bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic relationships and biobehavioral pathways between suicidality and comorbid mental disorders: a comprehensive cross-phenotype analysis
Authors: Huang Yunqi , Meng Ze , Tao Shiwan , Liu Yunjia , Miller-Matero Lisa R. , Iturralde Esti , Liang Xiaoyu , Levin Albert M. , Ahmedani Brian K. , Wang Qiang , Gui Hongsheng 
Published: January 2025

AbstractBackgroundThe close relationships between mental disorders and suicidality are frequently seen in epidemiology. Shared genetic liabilities and brain structure variation may underlie these associations. Therefore, we aimed to investigate the phenotypic and polygenetic associations between multiple mental disorders and different levels of suicidality, as well as mediation by grey morphology and white matter tracts.MethodsUsing raw data from the UK Biobank (UKB) European population, we first evaluated the phenotypic and polygenic relationships between 12 mental disorders and gradient scales of suicidality. We then accessed data from the All of Us (AoU) diverse cohort to replicate findings in European and African American populations. Demographic and social factors, including age, sex, BMI, education, deprivation, income, smoking, and chronic pain were included as covariates. Second, we used existing genome-wide association study (GWAS) summary statistics from 12 major mental conditions to estimate genetic correlations and identify pleiotropic genes using a combination of statistical genetics tools. Third, we further explored the potential mediation effects of brain structure on the relationship between mental disorders and suicidality through structural equation modeling and Mendelian randomization analyses.ResultsIn the UKB European population, 150,861 eligible individuals were retained after standard GWAS quality control. Nine out of 12 mental disorders showed both significant phenotypic and polygenic correlations with gradient suicidality (Pbonferroni<0.05). Using GWAS summary statistics, we also observed positive global and regional genetic correlations between the 12 mental disorders and suicidality (rgranging from 0.25 to 0.68,Pbonferroni<0.05). Across pairs of suicidality and other mental disorders, we identified 73 out of 136 pleiotropic functional genes (including 58 novel ones associated with suicidality) shared by two or more pairs. These genes were enriched in pathways including regulation of immune system process and DNA, nucleosome and chromatin organization, and phenotypes as common mental disorders and brain morphology. Finally, the association between mental disorders and suicidality was significantly mediated by several structural brain imaging features.ConclusionThis study underscores the urgent need to address the shared and distinct genetic architecture of suicidality and its related mental conditions. Combining longitudinal population-level biobanks with disease-ascertained GWAS data is warranted to further enhance our understanding of this complex phenomenon. Our research findings will guide future suicide prevention and precise treatment among individuals with or without major mental disorders.
Subcortically generated movements activate motor cortex during sleep and wake in rats through postnatal day 24
Authors: Reid Madilyn R. , Dooley James C. 
Published: January 2025

AbstractDuring early postnatal development, cortical motor control emerges from complex interactions between cortical and subcortical circuits. In primary motor cortex (M1), we know that this process depends on neural activity, but large gaps remain in our understanding of how M1 neural activity is patterned prior to the development of cortical motor control. To track the development of movement-related activity in M1 across sleep and wake, we performed acute, extracellular recordings of single-unit activity in the forelimb region of M1 of unanesthetized, head-fixed rats from postnatal day 12 (P12) to P24. At all ages, a subset of M1 neurons responded robustly and somatotopically to spontaneous limb twitches that occur during REM sleep. M1 neurons also showed robust responses to wake movements at these ages. From P12 to P24, the proportion of M1 neurons that showed twitch-related activity decreased, twitch-related activity became more temporally refined, and there was an increase in the proportion of activity that preceded movement onset. To compare M1’s developmentally nascent activity at P24 with that of an established motor structure, we performed simultaneous recordings in M1 and the red nucleus (RN). RN activity reliably preceded both twitches and wake movements, particularly compared to M1, reinforcing the conclusion that as late as P24 RN still predominantly drives limb movements. These results highlight M1’s protracted development and the continued importance of subcortically generated movements in driving activity that shapes M1’s circuitry, suggesting that movement-related activity during sleep and wake promotes the development of M1’s motor functions.
Identification and Engineering of UDP-rhamnosyltransferase fromTrillium tschonoskiifor Heterologous Biosynthesis of Polyphyllin II in Engineered Yeast
Authors: Yang Yuxin , Wang Haowen , Wu Ziya , Wang Xing , Tong Yuru , Huang Wei , Liu Xuan , Zhao Huan , Hu Yating , Zhang Xianan 
Published: January 2025

AbstractPolyphyllins, a class of isospirostan-type steroidal saponins, exhibit potent cytotoxicity against a variety range of cancer cells. Although extensive research efforts have been made, the complete biosynthetic pathway of these compounds remains unclear. In order to elucidate these pathways, different tissues from Trillium tschonoskii were collected for sequencing that yielded 173,382 high-quality unigene sequences, among which 353 were annotated as glycosyltransferases. Then, a novel rhamnosyltransferase gene, UGT738A3, was characterized, which catalyzes the conversion of triglycoside polyphyllin III and pennogenin 3-O-beta-chacotrioside into tetraglycoside polyphyllin II and polyphyllin VII. The key residues that affect the catalytic activity of UGT738A3 were identified through site-directed mutation that the mutant A158T/P101L exhibited improved catalytic activity towards polyphyllin III and pennogenin 3-O-beta-chacotrioside by 2.5-fold and 6.5-fold respectively. We thus reconstructed the biosynthesis pathway of polyphyllin II in yeast by introducing the UGT93M3(catalyzing the formation of polyphyllin VI) and UGT738A3A158T/P101L3. This study not only elucidates the pivotal role of UGT738A3 in catalyzing the formation of tetraglycoside, but also provides highly efficient enzymatic components essential for the heterologous biosynthesis of polyphyllin saponins.
Distal mutations in a designed retro-aldolase alter loop dynamics to shift and accelerate the rate-limiting step
Authors: Hunt Serena E. , Klaus Cindy , John Aqza E. , Zarifi Niayesh , Martinez Alec , Feixas Ferran , Garcia-Borràs Marc , Thompson Michael C. , Chica Roberto A. 
Published: January 2025

AbstractAmino-acid residues distant from an enzyme’s active site are known to influence catalysis, but their mechanistic contributions to the catalytic cycle remain poorly understood. Here, we investigate the structural, functional, and mechanistic impacts of distal and active-site mutations discovered through directed evolution of the computationally designed retro-aldolase RA95. Active-site mutations improve catalytic efficiency by 3,600-fold, while distal mutations alone offer no improvement. When combined with active-site mutations, distal mutations further increase efficiency by 6-fold, demonstrating an epistatic effect. X-ray crystallography and molecular dynamics simulations reveal that distal mutations promote active site opening by altering loop dynamics. Kinetic solvent viscosity effects and electrostatic analysis show that distal mutations accelerate the chemical transformation by 100-fold, shifting the rate-limiting step to product release, which is further accelerated by the increased opening of the active site. These findings highlight the critical role of distal residues in shaping the active-site environment and facilitating the structural dynamics essential for progression through the catalytic cycle.
Feedback regulation between FOXM1 and APC/CCdh1determines the changes in cell cycle dynamics during aging
Authors: Araújo Ana Rita , Gaspar-Silva Filipa , Logarinho Elsa 
Published: January 2025

ABSTRACTAging is characterised by a loss of regenerative capacity, though it remains elusive how aged proliferating cells slowdown cycling eventually becoming senescent. We previously found that repression of the FOXM1 transcription factor accounts for mitotic decline during aging due to a global transcriptional shutdown of mitotic genes in proliferating cells. Intriguingly, a 1.5-fold increase in both cell cycle and mitosis durations was observed in elderly cells in deviancy to a previous study showing mitosis to be temporally insulated from variability in earlier cell cycle phases due to the robustness of the positive feedback loop controlling CDK1-Cyclin B1 activity. Thus, we asked if molecular thresholds controlling cell cycle phase transitions become unfitted with aging. Here, we used live-cell imaging of primary human dermal fibroblasts of advancing age donors in combination with high-throughput image analysis, to investigate age-related changes in cell cycle dynamics. Interestingly, we found mitosis insularity to be gradually lost along aging due to defective switch-like activation of CDK1 at mitotic entry driven byFOXM1repression. Moreover, we found the levels of FZR1/Cdh1 co-activator of APC/C, the E3-ubiquitin ligase directing the proteolytic degradation of FOXM1 at mitotic exit, to increase with advancing age. Importantly,FZR1/Cdh1repression was shown to restore cell cycle fitness and FOXM1 levels in aged proliferating cells, preventing the accumulation of cell cycle inhibitors and senescence markers in their progeny. Thus, changes in FOXM1 and APC/CCdh1interlinked activities account for the loss of proliferative capacity and senescence accrual during aging, thereby delivering useful markers and/or targets to explore in anti-aging approaches.
Cerebellar Purkinje cell stripe patterns reveal a differential vulnerability and resistance to cell loss during normal aging in mice
Authors: Donofrio Sarah G. , Brandenburg Cheryl , Brown Amanda M. , Lin Tao , Lu Hsiang-Chih , Sillitoe Roy V. 
Published: January 2025

ABSTRACTAge-related neurodegenerative diseases involve reduced cell numbers and impaired behavioral capacity. Neurodegeneration and behavioral deficits also occur during aging, and notably in the absence of disease. The cerebellum, which modulates movement and cognition, is susceptible to cell loss in both aging and disease. Here, we demonstrate that cerebellar Purkinje cell loss in aged mice is not spatially random but rather occurs in a pattern of parasagittal stripes. We also find that aged mice exhibit impaired motor coordination and more severe tremor compared to younger mice. However, the relationship between patterned Purkinje cell loss and motor dysfunction is not straightforward. Examination of postmortem samples of human cerebella from neurologically typical individuals supports the presence of selective loss of Purkinje cells during aging. These data reveal a spatiotemporal cellular substrate for aging in the cerebellum that may inform about how neuronal vulnerability leads to neurodegeneration and the ensuing deterioration of behavior.
Simultaneous, real-time tracking of many neuromodulatory signals with Multiplexed Optical Recording of Sensors on a micro-Endoscope
Authors: Kalugin Peter N. , Soden Paul A. , Massengill Crystian I. , Amsalem Oren , Porniece Marta , Guarino Diana C. , Tingley David , Zhang Stephen X. , Benson Jordan C. , Hammell Madalon F. , Tong David M. , Ausfahl Charlotte D. , Lacey Tiara E. , Courtney Ya’el , Hochstetler Alexandra , Lutas Andrew , Wang Huan , Geng Lan , Li Guochuan , Li Bohan , Li Yulong , Lehtinen Maria K. , Andermann Mark L. 
Published: January 2025

AbstractDozens of extracellular molecules jointly impact a given neuron, yet we lack methods to simultaneously record many such signals in real time. We developed a probe to track ten or more neuropeptides and neuromodulators using spatial multiplexing of genetically encoded fluorescent sensors. Cultured cells expressing one sensor at a time are immobilized at the front of a gradient refractive index (GRIN) lens for 3D two-photon imagingin vitroandin vivo.The sensor identity and detection sensitivity of each cell are determined via robotic dipping of the probe into wells containing various ligands and concentrations. Using this probe, we detected stimulation-evoked release of multiple neuromodulators in acute brain slices. We also tracked endogenous and drug-evoked changes in cerebrospinal fluid composition in the awake mouse lateral ventricle, which triggered downstream activation of the choroid plexus epithelium. Our approach offers a first step towards quantitative, real-time, high-dimensional tracking of brain fluid composition.
The biochemical function of bivalent aptamer assemblies against B-cell markers CD19 and CD20
Authors: Cen Yilam Ng , Williams Nicole B. , Di Siervi Nicolás , Chen Lexi , Seneviratne Pramodh , Kreitzer Geri , Cerchietti Leandro , Mallikaratchy Prabodhika 
Published: January 2025

AbstractAptamers are synthetic oligonucleotides that bind to their specific receptors with high specificity, offering immense potential for the development of molecular tools. Using recently introduced Ligand-Guided Selection (LIGS), a variant of the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) we previously identified anti-CD19 and anti-CD20 aptamers with specificity and affinity. Given their high expression levels, B-cell markers CD19 and CD20 are widely utilized in the diagnosis of B-cell-related malignancies and autoimmune diseases. Here, we report the design and functional characterization of bivalent aptamer assemblies targeting CD19 and CD20 expressed in B-cell lymphomas. Using a strategic approach, we synthesized dimeric constructs of these aptamers with polyethylene glycol (PEG) linkers of varying lengths to tether the two aptamer units. The bivalent aptamers demonstrated enhanced binding affinity and specificity, with an optimal linker length of ∼3.96 nm. Functional studies revealed that dimeric CD19 aptamers selectively internalized in CD21-negative B-cells, while CD20 aptamers exhibited improved antigen binding without triggering calcium release. These findings highlight the potential of bivalent aptamers in engineering cost-effective, stable, and precise therapeutic agents for B-cell-related malignancies, such as diffuse large B-cell lymphoma (DLBCL). This work advances the development of aptamer-based synthetic therapeutics with promising clinical applications.
Evolution and development of segmented body plan revealed byengrailedandwnt1gene expression in the annelidAlitta virens
Authors: Kairov Arsenii I. , Kozin Vitaly V. 
Published: January 2025

AbstractSegmentation is one of the most striking features of bilaterians, and understanding its mechanisms provides insights into the evolution of body plans. In annelids, segmentation occurs at different developmental stages through a variety of processes, yet the molecular pathways remain underexplored. Aiming to compare segmentation patterns in ontogeny and phylogeny, we analysed the expression ofAvi-en(homologous toengrailed) andAvi-wnt1in the nereidid polychaeteAlitta virens. Using in situ hybridization, immunofluorescence, and cell proliferation assays, we mapped the spatiotemporal expression of these genes across embryonic, larval, and postlarval stages. We found thatAvi-enwas expressed in solid lateral domains early in the unsegmented protrochophore stage and progressed through a metameric pattern, whileAvi-wnt1expression appeared later, also aligning with segmental boundaries. At the nectochaete stage, the posterior domain ofAvi-enexpression in the growth zone expanded and splitted into two due to increased cell proliferation. The postlarval segment primordium then developed progressively, culminating in the activation ofAvi-wnt1at the posterior border. According to available published data, the revealed pattern of gradual segment formation is unique to nereidids. The observed divergence in gene expression and cell proliferation across annelids suggests that segmentation in bilaterians did not arise from a common ancestral mechanism. Our study enhances future progress in understanding the evolution of body patterning by providing a foundation for future comparisons.
A novel approach to tagging tubulin reveals MT assembly dynamics of the axoneme inTrypanosoma brucei
Authors: Abbühl Daniel , Pružincová Martina , Štěpánek Luděk , Bouscasse Eleonore , Azevedo Rita , Matondo Mariette , Varga Vladimir , Bonnefoy Serge , Bastin Philippe 
Published: January 2025

AbstractThe protozoan parasiteTrypanosoma bruceiis a mono-flagellated cell during the G1-phase of its cell cycle. In order to duplicate, it assembles a new flagellum alongside the mature one, in which further elongation is prevented. Our group proposed a model where the mature flagellum is locked after construction to full length (Bertiaux et al. 2018) and access of new building blocks for elongation is exclusive to the new flagellum. To test this hypothesis directly, we developed a tool for the inducible expression of tagged tubulin. Alpha-tubulin that was tagged with an intragenic Ty-1-epitope behaved indistinguishable from untagged tubulin. Its incorporation was monitored after inducible expression, to follow the assembly dynamics of microtubules in the cell body, the mitotic spindle and the flagellum. In this study we observed that integration of tubulin occurs at the distal flagellum tip at a linear rate and is indeed restricted to the new flagellum in bi-flagellated cells. This is direct evidence that trypanosomes avoid competition between the two flagella by allowing tubulin incorporation only in the new organelle. However, by tracing flagella over several cell cycles we could also show that mature flagella do not remain locked indefinitely. The restriction is lifted briefly after the bi-flagellated cell has divided and the daughter cell inheriting the old flagellum shows incorporation of newly synthesized building blocks again. It then has to lock again before the cell can assemble a new flagellum. Our findings suggest regular incorporation of tubulin at the tip of previously locked flagella. This evidence was supported with an orthogonal approach, with which we monitored the incorporation of HaloTag-tagged radial spoke protein 4/6. Since flagellum length in trypanosomes is stable, this indicates that the entire axoneme is subject to regular events of transient disassembly followed by assembly at its distal tip.
The role of cortico-thalamic feedback for visual information processing
Authors: Wei Wenqing , Rotter Stefan 
Published: January 2025

AbstractIn the early visual system, neurons in the dorsal lateral geniculate nucleus (dLGN) not only relay visual inputs from the retina to the primary visual cortex (V1), but also receive cortico-thalamic (CT) feedback inputs, which anatomically outnumber feedforward inputs. Most experimental and theoretical work so far has focused on the modulatory influence of CT feedback on relay cells in the dLGN. However, the role of feedback for the activity of V1 neurons, which are mainly driven by visual input meditated by dLGN neurons, is still unclear. To address this question, we devised a spiking neural network model of the thalamo-cortical and cortico-thalamic loop, where the CT feedback can be turned on and off to study its effect. We identified three main phenomena of the effect of CT feedback on V1 neurons: (i) orientation selectivity of cortical responses is increased for all contrasts, (ii) preferred orientations of input and output are better aligned with each other, (iii) neuronal population activity represents the stimulus orientation with higher confidence. Our analysis showed that CT feedback generally improves the signal-to-noise ratio (SNR) of the responses of dLGN neurons and therefore also increases the SNR of thalamic inputs to V1 neurons. Moreover, we found that the modulatory effects on visual processing depend on the geometry of the CT feedback projections. We conclude that CT feedback increases the selectivity of V1 neurons particularly at low contrasts by modulating the activity of dLGN neurons.Author summaryExtensive experimental and theoretical studies have been conducted to understand the functional role of cortico-thalamic (CT) feedback on relay cells in the dorsal lateral geniculate nucleus (dLGN) during visual processing. However, it remains unclear how CT feedback affects the neuronal responses of V1 neurons. To address this question, we developed a computational model of the thalamo-cortico-thalamic loop circuit based on biophysical parameters. Our results indicate that CT feedback modulates the orientation preference of V1 neurons in a contrast-dependent manner: The increase of orientation selectivity (OS) is stronger and the input preferred orientation (PO) is better preserved at lower contrasts. Our analysis suggests a mechanistic explanation: The CT feedback attenuates the untuned part of the thalamic input, while it amplifies the tuned part. This effectively increases the signal-to-noise ratio (SNR) in particular for weak contrasts. Our network model for the first time allows us to study the effect of feedback on cortical neurons and understand the impact of the number and the geometry of feedback connections.
High optical anisotropy of the
GaSb/GaxIn1−xAsySb1−y
interface
Authors: Rygała Michał , Ziembicki Jakub , Smołka Tristan , Bader Andreas , Knebl Georg , Pfenning Andreas , Ryczko Krzysztof , Hartmann Fabian , Scharoch Paweł , Sęk Grzegorz , Höfling Sven , Motyka Marcin 
Published: January 2025

We present the investigation of optical transitions in an GaSb/GaInAsSb-based heterostructure through different experimental and numerical methods. The transitions had high-temperature stability, with them being observed in the 10–300 K temperature range. Four pronounced optical transitions are observed at low temperature with three of them being nonpolarized and one showing a degree of linear polarization higher than 60%. Time-resolved measurements of the transitions showed a complex carrier dynamics with several distinct processes related to the investigated interface. Using several numerical methods, we identified that the highly polarized transition originates from the first electron state in the GaInAsSb layer and a two-dimensional hole gas created within a triangular quantum well at the interface with the -type doped GaSb layer. The optical polarization of the signal originates in directional elongation of the atomic bonds enhanced by possible local composition fluctuations and the inheritance of these properties by the signal from the triangular quantum well. Such physical phenomena have the potential to be used as an internal polarizing filter in structures designed for midinfrared optoelectronics.

Published by the American Physical Society
2025