bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Norm-Based Coding of Vocal Identity in the Primate Auditory Cortex
Authors: Esposito Yoan , Boë Louis-Jean , Trapeau Régis , Renaud Luc , Brochier Thomas , Giamundo Margherita , Belin Pascal
Published: January 2025

Voice identity recognition is vital for social communication, yet its neural encoding mechanisms remain unclear. We investigated whether neurons in the anterior temporal voice area (aTVA) of macaques use norm-based coding (NBC), similar to face encoding in vision. Using synthetic vocalizations morphed along identity trajectories, we found that early neuronal responses (100 to 150 ms) exhibited V-shaped tuning, with minimal activity for the average voice and increased responses for extreme identities. Later (200 ms), a distinct rebound in activity for the average voice emerged, driven by a unique subpopulation. These results highlight a dynamic, multi-stage encoding strategy, extending NBC principles to auditory processing.
Neural correlates of approach and avoidance tendencies toward physical activity and sedentary stimuli: An fMRI study
Authors: Cheval Boris , Ceravolo Leonardo , Igloi Kinga , Sander David , Zimmermann Myriam , van Ruitenbeek Peter , Boisgontier Matthieu P.
Published: January 2025

Automatic tendencies toward physical activity and sedentary stimuli are involved in the regulation of physical activity behavior. However, the brain regions underlying these automatic tendencies remain largely unknown. Here, we used an approach-avoidance task and magnetic resonance imaging (MRI) in 42 healthy young adults to investigate whether cortical and subcortical brain regions underpinning reward processing and executive function are associated with these tendencies. At the behavioral level, results showed more errors in avoidance behavior following sedentary stimuli than physical activity stimuli. At the brain level, avoidance behavior following sedentary stimuli was associated with more activation of the motor control network (dorsolateral-prefrontal cortex, primary and secondary motor cortices, somatosensory cortex). In addition, increased activation of the bilateral parahippocampal gyrus — and structural deformation of the right hippocampus - were associated with a tendency toward approaching sedentary stimuli. Together, these results suggest that avoiding sedentary stimuli requires higher levels of behavioral control than avoiding physical activity stimuli.
The dependency of TMS-evoked potentials on electric-field orientation in the cortex
Authors: Granö Ida , Mutanen Tuomas P. , Nieminen Aino E. , Nieminen Jaakko O. , Souza Victor H. , Ilmoniemi Risto J. , Lioumis Pantelis
Published: January 2025

Transcranial magnetic stimulation (TMS) stimulates the brain by electromagnetic induction. The outcome depends on multiple stimulation parameters such as the induced electric-field pattern (in particular, the location of the peak field and its orientation), intensity and timing. However, it is not clear how the TMS-evoked responses are affected by all the stimulation parameters. This study elucidates the dependency of the TMS-evoked electroencephalography (EEG) responses on the orientation of the stimulating electric field. To achieve this, we analysed a dataset from six subjects who were given pulses with 36 stimulus orientations to the pre-supplementary motor area (pre-SMA). The TMS-evoked potentials (TEPs) and induced oscillations were analysed with cluster-based statistics. Source estimation was performed to assess the effects of stimulus orientation on the TMS-evoked signal propagation. The amplitudes of the early peaks (20 and 40 ms after the TMS pulse) strongly depended on the electric field orientation. Our analysis suggested orientation dependency up to 100 ms post-stimulus in most subjects, indicating changes in stimulation efficacy and potential changes in signal propagation from the stimulated site. These results suggest that different orientations may perturb different networks. Thus, the orientation is a crucial parameter for the stimulation outcome and should be adjusted according to the cortical network under investigation.
Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells
Authors: Cooke Sean F. , Wright Thomas A. , Lappin Gillian , Kyurkchieva Elka , Sin Yuan Yan , Ling Jiayue , Zorn Alina , O’Gorman Bria , Banyard William , Chang Chih-Jung , Wheadon Helen , Huang Danny T. , Baillie George S. , Blair Connor M.
Published: January 2025

Novel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represents an increasingly attractive therapeutic strategy to treating solid and haematological cancers that are depdendent upon MDM2/MDMX, regardless of TP53 mutational status. Utilising a novel first-in-class cell-penetrating peptide disruptor of MDM2 homo- and heterodimerisation (DRx-098D), we demonstrate the anti-proliferative effect of blocking MDM2 dimerisation against a a panel of human cancer cell lines that are TP53 wild-type, mutant or null. DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. Idasanutlin (a Phase III clinical candidate MDM2-p53 small molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting MDM2 dimerisation in TP53 wild-type and mutant cancers.
Manual versus automatic annotation of transposable elements: case studies inDrosophila melanogasterandAedes albopictus, balancing accuracy and biological relevance
Authors: Carrasco-Valenzuela Tomas , Marino Alba , Storer Jessica M. , Bonnici Iago , Mazzoni Camila J. , Fontaine Michael C. , Haudry Annabelle , Boulesteix Matthieu , Fiston-Lavier Anna-Sophie
Published: January 2025

Transposable elements (TEs) play a pivotal role in genome evolution, yet their detection and annotation remain challenging due to the limitations of current methods. Manual curation is considered the gold standard for generating TE libraries, particularly for TE-focused studies, although it requires extensive training and time. With the rapid increase in the number of genome assembly publications and the growing need for large-scale comparative analyses, automated software for TE annotation has become indispensable. This study compares manual and automated approaches to TE detection and annotation, focusing on two species:Drosophila melanogasterandAedes albopictus.

InD. melanogaster, a species with a well-annotated TE repertoire and a smaller genome, the differences between manual curation (MCTE) and automated annotation (ATTE) are relatively minor. However, significant differences arise when analysingAe. albopictus, a species with a relatively large genome and high TE diversity. While automated methods identified a greater number of TEs, including many smaller and fragmented elements, manual curation provided more detailed classifications and, on average, larger consensi. Automated pipelines offer a viable alternative for genome-wide analyses such as TE content estimation, particularly when time and resources are limited. However, caution is advised when interpreting results, as finer details of TE dynamics may be overlooked.

This study highlights that the choice of annotation method depends on the intended analysis. Manual curation is more suitable for TE population genomics and studies focusing on recent transposable element activity, whereas automated methods are appropriate for larger comparative analyses or genome assembly projects. Both methods have strengths and limitations, and understanding the specific features of the genome and repeatome under study is essential for selecting the appropriate approach.
Pre-clinical validation of in vitro engineered but cell-free human tissue grafts for skeletal regeneration
Authors: Garcia Alejandro Garcia , Prithiviraj Sujeethkumar , Raina Deepak B. , Schmidt Tobias , Baudet-Quintino Aurelie , Anton Sara Gonzalez , Cajal Laura Rabanal , Kahn Robin , Tägil Magnus , Bourgine Paul
Published: January 2025

Tissue engineering strategies predominantly consist in the autologous generation of living substitutes capable of restoring damaged body parts. Persisting challenges with patient-specific approaches include an inconsistent performance, high costs and delayed graft availability. Towards developing a one-for-all solution, a more attractive paradigm lies in the exploitation of dedicated cell lines for the fabrication of human tissue grafts. Following decellularization, this new class of biomaterials relies on the sole extracellular matrix scaffold and embedded growth factors instructing endogenous repair. This conceptual approach was previously validated by manufacturing human cartilage using a custom mesenchymal line, exhibiting remarkable osteoinductive capacity following lyophilization. However, key criteria to ensure clinical translation include a proper decellularization as well as stringent assessment of both immunogenicity and regenerative performance. Here, we report the engineering and decellularization of human cartilage tissue with minimal matrix impairment. Ectopic evaluation in immunocompetent and immunocompromised animals reveal preserved osteoinductivity which correlates with M0 to M2 polarization from Day 7 post-implantation. By establishing in vitro human allogeneic co-culture models, we evidenced the immuno-regulatory properties of cell-free human cartilages, suppressing T cell activation upon mounting of an immune response by activated macrophages, monocytes and dendritic cells. Last, the regenerative performance was stringently assessed in a competent rat orthotopic models whereby human cartilage grafts fully restored critical-sized femoral defects within six weeks, achieving native bone-like biomechanical properties by twelve weeks. Taken together, our study compiles safety and efficacy pre-requisites towards a first-in-human trial for engineered and decellularized human tissue grafts.
An expanded palette of bright and photostable organellar Ca2+sensors
Authors: Moret Agathe , Farrants Helen , Fan Ruolin , Zingg Kelsey , Gee Christine E. , Oertner Thomas G. , Rangaraju Vidhya , Schreiter Eric R. , de Juan-Sanz Jaime
Published: January 2025

The use of fluorescent sensors for functional imaging has revolutionized the study of organellar Ca2+signaling. However, understanding the dynamic interplay between intracellular Ca2+sinks and sources requires bright, photostable and multiplexed measurements in each signaling compartment of interest to dissect the origins and destinations of Ca2+fluxes. We introduce a new toolkit of chemigenetic indicators based on HaloCaMP, optimized to report Ca2+dynamics in the endoplasmic reticulum (ER) and mitochondria of mammalian cells and neurons. Both ER-HaloCaMP and Mito-HaloCaMP present high brightness and responsiveness, and the use of different HaloTag ligands enables tunable red and far-red emission when quantifying organelle Ca2+dynamics, expanding significantly multiplexing capacities of Ca2+signaling. The improved brightness of ER-HaloCaMP using either red or far-red HaloTag ligands enabled measuring ER Ca2+fluxes in axons of neurons, in which the ER is formed by a tiny tubule of 30-60 nanometers of diameter that impeded measurements with previous red ER Ca2+sensors. When measuring ER Ca2+fluxes in activated neuronal dendritic spines of cultured neurons, ER-HaloCaMP presented increased photostability compared to the gold-standard ER Ca2+sensor in the field, ER-GCaMP6-210, while presenting the same responsiveness. On the other hand, Mito-HaloCaMP presented higher responsiveness than current red sensors, and enabled the first measurements of mitochondrial Ca2+signaling in far-red in cell lines and primary neurons. As a proof-of-concept, we used 3-plex multiplexing to quantify interorganellar Ca2+signaling. We show that effective transfer of Ca2+from the ER to mitochondria depends on the ER releasing a critical amount of Ca2+. When this threshold is not met, the mobilized Ca2+is diverted to the cytosol instead. Our new toolkit provides an expanded palette of bright, photostable and responsive organellar Ca2+sensors, which will facilitate future studies of intracellular Ca2+signaling.
Endogenously expressed P2X5 includes a proportion of isoforms or transcript variants sensitive to extracellular ATP
Authors: Yang Xiao-Na , Wang Dong-Ping , Shen Chen-Hui , Xi-Chen  , Yang Hui , Zhou Xing , Guo Chang-Run , Tian Yun , Zhu Michael X. , Yu Ye
Published: January 2025

The P2X receptor family comprises ATP-gated non-selective cation channels central to physiological processes across the nervous, immune, cardiovascular, respiratory, and reproductive systems. While P2X1, P2X2, P2X3, P2X4, and P2X7 are well-established as ATP-sensitive, P2X5 isoforms and transcript variants (TVs) have traditionally been considered ATP-insensitive, limiting their functional exploration. This study identifies previously overlooked ATP-sensitive P2X5 isoforms across diverse species. Through gene profiling and next-generation sequencing (NGS), we found that the zfP2X5TV2isoform dominates ATP-sensitive forms in zebrafish. In mice, ATP-sensitive mP2X5G317(mP2X5.1) comprises ∼90% of transcripts, while in rats, exon 3-containing rP2X5F191accounts for over 70%. In human cell lines, ATP-sensitive isoforms retaining exons 3, 7, and 10 represent ∼15-30% of P2X5 transcripts. RNA-seq from human tissues confirms frequent retention of exons 3 and 7 and polymorphic exon 10 expression. ATP-sensitive P2X5 variants were also identified in chickens, bullfrogs, dogs, cows, and naked mole-rats. These findings challenge the prevailing assumption of ATP-insensitivity, highlighting the need to reassess P2X5’s roles in physiological and pathological contexts.
The Neurocognitive efficiency score: Derivation, validation, and application of a novel combination of concurrent electrophysiological and behavioral data
Authors: Wenger Michael J. , Townsend James T. , Newbolds Sarah F.
Published: January 2025

Perceptual and cognitive work require the expenditure of brain energy, and the efficiency of that energy expenditure can vary as a function of a range of exogenous and endogenous factors. The same is true for physical work, and tools have been developed to quantify energetic efficiency in the performance of physical work. The same is not true for the study of perceptual and cognitive work. We here draw on two lines of research—the formal characterization of workload capacity in perception and cognition, and the study of physical work—to propose a novel measure of neurocognitive efficiency. This neurocognitive efficiency score (NES) combines reaction time data with measures on concurrently acquired electroencephalographic (EEG) data to form a ratio that can be interpreted in terms of work accomplished relative to energy. We consider three measures on the EEG and show that one of them—global field power (GFP)—evidences a strong relationship to measures of metabolic energy expended. We then show how the NES can provide insights into differences in perceptual performance as a function of biological state. We argue that the NES has the potential for a wide range of applications in the study of perception and cognition in the context of factors including (but not limited to) aging, disease, stress, and differences in levels of expertise.
ANGPTL6 variant induces cerebral vascular dysfunction and predisposes to intracranial aneurysm in mice
Authors: Baron-Menguy Céline , Freneau Milène , Mrad Mary-Adel , Lebot Corentin , Rio Marc , L’allinec Vincent , Quillard Thibaut , Desal Hubert , Redon Richard , Bourcier Romain , Vion Anne-Clémence , Loirand Gervaise
Published: January 2025

Background

Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal sub-arachnoid hemorrhage. Pathophysiological mechanisms responsible for AI remains largely unknown, but increasing evidence suggest that genetic susceptibility plays a predominant role. We recently identified a rare nonsense variant inANGPTL6gene that prevented angiopoietin-like 6 (ANGPTL6) secretion and predisposed to IA. The aim of this study is now to understand why the ANGPTL6 variant predisposes to IA.

Methods

Angptl6-knock in mice were generated by homologous recombination. Cerebral arteries of the circle of Willis have been analyzed under basal and hemodynamic overload conditions. Functional properties of cerebral arteries have been analyzed by pressure arteriography. Effect of recombinant ANGPTL6 have been assessed on vascular smooth muscle cells and ANGPTL6 partners have been analyzed by surface plasmon resonance.

Results

Angptl6-knock in mice display endothelial dysfunction expressed by reduced NO production in response to flow in cerebral arteries. They present exaggerated dilatation of cerebral arteries under hypertensive stress, and aggravated wall damage and aneurysmal remodeling of the intima and media at arterial bifurcations of the circle of Willis under hemodynamic overload. Matrix bound ANGPTL6 decreased VSMC migration and increased adhesion and FAK signaling activation, without affecting VSMC phenotype. Surface plasmon resonance analyses identified αvβ5 integrin as a new ANPTL6 receptor.

Conclusions

Angptl6-knock in mice mimicked the main features of IA in humans. ANGPTL6 appears to be an extracellular matrix component regulating vascular cell function, which may be involved in mechanosensing and generating adapted vascular cell responses to hemodynamic stress. Non-secreted ANGPTL6 variants would result in the loss of this function, thus favoring IA under conditions of hemodynamic overload.
Subthalamic Signature of Freezing of Gait in Parkinson’s Disease
Authors: Collomb-Clerc Antoine , Yeche Mathieu , Demain Adèle , Hamme Angèle Van , Olivier Claire , Belaid Hayat , Ziri Déborah , Derrey Stéphane , Fernandez-Vidal Sara , Lehongre Katia , Karachi Carine , Lau Brian , Welter Marie-Laure
Published: January 2025

Freezing of gait (FOG) is a significant disability in Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) only partially alleviates it, with approximately one-third of patients experiencing worsening FOG within a year after surgery. The precise role of STN dysfunction in gait disabilities and FOG remains not fully elucidated. To investigate this, we recorded gait and STN local field potential (LFP) activity in 38 PD patients, both Off and On dopamine medication. Our analysis focused on the relationship between gait performance and STN neuronal activity, particularly examining differences in LFP activity across the posterior-sensorimotor and central-associative regions of the STN. When Off dopamine medication, 12 patients experienced FOG during recordings, with a total of 263 FOG episodes documented. Even in trials without FOG episodes, these patients exhibited altered gait initiation strategies, prioritizing stepping rhythm to manage balance and initiate walking. In contrast, non-FOG patients maintained a higher walking pace. STN activity patterns revealed key differences. In FOG patients, weaker STN alpha/low beta band activity in the STN was associated with walking pace, while stronger decreased low beta band activity correlated with rhythm and balance control. This low beta band association extended from the posterior-sensorimotor to the central-associative STN. In contrast, non-FOG patients showed a more restricted relationship between low beta band activity and gait performance, confined to the posterior STN. As stepping rhythm deteriorated further in FOG patients, FOG episodes occurred. FOG episodes were preceeded by a significant positive relationship between high beta power and rhythm restricted to the posterior STN, with a reverse negative relationship with pace, and a disruption in low beta desynchronization across both posterior and central STN regions. Dopamine medication significantly improved gait patterns, and partially restored STN neuronal activity, reducing differences between FOG and non-FOG patients. These findings differentiate two FOG states, i.e. predisposition and occurrence, each associated with distinct gait initiation strategies and STN activity patterns. They suggest distinct pathophysiological roles of low and high beta band STN activity within specific STN regions in regulating gait and FOG. These findings provide key insights for refining targeted DBS therapies.
Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting
Authors: Yadollahi P. , McCord K.A. , Li Y. , Dayoub H. , Saab K. , Essien F. , Hyslop S. , Kan E. , Ahmed K.M. , Kirby P. R. , Putluri V. , Ambati C.S.R , Kami Reddy K.R. , Castro P. , Skinner H.D. , Coarfa C. , Decker W.K. , Osman A.A , Patel R. , Myers J.N. , Lai S.Y. , Putluri N. , Johnson F.M. , Frederick M.J. , Hudson W.H. , Sandulache V.C.
Published: January 2025

Background

For patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g.,NOTCH1mutations).

Purpose

We evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC.

Methods

We measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCsin vitroand tested efficacyin vivoin subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics.

Results

The PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in anin vivoshRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T lymphocytes.

Conclusion

Our findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC.

Statement of translational relevance

Cisplatin resistance, whether intrinsic or acquired, translates to treatment failure and nearly universal death in head and neck squamous cell carcinoma (HNSCC). However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease.
High resolution structures of Myosin-IC reveal a unique actin-binding orientation, ADP release pathway, and power stroke trajectory
Authors: Chavali Sai Shashank , Carman Peter J , Shuman Henry , Ostap E Michael , Sindelar Charles V
Published: January 2025

Myosin-IC (myo1c) is a class-I myosin that supports transport and remodeling of the plasma membrane and membrane-bound vesicles. Like other members of the myosin family, its biochemical kinetics are altered in response to changes in mechanical loads that resist the power stroke. However, myo1c is unique in that the primary force-sensitive kinetic transition is the isomerization that follows ATP binding, not ADP release as in other slow myosins. Myo1c also powers actin gliding along curved paths, propelling actin filaments in leftward circles. To understand the origins of this unique force-sensing and motile behavior, we solved actin-bound myo1c cryo-EM structures in the presence and absence of ADP. Our structures reveal that in contrast with other myosins, the myo1c lever arm swing is skewed, partly due to a different actin interface that reorients the motor domain on actin. The structures also reveal unique nucleotide-dependent behavior of both the nucleotide pocket as well as an element called the N-terminal extension. We incorporate these observations into a model that explains why force primarily regulates ATP binding in myo1c, rather than ADP release as in other myosins. Integrating our cryo-EM data with available crystallography structures allows the modeling of full-length myo1c during force generation, supplying insights into its role in membrane remodeling. These results highlight how relatively minor sequence differences in members of the myosin superfamily can significantly alter power stroke geometry and force sensing properties, with important implications for biological function.
A bispecific antibody overcomes limitations of prior strategies to achieve effective and tumor-selective Death Receptor 5 (DR5) clustering
Authors: Goldmacher Victor S. , Gershteyn Iosif M. , Chari Ravi , Kovtun Yelena
Published: January 2025

The bispecific antibody IMV-M was designed to bind and cluster Death Receptor 5 (DR5) specifically upon engaging the tumor antigen MUC16. This dual-binding mechanism induces apoptosis in MUC16-positive tumor cells through a novel enhancement process. IMV-M exhibited potent, MUC16-selective anti-tumor activityin vitroand in xenograft models, achieving efficacy at safe therapeutic doses without requiring secondary crosslinking. In contrast, earlier DR5-targeting tumor-selective bispecific antibodies either demonstrated limited anti-tumor activity or relied on secondary crosslinking, highlighting that binding of a bispecific antibody to a tumor antigen and DR5 alone is insufficient for effective DR5 clustering. Our findings reveal that an additional crowding mechanism for efficient DR5 clustering by bispecific antibodies is required. In contrast to the targeted delivery approach with antibody-drug conjugates (ADCs), our approach offers a pathway for developing more effective and safer cancer therapies. Importantly, the MUC16 antigen is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers while being almost completely absent in normal tissues, with highly limited expression in certain epithelial cells, indicating broad applicability of this bispecific antibody.
Influence of solvent, sex, and age on pharmacokinetic and acute behavioral effects of vaporized cannabis extract in mice
Authors: Westbrook S.R. , Jensen A.L. , Copeland-Solorzano V. , Buursma J. , Freeby G. , von Melville T. , Edwards T. , Hayashi K. , McLaughlin R.J. , Delevich K.M.
Published: January 2025

The legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Rodent models are particularly valuable in this respect because they provide precise control over external variables. Previous rodent studies have found age and sex differences in response to injected Δ9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. However, this route of administration does not mimic the most common way humans consume cannabis, i.e. through inhalation. Here, we sought to address this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis extract in mice. Adolescent (postnatal day [P] 35-50) and adult (≥ P70) mice of both sexes received noncontingent exposure to 0 mg/ml, 150 mg/ml, or 300 mg/ml vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerol (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC and its metabolites were analyzed. Measured THC levels were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions themselves when PEG was the solvent compared to PG/VG. Vaporized cannabis (dissolved in PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to the plasma THC levels achieved. Although we found no significant sex differences in the acute behavioral effects of vaporized cannabis, there were significant sex differences in plasma THC metabolites indicating that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, the current findings add to a growing number of studies implementing vaporized cannabinoid delivery approaches by revealing PEG as the superior solvent for studies involving cannabis extract.
Giant KASH proteins and ribosomes synergistically establish cytoplasmic biophysical propertiesin vivo
Authors: Ding Xiangyi , Hao Hongyan , Elnatan Daniel , Alinaya Patrick Neo , Kalra Shilpi , Kaur Abby , Kumari Sweta , Holt Liam J. , Luxton G. W. Gant , Starr Daniel A.
Published: January 2025

Understanding how cells control their biophysical properties during development remains a fundamental challenge. While cytoplasmic macromolecular crowding affects multiple cellular processes in single cells, its regulation in living animals remains poorly understood. Using genetically encoded multimeric nanoparticles forin vivorheology, we discovered thatC. eleganstissues maintain distinct cytoplasmic biophysical properties that differ from those observed across diverse systems, including bacteria, yeast species, and cultured mammalian cells. We identified two conserved mechanisms controlling cytoplasmic macromolecular diffusion: ribosome concentration, a known regulator of cytoplasmic crowding, works in concert with a previously unknown function for the giant KASH protein ANC-1 scaffolding the endoplasmic reticulum. These findings reveal mechanisms by which tissues establish and maintain distinct cytoplasmic biophysical properties, with implications for understanding cellular organization across species.

One-Sentence Summary

Living tissues maintain unique intracellular biophysical properties under the control of cytoplasmic constraints and crowding.
The bile acid-sensitive ion channel is gated by Ca2+-dependent conformational changes in the transmembrane domain
Authors: Freitas Makayla M. , Gouaux Eric
Published: January 2025

The bile acid-sensitive ion channel (BASIC) is the least understood member of the mammalian epithelial Na+channel/degenerin (ENaC/DEG) superfamily of ion channels, which are involved in a variety of physiological processes. While some members of this superfamily, including BASIC, are inhibited by extracellular Ca2+(Ca2+), the molecular mechanism underlying Ca2+modulation remains unclear. Here, by determining the structure of human BASIC in the presence and absence of Ca2+using single particle cryo-electron microscopy (cryo-EM), we reveal Ca2+-dependent conformational changes in the transmembrane domain and β-linkers. Electrophysiological experiments further show that a glutamate residue in the extracellular vestibule of the pore underpins the Ca2+-binding site, whose occupancy determines the conformation of the pore and therefore ion flow through the channel. These results reveal the molecular principles governing gating of BASIC and its regulation by Ca2+ions, demonstrating that Ca2+ions modulate BASIC function via changes in protein conformation rather than solely from pore-block, as proposed for other members of this superfamily.
Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord
Authors: Kandror Elena K. , Wang Anqi , Carriere Mathieu , Peterson Alexis , Liao Will , Tjärnberg Andreas , Fung Jun Hou , Mahbubani Krishnaa T. , Loper Jackson , Pangburn William , Xu Yuchen , Saeb-Parsy Kourosh , Rabadan Raul , Maniatis Tom , Rizvi Abbas H.
Published: January 2025

Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.
pH adjustment increases biofuel production from inhibitory switchgrass hydrolysates
Authors: Barten Lillian M. , Crandall Johnathan G. , Xie Dan , Serate Jose , Handowski Evan , Jen Annie , Overmyer Katherine A. , Coon Joshua J. , Hittinger Chris Todd , Landick Robert , Zhang Yaoping , Sato Trey K.
Published: January 2025

Biofuels derived from renewable and sustainable lignocellulosic biomass, such as switchgrass, offer a promising means to limit greenhouse gas emissions. However, switchgrass grown under drought conditions contains high levels of chemical compounds that inhibit microbial conversion to biofuels. Fermentation of drought switchgrass hydrolysates by engineeredSaccharomyces cerevisiaeandZymomonas mobilisgenerates less ethanol than fermentation of hydrolyzed switchgrass from an average rainfall year. Here, we demonstrate that this inhibitory effect can be alleviated by altering the pH of drought-switchgrass hydrolysates made from two different pretreatment methods: Ammonia Fiber Expansion (AFEX) and Soaking in Aqueous Ammonia (SAA). Fermentation rates and biofuel production from AFEX- and SAA-pretreated switchgrass hydrolysates from normal and drought years were higher at pH 5.8 than at pH 5.0 for both Saccharomyces cerevisiaeandZymomonas mobilis. Additionally, SAA pretreatment of drought switchgrass enabled increased fermentation rates and titers compared to AFEX pretreatment. Using a synthetic mimic of switchgrass hydrolysate, we identified relief from pH-dependent inhibition by lignocellulose-derived inhibitors as the cause of increased biofuel production above a pH of 5.0. These results demonstrate that SAA pretreatment and pH adjustment can significantly improve fermentation and biofuel production from switchgrass hydrolysates and especially from drought-switchgrass hydrolysates by industrial microorganisms.
CHOLINERGIC MODULATION OF CELLULAR RESONANCE IN NON-HUMAN PRIMATE HIPPOCAMPUS
Authors: Gambrill Abigail , Rueckemann Jon W. , Barria Andres
Published: January 2025

Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals1–3. In this and adjacent regions, synchronized neuronal activity within theta-band oscillations (4-10Hz) is correlated with attentive processing that leads to successful memory encoding4–10. Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations11,12.

Unlike rodents that exhibit constant theta oscillations during movement and exploration, primates only manifest theta oscillations in transient bouts during periods of acute attention—despite conserved hippocampal anatomy13–16. The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists17, suggest that acetylcholine afferents acutely modulate local circuitry, resulting in a temporary shift in hippocampal rhythmic dynamics. However, we lack a mechanistic understanding that links cellular physiology to emergent theta-rhythmic network dynamics.

We explored the hypothesis that acetylcholine induces a distinct modulation of cellular properties to facilitate synchronization within the theta band in non-human primate neurons.

Here we show that non-human primate neurons from the CA1 region of monkey hippocampus are not homogeneous in their voltage response to inputs of varying frequencies, a phenomenon known as cellular resonance18,19. We classified these neurons as ‘resonant’ or ‘non-resonant’. Under the influence of carbachol, these two classes of neurons become indistinguishable in their resonance, suggesting that acetylcholine transiently creates a homogeneous susceptibility to inputs within the theta range. This change is mediated by metabotropic acetylcholine receptors that enhance sag potentials, indicating that acetylcholine acts on principal neurons to modulate Hyperpolarization-activated Cyclic Nucleotide-gated channels.

Our results reveal a mechanism through which acetylcholine can rapidly modulate intrinsic properties of primate hippocampal neurons to facilitate synchronization within theta-rhythmic circuits, providing insight into the unique features of primate hippocampal physiology.
Attention Modulates Stimulus Representations in Neural Feature Dimension Maps
Authors: Thayer Daniel D. , Sprague Thomas C.
Published: January 2025

Computational theories posit that attention is guided by a combination of spatial maps for individual features that can be dynamically weighted according to task goals. Consistent with this framework, when a stimulus contains several features, attending to one or another feature results in stronger fMRI responses in regions preferring the attended feature. We hypothesized that multivariate activation patterns across feature-responsive cortical regions form spatial ‘feature dimension maps’, which combine to guide attentional priority. We tested this prediction by reconstructing neural feature dimension maps from fMRI activation patterns across retinotopic regions of visual cortex using a spatial inverted encoding model. Participants viewed a peripheral visual stimulus at a random location which always contained moving colored dots. On each trial, participants were precued to report the predominant direction of motion or color of the stimulus, or to attend fixation. Stimulus representations in reconstructed priority maps were selectively enhanced in color-selective regions when color was attended, and in motion-selective regions when motion was attended, and this effect was primarily observed at the stimulus location. While enhancement was localized to the stimulus in color-selective regions, motion-selective regions were globally enhanced when motion was task relevant. These results suggest different cortical regions support spatial maps of different visual features, and that each map is uniquely reweighted based on task demands to guide visual behavior towards the most relevant locations based on important features.
Atomic resolution structures of key enzyme MCR in anaerobic methanotrophy reveal novel and extensive post-translational modifications.
Authors: Müller Marie-Caroline , Wissink Martijn , Mukherjee Priyadarshini , von Possel Nicole , Laso-Pérez Rafael , Engilberge Sylvain , Carpentier Philippe , Kahnt Jörg , Wegener Gunter , Welte Cornelia , Wagner Tristan
Published: January 2025

Anaerobic methanotrophic archaea (ANME) are crucial to planetary carbon cycling. They oxidise methane in anoxic niches by transferring electrons directly to nitrate or metal oxides and alternatively to sulfate-reducing bacteria. Due to their physiological complexity, none of the ANME species have been isolated, hampering the biochemical investigation of the enzymatic processes involved in anaerobic methane oxidation. Here, we deciphered the methane-capturing enzyme through native purification directly from microbial enrichments. Freshwater ANME-2d reducing nitrate, grown in bioreactors, and marine microbial enrichment containing ANME-2c, along with its bacterial syntrophic partners, were used as model systems. The crystal structures of the Methyl-Coenzyme M Reductases (MCRs), refined to true atomic resolution, captured its most precise image to date. Despite their physiological differences, these ANMEs have extremely conserved MCR structures, similar to homologs from methanogenicMethanosarcinales, rather than the phylogenetically distant MCR of ANME-1 isolated from Black Sea mats. An exceptional content of seven post-translational modifications was observedin cristallo. Among them was a novel 3(S)-methylhistidine on the γ-chain of the ANME-2d MCR. Krypton gassing did not lead to the detection of an internal channel that would facilitate alkane diffusion to the active site, contrary to the ethane-activating homologue. Our results corroborate that MCRs from freshwater ANME-2d and marine ANME-2c should follow the conserved radical reaction mechanism of the methane-generating counterpart. The described pattern of post-translational modifications, different to ANME-1, highlights the importance of native purification as an unbiased approach to discovering intrinsic enzymatic features in uncultivated microorganisms existing in nature.
Baseline ferritin predicts myocardial iron uptake following intravenous iron therapy- a hypothesis generating study
Authors: Nunez Julio , Mollar Anna , Vera-Aviles Mayra , Kabir Syeeda , Shah Akshay , Polzella Paolo , Desborough Michael , Cardells Ingrid , Miñana Gema , del Canto Irene , Ferreira Vanessa , Piechnik Stefan , Maceira Alicia , Lakhal-Littleton Samira
Published: January 2025

Aims

Iron deficiency (ID) is a common co-morbidity in heart failure (HF). Intravenous iron therapy improves outcomes. Several mechanisms have been proposed, including myocardial iron repletion. However, it is unknown if clinical iron markers predict the extent of this repletion. The aim of this study is to address this question by harnessing data from two clinical studies that evaluated changes in myocardial iron using cardiac magnetic resonance (CMR).

Methods and Results

We performed a post-hoc analysis of two previously published trials. The Myocardial-IRON trial measured change in myocardial iron, denoted by a decrease in CMR T1-mapping, at 7 and 30 days after FCM in patients with ID and HF. The STUDY trial measured myocardial and spleen iron at multiple timepoints after FCM in patients with ID without HF. In this post-hoc analysis, we examined the association between baseline iron markers (Tsat and ferritin) and change in myocardial iron in the weeks after FCM therapy. Changes in spleen iron were also examined, due its role as an intermediary in the redistribution of iron from iron-carbohydrate complexes such as FCM. In patients with or without HF, higher plasma ferritin at baseline predicted lower rise in myocardial iron in the weeks after therapy with FCM. In contrast, higher plasma ferritin at baseline predicted a greater rise in spleen iron.

Conclusions

These data point towards the hypothesis that functional ID, which is characterized by elevated ferritin, could limit myocardial iron repletion after IV iron therapy, by favoring iron trapping in the spleen.
Predicting Hypertension Among HIV Patients on Antiretroviral Therapy in Rural Eastern Cape, South Africa Using Machine Learning
Authors: Tsuro Urgent , Ncube Trymore , Oladimeji Kelechi E. , Apalata Teke R.
Published: January 2025

Background

Hypertension continues to be a major challenge in developing countries like South Africa, as it significantly contributes to the cardiovascular disease burden in these countries. This study aimed to utilize the machine learning (ML) models to anticipate the incidence of hypertension in HIV patients under antiretroviral therapy (ART) in rural Eastern Cape, South Africa.

Methods

This research carried out a retrospective cohort study and created and tested six machine learning algorithms: Neural Networks, Random Forest, Logistic Regression, Naive Bayes, K-Nearest Neighbours and XGBoost. The goal was to predict the likelihood of developing hypertension. Feature selection was done using the Boruta method and the model was assessed using several metrics including aiming, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUC).

Results

XGBoost outperformed all other models with an AUC of 0.96, which further suggests it can effectively distinguish between hypertensives and normotensives. In the case of Boruta analysis, some aggravated risk factors were age category, time on ART, BMI category, waist to hip ratio, waist size, family history of HBP and relationship status, physical activity, LDL cholesterol level, awareness of high blood pressure, education level, use of ART and diabetes mellitus.

Conclusions

This study has highlighted the utility of XGBoost, as one of the advanced machine learning algorithms, in reliably forecasting the occurrence of hypertension in HIV ART patients in a rural setting. The established risk factors elucidate the complexity behind the hypertension emergence and hence the need for triad approaches which include lifestyle changes, clinical treatments, and demographic solutions to tackle the public health problem.
Effectiveness of Smoking Cessation Interventions in People With Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Aduse-Poku Livingstone , Cheng Hui G. , Palesh Oxana , Hong Susan
Published: January 2025

Introduction

Smoking at or following a cancer diagnosis increases both all-cause and cancer-specific mortality, adverse treatment outcomes, as well as the risk for disease progression and tobacco-related second primary cancers. This protocol outlines a systematic review and meta-analysis evaluating the effectiveness of smoking cessation interventions in cancer patients based on randomized controlled trials (RCTs), delivering the highest quality of evidence for causal inference.

Methods

A systematic search of the literature will be conducted across PsychInfo, EMBASE (through OVID), PubMed (also through OVID), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). RCTs published in English, designed to assist adult cancer survivors who smoke to quit, regardless of their cancer type, stage, or treatment, will be included. Title and abstract screening will be carried out independently by two authors. All potentially eligible full-text articles will be independently reviewed. Any disagreements will be resolved through discussion. Extracted data will encompass study characteristics, intervention details, participant numbers and attributes, outcomes, quit attempts, and follow-up duration. We will evaluate the risk of bias using the Cochrane Risk of Bias Tool 2 (ROB-2). To evaluate the outcomes of the combined studies, a meta-analysis and/or network meta-analysis will be performed with both fixed-effect models and random-effects models using R.

Conclusion

This systematic review will address a critical research gap and provide tailored insights for smoking cessation among cancer survivors.