bluuebunny/crossref_metadata_2025 huggingface dataset:
Less is more: The use of single biodegradable stenting to treat biliary anastomotic strictures in pediatric liver transplantation
Authors: Quintero Bernabeu Jesús , Juamperez Goñi Javier , Mercadal Hally Maria , Padrós Fornieles Cristina , Larrarte King Mauricio , Molino Gahete José Andrés , Coma Muñoz Anna , Diez Miranda Iratxe , Pérez Lafuente Mercedes , Charco Torra Ramon , Hidalgo Llompart Ernest
Published: September 2024

This study reports our experience of using biodegradable biliary stents (BBSs) for anastomotic biliary strictures (ABSs) in pediatric patients undergoing liver transplants. It involves the analysis of a retrospective data collection from January 2014 to January 2023, including all pediatric recipients of liver transplants in our center treated for ABSs with BBSs. In phase 1 (2014–2019), there was an initial percutaneous transhepatic cholangiography with anastomotic dilatation followed 2 weeks after a second percutaneous transhepatic cholangiography with BBS insertion. In phase 2 (2019–2023), the BBS was placed shortly after ABS dilatation, requiring only 1 percutaneous transhepatic cholangiography. All patients were followed up with routine tests and ultrasound. Forty-six ABSs were diagnosed in 43 pediatric recipients of liver transplants with a median of 6.7 months after liver transplantation (0.1–246.8 mo). Eight out of 46 ABSs (17.4%) treated with BBSs relapsed (median recurrence time: 6.5 mo; 1.6–17.0 mo). Four resolved with further BBS placement; only 4 needed surgical revision (8.7%) after a median follow-up time of 43.9 months (0.3–106.3). There were no differences in ABS recurrence rate, time between stent placement and recurrence, or the presence of cholangitis based on whether the BBS was deployed in 1 or 2 steps. Patients with end-to-end anastomosis had a higher ABS recurrence (OR 10.8; 1.4–81.3, p = 0.008) than those with bilioenteric anastomosis. The use of biodegradable stents could be a good option for treating ABSs in pediatric patients undergoing liver transplants, with our series showing a success rate of over 90% and an average follow-up of 43.9 months.
Modified McKissock Technique for Secondary Breast Reduction – A Prospective Study on Safety, Surgical and Aesthetic Outcomes
Authors: Feldler Sandra , Zaussinger Maximilian , Ehebruster Gudrun , Bachleitner Kathrin , Steinkellner Theresia , Schmidt Manfred
Published: September 2024

Numbers of secondary breast reductions are increasing but those are potentially associated with higher complication rates than primary mammaplasty. Necrosis of the Nipple-Areola-Complex (NAC) is a devastating complication that can occur after repeated NAC transposition, particularly when the initially used pedicle is unknown. Thus, the authors established a modification of McKissock’s technique for secondary breast reductions including three pedicle components to ensure safe vascular supply of the NAC. The presented technique incorporates a superior and inferior dermoglandular pedicle according to McKissock and an additional central pedicle. The technique was applied for secondary breast reduction in a series of 25 breasts (14 patients: 11 bilateral, 3 unilateral). Complication rates, pre- and postoperative BREAST-Q scores, and aesthetic outcomes were evaluated. Mean resection weight was 299 g (range, 40-646), and the NAC was transposed by 4.2 cm on average (range, 1-10). No case of NAC-necrosis was observed, and comparison of pre- and postoperative BREAST-Q values indicated substantial improvement in all domains. Postoperatively, 84.6% of patients reported excellent satisfaction with breast appearance. According to those results, the modified McKissock-technique is a safe technique for patients requiring secondary breast reduction, even if the primarily used pedicle is unknown. Additionally, the established technique is associated with improved postoperative patient-reported outcomes and yields aesthetically favorable results.
Caveolin-1 regulates context-dependent signaling and survival in Ewing sarcoma
Authors: Segal Dagan , Wang Xiaoyu , Mazloom-Farisbaf Hanieh , Rajendran Divya , Butler Erin , Chen Bingying , Chang Bo-Jui , Ahuja Khushi , Perny Averi , Bhatt Kushal , Reed Dana Kim , Castrillon Diego H. , Lee Jeon , Jeffery Elise , Wang Lei , Nguyen Khai , Williams Noelle S. , Skapek Stephen X. , Rajaram Satwik , Fiolka Reto , Jaqaman Khuloud , Hon Gary , Amatruda James F. , Danuser Gaudenz
Published: September 2024

Plasticity is a hallmark function of cancer cells, but many of the underlying mechanisms have yet to be discovered. In this study, we identify Caveolin-1, a scaffolding protein that organizes plasma membrane domains, as a context-dependent regulator of survival signaling in Ewing sarcoma (EwS). Single cell analyses reveal a distinct subpopulation of EwS cells, which highly express the surface marker CD99 as well as Caveolin-1.CD99 Highcells exhibit distinct morphology, gene expression, and enhanced survival capabilities compared toCD99 Lowcells, both under chemotherapeutic challenge andin vivo.Mechanistically, we show that elevated Caveolin-1 expression inCD99 Highcells orchestrates PI3K/AKT survival signaling by modulating the spatial organization of PI3K activity at the cell surface. Notably, CD99 itself is not directly involved in this pathway, making it a useful independent marker for identifying these subpopulations. We propose a model where theCD99 Highstate establishes a Cav-1-driven signaling network to support cell survival that is distinct from the survival mechanisms ofCD99 Lowcells. This work reveals a dynamic state transition in EwS cells and highlights Caveolin-1 as a key driver of context-specific survival signaling.
Video-based biomechanical analysis captures disease-specific movement signatures of different neuromuscular diseases
Authors: Ruth Parker S. , Uhlrich Scott D. , de Monts Constance , Falisse Antoine , Muccini Julie , Covitz Sydney , Vogt-Domke Shelby , Day John , Duong Tina , Delp Scott L.
Published: September 2024

Assessing human movement is essential for diagnosing and monitoring movement-related conditions. Timed function tests (TFTs) are among the most widespread assessments due to their speed and simplicity. However, TFTs cannot capture disease-specific movement patterns. Recent advances in smartphone video-based biomechanical analysis allow detailed movement quantification with the ease and speed required for clinical settings. To compare video-based analysis against TFTs, we collected data from 129 individuals: 28 with facioscapulohumeral muscular dystrophy, 58 with myotonic dystrophy, and 43 with typical movement. Video-based movement recordings took a median time of 16 minutes per participant. In addition to reproducing TFTs (r > 0.98), video metrics can outperform TFTs at disease classification (p < 0.001). Video-based analysis also identifies differences in gait kinematics and arm range of motion not evident in TFTs. We conclude that video-based biomechanical analysis can complement existing functional movement assessments and capture more sensitive, disease-specific outcomes from human movement.
Cannabidiol treatment is associated with broadband spectral electrophysiological changes and improved cognition in boys with low-functioning autism spectrum disorder
Authors: Cazares C. , Hutton A. , Paez G. , Trauner D. , Voytek B.
Published: September 2024

Oral cannabidiol (CBD) treatment has been suggested to alleviate negative symptoms of autism spectrum disorder (ASD). While many CBD preparations have been studied in randomized clinical trials involving ASD, none have used purified CBD preparations or preparations approved by the U.S. Food and Drug Administration, nor have they focused on low-functioning children with ASD. Previous studies have identified several candidate electrophysiological biomarkers for the cognitive and behavioral disabilities in ASD, with one emerging biomarker being aperiodic neural activity. Here we examined whether periodic (oscillatory) and/or aperiodic electroencephalography (EEG) features are predictive of any symptomatic changes in ASD following pharmacological CBD intervention. To do this, we leveraged resting-state EEG from children with low-functioning ASD (24 boys, aged 7-14 years) using data obtained during a prior double-blind, placebo-controlled, crossover Phase III Clinical Trial (NCT04517799) that investigated using cannabidiol to treat severe behavior problems in children with ASD. Using linear mixed effect models, we found that aperiodic EEG signal features varied directly with 7-COOH-CBD metabolite levels in blood, as evidenced by a larger aperiodic offset (p < 0.001) and decreased aperiodic exponent (p < 0.05) across the scalp. Furthermore, 7-COOH-CBD metabolite levels in blood had a positive association with nonverbal intelligence and visuomotor coordination (p < 0.05). Finally, changes in visuomotor coordination attributed to occipital oscillatory EEG activity were mediated by changes in 7-COOH-CBD metabolite levels in blood, with distinct effects observed for the delta frequency band (p < 0.05). Our analytical results suggest that this daily CBD preparation and administration schedule exerted some benefits, with improvements to cognitive and behavioral abilities in a low-functioning ASD children population. Our findings support the inclusion of resting-state, aperiodic signal features as candidate biomarkers for tracking the clinical impact of CBD treatment, in addition to traditional oscillatory EEG measures, within a neurodevelopmental context.
Breaking the cycle: How targeting CD44v6/MET signaling disrupts colorectal cancer cell plasticity
Authors: Sonnentag S. J. , Goldbach S. , Hoch D. , Andrieux G. , Becker J. , Fromm H. , Munoz-Sagredo L. , Heneka Y. M. , Grimm D. , Greten F. R. , Orian-Rousseau Veronique
Published: September 2024

The concept of cancer stemness is undergoing rapid evolution, facilitated by technological advances allowing the tracking and elimination of stem cellsin vivo. Following their identification in solid tumors, cancer stem cells were placed at the center of tumor initiation, growth and metastasis. However, increasing evidence suggests that stemness is a cellular state that can be acquired by differentiated cells in a process called plasticity. Here we show that CD44v6 may act as a molecular switch controlling plasticity of colorectal cancer cells. CD44v6/MET signaling controls the reappearance of Lgr5+cells after ablation,in vitroandin vivoas demonstrated in tumor organoids derived fromLgr5DTR/eGFPmice using a CD44v6 blocking peptide. CD44v6 also affects the YAP/TAZ signaling pathway, involved in the very first steps of plasticity. In view of the essential role of plasticity for the establishment of metastases, blocking CD44v6 signaling may represent a pivotal and promising therapy.

Graphical Abstract
A balanced CAR-T cell metabolism driven by CD28 or 4-1BB co-stimulation correlates with clinical success in lymphoma patients
Authors: Cook Molly S. , Flaherty Katie R. , Papa Sophie , Benjamin Reuben , Schurich Anna
Published: September 2024

Chimeric antigen receptor (CAR) T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signalling pathways. Previous work has highlighted the importance of T cell metabolism in fuelling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cellsex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signalling endows T cells with a preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite this divergent programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator, suggesting that efficient fuelling of CAR-T cells in lymphoma requires a ‘balanced’metabolism. In contrast, CAR-T cells in non-responders were pushed to their metabolic extremes.

One sentence summary

CD28 and 4-1BB signalling drive divergent metabolic profiles in patient CAR-T cells, however patients that respond to therapy have CAR-T cells that maintain metabolic balance.
AMEF2Ctranscription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease
Authors: Ferreira Ricardo Melo , Gisch Debora L. , Phillips Carrie L. , Cheng Ying-Hua , Asthana Maansi , Lake Blue B. , Bowen William S. , Fang Fang , Asghari Mahla , Sabo Angela , Barwinska Daria , Ferkowicz Michael J. , Toto Robert D. , Sedor John R. , Rosas Sylvia E. , Bjornstad Petter , Hodgin Jeffrey B , Alpers Charles E. , Sarder Pinaki , Himmelfarb Jonathan , Schaub Jennifer A. , Nair Viji , Winfree Seth , Sutton Timothy A. , Kelly Katherine J. ,   The Kidney Precision Medicine Project, Kretzler Matthias , Jain Sanjay , El-Achkar Tarek M. , Dagher Pierre C. , Eadon Michael T.
Published: September 2024

The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells. Data were culled from single nucleus RNA and ATAC sequencing and three orthogonal spatial transcriptomic technologies for correlation with histopathological and clinical trial data. We identified a cellular niche in diabetic glomeruli enriched in a proliferative endothelial cell subtype (prEC) and altered vascular smooth muscle cells (VSMCs). Cellular communication within this niche maintained pro-angiogenic signaling with loss of anti-angiogenic factors. We identified a TF network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the TF network accelerated the transition from healthy EC-GCs toward a degenerative (injury) endothelial phenotype, with concomitant disruption of EC-GC and prEC expression patterns. Glomeruli enriched in the prEC niche had histologic evidence of neovascularization. MEF2C activity was increased in diabetic glomeruli with nodular mesangial sclerosis. The gene regulatory network (GRN) of MEF2C was dysregulated in EC-GCs of patients with DKD, but sodium glucose transporter-2 inhibitor (SGLT2i) treatment reversed the MEF2C GRN effects of DKD. The MEF2C, MEF2A, and TRPS1 TF network carefully balances the fate of the EC-GC in DKD. When the TF network is “on” or over-expressed in DKD, EC-GCs may progress to a prEC state, while TF suppression leads to cell death. SGLT2i therapy may restore the balance of MEF2C activity.
Implications of carbon source-sink feedbacks for plant growth responses to environmental factors
Authors: Friend Andrew D. , Chen Yizhao , Eckes-Shephard Annemarie H. , Fonti Patrick , Hellmann Eva , Rademacher Tim T. , Richardson Andrew D. , Thomas Patrick R.
Published: September 2024

Global models of vegetation dynamics are largely carbon (C) source-driven, with behaviour primarily determined by the environmental responses of photosynthesis. However, real plants operate as integrated wholes, with feedbacks between sources and sinks resulting in homeostatic concentrations of metabolites such as sugars. An approach to implementing such behaviour in a plant growth model is presented and its implications for responses to generic environmental factors assessed. The approach is based on Hill functions representing inhibition of C sources (net photosynthesis) and activation of sinks (structural growth) based on sugar concentrations. The model is parameterised for a mature tropical rainforest site and its qualitative behaviour is found to be consistent with experimental observations. Key findings are that sinks and sources strongly regulate each other. For example, doubling potential net photosynthesis (i.e. the rate that would occur without feedback) results in growth increasing by only 1/3 at equilibrium, with increased sugar concentration causing feedback-inhibition of photosynthesis. A source-only driven response, as in current global models, would result in close to a doubling of growth. Hence environmental factors that affect potential net photosynthesis, such as atmospheric CO2, have greatly reduced effects on growth when homeostatic behaviour of sugars is considered. The implications of considering source-sink coupling for the behaviour of models of vegetation dynamics are likely to be profound.
In Silicoidentification and modelling of FDA-approved drugs targeting T-type calcium channels
Authors: Fong Pedro , Garcia Susana Roman , Stefan Melanie I , Sterratt David C
Published: September 2024

Studies have shown that inhibition of the Cav3.1 T-type calcium channel can prevent or suppress neurological diseases, such as epileptic seizures and diabetic neuropathy. In this study we aimed to usein silicosimulations to identify a U.S. Food and Drug Administration (FDA)-approved drug that can bind to the Cav3.1 T-type calcium channel. We used the automated docking suite GOLD v5.5 with the genetic algorithm to simulate molecular docking and predict the protein-ligand binding modes, and the ChemPLP empirical scoring function to estimate the binding affinities of 2,115 FDA-approved drugs to the human Cav3.1 channel. Drugs with high binding affinity and appropriate pharmacodynamic and pharmacokinetic properties were selected for molecular mechanics Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) binding free energy calculations, GROMACS molecular dynamics (MD) simulations and Monte Carlo Cell (MCell) simulations. The docking results indicated that the FDA-approved drug montelukast has a high binding affinity to Cav3.1, and data from the literature suggested that montelukast has the appropriate drug-like properties to cross the human blood-brain barrier and reach synapses in the central nervous system. MMPBSA, MMGBSA and MD simulations showed the high stability of the montelukast-Cav3.1 complex. MCell simulations indicated that the blockage of Cav3.1 by montelukast reduced the number of synaptic vesicles being released from the pre-synaptic region to the synaptic cleft, which may reduce the probability and amplitude of postsynaptic potentials.

Author Summary

New drugs for current illnesses or disorders are always necessary to enhance therapeutic outcomes or can be utilised for patients who have experienced side effects from current medicines. The Cav3.1 T-type calcium channel has been found to be linked to neurological diseases, such as epilepsy and diabetes. Consequently, identifying a drug that could bind to these receptors may yield therapeutic effects on these neurological conditions. This study utilises various computational methods to sift through 2,115 FDA-approved drugs that have been used for other diseases, not neurological ones, to determine whether some of these drugs could bind to the Cav3.1 T-type calcium channel and potentially produce therapeutic effects on neurological diseases. Our research indicates that the current asthma drug montelukast has the potential to bind to the calcium channel and is worthy of further investigation.
Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of extra-nigral Synucleinopathy
Authors: Lin Lin , Jensen Nanna M. , Ferreira Sara A. , Delaidelli Alberto , Gomes Moreira Diana , Ahlgreen Ole A. , Richner Mette , Sorensen Poul H. , Romero-Ramos Marina , Vægter Christian B. , Jensen Poul H. , Mackenzie Ian R. , Nyengaard Jens R. , Jan Asad
Published: September 2024

A pathological role of alpha-Synuclein (aSyn) aggregation in the central nervous system (CNS) is a recognized feature in Parkinson disease (PD) and related neurodegenerative conditions termed synucleinopathies. In order to characterize the cellular response in CNS to incipient and advanced aSyn pathology, we applied spatial transcriptomics on brain sections derived from a transgenic mouse model (M83+/+line,Prnp-SNCA*A53T) in which aSyn aggregation was induced in a prion-like fashion through hindlimb intramuscular delivery of pre-formed fibrillar (PFF) murine aSyn. Our spatially-resolved transcriptomics (ST) data point to unique perturbations in brain energy metabolism during the progression of aSyn pathology, such that the early stage of aSyn aggregate pathology activates molecular pathways controlling metabolic flux through glycolysis, oxidative phosphorylation and fatty acid metabolism. In contrast, the ST data indicate a profound decline in mitochondrial metabolism in the brains of symptomatic animals with advanced aSyn pathology. The latter stage was also associated with drastic reduction in mRNA translation machinery, along with aberrant expression of molecular drivers involved in RNA splicing and inflammatory response. Intriguingly, our ST data also point to perturbed regulation of circadian rhythm, was corroborated by increased immunodetection of CREB-binding protein (a modulator of core clock machinery) in the brains of symptomatic animals, and transcriptional upregulation ofCREBBPin 4 independent PD microarray datasets. Collectively, we anticipate that our findings offer novel opportunities in knowledge translation for mechanism-based drug discovery and biomarkers in neurodegenerative synucleinopathies.
Sedentary lifestyle induces oxidative stress and atrophy in rat skeletal muscle
Authors: Gungor-Orhan Irem , Akin Senay , Powers Scott K. , Olgaz-Bingol Seda , Demirel Haydar
Published: September 2024

Abundant evidence indicates that skeletal muscle is an important endocrine organ that plays a key role in regulating metabolic homeostasis. Therefore, maintaining healthy skeletal muscles is essential to good health. While it is established that prolonged skeletal muscle inactivity results in both oxidative stress and muscle atrophy, it remains unknown if the change from an active to a sedentary lifestyle promotes a similar increase in oxidative stress and locomotor muscle atrophy. We tested the hypothesis that the transition from active to sedentary living results in the rapid development of oxidative damage and fiber atrophy in locomotor skeletal muscles. Adult Wistar rats were randomly divided into control (CON; n=8) and sedentary (SED; n=8) groups. During a seven-day experimental period, animals in the CON group were housed in standard size cages permitting free movement, while animals in the SED group were housed in small cages that promoted sedentary behavior. At the end of the experimental protocol, soleus muscles were removed and the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were determined along with two biomarkers of muscle oxidative stress (i.e., levels of advanced protein oxidation (AOPP) and 4-hydroxynonenal (4-HNE)). Living in the reduced-size cage resulted in muscle atrophy as evidenced by a 17.2% decrease in the soleus to body weight ratio (P<0.001). Moreover, the activities of SOD, CAT and GPX in the soleus muscle were significantly decreased in SED animals compared to CON (P<0.05). Finally, compared to CON, sedentary living increased both AOPP and 4-HNE levels in muscles of SED animals (P<0.001 andP<0.05, respectively). These findings provide the first evidence that the transition from an active to sedentary lifestyle results in the rapid onset of oxidative stress and atrophy in locomotor skeletal muscles. Importantly, these results suggest that an impaired antioxidant defense contributes to sedentary behavior-induced oxidative stress in locomotor muscles.
Dynamic modulation of auditory hair cell stereocilia membrane mechanics by the scrambling mechanotransduction complex
Authors: George Shefin S. , Ricci Anthony J.
Published: September 2024

Inner ear sensory hair cells convert mechanical deflection of their hair bundle into an electrical signal by gating novel mechanoelectrical transduction (MET) channels. Transmembrane channel-like proteins (TMCs) are a component of the MET machinery and part of a superfamily of molecules whose members are ion channels or lipid scramblases. As the stereocilia membrane modulates MET channels properties and the stereocilia membrane has different properties than the soma, we investigated the potential scramblase activity of the MET machinery using a novel viscosity sensor BODIPY 1c. Developmental, genetic, electrophysiological and pharmacological data demonstrate that both TMC1 and TMC2 are mechanosensitive scramblases as activity depends on MET channel being open. Blockage of scramblase activity unmasks a second process that increases effective membrane viscosity independent of MET machinery. Together our data reveal a dynamic regulation of stereocilia membrane that may underlie the speed and sensitivity of the MET process.
Long non-coding RNA UCA1 affects chromatin remodeling via SMARCA2-containing SWI/SNF complex in human colorectal cancer
Authors: Neve Bernadette , Bachir Elsa Hadj , Duchêne Belinda , Souidi Mouloud , Figeac Martin , Meneboo Jean-Pascal , Leteurtre Emmanuelle ,   OrgaRES consortium, Jonckheere Nicolas , Vincent Audrey , Van Seuningen Isabelle
Published: September 2024

Differential lncRNA expression has been correlated to clinical characteristics of colorectal cancers (CRC), which are the second leading cause of cancer-related deaths. LncRNA UCA1 plays a role in epigenetic gene regulation in diverse cancers. We studied CRC cell properties in CRISPR/Cas9 HT29-derived models and, interestingly, UCA1-depleted HT29 cells presented an increased stem-cell phenotype. We show that loss of UCA1 affected SWI/SNF chromatin remodeling complexes, which are previously shown to be involved in maintaining stem-cell properties. Not only was UCA1 permissive for induced SWI/SNF subunit SMARCA2 (BRM) expression upon chemo-drug treatment, but it also affected subunit compositions of SWI/SNF complexes by direct interaction of UCA1 with both ATP helicase BRM and BRG1. UCA1 is known to stimulate proliferation and decrease apoptosis, and we here show that it can restrain cells from a stem cell phenotype. The dual action of UCA1 revealed in this study highlights the complex actions of lncRNAs in cancer.
CPK3-mediated cytosolic-nuclear translocation of bHLH107 recruits HY5 to regulate the Cu2+-triggered upregulation ofACS8
Authors: Yu Yue , Liu Haifeng , Chen Xiangsong , Chu Zhaohui
Published: September 2024

Copper serves as a micronutrient for plant growth and development and has been a key component of copper-based antimicrobial compounds (CBACs) for protection against plant diseases for more than 130 years. We previously revealed that nanomolar- to-micromolar concentrations of Cu2+elicit plant immune responses by activating the expression of the ethylene synthesis rate-limiting enzymeACS8, which is dependent on the promoter copper response element (CuRE)cis-element. Here, we genetically confirmed that Cu2+-induced resistance toPseudomonas syringaepv.tomato(Pst) DC3000 is dependent on the CuRE inACS8. Upon screening for CuRE-binding transcription factors, bHLH107, which is required for Cu2+-triggered activation ofACS8expression and resistance toPstDC3000, was identified via DNA-pull-down and mass spectrometry (MS) assays. Calcium-dependent protein kinase 3 (CPK3) interacts with and phosphorylates bHLH107 at Ser62 and Ser72 to mediate bHLH07 translocation from the cytoplasm into the nucleus, where it interacts withArabidopsisELONGATED HYPOCOTYL5 (HY5). HY5 directly binds to the G-box and acts as a coactivator to promote bHLH107 binding to the CuREcis-element and to increase transcription ofACS8upon Cu2+treatment. Overall, we revealed a CPK3-bHLH107-HY5 module that regulates the Cu2+-responsive regulatory network upstream ofACS8that is involved in the cytosolic-nuclear translocation of bHLH107.
Measurement of cellular traction forces during confined migration
Authors: Hockenberry Max A. , Ulmer Andrew J. , Rapp Johann L. , Leibfarth Frank A. , Bear James E. , Legant Wesley R.
Published: September 2024

To migrate efficiently through tissues, cells must transit through small constrictions within the extracellular matrix. However, in vivo environments are geometrically, mechanically, and chemically complex, and it has been difficult to understand how each of these parameters contribute to the propulsive strategy utilized by cells in these diverse settings. To address this, we employed a sacrificial micromolding approach to generate polymer substrates with tunable stiffness, controlled adhesivity, and user-defined microscale geometries. We combined this together with live-cell imaging and three-dimensional traction force microscopy (TFM) to quantify the forces that cells use to transit through constricting channels. Surprisingly, we observe that cells migrating through compliant constrictions take longer to transit and experience greater nuclear deformation than those migrating through more rigid constrictions. TFM reveals that this deformation is generated by inwardly directed contractile forces that decrease the size of the opening and pull the walls closed around the nucleus. These findings show that nuclear deformation during confined migration can be accomplished by internal cytoskeletal machinery rather than by reactive forces from the substrate, and our approach provides a mechanism to test between different models for how cells translocate their nucleus through narrow constrictions. The methods, analysis, and results presented here will be useful to understand how cells choose between propulsive strategies in different physical environments.

Significance Statement

Cell migration is critical for both physiological events like wound healing and pathological events like metastasis. Understanding how cells move through complex environments will assist efforts to enhance or inhibit such processes. We developed a method to quantify the forces that cells use to move through multidimensional environments, including through narrow constrictions like those in tissues. Surprisingly, we find that cells transiting through soft constrictions take longer and deform more than those transiting through rigid constrictions, and we connect this finding to inwardly directed contractile forces generated by migrating cells. Together, this work reveals a key role for substrate rigidity to regulate cell transit through confining geometries and provides a quantitative platform to investigate similar processes in other settings.
Endosomal hyper-acidification via proton-activated chloride channel deletion in neurons impairs AMPA receptor endocytosis and LTD
Authors: Chen Kevin H. , Yang Junhua , Liu Bian , Jiang Chaohua , Koylass Nicholas , Zhang Zhe , Sun Shuying , Huganir Richard , Qiu Zhaozhu
Published: September 2024

Endosomal homeostasis is critical for neuronal function, including the post-synaptic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Dynamic AMPAR trafficking is a major component of synaptic plasticity, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD) and is thought to be required for learning and memory. Dramatic alteration of endosomal pH has been reported to negatively affect synaptic transmission and neural development, but the underlying mechanisms by which pH is involved in AMPAR trafficking are unclear. Here, we show that the proton-activated chloride (PAC) channel localizes to early and recycling endosomes along neuronal dendrites and prevents hyper-acidification of endosomes. To directly measure AMPAR endocytosis, we used a new method to assess LTD using HaloTag-GluA2 and found that the loss of PAC reduces AMPAR internalization during chemical LTD in primary neurons, while AMPAR trafficking in unstimulated cells or during chemical LTP is unaffected. Consistently, pyramidal neuron-specific PAC knockout mice had impaired hippocampal LTD, but not LTP, and performed poorly in the Morris water maze reversal test, exhibiting an inability to adapt to changing environments (also referred to as behavioral flexibility). We conclude that proper maintenance of pH by PAC is important during LTD to regulate AMPAR trafficking in a manner critical for animal physiology and behavior.

The ability to adapt to changing environments stems from the plasticity of neurons, which can modulate their synaptic strength in response to neural activity. We discovered a novel mechanism by which an endosomal proton-activated chloride channel (PAC) is involved in synaptic weakening, or long-term depression (LTD). To improve tools used to study LTD, we developed a live-cell imaging assay to directly observe α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis. PAC-deficient neurons have hyper-acidified endosomes and fail to endocytose AMPARs during LTD. Neuron-specific PAC knockout mice have impaired hippocampal LTD and fail to adapt to changes in their environment. The role of endosomal pH in synaptic function is understudied, and our results provide a novel mechanism whereby PAC can affect synaptic LTD.
Three-fold Quantum Leap in Butterfly Nectar Knowledge: A Comprehensive Study Revolutionizing Conservation Strategies
Authors: Dunlap Susan C.
Published: September 2024

This study addresses a critical gap in butterfly conservation: the lack of comprehensive data on nectar plants preferred by US butterflies. The research presented has dramatically improved our understanding, increasing knowledge of nectar plant genera used by butterflies from representing just 25% of all species to an impressive 90%, a more than three-fold or 260% improvement in species representation. This substantial expansion in data has significant implications for conservation strategies and will shift our approach to butterfly habitat restoration. A seven-year longitudinal study of adult butterfly nectaring behavior resulted in over 12,000 detailed records of nectar plant usage by US butterflies. This curated dataset provides a valuable resource with significant implications for all levels of effort directed at butterfly conservation.

Recent recommendations for monarch habitat restoration suggest a balanced mix of host and nectar plants. However, the implementation of this guideline has been hampered by a lack of specific data on monarchs’ preferred nectar plants. New research addresses this gap, providing necessary information to refine plant selection for butterfly habitats. This study also gives cause to modify the current approach of creating generalized pollinator habitats, suggesting that focusing on plants preferred by long-distance migrating butterflies like monarchs may effectively support a broad range of pollinators.
GoldPolish-Target: Targeted long-read genome assembly polishing
Authors: Zhang Emily , Coombe Lauren , Wong Johnathan , Warren René L , Birol Inanç
Published: September 2024

Background

Advanced long-read sequencing technologies, such as those from Oxford Nanopore Technologies and Pacific Biosciences, are finding a wide use inde novogenome sequencing projects. However, long reads typically have higher error rates relative to short reads. If left unaddressed, subsequent genome assemblies may exhibit high base error rates that compromise the reliability of downstream analysis. Several specialized error correction tools for genome assemblies have since emerged, employing a range of algorithms and strategies to improve base quality. However, despite these efforts, many genome assembly workflows still produce regions with elevated error rates, such as gaps filled with unpolished or ambiguous bases. To address this, we introduce GoldPolish-Target, a modular targeted sequence polishing pipeline. Coupled with GoldPolish, a linear-time genome assembly algorithm, GoldPolish-Target isolates and polishes user-specified assembly loci, offering a resource-efficient means for polishing targeted regions of draft genomes.

Results

Experiments usingDrosophila melanogasterandHomo sapiensdatasets demonstrate that GoldPolish-Target can reduce insertion/deletion (indel) and mismatch errors by up to 49.2% and 53.4% respectively, achieving base accuracy values upwards of 99.9% (Phred score Q>30). This polishing accuracy is comparable to the current state-of-the-art, Medaka, while exhibiting up to 36-fold shorter run times and consuming 94% less memory, on average.

Conclusion

GoldPolish-Target, in contrast to most other polishing tools, offers the ability to target specific regions of a genome assembly for polishing, providing a computationally light-weight and highly scalable solution for base error correction.

Availability

https://github.com/bcgsc/goldpolish
TRACKing Tandem Repeats: a customizable pipeline for identification and cross-species comparisons
Authors: Adam Carolina L. , Rocha Joana , Sudmant Peter , Rohlfs Rori
Published: September 2024

TRACK is a user-friendly command-line pipeline designed to consolidate the discovery and comparison of tandem repeats (TRs) across species. TRACK facilitates the cataloging and filtering of TRs based on reference genomes or T2T transcripts, and applies reciprocal LiftOver and sequence alignment methods to identify putative homologous TRs between species. For further streamlined analyses, TRACK can be used to genotype TRs and subsequently estimate and plot basic population genetic statistics. By integrating existing tools into one integrated workflow, TRACK enhances TR analysis accessibility and reproducibility, while offering flexibility for the user.

Availability

The TRACK toolkit with step-by-step tutorial is freely available athttps://github.com/caroladam/track.
Validity and reliability of the Hypersensitive Narcissism Scale (HSNS) in China
Authors: Li Yuxin , Zou Fan , Cheng Hao
Published: September 2024

Background

Wink distinguishes between explicit and implicit narcissism, the latter being vulnerability-sensitive narcissism, which manifests itself as outward humility and inhibition masking an underlying pompous outlook and sense of entitlement. Early measures of vulnerability-sensitive narcissism used Murray’s Narcissism Scale, which was explored by measuring the narcissism levels of Harvard undergraduates. Hendin and Cheek subsequently developed the Vulnerable Sensitive Narcissism Scale based on this narcissism scale. In addition to this, there are few ways to measure vulnerability-sensitive narcissism, and Chinese measurement tools on narcissism mainly measure explicit narcissism, neglecting to accurately measure vulnerability-sensitive narcissism, and failing to completely respond to an individual’s implicit narcissistic traits.

Aim

The hypersensitive narcissism scale was applied to college students to explore the factor structure of the scale under the background of Chinese culture, and to test its reliability and validity.

Methods

1000 questionnaires were distributed to college students, and 912 valid questionnaires were collected. Self-Esteem Scale, Aggression Scale and Narcissism subscale of Dark Triad Scale were used as the criterion. After 3 weeks, 100 college students were randomly selected for retest.

Results

The exploratory factor analysis showed that one dimension should be extracted. Eigenvalue was 5.352 and 53.518% cumulative variance interpretation rate. The confirmatory factor analysis showed that the scale structure validity was good (χ2/df=3.237,CFI=0.936,TLI=0.931, RMSEA=0.066,SRMR=0.053). Internal consistency reliability of the scale was 0.785; The test-retest reliability was 0.833, and the criterion correlation validity reached a significant level.

Conclusion

The Chinese version of hypersensitive narcissism scale has good reliability and validity, which can effectively measure hypersensitive narcissism. The localisation of the scale can better serve the research and development of the university student population on the one hand, and on the other hand, it can help the research in this field to have a more in-depth development in China.
Aspergillus nidulanscell wall integrity kinase, MpkA, impacts cellular phenotypes that alter mycelial-material mechanical properties
Authors: Gray Kelsey , Edwards Harley , Doan Alexander G. , Huso Walker , Lee JungHun , Pan Wanwei , Bolima Nelanne , Morse Meredith E. , Yoda Sarah , Gautam Isha , Harris Steven D. , Zupan Marc , Wang Tuo , deCarvalho Tagide , Marten Mark R.
Published: September 2024

Mycelial materials are an emerging, natural material made from filamentous fungi that have the potential to replace unsustainable materials used in numerous commercial applications (e.g., packaging, textiles, construction). Efforts to change the mechanical properties of mycelial-materials have typically involved altering growth medium, processing approaches, or fungal species. Although these efforts have shown varying levels of success, all approaches have shown there is a strong correlation between phenotype (of both fungal mycelia and mycelial material’s assembly) and resultant mechanical properties. We hypothesize that genetic means can be used to generate specific fungal phenotypes, leading to mycelial materials with specific mechanical properties. To begin to test this hypothesis, we used a mutant of the model filamentous fungus,Aspergillus nidulans, with a deletion of the last kinase in the cell wall integrity (CWI) signaling pathway, mpkA. We generated one set of mycelial materials from the ΔmpkAdeletion mutant (A1404), and another from its isogenic parent (A1405; control). When subjected to tensile testing, and compared to material generated from the control, ΔmpkAmaterial has similar elastic modulus, but significantly increased ultimate tensile strength, and strain at failure. When subjected to a fragmentation assay (i.e., resistance to shear-stress), the ΔmpkAmaterial also had higher relative mechanical strength. To determine possible causes for this behavior, we carried out a comprehensive set of phenotype assessments focused on: three-dimensional structure, hyphal morphology, hyphal growth behaviors, and conidial development. We find, compared to the control, material generated from the ΔmpkAmutant manifests significantly less development, a modified cell wall composition, larger diameter hyphae, more total biomass, higher water capacity and more densely packed material, which all appear to impact the altered mechanical properties.
Cross-trial prediction of treatment response to transcranial direct current stimulation in patients with major depressive disorder
Authors: Burkhardt Gerrit , Goerigk Stephan , Bulubas Lucia , Dechantsreiter Esther , Keeser Daniel , Vogelmann Ulrike , von Wartensleben Katharina , Wolf Johannes , Plewnia Christian , Fallgatter Andreas , Langguth Berthold , Normann Claus , Frase Lukas , Zwanzger Peter , Kammer Thomas , Schönfeldt-Lecuona Carlos , Kamp Daniel , Bajbouj Malek , Koutsouleris Nikolaos , Brunoni Andre R , Padberg Frank
Published: September 2024

Machine-learning (ML) classification may offer a promising approach for treatment response prediction in patients with major depressive disorder (MDD) undergoing non-invasive brain stimulation. This analysis aims to develop and validate such classification models based on easily attainable sociodemographic and clinical information across two randomized controlled trials on transcranial direct-current stimulation (tDCS) in MDD. Using data from 246 patients with MDD from the randomized-controlled DepressionDC and ELECT-TDCS trials, we employed an ensemble machine learning strategy to predict treatment response to either active tDCS or sham tDCS/placebo, defined as ≥ 50% reduction in the Montgomery-Åsberg Depression Rating Scale at 6 weeks. Separate models for active tDCS and sham/placebo were developed in each trial and evaluated for external validity across trials and for treatment specificity across modalities. Additionally, models with above-chance detection rates were associated with long-term outcomes to assess their clinical validity. In the DepressionDC trial, models achieved a balanced accuracy of 63.5% for active tDCS and 62.5% for sham tDCS in predicting treatment responders. The tDCS model significantly predicted MADRS scores at the 18-week follow-up visit (F(1,60)= 4.53, pFDR= .037, R2= 0.069). Baseline self-rated depression was consistently ranked as the most informative feature. However, response prediction in the ELECT-TDCS trial and across trials was not successful. Our findings indicate that ML-based models have the potential to identify responders to active and sham tDCS treatments in patients with MDD. However, to establish their clinical utility, they require further refinement and external validation in larger samples and with more features.
The father’s singing voice may impact premature infants’ brain more than their mother’s: A study protocol and preliminary data on a singing and EEG randomized controlled trial (RCT) based on the fundamental frequency of voice and kinship parameters
Authors: Papatzikis Efthymios , Dimitropoulos Kyriakos , Tataropoulou Kassandra , Kyrtsoudi Maria , Pasoudi Elena , O’Toole John M. , Nika Angeliki
Published: September 2024

This article presents the study protocol for a randomized controlled trial (RCT) investigating the impact of singing on the brain activity of premature infants in the Neonatal Intensive Care Unit (NICU). The study focuses on how the differentiation of voices, as defined by the fundamental frequency (F0) shaped by biological sex and kinship, influences neurophysiological responses when measured by electroencephalography (EEG). Premature infants, who are highly sensitive to auditory stimuli, may benefit from music-based interventions; however, there is limited understanding of how voice variations between male and female caregivers, and whether they are biologically related, affect brain activity. Our protocol outlines a structured intervention where infants are exposed to singing by four facilitators - a male music therapist, a female music therapist, the mother, and the father - and includes two singing stages: a sustained note (A at 440 Hz) and a 90-second lullaby, both interspersed with silent periods to allow for baseline measurements. EEG recordings track brain activity throughout these sessions, followed by quantitative EEG (qEEG) analysis and thorough statistical computations (e.g., mixed-effects models, spectral power analysis, and post-hoc tests) to explore how these auditory stimuli influence brain function. Preliminary data from five infants show that maternal singing elicits the highest delta spectral power in all measured conditions except during the ‘lullaby song’, where paternal singing elicits the highest effects followed by the male music therapist and then the mother. These early findings highlight the potential influence of parental voices, particularly the fathers’ voice, on neonatal brain development, while the detailed study protocol ensures rigor and replicability, providing a robust framework for future research. Additionally, this protocol lays the groundwork for exploring the long-term effects of music-based interventions, with the goal of improving neurodevelopmental outcomes in premature infants through tailored auditory stimulation. (clinincaltrials.govunique identifier:NCT06398912)