Browse Articles

Explainable machine learning framework for biomarker discovery by combining biological age and frailty prediction

Receptor kinase pathway signal tuning through a nontranscriptional incoherent feedforward loop

Cellular signaling processes can elicit powerful responses and may need to be amplified to be efficient or dampened to prevent overstimulation. Therefore, they often involve autoregulatory feedbacks. Receptor kinase signaling pathways are abundant in plants, where they convey the presence of both exogenous and endogenous ligands. Among them, endogenous CLAVATA3/EMBRYO SURROUNDING REGION (CLE) peptide signaling acts in an inherently quantitative manner to determine the size of stem cell pools and direct tissue formation. The plant-specific MEMBRANE-ASSOCIATED KINASE REGULATOR (MAKR) family proteins act downstream of receptor kinases. Among the seven family members in Arabidopsis ( Arabidopsis thaliana ), MAKR5 conveys CLE45 signaling downstream of the receptor kinase BARELY ANY MERISTEM 3 (BAM3). Here, we show that the distinct MAKR5 mode of action can only be fully mimicked by MAKR3, suggesting functional diversification of MAKR proteins. Moreover, we find that CLE45-stimulated and BAM3-dependent MAKR5 recruitment to the plasma membrane can be triggered independent of receptor-like cytoplasmic kinases that act downstream of BAM3 and depends on membrane charge. The CLE45-BAM3-triggered enhancement of MAKR5 production and plasma membrane association is mediated by autoregulatory feedback on MAKR5 mRNA translation, for which the 5′ UTR is required. At the same time, this signal amplification is dampened through CLE45-stimulated MAKR5 phosphorylation, which inactivates MAKR5, enhances its turnover, and impinges on MAKR5 mRNA levels. In summary, our results reveal a nontranscriptional incoherent feedforward loop in which receptor kinase signaling is amplified via ligand-triggered translation of a signal enhancer’s mRNA yet also balanced via ligand-triggered inactivation of the signal enhancer protein.

Soil organic carbon stabilization is influenced by microbial diversity and temperature

Pulse timing dominates binaural hearing with cochlear implants

Although cochlear implants (CIs) provide valuable auditory information to more than one million profoundly deaf patients, these devices remain inadequate in conveying fine timing cues. Early deaf patients in particular struggle to use interaural time differences (ITDs) for spatial hearing and auditory scene analysis. Why CI patients experience these limitations remains controversial. One possible explanation, which we investigate here, is that the stimulation by clinical CIs is inappropriate, as it encodes temporal features of sounds only in the envelope of electrical pulse trains, not the pulse timing. We have recently demonstrated that early deaf, adult implanted rats fitted with bilateral CIs that deliver carefully timed pulses routinely develop sensitivity to very small ITDs. Here we show that, while the early deafened mammalian auditory pathway can innately easily resolve pulse timing ITDs as small as 80 µs, it is many times less sensitive to the ITDs of pulse train envelopes. Our results indicate that the stimulation strategies in current clinical use do not present ITD cues in a manner that the inexperienced auditory pathway is highly sensitive to. This may deprive early deaf CI patients of the opportunity to hone their submillisecond temporal processing skills as they learn to hear through their prosthetic devices.

Light brightened aggregates extracted from by-products of kaolin raw material classification processes, used to reduce urban heat islands

RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis

Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Artificial intelligence real-time automated recognition of the gastric antrum cross-sectional area and motility rhythm via bedside ultrasound: a pilot study

Cryo-EM structure of the conjugation H-pilus reveals the cyclic nature of the TrhA pilin

Conjugation, the major driver of the spread of antimicrobial resistance genes, relies on a conjugation pilus for DNA transfer. Conjugative pili, such as the F-pilus, are dynamic tubular structures, composed of a polymerized pilin, that mediate the initial donor–recipient interactions, a process known as mating pair formation (MPF). IncH are low-copy-number plasmids, traditionally considered broad host range, which are found in bacteria infecting both humans and animals. The reference IncHI1 plasmid R27, isolated from Salmonella enterica serovar Typhi, encodes the conjugative H-pilus subunit TrhA containing 74 residues after cleavage of the signal sequence. Here, we show that the H-pilus forms long filamentous structures that mediate MPF and describe its cryoelectron-microscopic (cryo-EM) structure at 2.2 Å resolution. Like the F pilus, the H-pilin subunits form helical assemblies with phospholipid molecules at a stoichiometric ratio of 1:1. While there were previous reports that the T-pilus from Agrobacterium tumefaciens was composed of cyclic subunits, three recent cryo-EM structures of the T-pilus found no such cyclization. Here, we report that the H-pilin is cyclic, with a covalent bond connecting the peptide backbone between the N and C termini. Both the cryo-EM map and mass spectrometry revealed cleavage of the last five residues of the pilin, followed by cyclization via condensation of the amine and carboxyl residues. Mutagenesis experiments revealed that loss of cyclization abolished pilus biogenesis and efficient plasmid transfer. The cyclic nature of the pilin could stabilize the pilus and may explain the high incidence of IncH plasmid dissemination.

An IPv6 target generation approach based on address space forest

Intussusceptive angiogenesis-on-a-chip: Evidence for transluminal vascular bridging by endothelial delamination

Intussusceptive angiogenesis is an increasingly recognized vessel duplication process that generates and reshapes microvascular beds. However, the mechanism by which a vessel splits into two is poorly understood. Particularly vexing is formation of the hallmark transluminal endothelial cell bridge. How an endothelial cell comes to cross a flowing lumen rather than line it is enigmatic. To elucidate this, we used a microvessel-on-a-chip strategy, creating a microconduit coherently lined with flow-sensitive endothelial cells but in which transluminal bridges also formed. Bridge morphologies ranged from filamentous strand to multicellular columns with a central extracellular matrix-containing core. These bridge architectures were found to recapitulate those in microvessels in embryos, tumors, diseased organs, and the dermis of patients with limb-threatening ischemia. Time-lapse, multiplane, three-dimensional (3D) microscopy of the microphysiologic conduit revealed that bridges arose from endothelial cells oriented orthogonal to flow that partially released from the wall while retaining attachments at the ends. This delamination process was blocked by hyperactivation of Rho and augmented by interventions that weaken cell–substrate interactions, including inhibiting nonmuscle myosin II and blocking α5ß1 integrin. Thus, endothelial cells can leave their monolayer and transect a flowing lumen through controlled delamination. This previously unrecognized lumen entry program could explain the launch of intussusceptive angiogenesis and opens a framework for intervening.

ACE inhibitory casein peptide lowers blood pressure and reshapes gut microbiota in a randomized double blind placebo controlled trial

Dynamic coexistence driven by physiological transitions in microbial communities

Microbial ecosystems are commonly modeled by fixed interactions between species in steady exponential growth states. However, microbes in exponential growth often modify their environments so strongly that they are forced out of the growth state into stressed, nongrowing states. Such dynamics are typical of ecological succession in nature and serial-dilution cycles in the laboratory. Here, we introduce a phenomenological model, the Community State Model, to gain insight into the dynamic coexistence of microbes due to changes in their physiological states during cyclic succession. Our model specifies the growth preference of each species along a global ecological coordinate, taken to be the biomass density of the community, but is otherwise agnostic to specific interactions (e.g., nutrient starvation, stress, aggregation), in order to focus on self-consistency conditions on combinations of physiological states, “community states,” in a stable ecosystem. We identify three key features of such dynamical communities that contrast starkly with steady-state communities: enhanced community stability through staggered dominance of different species in different community states, increased tolerance of community diversity to fast growing species dominating distinct community states, and increased requirement of growth dominance by late-growing species. These features, derived explicitly for simplified models, are proposed here as principles aiding the understanding of complex dynamical communities. Our model shifts the focus of ecosystem dynamics from bottom–up studies based on fixed, idealized interspecies interaction to top–down studies based on accessible macroscopic observables such as growth rates and total biomass density, enabling quantitative examination of community-wide characteristics.

Evaluation of a near infrared spectroscopy based method for the estimation of substance P in saliva of patients with COPD

Active control of mitochondrial network morphology by metabolism-driven redox state

Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)—through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.

High precision control moment gyroscope fault diagnosis via joint attention mechanism

Inhibitory control explains locomotor statistics in walking <i>Drosophila</i>

In order to forage for food, many animals regulate not only specific limb movements but the statistics of locomotor behavior, switching between long-range dispersal and local search depending on resource availability. How premotor circuits regulate locomotor statistics is not clear. Here, we analyze and model locomotor statistics and their modulation by attractive food odor in walking Drosophila . Food odor evokes three motor regimes in flies: baseline walking, upwind running during odor, and search behavior following odor loss. During search, we find that flies adopt higher angular velocities and slower ground speeds and turn for longer periods in the same direction. We further find that flies adopt periods of different mean ground speed and that these state changes influence the length of odor-evoked runs. We next developed a simple model of neural locomotor control that suggests that contralateral inhibition plays a key role in regulating the statistical features of locomotion. As the fly connectome predicts decussating inhibitory neurons in the premotor lateral accessory lobe (LAL), we gained genetic access to a subset of these neurons and tested their effects on behavior. We identified one population whose activation induces all three signature of local search and that regulates angular velocity at odor offset. We identified a second population, including a single LAL neuron pair, that bidirectionally regulates ground speed. Together, our work develops a biologically plausible computational architecture that captures the statistical features of fly locomotion across behavioral states and identifies neural substrates of these computations.

Comparison of bariatric surgery and community weight management for idiopathic intracranial hypertension in a multicenter retrospective cohort study

Abstract Idiopathic Intracranial Hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure without definitive etiology, primarily affecting young, obese women. This study aimed to compare the efficacy of bariatric surgery versus conventional community weight management in treating IIH. We conducted a retrospective cohort study in IIH patients undergoing bariatric procedures versus conventional weight loss interventions. Propensity score matching was employed to balance study groups. Outcomes were assessed at 3, 6, 12, and 24 months, including papilledema, headache, visual symptoms, and therapeutic interventions. Bariatric surgery demonstrated superior outcomes compared to community weight management. Papilledema incidence was consistently lower in the bariatric group (RR = 0.591 at 24 months, p = 0.0001). Headache prevalence and visual symptoms were also reduced in the surgical group. Acetazolamide dose was lower in bariatric patients, starting at 12 and 24 months. Subgroup analysis of different bariatric procedures showed comparable efficacy. Body mass index reduction was significantly greater in the bariatric group throughout the follow-up period. This study provides evidence supporting the efficacy of bariatric surgery in managing IIH, with superior outcomes across multiple parameters compared to conventional weight management. The sustained improvements in papilledema, headache, and visual symptoms, coupled with for the reduction in pharmacological intervention dose, suggest that bariatric surgery may offer a more definitive solution for IIH patients with concurrent obesity. Further research is needed to develop evidence-based guidelines for patient selection and optimize post-operative care protocols.

Verapamil and its metabolite norverapamil inhibit the <i>Mycobacterium tuberculosis</i> MmpS5L5 efflux pump to increase bedaquiline activity

Bedaquiline is the cornerstone of a new regimen for the treatment of drug-resistant tuberculosis. However, its clinical use is threatened by the emergence of bedaquiline-resistant strains of Mycobacterium tuberculosis . Bedaquiline targets mycobacterial ATP synthase but the predominant route to clinical bedaquiline resistance is via upregulation of the MmpS5L5 efflux pump due to mutations that inactivate the transcriptional repressor Rv0678 . Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832. Furthermore, the increased resistance of Rv0678 mutants stems entirely from increased MmpS5L5 expression. These results highlight the potential of a pharmacological MmpS5L5 inhibitor to increase drug efficacy. Verapamil, primarily used as a calcium channel inhibitor, is known to inhibit diverse efflux pumps and to potentiate bedaquiline and clofazimine activity in M. tuberculosis . Here, we show that verapamil potentiates the activity of multiple diverse MmpS5L5 substrates. Using biochemical approaches, we demonstrate that verapamil does not exert this effect by acting as a disruptor of the protonmotive force used to power MmpS5L5, as previously proposed, suggesting that verapamil inhibits the function of the MmpS5L5 pump. Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil’s potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors.

Rapid generation advancement of RIL population and assessing the impact of Rhizobium nodulation on crop yields in Chickpea

Psychological impacts of climate change on US youth

Awareness of the threats of climate change is causing distress in increasingly documented ways, with youth particularly affected. Experiences such as climate distress and eco-anxiety have implications for the health and well-being of societies and economies, including individuals’ mental health and future planning, as well as their agency beliefs. Here, we show in a large sample of US youth (n = 2,834, ages 16 to 24) that the majority of US youth experience moderate climate distress and some functional interference from climate-related thoughts and feelings and a neutral to slightly positive sense of agency. They feel concern, interest, disappointment, frustration, sadness, anxiousness, and anger as affective responses to the crisis, and a majority report that their climate awareness may influence their plans for education, travel, and family planning. The key takeaway of this study is that the psychological impacts of climate change in US youth can have either impairing or strengthening effects, especially in the face of increased perceived direct exposure. Results show that self-reported direct experience of climate-related events is associated with increased eco-anxiety, climate distress, and impact of climate change on future planning, but also fortifying responses such as psychological adaptation and agency. These findings highlight the need for health systems and communities to prepare to address increased climate distress and related concerns in US youth as perceived exposure to climate-related hazards increases, in ways that strengthen healthy coping and agency to act. These findings have implications for the mental health of populations, climate behaviors, and life choices of young people experiencing these threats.