iScience

The end-Permian mass extinction (EPME) represents the most severe biotic crisis of the Phanerozoic Eon on Earth and has been well documented in marine taxa. However, its impact on terrestrial organisms and ecosystems remains incompletely understood. Here we present a high-resolution reconstruction of terrestrial diversification dynamics and spatial reorganization across the Permo-Triassic boundary (PTB) using comprehensive occurrence data of macroplants, sporomorphs and vertebrates. Terrestrial responses to the EPME show highly temporal, regional and taxonomic heterogeneities. Plants experienced a genus-level diversity loss of [~] 6.7%, across the PTB, whilst vertebrates, a lagged decline from the late Permian, peaking at a diversity loss of [~] 66.7%. Global distributions of plant and vertebrate show converging on similar latitudinal gradients post the PTB. Plant diversity loss is disproportionately high in low-latitude and tropical regions and progressively lower toward mid- and high-latitudes. Our study facilitates a fine-grained understanding to terrestrial macroevolution in geologic history through multi-analysis of a large volume of fossil data. Our findings challenge the long-held notion of global terrestrial collapse and mass extinction in plants during the PTB and offer a deep-time analogue for uneven response of extant terrestrial biodiversity to ongoing climate change.

Recent advancements in tomography produce imaging data of geological materials (rocks and fossils) at trillion-voxel scales with multi-channels. Such high-resolution datasets are potentially keys to unveil evolutionary biological information with various shapes and sizes that have not been ever discovered. Volume rendering is an ideal visualization approach for them because it treats all voxels without relying on user-defined surface boundaries. However, these large-scale real-world tomographic data have rarely been volume-rendered at their native resolution, limiting the examination of rich morphological information. Here, we demonstrate a de facto standard volume-rendering pipeline running on a graphical processing unit (GPU)-equipped supercomputing system toward multi-channel, trillion-voxel tomographic data. Our workflow preserves original resolution, capturing detailed morphological information spanning microscopic to macroscopic scales. Systematic comparison of node types shows that GPU memory, rather than host memory, is the primary bottleneck. Our results establish a baseline for large-scale, multi-channel volume rendering of real tomographic data and demonstrate its applicability to geological samples. This work is presented as a practical demonstration of large-scale volume visualization.

A delicate balance between the quiescent and proliferative states of neural stem cells (NSCs) is important for neurogenesis and homeostasis. Histone deacetylase 4 (HDAC4) variants are associated with neurodevelopmental disorders, however, its role in early brain development remains elusive. In this study, we demonstrate that Drosophila HDAC4 plays a crucial role in neural stem cells (NSCs) reactivation and brain development. Depletion of HDAC4 results in notable defects in NSC reactivation, while its overexpression leads to premature reactivation. HDAC4 is SUMOylated at Lys902, which enhances its protein stability by preventing HDAC4 from undergoing ubiquitin-proteasome-mediated degradation. Moreover, phosphorylation of HDAC4 by salt-inducible kinase 3 (SIK3), an AMPK-related kinase, allows cytoplasmic localization of HDAC4 and enhances the association between HDAC4 and Warts, a core kinase of the Hippo pathway. This HDAC4-Wts association inhibits Warts activity, and in turn, the inactivation of the Hippo pathway, triggering NSC reactivation. Finally, genetic epistasis experiments support the SIK3-HDAC4-Warts axis during NSC reactivation. In conclusion, our findings identify HDAC4 as a molecular switch that integrates SUMOylation, ubiquitination, and the Hippo pathway to govern NSC reactivation.

The blood vasculature has a high capacity for structural regeneration, driven by the blood endothelial cells (BECs) that comprise it. This regenerative process, which involves BEC migration and proliferation to form these complex tissues, is linked to low frequency (< 0.1 Hz) calcium spiking that precedes these activities. However, we need new approaches to stimulating angiogenic responses in tissue engineering applications. By conducting experiments that manipulate local ionic concentrations and developing a simple, yet powerful, computational analysis, we demonstrate that sodium-calcium cross-talk is a crucial component that regulates the calcium signaling and downstream angiogenic responses. Activation and deactivation of the inositol triphosphate 3 receptors (IP3Rs) on the endoplasmic reticulum (ER) and the switch between forward and reverse modes of the sodium-calcium exchanger (NCX) are proposed to be the key mechanisms underlying calcium oscillations when cells are exposed to temporary cationic depletion. The spiking is suggested to be a release of intracellular calcium mediated by IP3R activity, and transport in or out of the cell is driven by NCX for the calcium oscillatory signaling pattern. The NCX and IP3R both contribute to manage intracellular calcium and ionic concentration as initially there is a long ER deactivation period while intracellular sodium slowly increases until a sudden onset of calcium is released by the ER. Other calcium and sodium ion channels can change this resonant coupling of ER and NCX to alter the inter-spike duration. Synchronization of the spiking intervals between cells is triggered by stimulating with vascular endothelial growth factor (VEGF), which induces a propagating wave of intracellular calcium across the 2D tissue culture, prior to coordinated cell migration and proliferation towards the VEGF source. This wave, which can be artificially induced and studied using electrical stimulation, suggests that the underlying sodium-calcium crosstalk mechanism introduces intracellular calcium polarization, whose orientation is transferred across cells through spike synchronization. Thus, control of calcium signaling dynamics through regulation of ionic depletion can serve as useful method for generating angiogenic responses in engineered tissue constructs.

Muscular hydrostats, muscular structures with no rigid skeleton, are ubiquitous within the animal kingdom, from vertebrate tongues to cephalopod arms1,2, but how they perform complex actions remains poorly understood. One model hydrostat studied for its neural control3-7 and biomechanics8-17 is the feeding system (buccal mass) of the sea hare Aplysia (Fig. 1). The buccal mass (Fig. 1b) performs multiple feeding behaviors by coordinating intrinsic muscles to move a grasper (odontophore)18,19. In this paper, we investigated how mechanical reconfiguration from interacting shape-changing elements facilitates large odontophore protractions. During rejection behaviors, mechanical reconfiguration of the odontophore (elongating its shape to a higher aspect ratio) stretches a protractor muscle (I2), allowing I2 to generate stronger protractions12. In biting behaviors, the odontophore has a similar range of motion. However, during biting, the odontophore has a lower aspect ratio throughout protraction, meaning the I2 muscle alone is insufficient to reach observed protractions due to its length/tension property and reduced mechanical advantage9,10,12,18. By combining new analysis of MRI movies of Aplysia feeding12,18 (Fig. 1) with a new biomechanical model for biting and rejection (Fig. 2), we demonstrate two context-dependent mechanical reconfiguration mechanisms that explain the different ways large protractions are produced in biting and rejection (Fig. 3). The mechanisms integrate shape changes, bending and conforming of muscle structures, and shifts in contact interactions. We propose two mechanical subclasses of muscular hydrostats, "constrained" or "unconstrained" (Fig. 4), that may be morphologically similar but employ different control strategies depending on whether mechanical constraints are reliably present. O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/715937v1_fig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@1c60cbeorg.highwire.dtl.DTLVardef@16ebd04org.highwire.dtl.DTLVardef@13b65d5org.highwire.dtl.DTLVardef@9aafb0_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1.C_FLOATNO Anatomy and kinematics of the Aplysia feeding system (a1) Adult Aplysia californica searching for food and (a2) feeding on Gracilaria macroalgae ((a1) photo credit: Dr. Jeffrey P. Gill, (a2) modified with permission from Bennington et al. 202514). Gray highlight shows the location of the feeding structure, the buccal mass (b). (b) An anatomical diagram of a midline sagittal view of a buccal mass. During feeding, the odontophore (the internal grasper of the buccal mass) protracts through the tubelike I3 muscle. In the midsagittal plane, the I3 is visible as two longitudinal elements, but is one continuous structure that runs circumferentially around the buccal mass. The inner wall of the distal I3 is shown in dark blue. The dashed white line shows the jaw line, which is used as the reference for both the translation and rotation measurements. (c) Configuration of the buccal mass (left: anatomical diagram; middle: MRI frames) showing (c1) peak retraction and (c2) peak protraction. (right) A diagram of the buccal mass was created to highlight key anatomical landmarks for each frame of the MRI video showing a complete biting sequence (d-e). The same diagrammatic representations of the landmarks are shown in (d) and (e) for the protraction and retraction portions of the biting sequence, respectively (See STAR Methods). The frames shown in (c1) and (c2) correspond to the 0 ms and 3410 ms frames, respectively, and are the same between the middle and right portions of the figure. Key frames referred to in the text: t0: start of the behavioral cycle, t1: peak rotation reached, t2: peak translation reached, t3: rotation plateau ended, t4: end of behavioral cycle. (f) Kinematic measurements were taken using the drawn diagrams for each frame in the sequence. See main text for definitions of variables. All scale bars correspond to 10 mm. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/715937v1_fig2.gif" ALT="Figure 2"> View larger version (34K): org.highwire.dtl.DTLVardef@1848bb9org.highwire.dtl.DTLVardef@f126a4org.highwire.dtl.DTLVardef@1ffd5forg.highwire.dtl.DTLVardef@336910_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 2.C_FLOATNO Kinetic/Kinematic biomechanical model of the buccal mass (a) Rest geometry of the biomechanical model. The grasper (odontophore) is modeled as a rigid ellipse (magenta with yellow radula). It is connected to the I1/I3 lumen (blue trapezoid) by the hinge muscle (green). The I2 protractor muscle (red) wraps conformally around the odontophore and attaches at the lateral groove. The net force and torque from the I2 on the odontophore are found by performing an instantaneous force balance on a small arc of the ellipse and integrating across the full region of contact between the I2 and the odontophore. The hinge muscle is modeled as a linearly elastic, geometrically exact beam. At each position along the beams midline, a quasistatic force balance is performed (see STAR Methods). (b1) The tension in the I2 is modeled using the length-tension relationship reported in Yu et al. 1999 scaled by a normalized activation level. (b2) The axial and bending stiffness of the beam hinge were calibrated to ex vivo animal data reported in Sutton et al. 2004. Gray region indicates odontophore displacements observed during biting behaviors (Sutton et al. 2004). (c1-c2) To investigate the effects of mechanical reconfiguration on odontophore position at peak protraction, (c1) the aspect ratio of the odontophore ellipse and (c2) the stretch of the lateral groove were added as additional kinematic constraints. (c1) and (c2) show results from the model but do not correspond to any particular behavior or configuration observed in the animal. These constraints impact the biomechanical model via contact forces from the I1/I3 (see STAR Methods). The lateral groove stretch is converted to a depression angle of the dorsal I1/I3 muscle as a proxy for the wrapping of the dorsal I3 around the odontophore observed during in vivo feeding behaviors (Fig 1). (d-e) MRI frames at peak protraction in (d1, with and without overlay) biting (t2) and (e1, with and without overlay) rejection ({tau}2) compared to corresponding frames from the biomechanical model (d2 and e2, respectively). C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/715937v1_fig3.gif" ALT="Figure 3"> View larger version (56K): org.highwire.dtl.DTLVardef@1369a90org.highwire.dtl.DTLVardef@1dda429org.highwire.dtl.DTLVardef@4485d5org.highwire.dtl.DTLVardef@ae6523_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 3.C_FLOATNO Mechanical reconfiguration of the buccal mass (a) Midsagittal kinematics of the buccal mass during a (left) biting and (right) rejection behavior (see also Figs. S1 and S2). Colored circles (diamonds) show data for an individual frame, and the black line shows the two-point moving average of the signal. Vertical dashed lines show concurrent time points in the different kinematic signals (biting: t0: cycle starts, t1: peak rotation, t2: peak translation, t3: rotation plateau ended, t4: cycle ends. Rejection: {tau}0: cycle starts, {tau}1: rotation plateau ends, {tau}2: peak translation, {tau}3: peak rotation, {tau}4: cycle ends). (b) Model configurations for nine different pairs of aspect ratios ({Phi}) and lateral groove stretches ({lambda}LG ) (numbers correspond to the labeled points in (Fig. S6c)). Note that these simulated results from the model do not necessarily correspond to configurations observed in the animal but rather show changes in the systems configuration due to changes in the kinematic parameters. All configurations here were achieved with an I2 activation of AI2 = 65%. (c-d) Sensitivity of the model translation and rotation at peak protraction to lateral groove shortening ({lambda}LG, top row) and aspect ratio change ({Phi}, bottom row) for biting (c) and rejection (d). The y-axis for all panels reports the difference between the model prediction and observed animal value at peak protraction (for translation or rotation) normalized by the range of motion (ROM) for each behavior. For each panel, one kinematic parameter is held fixed (top:{Phi} fixed; bottom:{lambda} LG fixed) at the value observed in the animal at peak protraction, and the other is varied to determine the effect of changing this parameter on the translation and rotation of the odontophore. Vertical dashed lines show the observed value of the varied parameter in the animal at peak protraction. The horizontal dashed line shows 0 difference for reference. The steepness of the difference curve in the vicinity of the vertical dashed line indicates how sensitive the system is to changes in each kinematic parameter near peak protraction. Here, a steeper curve (with a positive or negative slope) indicates greater sensitivity. For biting simulations, AI2 = 15%, and for rejection, AI2 = 90% based on the results of the model validation. Each curve in (c) and (d) is a 1D cross-section of the 2D contour plots shown in Figs. S6-S7. For a complete view of the sensitivity of translation and rotation to lateral groove stretch and aspect ratio across the kinematic configuration space at different I2 activations, see Figs. S6-S7. Note that (c) and (d) use different vertical scales. The smaller scale for the rejection plots was chosen to better show the difference curves for rejection, and it reflects the overall decreased sensitivity to both lateral groove stretch and aspect ratio changes for the rejection behaviors. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/715937v1_fig4.gif" ALT="Figure 4"> View larger version (36K): org.highwire.dtl.DTLVardef@171f4c6org.highwire.dtl.DTLVardef@7d11a7org.highwire.dtl.DTLVardef@11206e3org.highwire.dtl.DTLVardef@82489c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 4.C_FLOATNO Mechanical reconfiguration facilitates behaviors in a variety of constrained hydrostat systems Combinations of the active shape change of internal structures (cyan), changes to the movement constraints and contact interaction (blue), and bending and conforming of structures (magenta) allow constrained hydrostats to mechanically reconfigure their neuromusculature (purple) to perform various behaviors. This can be seen in various systems across various species. As discussed here, the Aplysia buccal mass uses combinations of these mechanisms in (a) biting and (b) rejection behaviors to protract the buccal mass. (c) The pond snail, Lymnaea, has a morphologically similar buccal mass to Aplysia, but its I1/I3 homolog, the anterior jugalis, sits further posterior to the odontophore35, meaning it may more readily rely on the bending of the anterior jugalis and contact interactions during protraction. (d) The octopus and, more broadly, cephalopod buccal masses contain a beak that lacks a fixed articulation. Instead, by activating the lateral mandibular muscle (LMM), the buccal mass can create a stiff rotation point and may shift the function of the posterior mandibular muscle (PMM) from compressing the buccal mass to opening the beak36,37. (e) The human tongue (and other Type I tongues38) sits within the skull and makes use of contact with the hard palate to push food from the oral cavity into the pharynx27,48. (f) Additionally, by changing how the tongue interacts with the palate and teeth, while maintaining the same internal shape, humans can produce various vowel and consonant sounds39,49,50. This use of contact with the palate and teeth is known in the phonetics community as "bracing." Here, by creating a groove in the middle of the tongue, the phonemes /{varepsilon}/ and /ae/ can be produced. By raising the tongue and creating palatal contact while maintaining that groove, these vowels shift to the fricative consonants /s/ and /{theta}/49. Small insets show which of the mechanical configurations are used in each behavior. C_FIG

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions. HighlightsO_LISex chromosome aneuploidy induces cell-type specific changes in gene expression C_LIO_LIDampening of the inactive X chromosome in XXY alleviate X overexpression C_LIO_LIHigh Y-linked gene expression in XXY neuronal precursor cells but not cardiomyocytes C_LIO_LISex chromosome aneuploidy disrupts sex biases in autosomal gene expression C_LI

Human activity is transforming the shape, size, and resilience of Earths biosphere, degrading and augmenting Holocene baseline conditions at various scales, and replacing the wild biosphere with an anthropogenically modified one. We evaluate episodes of biosphere change throughout Earth history and compare them with contemporary and near-future anthropogenic changes, developing the concept of biosphere disruptors - agents that force global-scale macroevolutionary change. Transient disruptors are short-lived agents (mean 8.0x105 years), including massive volcanism and asteroid impacts. Persistent disruptors, including atmospheric and ocean oxygenation and land plant evolution, remain in the Earth System over long timescales (mean 1.6x108 years). In the geological record, transient disruptors are associated with temporary but sometimes massive biosphere degradation, whereas persistent disruptors are associated with sustained biosphere enhancement. Most anthropogenic biosphere impacts resemble those of past transient disruptors, globally degrading wild biomass and biodiversity. Humanity is driving the second highest rate of biosphere degradation in Earth history after the Cretaceous-Palaeogene bolide impact. However, humanity is the first disrupting agent capable of reflecting on and potentially transforming its impact on planetary habitability. If we can achieve this, humanity could drive the greatest rate of increase in planetary habitability in Earth history on centennial to millennial timescales.

The variable regions of antibody heavy chains (HCs) and light chains (LCs) are assembled by V(D)J recombination in progenitor B cells to generate an immense repertoire of primary B cell receptors (BCRs), the precursors of affinity-matured antibodies secreted in response to antigen stimulation. The complementarity determining region (CDR) 1, 2 and 3 of antibodies are the principal antigen contact sites, with CDR3 being highly diverse due to V(D)J junctional diversification by terminal deoxynucleotidyl transferase (TdT). The HC CDR3 (CDR H3) plays a prominent role in broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus-1 (HIV-1). BnAbs overcome the genetic heterogeneity of HIV-1 by recognizing conserved epitopes on the HIV-1 Envelope (Env) protein. Reaching these targets requires long CDR H3s that penetrate through the glycan shield or other structural hindrances on the Env protein. The shortage of human antibodies with such long CDR H3s poses a challenge for bnAb elicitation by vaccination. To aid immunogen design, we generated six mouse models for inducing bnAbs against particular HIV-1 Env epitopes. In each mouse model, we integrated the human HC VH, D, JH segments and LC VL, JL segments of a bnAb lineage into the mouse HC and LC loci, with each set engineered to undergo V(D)J recombination and to generate diverse human HC and LC variable regions. Combined action of V(D)J recombination and TdT- mediated junctional diversification in developing B cells generated a range of human variable region exons for a given bnAb lineage that contained highly diverse CDR3s in each mouse model. Moreover, these repertoires contained humanized antibodies that had bnAb-like long CDR H3s that could potentially serve as bnAb precursors. Therefore, these mouse models can be used to test whether immunogens can induce bnAbs from rare and diverse precursors in a complex antibody repertoire. Author summaryThe human immunodeficiency virus-1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS). An efficacious HIV-1 vaccine is needed to control the AIDS pandemic. However, in multiple clinical trials, vaccine candidates failed to confer protection against HIV-1 infection. The lack of efficacy is mainly due to the enormous heterogeneity of HIV-1 strains in human circulation. A breakthrough in the field has been the identification of broadly neutralizing antibodies (bnAbs) in a small fraction of HIV-1 infected patients. Because these antibodies recognize conserved targets on different HIV-1 strains, they can inhibit a wide spectrum of viruses. Eliciting HIV-1 bnAbs is a top priority for vaccine development. For this endeavor, a major difficulty is that most bnAbs have unusual properties. To induce bnAbs, vaccines must be highly selective for rare human antibodies that can develop into bnAbs. To facilitate this effort, we have generated a panel of mouse models that can produce potential precursors for major types of HIV-1 bnAbs. We engineered mouse models to produce diverse precursors in complex antibody repertoires, which mimic the challenging condition in human vaccination. These mouse models can be used to assess and optimize vaccine candidates at the preclinical stage.

Ultrasonic vocalizations (USVs) are widely used in rodent social communication, yet the functional significance of male-male vocal interactions in mice remains unclear. Here, we investigated whether USVs produced during specific social behaviors influence the behavior of conspecifics. Using playback experiments, we compared responses to vocalizations recorded during chasing and being chased in male-male interactions. We found that USVs emitted by chased intruders consistently elicited approach behavior in receiver mice, whereas those emitted by chasing individuals did not. Acoustic analyses revealed that these vocalizations differed in syllable composition, with intruder calls containing a higher proportion of upward frequency-modulated syllables and exhibiting higher mean frequencies. In addition, the temporal organization of syllables appeared to contribute to the behavioral response. Together, these results suggest that male mice respond selectively to certain USV patterns associated with specific social contexts, indicating that acoustic features and temporal structure may jointly influence social approach behavior in mice. HighlightsO_LIBehavioral context (chased vs. chasing) shapes the composition of USV syllable types C_LIO_LIMale mice selectively approach USVs from chased intruders, but not chasing residents C_LIO_LIThe approach response exhibits high temporal synchrony across individual receivers C_LIO_LITemporal organization of syllables modulates approach behavior based on acoustic features C_LI

T cells play an essential role in protecting tissues against pathogens and regulating tissue homeostasis. Previous studies highlight that T cells display tissue-specific phenotypic and functional properties, suggesting that T cells adapt to their local environment. However, whether this holds true in inflamed tissues or whether inflammation disrupts any tissue-specific T cell adaptations remains poorly understood. To address this open question, we examined the T cell compartment including conventional CD4 and CD8 T cells, regulatory T cells, gd T cells, and MAIT cells from healthy and inflamed human mucosal tissues. Using high-parameter spectral flow cytometry, we examined phenotype ex vivo and the functional capacity following stimulation, utilizing conventional gating and unsupervised clustering analysis approaches. Overall, we analyzed 65 tissue samples including mild, moderate, and severely inflamed oral gingiva, healthy and inflamed lung, along with healthy and inflamed tissue from the decidual-placental interface. Across these mucosal barrier tissues, we find that tissue location plays a dominant role in shaping the composition, phenotype, and functional capacity of the T cell compartment. Importantly, these tissue-specific adaptations were largely maintained during states of tissue inflammation. This included the ability to exert tissue repair functions, which was preserved across T cell subsets, even in severely inflamed tissues.

Moth pheromone-sensitive olfactory receptor neurons (Phe-ORNs) encode the intermittent structure of pheromone plumes through precisely timed spikes, a mechanism that is essential for odor plume tracking behavior in flying insects. However, natural olfactory scenes are composed of diverse volatile plant compounds (VPCs) with complex temporal dynamics whose effects on pheromone signal intermittency encoding remain unclear. Two lines of research, encoding of pheromone intermittency and background interference, remain largely disconnected. Here, we performed electrophysiological recordings from moth Phe-ORNs to quantify their responses to turbulent plume-like flickering pheromone stimuli in constant or fluctuating backgrounds of a diversity of VPCs. We found that some VPCs reversibly disrupted the temporal coding of various subregions of the pheromone stimulus and the trial-to-trial variability. While Phe-ORN activation by VPCs partially accounted for the decrease in coding performance, Phe-ORN gain reduction was insufficient to explain the full extent of the disruption. Some VPCs disrupt temporal coding without activating Phe-ORNs, and others activate Phe-ORNs without altering temporal coding. A continuous background noise can induce strong adaptation and limit dynamic range, whereas a fluctuating background can interfere with pheromone pulse encoding by disrupting spike timing. Altogether, these results indicate that the pheromone detection system must contend with multiple forms of background noise rather than a uniform disturbance. Timing is key for olfactory navigation, and our results raise questions regarding how downstream circuits would process noisy sensory inputs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/713794v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c44fb6org.highwire.dtl.DTLVardef@14d5982org.highwire.dtl.DTLVardef@12f94a2org.highwire.dtl.DTLVardef@c731ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

Spinal muscular atrophy (SMA), traditionally defined as a neuromuscular disorder characterized by degeneration of lower motor neurons, is increasingly recognized as a multi-organ disease. SMA is caused by deficiency of the survival motor neuron (SMN) protein below a critical threshold required for cellular homeostasis. While motor neurons are particularly vulnerable, the ubiquitous expression and fundamental functions of SMN result in widespread perturbations across multiple tissues. Here, we generated a label-free quantitative proteomics atlas of spinal cord, heart, and gastrocnemius muscle from wild-type, heterozygous, and SMA mice at the symptomatic stage, including cohorts treated, at postnatal day 1 (P1), with a systemic suboptimal dose of SMN antisense oligonucleotides (SMN-ASOs), resulting in partial SMN restoration. SMN deficiency induced pronounced, tissue-specific proteome remodeling, with peripheral tissues exhibiting broader molecular alterations than spinal cord. Cross-tissue analyses revealed limited overlap, although heart and muscle showed partial convergence in metabolic and mitochondrial-associated pathways. SMN-ASO treatment partially repositioned these proteomes toward control states; however, restoration was incomplete and strongly tissue-dependent, with persistent dysregulation of mitochondrial and metabolic pathways. These findings demonstrate that SMN deficiency drives systemic yet heterogeneous proteome remodeling and that partial SMN restoration does not fully reverse established molecular alterations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/715402v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@114d73borg.highwire.dtl.DTLVardef@13e8c13org.highwire.dtl.DTLVardef@15e4ba0org.highwire.dtl.DTLVardef@1b70fb8_HPS_FORMAT_FIGEXP M_FIG C_FIG

Glutamatergic neuronal synapses in the mouse neocortex mature during the first two months after birth. A key event during synaptic maturation is a change in short-term synaptic plasticity (STP), i.e. a switch from strong synaptic depression to a weaker depression or even facilitation. Glutamatergic pyramidal neurons located in the cortical layers II/III, layer V, and layer VI project axons through the corpus callosum where they release glutamate along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). Here, we used single-cell electrophysiological recordings in brain slices to investigate synaptic plasticity at neuron-OPC synapses along axonal shafts in the white matter, and applied computation approaches to pinpoint the mechanisms of this plasticity. We found that during postnatal development of mice, there is a switch from short-term synaptic depression to short-term synaptic facilitation at glutamatergic neuron-OPC synapses in the corpus callosum. Synaptic delay of phasic neuron-OPC excitatory postsynaptic current shortens, and the amount of asynchronous release at neuron-OPC synapses decrease as animals mature, indicating that glutamate release becomes more synchronized. Our computational modelling suggests that both pre- and postsynaptic changes may contribute to the functional development and changes of plasticity at neuron-OPC synapses in the white matter. Taking together, our findings indicate that synaptic release machineries located at different sites along the same axon (i.e. axonal shaft in the white matter vs synaptic boutons in the grey matter) mature in a very similar fashion, STP occurs at both synaptic sites, and STP dynamics represent an important event during brain maturation.

Relay neurons of the dorsal lateral geniculate nucleus (dLGN) receive convergent inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses exhibit a highly skewed distribution of synaptic strength, with a few strong inputs and many weak ones. Strong synapses are thought to dominate relay neuron activity. However, the contribution of individual inputs might not just depend on strength but also on short-term plasticity Using minimal stimulation recordings in acute mouse brain slices, we analyzed the electrophysiological properties of individual retinogeniculate synapses. We observed a robust inverse correlation between synaptic strength and short-term plasticity: weak synapses showed facilitation, whereas strong synapses exhibited pronounced depression. This was consistent with increasing vesicle release probability and enhanced AMPA receptor desensitization at stronger synapses. Analysis of synaptic current kinetics further suggested that variability in synaptic strength reflects not only differences in synapse size and AMPA receptor content but also differences in the electrotonic distance of synapses from the soma. Together, these results reveal systematic heterogeneity in both presynaptic and postsynaptic properties of retinogeniculate synapses. Therefore, the relative contribution of weak and strong inputs to relay neuron firing is likely activity-dependent, with strong synapses dominating when RGCs fire few action potentials and weaker inputs contributing more during sustained or high-frequency firing with several action potentials.

The ability of flying insects to locate distant food and mates by tracking odor plumes through turbulent and unsteady flow represents a remarkable feat of sensorimotor integration. Successful navigation requires not only extracting a reliable directional estimate from an intermittent olfactory signal, but also contending with the challenging dynamics of variable winds. While prior work has established that insects integrate the history of odor encounters to shape search decisions, whether they also retain a working memory of recently experienced wind conditions has remained unknown. Here, we use optogenetics combined with controlled wind perturbations in a free-flight wind tunnel to investigate how wind history modulates the olfactory search behavior of Drosophila melanogaster. By introducing lateral "gust" flow via auxiliary fans and independently delivering olfactory stimuli, we show that the wind experienced during an olfactory stimulus shapes both the immediate surge response and the subsequent spatial search. Flies that received an olfactory stimulus while being displaced by a crosswind gust were significantly more likely to return to the gust zone during the post-stimulus search phase compared to flies that received the same odor cue in steady laminar flow. Meanwhile, surge responses and course directions exhibited during search indicate that moment-to-moment flight kinematics may be driven more by instantaneous flow. These results reveal that wind experience is tracked in addition to olfactory experience, and provide evidence that Drosophila maintain a short-term working memory of ambient wind conditions to guide olfactory navigation.

The number of offspring produced per reproductive cycle varies widely across animals and is constrained by the number of ovarian follicles that proceed to ovulation. In vertebrates, this phenomenon has been explained by a luteinizing hormone receptor (LHR)-threshold model, in which only follicles expressing sufficient levels of LHR respond to the LH surge and proceed to ovulation. Here we propose a novel mechanism that explains the difference between ovulatory (F1) and non-ovulatory (F2) follicles using the cloudy catshark as a model. The cloudy catshark possesses a hierarchical ovary and produces only two eggs per reproductive cycle. Both F1 and F2 follicles are capable of receiving and responding to LH, as evidenced by their comparable expression of lhr and the downregulation of lhr following LH surge. Nevertheless, LH stimulation selectively activates transcriptional programs associated with the ovulatory process exclusively in F1 follicles. These include progesterone production via star2 upregulation, as well as cancer-associated transcriptional pathways, including transcription factors runxs, prostaglandin-related genes (ptgs2 and ptger1), and matrix metalloproteinases. These results indicate that ovulatory and non-ovulatory follicles may exhibit qualitatively distinct transcriptional responses to the LH surge, potentially challenging the prevailing LHR-threshold model in vertebrates, in which LHR expression is considered a key determinant of ovulatory competence.

Understanding host-pathogen interactions at the molecular level is essential to elucidating the mechanisms that govern immunity and pathogenesis. While diverse responses to viral infection have been documented, it remains unclear if this variability arises from the complex host milieu or represents an intrinsic property of the infection itself. To investigate this, we performed single-cell (sc) RNA sequencing analysis of infected MRC-5 fibroblast cells with human coronavirus 229E (HCoV-229E), which revealed pronounced variation in viral load across time points and biological replicates. While viral sequences were higher at 24 hours post-infection (hpi), more host genes were differentially expressed at 48 hpi, indicating dynamic responses during infection progression. Cells with higher viral load upregulated expression of unfolded protein response genes and NF-{kappa}B regulators, and downregulated expression of fibroblast identity and cell cycle genes, reflecting a shift toward a stress-adaptive, antiviral state. Network analyses identified NF-{kappa}B signaling as a central regulatory axis, with negative regulators overexpressed in high-viral-load clusters. Additionally, ATAC-seq analysis showed that regions of increased chromatin accessibility were enriched for NF-{kappa}B subunits, further supporting its role in transcriptional control. These findings demonstrate that even within ostensibly uniform cell cultures, viral infection induces distinct heterogeneous transcriptional and regulatory responses.

Synapses are known to remodel their proteome during sleep. However, the exact mechanisms driving this remodelling and its impact on synaptic function or cognition are not well understood. We combine 24-hour EEG recordings with time-resolved synaptic proteomics in a model of SYNGAP1-Related Disorders to reveal a mechanism by which slow-waves and spindles, two NREM sleep oscillations, mediate the remodelling of the synaptic proteome. Moreover, we uncover that this remodelling promotes synaptic stabilization, which could support sleep-dependent memory consolidation. In contrast, the increase of slow-waves and decrease of spindles found in Syngap1+/- mice would activate molecular pathways involved in synaptic weakening instead of stabilization. This is consistent with the proposed roles of slow-waves and spindles in synaptic downscaling and potentiation, respectively. Here, we provide evidence on how NREM oscillations regulate the synaptic proteome and reveal a pathological mechanism that could be of relevance to all neurodevelopmental disorders coursing with sleep disturbances.

Planarian flatworms represent one of the most evolutionarily informative nervous systems for an account of ancient bilaterian brains. Likewise, the unparalleled regenerative ability of planarians makes possible certain investigations of neural development, memory, and behavior that are simply impossible with other model organisms. Despite these facts, learning and memory are today underexplored in planarians, likely due in part to the shadow of controversial 20th-century experiments on the transfer of memories between individual flatworms. Here, we attempted to replicate and extend the classical conditioning experiments in planarians that were the basis of the later memory transfer work. We failed to find evidence for classical conditioning in any of our procedural variations and obtained similar results using computer vision methods to avoid subjectivity in manual video annotation. Our results cast doubt on the suitability of planarian flatworms for studying primitive learning processes and the molecular basis of memory using classical conditioning.

The central role of microglia in CNS function in health and disease has resulted in large interest in targeting microglial as treatments for neurodegenerative disease; understanding the factors that regulate microglial gene expression will be crucial to this goal. microRNAs (miRNAs) are among the most abundant post transcriptional regulators of gene expression. miRNAs suggests miRNA were likely key to significant evolutionary events as regulators of gene expression. The miRNAome of microglia is critical to their correct functioning but the miRNA that define microglia identity and regulate key functions have not been fully defined. In this study we performed a detailed analysis of the microglial miRNAome to identify miRNA enriched in microglia that are conserved across species (human, mouse, and xenopus). We further characterised the expression of these conserved miRNAs during demyelination and remyelination and identified conserved function of a microglial-enriched miRNA across species. These findings reveal evolutionary conservation of specific miRNAs, suggesting an important role in establishing and maintaining microglial identity. They also highlight miRNAs that may be critical for microglial function in the central nervous system in both health and disease. Overall, this work advances our understanding of the factors that regulate microglial gene expression.