, poised for catalysis, and an open state, able to release cleavage products and bind a new substrate. Here, we present six cryo-EM structures of the IDE dimer at 3.0–5.1 Å resolution, obtained in the presence of a sub-saturating concentration of insulin. Combining cryo-EM heterogeneity analysis with all-atom molecular dynamics (MD) simulations, we identified the structural basis and key residues for IDE conformational dynamics that were not previously revealed by IDE static structures. Notably, R668 serves as a molecular latch mediating the open-close transition and facilitates key protein motions through charge-swapping interactions at the IDE-N/C interface. Our small-angle X-ray scattering analysis and enzymatic assays of an R668A mutant indicate a profound alteration of conformational dynamics and catalytic activity. By integrating coarse-grained MD simulations, our analysis reveals that IDE unfolds its substrates through the coordinated motion between IDE-N and IDE-C, as well as β-sheet formation between IDE and insulin. Additionally, our time-resolved cryo-EM analysis uncovers IDE allostery within the IDE dimer. Collectively, our findings demonstrate the strength of combining experimental and computational approaches to probe protein dynamics and pave the way for developing substrate-specific modulators of IDE activity.
Bacteria precisely regulate the place and timing of their cell division. One of the best-understood systems for division site selection is the Min system in <i>Escherichia coli</i>. In <i>E. coli</i>, the Min system displays remarkable pole-to-pole oscillation, creating a time-averaged minimum at the cell’s geometric center, which marks the future division site. Interestingly, the Gram-positive model species <i>Bacillus subtilis</i> also encodes homologous proteins: the cell division inhibitor MinC and the Walker-ATPase MinD. However, <i>B. subtilis</i> lacks the activating protein MinE, which is essential for Min dynamics in <i>E. coli</i>. We have shown before that the <i>B. subtilis</i> Min system is highly dynamic and quickly relocalizes to active sites of division. This raised questions about how Min protein dynamics are regulated on a molecular level in <i>B. subtilis</i>. Here, we show with a combination of in vitro experiments and in vivo single-molecule imaging that the ATPase activity of <i>B. subtilis</i> MinD is activated by membrane binding. Additionally, both monomeric and dimeric MinD bind to the membrane, and binding of ATP to MinD is a prerequisite for fast membrane detachment. Single-molecule localization microscopy data confirm membrane binding of monomeric MinD variants. However, only wild-type MinD enriches at cell poles and sites of ongoing division, likely due to interaction with MinJ. Monomeric MinD variants and locked dimers remain distributed along the membrane and lack the characteristic pattern formation. Single-molecule tracking data further support that MinD has a freely diffusive population, which is increased in the monomeric variants and a membrane-binding defective mutant. Thus, MinD dynamics in <i>B. subtilis</i> under the tested conditions do not require any unknown protein component and can be fully explained by MinD’s binding and unbinding kinetics with the membrane. The spatial organization of MinD relies on the short-lived …
TFIIH is an essential transcription initiation factor for RNA polymerase II (RNApII). This multi-subunit complex comprises two modules that are physically linked in <i>Saccharomyces cerevisiae</i> by the subunit Tfb3 (MAT1 in metazoans). The Core Module, with two DNA-dependent ATPases and several additional subunits, promotes DNA unwinding. The Kinase Module phosphorylates the C-terminal domain (CTD) of RNApII subunit Rpb1, initiating a cycle of CTD modifications that coordinate the exchange of initiation and elongation factors. Why these two disparate activities are bundled into one factor is not obvious, but the connection may provide temporal coordination during early initiation. When Tfb3 is split into two parts to uncouple the TFIIH modules, the resulting cells are viable but grow very slowly. Chromatin immunoprecipitation of the split TFIIH shows that the Core Module, but not the Kinase, is properly recruited to promoters. Instead of the normal promoter-proximal peak, high CTD Serine 5 phosphorylation is seen throughout transcribed regions. Therefore, coupling the TFIIH modules is necessary to localize and limit CTD kinase activity to early stages of transcription. These results are consistent with the idea that the two TFIIH modules began as independent functional entities that later became connected by Tfb3 during early eukaryotic evolution.
<p>by Abul K. Tarafder, Miles Graham, Luke K. Davis, Shawna Pratt, Jan Böhning, Pavithra Manivannan, Zhexin Wang, Camila M. Clemente, Aaron Weimann, R. Andres Floto, Raymond J. Owens, George A. O’Toole, Philip Pearce, Tanmay A. M. Bharat</p>
All bacterial biofilms contain an extracellular matrix rich in filamentous molecules that self-associate, conferring emergent properties to bacteria, including antibiotic tolerance. <i>Pseudomonas aeruginosa</i> is a human pathogen that forms biofilms in diverse infectious settings, where the upregulation of a filamentous bacteriophage Pf4, has been shown to be a key virulence factor that protects bacteria from antibiotics. Here, we modeled biophysical characteristics of biofilm-linked liquid crystalline droplets formed by Pf4, which predicted that sub-stoichiometric phage binders had the ability to disrupt liquid crystals by changing the surface properties of the phage. We tested this prediction by developing nanobodies targeting the outer surface of the Pf4 phage, which disrupted in vitro reconstituted droplets, promoted antibiotic diffusion into bacteria, disrupted <i>P. aeruginosa</i> biofilm formation under a variety of conditions, and abolished antibiotic tolerance of biofilms. The inhibition strategy illustrated in this study could be extended to biofilms of other pathogenic bacteria, where filamentous molecules are pervasive in the extracellular matrix. Furthermore, our findings exemplify how targeting a biophysical mechanism, rather than a defined biochemical target, is a promising avenue for intervention, with the potential of applying this concept to other disease-related contexts.
Here, we review the history, advancements, and broad utility of the NTR/prodrug system, and suggest future strategies for developing versatile ablation models. As a chemogenetic tool, the nitroreductase (NTR)/prodrug system enables precise spatiotemporal control over cell ablation. The technology leverages bacterial NTR enzymes (e.g. <i>nfsB</i>) to convert inert prodrugs into cytotoxic agents, thereby allowing researchers to induce targeted cell death. Although the NTR/prodrug approach was first implemented in transgenic mice, it was subsequently adapted to zebrafish, where it has been extensively optimized and applied. Consequently, zebrafish remain the primary focus of this review. Nevertheless, the utility of the NTR/prodrug system has expanded to other important model organisms, including <i>Drosophila</i>, <i>Nematostella</i>, <i>Xenopus</i>, medaka, and rats, enabling detailed studies of tissue damage and regeneration. This review highlights how the NTR system has been deployed to model a spectrum of human diseases, including Parkinson’s disease, retinal degeneration, demyelinating disorders, and kidney disease. These models provide valuable platforms to study pathogenesis in vivo. Furthermore, the precise and controllable nature of NTR ablation makes it an ideal tool for high-throughput chemical and genetic screens aimed at discovering pro-regenerative and protective compounds. The development of NTR2.0, an enzyme variant with over 100-fold greater activity, along with more potent prodrugs such as ronidazole (RNZ), has dramatically broadened experimental possibilities. These improvements permit chronic ablation and long-term disease modeling at well-tolerated drug concentrations. Here, we present some key considerations, including transgenic design for optimal cell-type specificity, calibrating expression levels for desired ablation kinetics, and suitable controls to allow interpretation. These best practices will allow the researcher to develop a precise…
Functional brain network organisation, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, for example undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onwards. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5–24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3–5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the possible subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.
<p>by Federica Palma, Melanie Hennart, Keith A. Jolley, Chiara Crestani, Kelly L. Wyres, Sebastien Bridel, Corin A. Yeats, Bryan Brancotte, Brice Raffestin, Sophia David, Margaret M.C. Lam, Radosław Izdebski, Virginie Passet, Carla Rodrigues, Martin Rethoret-Pasty, Audrey Combary, Solene Cottis, Martin C.J. Maiden, David M. Aanensen, Kathryn E. Holt, Alexis Criscuolo, Sylvain Brisse</p>
Unified strain taxonomies are needed for the epidemiological surveillance of bacterial pathogens and international communication in microbiological research. Core genome multilocus sequence typing (cgMLST) holds great promise for standardized high-resolution strain genotyping. However, this approach faces challenges including classification instability and disconnection of new nomenclature from widely adopted classical MLST identifiers. This Essay discusses the cgMLST-based Life Identification Number (LIN) method, recently proposed as a stable multilevel strain taxonomy system applicable to most bacterial pathogens, covering how LIN codes are implemented and used in practice for precise strain definitions and epidemiological tracking.
<p>by Boris Taillefer, Florian Schattenberg, Thierry Doan, Susann Müller, Eric Cascales</p>
The type VI secretion system (T6SS) is a widespread nanoweapon deployed by bacteria to eliminate competitors in polymicrobial environments, allowing niche colonization or host invasion. Fluorescent microscopy recordings have shown that T6SS expression and/or activation is heterogeneous in clonal populations of many bacterial species. However, it is still unknown whether T6SS heterogeneity is genetically controlled or arises from stochastic processes and what its physiological relevance is. Here, we report that enteroaggregative <i>Escherichia coli</i> (EAEC) exhibits stable phenotypic heterogeneity in T6SS expression. Under iron-limiting conditions, the Sci1 T6SS is expressed in only a subset of the population, creating distinct ON and OFF subpopulations in a reversible, heritable, and epigenetically controlled equilibrium. This heterogeneity is governed by the interplay between the iron-responsive regulator Fur- and Dam-dependent DNA methylation at the <i>sci1</i> promoter. Mutations in Fur binding sites or GATC methylation motifs shift the population to homogeneous ON or OFF states, respectively. Functional analyses reveal that while ON cells mediate antibacterial activity, OFF cells buffer the population against lethal retaliatory responses from defensive T6SS⁺ competitors. Our results suggest that T6SS heterogeneity in EAEC represents a finely tuned attenuation strategy optimizing the trade-off between competitive killing and survival in hostile microbial communities. This work uncovers a novel layer of regulation in T6SS deployment and highlights phenotypic heterogeneity as an adaptive trait in interbacterial warfare.
Collagen is the most abundant protein in the human body and has an important role in healthy tissue as well as in a range of prevalent diseases. Medical research and diagnostics, hence, call for means of mapping collagen in vivo. Magnetic resonance imaging (MRI) is a natural candidate for this task, offering full 3D capability and versatile contrast non-invasively. However, collagen has so far been invisible to MRI due to extremely short lifetime of its resonances. Here, we report the direct imaging of collagen in vivo by magnetic resonance on the microsecond scale. The dynamics of resonance signals from collagen were first assessed in samples of bovine tendon and cortical bone. On this basis, imaging was performed at echo times down to 10 microseconds, yielding collagen-specific depiction by echo subtraction. The same approach was then extended for use in vivo, enabling direct collagen imaging of a human forearm. This capability suggests significant promise for biomedical science and clinical use.
Pseudouridine (Ψ) modifications are the most abundant RNA modifications; however, their distribution and functional significance in bacteria remain largely unexplored compared to eukaryotic systems. In this study, we present the first transcriptome-wide and quantitative mapping of Ψ modifications across five diverse bacterial species (<i>Bacillus cereus</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Pseudomonas aeruginosa</i>, and <i>Pseudomonas syringae</i>) at single-base resolution, utilizing the optimized baBID-seq method for bacterial RNA. Our analysis revealed growth phase-dependent dynamics of pseudouridylation in bacterial tRNA and mRNA, particularly in genes enriched in core metabolic pathways. Comparative analysis demonstrated evolutionarily conserved features of Ψ modifications, such as dominant motif contexts, Ψ clustering within operons, etc. Functional analysis indicated Ψ modifications affect bacterial mRNA stability, translation, and interactions with specific RNA-binding proteins in response to changing cellular demands during growth phase transitions. The integrated computational analysis on local RNA architecture was conducted to elucidate the structure-dependent Ψ modifications in bacterial RNA. Furthermore, we developed an integrated deep learning framework, combining LSTM-transformer-GNN-based neural networks (pseU_NN) to capture both RNA sequence and local structure features for effective prediction of Ψ-modified sites. Overall, our study provides valuable insights into the landscapes of bacterial RNA Ψ modifications and establishes a foundation for future mechanistic investigations on bacterial Ψ functions.
<p>by Lucas M. Bietti, Adrian Bangerter</p>
Artificial intelligence (AI) is rapidly transforming scientific writing by expanding access and efficiency, yet it risks decoupling writing from thinking. Scientific writing is a core cognitive and epistemic practice that must be cultivated and preserved alongside AI use.
The use of large language models is rapidly transforming the scientific writing process, making it quicker and easier to write research papers. However, this Perspective urges caution when using such tools, arguing that it can risk decoupling writing from thinking.
Sequence and structure comparisons between alpha and beta connexins, Cx43 and Cx26, revealed that Cx43 has a motif, the carbamylation motif, that confers CO<sub>2</sub>-sensitivity on a subset of beta connexins. By using a fluorescent dye loading assay, whole cell patch clamp recordings and real-time measurement of ATP release via GRAB<sub>ATP</sub>, we have demonstrated that Cx43 hemichannels open in a highly CO<sub>2</sub>-sensitive manner over the range 20–70 mmHg. Mutational analysis confirms that the equivalent residues to those in Cx26, known to be involved in mediating the effects of CO<sub>2</sub> on gating of hemichannels and gap junction channels, also mediate Cx43 hemichannel gating. These data predict that Cx43 will be partially open at resting physiological levels of PCO<sub>2</sub>. In acute mouse hippocampal slices, we have demonstrated a CO<sub>2</sub>-dependent enhancement of synaptic transmission that was blocked by the Cx43-selective mimetic peptide Gap26. Our data resolves an inconsistency in the literature between in vivo studies suggesting that Cx43 hemichannels are at least partially open at rest and in vitro studies performed in the absence of HCO<sub>3</sub><sup>-</sup>/CO<sub>2</sub> buffering that show Cx43 hemichannels are shut.
Cholesterol homeostasis is fundamental to cellular function, and its disruption underlies a wide range of human diseases. However, the contribution of cholesterol biosynthesis to auditory physiology remains poorly understood. HSD17B7 (17β-Hydroxysteroid dehydrogenase type 7) catalyzes the conversion of zymosterone to zymosterol, a key step in the post-lanosterol cholesterol biosynthetic pathway. Here, we found that Hsd17b7 is highly enriched in sensory hair cells of zebrafish and mice. The deficiency of Hsd17b7 reduced intracellular cholesterol levels in HEI-OC1 cells and zebrafish hair cells, thereby compromising MET and acoustic startle responses. A heterozygous nonsense variant (c.544G>T; p.E182*) in <i>HSD17B7</i> was identified in an individual with bilateral profound hearing loss. mRNA of c.544G>T HSD17B7 failed to rescue the impaired MET and acoustic startle response of hsd17b7 mutants. Mechanistically, the mutation decreases mRNA abundance and significantly reduces protein. Moreover, expression of the p.E182* mutation disrupted the interaction between HSD17B7 and the ER retention receptor RER1, leading to aberrant subcellular localization and altered cholesterol distribution, thereby exacerbating HC dysfunction. Together, our findings suggest a conserved and essential role for HSD17B7-mediated cholesterol biosynthesis in sensory hair cell function and identify HSD17B7 as a candidate gene for sensorineural hearing loss.
<p>by Fuxi Rong, Yaqi Zhang, Fangrui Ni, Lantian Zhang, Mingxin Yu, Zheyuan Hong, Muhammad Fahad, Yuxin Shen, Chuanjia Liu, Shengke Tian, Dezhi Wu, Liang Wu</p>
In plants, a subset of miRNA precursors can yield multiple mature miRNAs; however, how they simultaneously regulate a single biological process remains poorly understood. Cadmium (Cd) is a non-essential heavy metal toxic to plants, posing serious risks to human health via the food chain. As rice is a major dietary source of Cd, elucidating the molecular mechanisms underlying Cd accumulation is crucial for ensuring food safety. Here, we show that a pair of miRNAs derived from the <i>MIR408</i> precursor cooperatively represses Cd uptake in roots by targeting distinct genes, consequently reducing Cd accumulation in rice grains. miR408-5p inhibits translation of <i>Heavy metal-associated Isoprenylated Plant Protein 9</i> (<i>HIPP19</i>), which is specifically expressed in exodermis and endodermis cells and facilitates Cd binding. Meanwhile, miR408-3p cleaves <i>Uclacyanin 7</i> (<i>UCL7</i>) mRNA, leading to enhance the activity of superoxide dismutases (SODs), and increase production of reactive oxygen species (ROS), particularly hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), which in turn suppresses Cd absorption and accumulation. Furthermore, knockout mutants of <i>HIPP19</i> and <i>UCL7</i>, as well as <i>MIR408</i> overexpressing lines, exhibit significantly decreased Cd content in grains, while the accumulation of other essential metals remains comparable to that of wild-type plants. These findings establish a promising strategy for producing “low-Cd rice” without compromising agronomic traits for food safety.
When I doctor sometimes I read about psychedelics and long to dissolve the boundaries of self when I palpate a pulse first my patient’s then the faint rhythm in my own fingertips and, just briefly, let them play one music indecipherable
The study evaluated whether adjunctive intra-arterial alteplase given after successful thrombectomy improves functional recovery and tissue perfusion in patients with acute ischemic stroke caused by large vessel occlusion.
Kratom use in the US has increased significantly over the past decade, as have severe medical outcomes, a study published in Addiction found.