Science Journals

<p>by Swathi Radha, Martina Arends, Georg Kislinger, Agata Rhomberg, Martina Schifferer, Minou Djannatian, Mikael Simons</p> Rapid information processing in complex organisms depends on myelin, which consists of a multilamellar membrane that tightly adheres to the axonal surface along the internode and at paranodal loops, where specialized adhesion proteins maintain axon-glial contact. Because the decision to myelinate an axon profoundly influences neuronal transmission, this process must be precisely regulated. Yet, it remains unclear which specific molecules enable oligodendrocytes to select appropriate axonal substrates for myelination. Several key myelin-associated adhesion systems have been identified, including Myelin-associated glycoprotein (Mag) and Cell Adhesion Molecule 4 (Cadm4) at the internode, as well as Contactin1 (Cntn1) at the paranode; however, these three adhesion molecules have not previously been deleted in combination. Here, using zebrafish, we systematically disrupted all three myelin-associated adhesion systems. We found that the combined loss of Mag, Cadm4, and Cntn1 severely impairs myelin initiation and destabilizes the few nascent sheaths that do form, resulting in a phenotype characterized by oligodendrocytes exhibiting membrane “stubs”. The failure to form myelin triggered cell death of early myelinating oligodendrocytes and resulted in profound hypomyelination. Our findings reveal that axonal target selection and myelin formation depend on a redundant set of adhesion molecules, and that their simultaneous loss largely abolishes myelin biogenesis.

<p>by Jing Mo, Ding-Hao Zhuo, Min Gao, Ying Huang, Tao Cheng, Yang Dong, Yan-Yi Xing, Yun-Fei Li, Zi-Xin Jin, Xiang Liu, Guo-Qin Zhao, Hai-Rong Pu, Yu-Meng Liu, Li-Ping Shu, Peng-Fei Xu</p> Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult hematopoiesis. However, the mechanisms that modulate RA signaling in hematopoietic processes remain poorly understood. Using zebrafish as a model, we identified angiopoietin-like protein 5 (Angptl5) as a critical regulator of hematopoietic homeostasis. Loss of Angptl5 function resulted in myeloid hyperplasia in the anterior lateral plate mesoderm (ALPM) and anterior expansion of erythroid progenitors in the posterior lateral plate mesoderm (PLPM)—phenotypes consistent with attenuated RA signaling. Molecular analyses confirmed impaired RA signaling in <i>angptl5</i>^Δ10/Δ10 mutants, and exogenous RA supplementation fully rescued the hematopoietic defects. Mechanistically, we found that Angptl5 transcriptionally activates retinol dehydrogenase <i>dhrs9</i> through its interaction with Integrin α6lβ5. Our findings establish Angptl5 as a novel and essential regulator of embryonic hematopoiesis and reveal a previously unrecognized mechanism controlling hematopoietic homeostasis. These insights position Angptl5 as a potential therapeutic target for hematological disorders.

<p>by Ying Yao, Simon Hanslmayr</p> A new study in PLOS Biology shows that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, suggesting an additional dimension in how brain rhythms may organize neural activity. This primer discusses a study in PLOS Biology showing that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, and suggesting an additional dimension in how brain rhythms may organize neural activity.

<p>by Han Gong, Kehui Liu, Shanjun Deng, Jinwen Wang, Xionglei He, Li Liu</p> The dynamics of stem cell maintenance and proliferative patterns are key determinants of tissue aging in multicellular organisms. Leveraging our previously developed SMALT system with enhanced sequencing compatibility, we performed longitudinal lineage tracing of the adult <i>Drosophila melanogaster</i> midgut across different developmental stages. Using ubiquitous Tubulin-GAL4-driven labeling, we first profiled midgut-wide clonal dynamics during early adulthood (3–33 days post-eclosion). Phylogenetic reconstruction revealed that clonal diversity peaked immediately after eclosion and began to decline earlier than anticipated, accompanied by a reduction in effective population size. To further investigate stem cell-specific dynamics during late adulthood, we employed intestinal stem cell (ISC)-specific Dl-GAL4-driven labeling (33–63 days post-eclosion) and observed sustained clonal attrition in the posterior midgut. This progressive loss of diversity was consistent with an age-associated change in effective proliferative behavior and reduced lineage maintenance capacity, as reflected by a decline in net proliferative output inferred from lineage topology. Remarkably, ISC lineages emerging within the first 10 days post-eclosion exhibited sustained clonal dominance in aging populations, with a single lineage comprising over 63% of sampled cells by Day 63. Bayesian survival modeling confirmed that these early-origin lineages have the highest probabilities of long-term persistence, while a graph neural network model accurately predicted their structural evolution across successive stages. Together, we delineate a timeline for clonal attrition and deliver topology-driven predictors of clone survival and structural change, enabling prospective identification of dominant and failing clones during aging.

<p>by Teemu Kuosmanen, Juhani Rantanen, Dovydas Kičiatovas, Sanna Pausio, Ville-Petri Friman, Teppo Hiltunen, Ville Mustonen</p> Understanding and predicting how communities assemble is a paramount challenge in ecology. Here we address these questions normatively by comparing the observed species abundance distribution to a game-theoretically fair distribution based on each species’ Shapley value. By analyzing in total 56 distinct community outcomes, we assess how fairly biomass is distributed in microbial communities displaying both competitive and cooperative interactions in different growth conditions. We find examples of fair communities that closely follow their Shapley value across all environments as well as counterexamples where the true abundances deviate from the species’ objective contribution to community biomass. Next, we develop a fair assembly rule based on the recursive definition of Shapley value and show that also unfair community compositions are consistent with the principles of fair assembly after the lower-level competitive outcomes are known. Our results give unique empirical insights into the distributive function of ecological dynamics and lay down the theoretical foundations of what might become a normative community assembly theory.

<p>by Marvin van Aalst, Alienor Lahlou, Tanvir Hassan, William Gaultier, David Colliaux, Anna Matuszyńska</p> Web-based modeling platforms can enhance collaboration between modelers and experimentalists during early model development. Drawing on two interdisciplinary case studies, we provide guiding principles on how to build interactive agile modeling tools. Web-based modelling platforms can enhance collaboration between modelers and experimentalists during early model development. This Community Page provides guiding principles on how to build agile interactive modelling tools.

<p>by David Elmenhorst, Anna L. Foerges, Ali Gordji-Nejad, Eva-Maria Elmenhorst, Tina Kroll, Andreas Matusch, Simone Beer, Bernd Neumaier, Philipp Krapf, Christoph Lerche, Alexander Drzezga, Andreas Bauer</p> <p>Sleep is essential for synaptic homeostasis, a proposed mechanism whereby wakefulness leads to synaptic potentiation and sleep facilitates synaptic down-selection. Synaptic vesicle glycoprotein 2A (SV2A), whose availability is quantifiable by [¹⁸F]SynVesT-1 positron emission tomography (PET), is commonly interpreted as a proxy for synaptic density. In this randomized study, we examined 40 healthy adults (mean age 27.5 ± 6.5 years) who underwent two [¹⁸F]SynVesT-1 PET scans on consecutive days. Half of the participants were assigned to the normal sleep (i.e., control) condition and half to the sleep deprivation condition. Scans were performed at the same circadian time point, approximately 4 h after awakening in the control group and during baseline in the sleep deprivation group or after ~28 h of continuous wakefulness in the sleep deprivation group after sleep deprivation. Sleep deprivation led to significant increases in synaptic vesicle glycoprotein 2A binding in multiple brain regions, including the thalamus (+4.6%), hippocampus (+5.6%), and parietal cortex (+3.2%), whereas no changes were observed in controls. The degree of increase in synaptic vesicle glycoprotein 2A positively correlated with elevated slow wave activity during recovery sleep, a physiological marker of sleep pressure. These findings provide in vivo support for the synaptic homeostasis hypothesis in humans and suggest that synaptic vesicle glycoprotein 2A PET imaging is sensitive to sleep-wake dependent synaptic plasticity.</p> Trial Registration <p>The study was prospectively registered on 19.01.2022 here: German Clinical Trials Registry: DRKS # DRKS00027867, https://drks.de/search/en/trial/DRKS00027867.</p>

<p>by Zahra Jourahmad, Raissa K. Mathura, Layth S. Mattar, Melissa C. Franch, Danika L. Paulo, Mohammed Hasen, Nicole R. Provenza, Benjamin Y. Hayden, Sameer A. Sheth, Eleonora Bartoli, Andrew J. Watrous</p> Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing (“phase tuning”) has been extensively studied in animal models and human invasive recordings, much less is known about whether neurons show preferential firing at specific oscillatory frequencies, termed frequency tuning. Here, we employ human intracranial recordings across several brain regions including hippocampus, entorhinal cortex, anterior and posterior cingulate cortex, and orbitofrontal cortex to test the hypothesis that neurons exhibit frequency-specific firing. We analyzed 357 single units recorded simultaneously with local field potentials in 19 neurosurgical patients during awake resting. We estimated the instantaneous frequency of the LFP using adaptive spectral decomposition and assessed frequency tuning of each neuron while controlling for changes in firing rate unrelated to frequency changes. We found 27% of neurons exhibited increased or decreased firing within specific frequencies, most commonly within the low-frequency range (<10 Hz). Neurons exhibiting frequency tuning were distinct from those displaying phase tuning, and both types of tuning were observed across multiple brain regions with no anatomical preference. Together, our results demonstrate that the instantaneous frequency of neural oscillations modulates neuronal firing which may serve as an additional mechanism for information processing in the human brain, opening new avenues for frequency-targeted neural stimulation.

<p>by Yueyue Sapphire Hou, Pooya Laamerad, Liu D. Liu, Christopher C. Pack</p> Fluctuations in single-neuron activity in the sensory cortex often correlate with perceptual decisions. This kind of correlation is often hypothesized to reflect a causal influence of sensory signals on decisions, but it can be attributed to various noncausal factors as well. To disentangle these different possibilities, we have examined local field potentials (LFPs) recorded from the middle temporal (MT) area and area V4 of nonhuman primates (<i>Macaca mulatta</i>) while they performed two different perceptual decision-making tasks. Compared to single-neuron spiking, LFPs have the advantage of being decomposable into frequency bands that are associated with different anatomical sources of input. More importantly, they persist when spiking activity is inactivated, which precludes a causal influence of the corresponding neural activity on behavior. We found that high-gamma frequency (70–150 Hz) LFP power was correlated with perceptual decisions and that this correlation disappeared when spikes were inactivated, consistent with a causal role for this frequency band in decision-making. These signals overlapped in time with decision signals in the lower gamma band (30–70 Hz), which persisted after spiking inactivation, suggesting a noncausal input. Interestingly, lower-frequency LFP signals (5–30 Hz) reflected both impending perceptual decisions and the outcome of preceding trials, suggesting a modulatory influence of recent experience on neural dynamics. Our results, therefore, reveal that neural activity multiplexes different sources of information about perceptual decisions and that these types of information can be estimated reliably from different LFP frequencies.

<p>by Eun Seon Chung, William C. Johnson, Maliwan Kamkaew, Timothy A. Fitzgerald, Morgan E. McNellis, Trever C. Smith II, Srinivasan Vijay, Nguyen Thuy Thuong Thuong, Shumin Tan, Bree Beardsley Aldridge</p> The ability of <i>Mycobacterium tuberculosis</i> (Mtb) to dynamically adjust its growth behavior in response to host environments is critical for survival under immune and drug stress, but how these behaviors shift at the single-cell level remains poorly understood. Here, using high-resolution single-cell analysis, we show that Mtb adapts to acidic conditions by increasing the proportion of bacteria in a growth-arrested state, rather than uniformly slowing the growth rate of the entire population. This nongrowing subpopulation exhibits enhanced tolerance to ethambutol, highlighting its role in drug survival. Clinical strains displayed higher proportions of growth-arrested cells under both neutral and acidic conditions, suggesting that growth arrest may serve as one of the strategies for persistence during infection. While the PhoPR two-component system partially regulates this state, our RNA sequencing analysis revealed additional transcriptional regulators that are upregulated following acidic adaptation and may contribute to entry into the growth-arrested state and increased tolerance to ethambutol. Our study demonstrates that increasing the proportion of nongrowing subpopulations is an active adaptive strategy that can influence antibiotic susceptibility under acidic conditions, offering new perspectives for targeting bacterial heterogeneity in tuberculosis therapy.

<p>by Ron Sender, Tal Kedar, Yoav Navon, Moriya Raz, Shirley Bikel, Rina Hemi, Ron Milo, Shai Fuchs</p> The human endocrine system orchestrates critical physiological processes, yet a systematic quantitative synthesis of clinically relevant circulating hormones has been lacking. Here, we present a comprehensive, integrative analysis of circulating human hormones, leveraging clinically validated reference intervals across major endocrine subsystems. We use clinically validated reference intervals that we further validate using published datasets. Our analysis reveals that the total mass of circulating hormones is approximately 40 ± 2 mg. We find that this mass in healthy young adults is dominated by Adiponectin and DHEAS, which constitute over 90% of both total hormone weight and copy number. We show there are on the order of a million hormone molecules per cell in the human body. Females have about half the number of circulating hormone molecules compared to males. Across 56 hormones with curated affinity data, free (receptor-available) concentration correlates with receptor binding affinity, with class-specific scaling. Bioavailability mechanisms segregate by chemical class, consistent with chemical structure constraining available buffering strategies. Together, these data provide a quantitative reference for the human endocrine system and highlight relationships linking receptor affinity, bioavailability, and chemical class.

<p>by Lillith C. Zijmers, Katie L. Abson, Jarrod D. Hadfield, Adam Eyre-Walker</p> A population’s ability to adapt is determined by its levels of additive genetic variance (<i>V</i>_A), and while it is agreed that most organisms have genetic variation for most traits, the extent to which it varies between species is poorly characterized. Here, we investigate this question by compiling 3,209 and 1,852 estimates of heritability and evolvability (the additive genetic variance divided by the square of the mean), respectively, for a variety of traits from 220 and 172 multicellular eukaryotic species. Using phylogenetic generalized linear mixed models, we find substantial and highly significant interspecific variation in evolvability. Much of the variation is explained by phylogenetic relatedness, with plants in our data having substantially higher evolvability than animals. While heritability also varies between species, the differences are more subtle, and plants are not exceptional. We investigate whether the variation in evolvability and heritability between species is due to variation in the mutation rate, effective population size, genome size, ploidy, and recombination rate, but find little evidence of any factor being important. However, the confidence intervals are large suggesting that we have little power to detect any associations between these factors and our estimates of <i>V</i>_A.

<p>by Yoshiko M. Ikushima, Kuan-Chan Chen, Richard J. Sulston, Domenico Mattiucci, Eleanor J. Brain, Stefanie A. Fung Xin Zi, Karla J. Suchacki, Benjamin J. Thomas, Andrea Lovdel, Matthew Bennett, Hiroshi Kobayashi, Phillip D. Whitfield, Keiyo Takubo, Andrew H. Baker, Nicholas M. Morton, Robert K. Semple, William P. Cawthorn</p> Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed either <i>ad libitum</i> (AL) or a 30% CR diet from 9–13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both with fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency during AL feeding or obesity and occurred without changes in insulin concentrations or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance on both AL and CR diets. These effects on lipid metabolism were associated with sex- and diet-specific KO effects on white adipose tissue, including altered adipocyte size and expression of key regulators of adipocyte lipid metabolism. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilization that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional…

<p>by Dario Pasquale Anobile, Layla Barbar, Emile Maucotel, Alexis Cornec, Valeria Manriquez, Wilfrid Richer, Jordan Denizeau, Christine Sedlik, Charlie Bories, Elodie Couderc, Renaud Leclere, Judith Sobas, Emeline Papillon, Rafael Mena Osuna, Jimena Tosello-Boari, Marianne Burbage, Eliane Piaggio, Enzo Z. Poirier</p> One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlates with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.

<p>by Alberto Docampo-Seara, Mehmet Ilyas Cosacak, Kim Heilemann, Friederike Kessel, Ana-Maria Oprişoreanu, Markus Westphal, Özge Çark, Daniela Zöller, Josi Arnold, Anja Bretschneider, Alisa Hnatiuk, Nikolay Ninov, Catherina G. Becker, Thomas Becker</p> Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that <i>sema4ab</i>, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of <i>sema4ab</i> doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the <i>plxnb1a/b</i> receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of <i>sema4ab</i> alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine <i>tgfb3</i>, which strongly promotes regenerative neurogenesis. Hence, we propose that <i>sema4ab</i> expression in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through <i>plxnb1a/b</i> receptors and indirectly, by controlling the inflammatory milieu and <i>tgfb3</i> levels<i>.</i> Targeting Sema4A-dependent signaling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes.

<p>by Guillermina Griffa, Marco Palombo, Abraham Yeffal, Hong-Hsi Lee, Agustin Solano, Susie Y. Huang, Valeria Della-Maggiore</p> Structural neuroplasticity supports learning, development, and shapes vulnerability to brain disorders, making it a central priority in neuroscience research. However, progress in humans has remained limited by the inability to probe cellular processes in vivo, leaving mechanistic insight largely dependent on animal models. To address this gap, here we combined the sub-voxel sensitivity of ultra–high-gradient diffusion MRI with the cell-compartment specificity of the Soma and Neurite Density Imaging (SANDI) model to probe structural plasticity directly in the living human brain. By tracking how learning modulates the temporal dynamics of cell bodies and cell processes, we aimed to distinguish plastic from nonplastic biological processes driving changes in microstructure. We found that learning a motor skill triggered two distinct temporal responses: a transient expansion of cell bodies across all brain regions engaged by the task, consistent with a short-lived homeostatic mechanism, and a sustained increase in cell-process density restricted to key motor regions, consistent with structural plasticity. Our approach provides a mechanistic window into human neuroplasticity and marks a significant step toward bridging the gap between animal and human neuroscience.

<p>by Marlis Reich</p> Marine fungi were assumed to have a minor role in carbon cycling, unable to compete with bacteria. A new PLOS Biology study challenges this dogma, showing fungi can dominate labile dissolved organic matter assimilation, reshaping our understanding of ocean carbon retention and storage. Marine fungi were assumed to have a minor role in the carbon cycling, unable to compete with bacteria. A new PLOS Biology study challenges this dogma, showing fungi can dominate labile dissolved organic matter assimilation, reshaping our understanding of ocean carbon retention and storage.

<p>by Hongtao Zhang, Wenqing Liang, Meng Li, Yuejun Yang, Lei He, Wencong Nan, Guoteng Liu, Bin Wang, Ye Hong</p> Crossover (CO) formation ensures accurate segregation of homologous chromosomes during the first meiotic division. The pro-crossover proteins are essential for crossover formation and undergo dynamic changes during meiotic prophase I, although the underlying regulatory mechanism is largely unknown. Here, we found that the ubiquitin-proteasome system (UPS) plays a pivotal role in orchestrating pro-crossover protein dynamics and crossover patterning during meiosis in <i>Caenorhabditis elegans</i>. Knockdown of either the ubiquitin-activating enzyme E1 or the proteasome resulted in elevated pro-crossover protein levels and crossover designation. Impairing ubiquitination, but not proteasome activity, led to persistent association of pro-crossover proteins on meiotic chromosomes, a process mediated by the CDC-48^UFD-1/NPL-4 segregase. Utilizing a hypomorphic allele of <i>cosa-1</i>, a well-characterized pro-crossover protein-encoding gene, we further demonstrate that the UPS restricts crossover formation. Collectively, our findings reveal a multilayered UPS-mediated regulatory network that maintains proper pro-crossover protein dynamics, thereby coordinating crossover formation with meiotic chromosome segregation.

<p>by Juan Carlos Trejos-Espeleta, James A. Bradley, Ömer K. Coskun, Laura M. Wehrmann, Gonzalo V. Gomez-Saez, William D. Orsi</p> Fungi serve as critical biological carbon storage reservoirs in soil ecosystems, but whether this fungal trait is also important for marine sediment carbon storage processes is poorly understood. Here, we quantify for the first time assimilation of dissolved free amino acids by fungi in marine sediments from a high Arctic fjord and show that a distinct community of marine fungi promoted the stabilization of assimilated carbon via a relatively high metabolic efficiency. This corresponded to higher in situ ratios of fungi:prokaryote biomass in the fjord benthos, indicating efficient fungal metabolism promotes increased retention of microbial biomass at the seafloor. Quantitative stable isotope probing linked this efficient assimilation of amino acids to more than 80 fungal taxa in the fjord sediments, primarily associated with aquatic hyphomycetes. An efficient assimilation of amino acids is shown here to be a trait of marine fungi that plays a role in retaining labile dissolved organic matter as microbial biomass in Arctic fjord benthic ecosystems, hotspots for carbon sequestration that are currently experiencing rapid change due to climate warming. Our results indicate that fungal metabolism and biomass in marine sediment should be considered as an important contributor to seafloor carbon storage.

<p>by Asa Farahani, Zhen-Qi Liu, Filip Morys, Roqaie Moqadam, Yashar Zeighami, Mahsa Dadar, Alain Dagher, Bratislav Misic</p> The brain and body undergo coordinated changes throughout the life span, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to aging and peripheral biomarkers of metabolic and vascular function, including body mass index, blood pressure, and blood biochemistry. We use multivariate pattern learning to identify generalizable patterns of covariance between multi-modal neuroimaging data (structural, functional, diffusion, and arterial spin labeling MRI), demographic, and physiological markers in two large-scale deeply phenotyped datasets: the Human Connectome Project–Aging and UK Biobank. This data-driven approach isolates two principal axes of brain–body associations in both biological sexes. The first axis is driven by the dominant contribution of age. Across multiple brain measures, aging is associated with loss of brain structural integrity and cerebral vascular dysfunction. The second axis is driven by metabolic features, characterized by low high-density lipoprotein cholesterol, elevated body mass index, blood pressure, glycosylated hemoglobin, insulin, glucose, and alanine aminotransferase that predominantly converge on reduced cerebral perfusion. Importantly, the aging and the metabolic axes are independent of each other, meaning that age and metabolic dysfunction have separable influences on the brain. Finally, we show that deviations from a healthy metabolic profile are linked to cognitive deficits, particularly in females. Our study contributes to development of comprehensive translatable biomarkers for brain health assessment, and highlights the importance of metabolic health as a determinant of brain health in aging population.

<p>by Nuria Galiana, Miguel B. Araújo</p> The integration between biogeography and ecology has been historically limited due to the lack of data on biotic interactions across large spatial scales. The emergence of new methods and high-quality ecological network data at biogeographical scales are paving the way for a deeper integration of biogeography and ecology. This Essay examines this integration through three interconnected research areas: the effects of biotic interactions on species distributions; the influence of environmental gradients on biotic interactions; and the effects of biotic interactions on the environment. Recent progress and primary challenges are discussed, and suggestions provided on how to advance understanding of biodiversity patterns and processes across scales.

<p>by Benjamin Parrell, Minju Bae, Chris Naber, Olivia A. Kim, Caroline A. Niziolek, Samuel D. McDougle</p> Observed outcomes of our movements sometimes differ from our expectations. These sensory prediction errors recalibrate the brain’s internal models for motor control, reflected in alterations to subsequent movements that counteract these errors (motor adaptation). While leading theories suggest that all forms of motor adaptation are driven by learning from sensory prediction errors, dominant models of speech adaptation argue that adaptation results from integrating time-advanced copies of corrective feedback commands into feedforward motor programs. Here, we tested these competing theories of speech adaptation by inducing planned, but not executed, speech. Human speakers were prompted to speak a word and, on a subset of trials, were rapidly cued to withhold the prompted speech. On standard trials, speakers were exposed to real-time playback of their own speech with an auditory perturbation of the first formant to induce single-trial speech adaptation. Speakers experienced a similar sensory error on movement cancellation trials, hearing a perturbation applied to a recording of their speech from a previous trial at the time they would have spoken. Speakers adapted to auditory prediction errors in both contexts, altering the spectral content of spoken vowels to counteract formant perturbations even when no actual produced speech coincided with the perturbed feedback. Such adaptation was not observed when participants passively listened to perturbed feedback without the intention to speak, ruling out observational learning as the cause of adaptation in movement cancellation trials. These results suggest that prediction errors, rather than corrective motor commands, drive audiomotor adaptation in speech, building on recent findings in reaching.

<p>by Joseph Westley, Paritosh Bedekar, Elizabeth Pursey, Mark D. Szczelkun, Mario Recker, Stineke van Houte, Edze R. Westra</p> Bacterial pathogens commonly become drug resistant via horizontal acquisition of antimicrobial resistance genes (ARGs), which are often encoded on mobile genetic elements (MGEs). Although bacterial defence systems are typically considered barriers to horizontal gene transfer (HGT), previous studies revealed that bacteria with more restriction-modification (RM) systems (the most abundant bacterial defences) frequently carry more MGEs. It was suggested that this counterintuitive relationship might result from stronger selection for RM systems when exposure to costly MGEs increases. Here, we test this hypothesis using a combination of modeling and bioinformatics analysis of >40,000 bacterial genomes to better understand how eco-evolutionary feedbacks between selection for RM and acquisition of MGEs shape bacterial genome evolution. Our model predicts negative associations between HGT and RM, but only if RM diversity is high. By contrast, at low RM diversity, eco-evolutionary feedbacks drive the emergence of positive associations between HGT and RM. Consistent with these predictions, we identified negative relationships between acquired ARG counts and RM counts across species but positive relationships within individual species. Collectively, our work helps to understand how RM systems shape patterns of HGT of ARGs, which may offer opportunities for targeted surveillance of strains at higher risk of horizontally acquiring novel drug resistance alleles.

<p>by Alex M. Francette, Aakash Grover, Nathan Clark, Karen M. Arndt</p> In eukaryotes, transcription elongation factors (TEFs) associate with RNA Polymerase II (RNAPII) to facilitate gene expression and couple transcription to co-transcriptional processes, including chromatin regulation and RNA processing. To further our understanding of TEF biology, we developed a domain-centric analysis pipeline to perform a broad survey of 10 TEF orthologs—Paf1, Ctr9, Cdc73, Rtf1, Leo1, Spt4, Spt5, Spt6, Spn1, and Elf1—across the Tree of Life and analyze their evolutionary patterns in a structural context. We report evidence for all 10 TEFs being present in the last eukaryotic common ancestor, indicating that mechanisms of TEF-mediated transcription regulation are both ancient and conserved. However, some early-diverging eukaryotic clades exhibit signs of altered TEF domain composition. A comparative phylogenetic analysis highlighted conserved regions of TEFs that are detected in both metazoans and fungi and other regions that appear clade-specific, detected only in metazoans. These observations, together with additional insights generated from evolutionary rate covariation analysis, shed light on under-characterized aspects of TEFs, including domains for which functions have yet to be dissected.

<p>by Olav N. L. Aga, Sabrina J. Moyo, Joel Manyahi, Upendo Kibwana, Iren H. Löhr, Nina Langeland, Bjørn Blomberg, Iain G. Johnston</p> Antimicrobial resistance (AMR) is a substantial and growing global health burden. Understanding, and predicting, its evolution in specific pathogens will help responses across scales from individual patient cases to large-scale policy. Here, we use global data on AMR features, predicted from 47k <i>Klebsiella pneumoniae</i> genomes, with hypercubic transition path sampling to infer the evolutionary pathways by which AMR features in <i>K. pneumoniae</i> (KpAMR) are acquired across 102 countries, territories, and areas. We identify “globally consistent” evolutionary behaviors that hold across countries, and “globally divergent” behaviors including carbapenem and fluoroquinolone resistance that vary across countries. We show how these divergent dynamics covary both with public health superregion and drug use policy, and reveal competing evolutionary pathways within and between countries. Using newly sequenced data across several decades from sub-Saharan Africa, we show that this inferred global roadmap of KpAMR evolution successfully predicts prospective evolutionary dynamics. Together, we hope that the ability to characterize and predict evolutionary dynamics of AMR acquisition, connected to socio-economic and drug policy predictors, will help strengthen our understanding of AMR evolution worldwide.