bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective effects of polyphenol-rich extracts against neurotoxicity elicited by paraquat or rotenone in cellular models of Parkinson’s disease
Authors: Tambe Mitali A. , de Rus Jacquet Aurelie , Strathearn Katherine E. , Yousef Gad G. , Grace Mary H. , Ferruzzi Mario G. , Wu Qingli , Simon James E. , Lila Mary Ann , Rochet Jean-Christophe 
Published: April 2023

AbstractParkinson’s disease (PD) is a neurodegenerative disorder involving motor symptoms caused by a loss of dopaminergic neurons in the substantia nigra region of the brain. Epidemiological evidence suggests that anthocyanin (ANC) intake is associated with a low risk of PD. Previously, we reported that extracts enriched with ANC and proanthocyanidins (PAC) suppressed dopaminergic neuron death elicited by the PD-related toxin rotenone in a primary midbrain culture model. Here, we characterized botanical extracts enriched with a mixed profile of polyphenols, as well as a set of purified polyphenolic standards, in terms of their ability to mitigate dopaminergic cell death in midbrain cultures exposed to another PD-related toxicant, paraquat (PQ), and we examined underlying neuroprotective mechanisms. Extracts prepared from blueberries, black currants, grape seeds, grape skin, mulberries, and plums, as well as several ANC, were found to rescue dopaminergic neuron loss in PQ-treated cultures. Comparison of a subset of ANC-rich extracts for the ability to mitigate neurotoxicity elicited by PQ versus rotenone revealed that a hibiscus or plum extract was only neuroprotective in cultures exposed to rotenone or PQ, respectively. Several extracts or compounds with the ability to protect against PQ neurotoxicity increased the activity of the antioxidant transcription factor Nrf2 in cultured astrocytes, and PQ-induced dopaminergic cell death was attenuated in Nrf2-expressing midbrain cultures. In other studies, we found that extracts prepared from hibiscus, grape skin, or purple basil (but not plums) rescued defects in O2consumption in neuronal cells treated with rotenone. Collectively, these findings suggest that extracts enriched with certain combinations of ANC, PAC, stilbenes, and other polyphenols could potentially slow neurodegeneration in the brains of individuals exposed to PQ or rotenone by activating cellular antioxidant mechanisms and/or alleviating mitochondrial dysfunction.
Learning the Language of Antibody Hypervariability
Authors: Singh Rohit , Im Chiho , Qiu Yu , Mackness Brian , Gupta Abhinav , Sorenson Taylor , Sledzieski Samuel , Erlach Lena , Wendt Maria , Nanfack Yves Fomekong , Bryson Bryan , Berger Bonnie 
Published: April 2023

Protein language models (PLMs) based on machine learning have demon-strated impressive success in predicting protein structure and function. However, general-purpose (“foundational”) PLMs have limited performance in predicting antibodies due to the latter’s hypervariable regions, which do not conform to the evolutionary conservation principles that such models rely on. In this study, we propose a new transfer learning framework called AbMAP, which fine-tunes foundational models for antibody-sequence inputs by supervising on antibody structure and binding specificity examples. Our feature representations accurately predict an antibody’s 3D structure, mutational effects on antigen binding, and paratope identification. AbMAP’s scalability paves the way for large-scale analyses of human antibody repertoires. AbMAP representations of immune repertoires reveal a remarkable overlap across individuals, overcoming the limitations of sequence analyses. Our findings provide compelling evidence for the hypothesis that antibody repertoires of individuals tend to converge towards comparable structural and functional coverage. We validate AbMAP for antibody optimization, applying it to optimize a set of antibodies that bind to a SARS-CoV-2 peptide and obtaining 82% hit-rate and upto 22-fold increase in binding affinity. We anticipate AbMAP will accelerate the efficient design and modeling of antibodies and expedite the discovery of antibody-based therapeutics.Availability:https://github.com/rs239/ablm
Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2receptors in humans
Authors: Henderson Tyler T. , Taylor Janet L. , Thorstensen Jacob R. , Kavanagh Justin J. 
Published: April 2023

AbstractSerotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 ± 4 years old) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs) and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). Compared to placebo, 5-HT2antagonism reduced maximal elbow flexion torque (p = 0.004), unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033), and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2receptors to regulate motoneurone excitability but not intracortical circuits.Significance statementCellular and animal preparations have revealed that somatodendritic 5-HT2receptors on motoneurones can modulate motoneurone excitability. However, it is mostly unknown how 5-HT2receptors modulate motor cortical and motoneurone activity to generate muscle contractions in humans. Here we show that antagonism of 5-HT2receptors reduced muscle responses to motor cortical stimulation only when the muscle was at rest, or when voluntary motor activity was interrupted by a conditioning TMS stimulus. In contrast, antagonism of 5-HT2receptors increased the muscle response to cervicomedullary electrical stimulation, but only when descending drive to motoneurones was present. These findings not only suggest that 5-HT2receptors modulate intracortical and motoneurone activity, but sustained synaptic excitation of motoneurones is required for serotonergic mechanisms to modulate motoneurones.
Exploring Correlation-Based Brain Networks with Adaptive Signed Random Walks
Authors: Sotero Roberto C. , Sanchez-Bornot Jose M. 
Published: April 2023

AbstractThe human brain is a highly connected network with complex patterns of correlated and anticorrelated activity. Analyzing functional connectivity matrices derived from neuroimaging data can provide insights into the organization of brain networks and their association with cognitive processes or disorders. Common approaches, such as thresholding or binarization, often disregard negative connections, which may result in the loss of critical information. This study introduces an adaptive signed random walk (ASRW) model for analyzing correlation- based brain networks that incorporates both positive and negative connections. The model calculates transition probabilities between brain regions as a function of their activities and connection strengths, dynamically updating probabilities based on the differences in node activity and connection strengths at each time step. Results show that the classical random walk approach, which only considers the absolute value of connections, underestimates the mean first passage time (MFPT) compared to the proposed ASRW model. Our model captures a wide range of interactions and dynamics within the network, providing a more comprehensive understanding of its structure and function. This study suggests that considering both positive and negative connections, has the potential to offer valuable insights into the interregional coordination underlying various cognitive processes and behaviors.
p53 promotes revival stem cells in the regenerating intestine after severe radiation injury
Authors: Morral Clara , Ayyaz Arshad , Kuo Hsuan-Cheng , Fink Mardi , Verginadis Ioannis , Daniel Andrea R. , Burner Danielle N. , Driver Lucy M. , Satow Sloane , Hasapis Stephanie , Ghinnagow Reem , Luo Lixia , Ma Yan , Attardi Laura D. , Koumenis Costas , Minn Andy J , Wrana Jeffrey L. , Lee Chang-Lung , Kirsch David G. 
Published: April 2023

AbstractIonizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced GI injury. Through single-cell RNA-sequencing of the irradiated mouse intestine, we find that p53 target genes are specifically enriched in stem cells of the regenerating epithelium, including revival stem cells that promote animal survival after GI damage. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce revival stem cells. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells that is controlled by an Mdm2-mediated negative feedback loop. These results suggest that p53 suppresses severe radiation-indued GI injury by promoting intestinal epithelial cell reprogramming.One-Sentence SummaryAfter severe radiation injury to the intestine, transient p53 activity induces revival stem cells to promote regeneration.
Macrophage migration is differentially regulated by distinct ECM components
Authors: Stinson Matthew W. , Laurenson Alexander J. , Rotty Jeremy D. 
Published: April 2023

AbstractMacrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). The present work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses to macrophages in 2D environments. Laminin 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared to cells on fibronectin. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. The present study also demonstrates that laminin 111 exerts a suppressive effect toward fibronectin, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell’s ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory modes based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in 3D andin vivocontexts warrants further study.
Development of heat shock resistance inL. pneumophilamodeled by experimental evolution
Authors: Liang Jeffrey , Faucher Sebastien P. 
Published: April 2023

AbstractBecause it can grow in buildings with complex hot water distribution systems (HWDS), healthcare facilities recognize the waterborne bacteriumLegionella pneumophilaas a major nosocomial infection threat and often try to clear the systems with a pasteurization process known as superheat-and-flush. After this treatment, many facilities find that the contaminating populations slowly recover, suggesting the possibility ofin situevolution favouring increased survival in high temperature conditions. To mimic this process in a controlled environment, an adaptive laboratory evolution (ALE) model was used to select a wild-type strain ofL. pneumophilafor survival to transient exposures to temperatures characteristic of routine hot water use or failed pasteurization processes in HWDS. Over their evolution, these populations became insensitive to exposure to 55 °C and innovated the ability to survive short exposures to 59 °C heat shock. Heat-adapted lineages maintained a higher expression of heat shock genes during low-temperature incubation in freshwater, suggesting a pre-adaptation to heat stress. Although there were distinct mutation profiles in each of the heat-adapted lineages, each acquired multiple mutations in the DnaJ/DnaK/ClpB disaggregase complex, as well as mutations in chaperonehtpGand proteaseclpX.These mutations were specific to heat shock survival and were not seen in control lineages included in the ALE without exposure to heat shock. This study supportsin situobservations of adaptation to heat stress and demonstrate the potential ofL. pneumophilato develop resistance to control measures.ImportanceAs a bacterium that thrives in warm water ecosystems,Legionella pneumophilais a key factor motivating regulations on hot water systems. Two major measures intended to controlLegionellaare the maintenance of high circulating temperatures to curtail growth and the use of superheat-and-flush pasteurization processes to eliminate established populations. Although hospitals are particularly vulnerable to nosocomial pneumoniae caused byLegionella, they recurrently experience recolonization of their hot water systems after treatment. To understand these long-term survivors, we have used an experimental evolution model to replicate this process. We find major differences between the mutational profiles of heat-adapted and heat-naïveL. pneumophilapopulations, including mutations in major heat shock genes like chaperones and proteases. This model demonstrates the value of appropriate heat treatment ofL. pneumophilacontaminated systems and – in an analogue to antibiotic resistance – the importance of complete eradication of the resident population to prevent selection for more persistent bacteria.
GluN2C/D-containing NMDA receptors enhance temporal summation and increase sound-evoked and spontaneous firing in the inferior colliculus
Authors: Drotos Audrey C. , Zarb Rachel L. , Booth Victoria , Roberts Michael T. 
Published: April 2023

AbstractAlong the ascending auditory pathway, there is a broad shift from temporal coding, which is common in the lower auditory brainstem, to rate coding, which predominates in auditory cortex. This temporal-to-rate transition is particularly prominent in the inferior colliculus (IC), the midbrain hub of the auditory system, but the mechanisms that govern how individual IC neurons integrate information across time remain largely unknown. Here, we report the widespread expression ofGlun2candGlun2dmRNA in IC neurons. GluN2C/D-containing NMDA receptors are relatively insensitive to voltage-dependent Mg2+block, and thus can conduct current at resting membrane potential. Using in situ hybridization and pharmacology, we show that VIP neurons in the IC express GluN2D-containing NMDA receptors that are activatable by commissural inputs from the contralateral IC. In addition, GluN2C/D-containing receptors have much slower kinetics than other NMDA receptors, and we found that GluN2D-containing receptors facilitate temporal summation of synaptic inputs in VIP neurons. In a model neuron, we show that a GluN2C/D-like conductance interacts with the passive membrane properties of the neuron to alter temporal and rate coding of stimulus trains. Consistent with this, we show in vivo that blocking GluN2C/D-containing receptors decreases both the spontaneous firing rate and the overall firing rate elicited by amplitude-modulated (AM) sounds in many IC neurons. These results suggest that GluN2C/D-containing NMDA receptors influence rate coding for auditory stimuli in the IC by facilitating the temporal integration of synaptic inputs.Significance statementNMDA receptors are critical components of most glutamatergic circuits in the brain, and the diversity of NMDA receptor subtypes yields receptors with a variety of functions. We found that many neurons in the auditory midbrain express GluN2C and/or GluN2D NMDA receptor subunits, which are less sensitive to Mg2+block than the more commonly expressed GluN2A/B subunits. We showed that GluN2C/D-containing receptors conducted current at resting membrane potential and enhanced temporal summation of synaptic inputs. In a model, we show that GluN2C/D-containing receptors provide additive gain for input-output functions driven by trains of synaptic inputs. In line with this, we found that blocking GluN2C/D-containing NMDA receptors in vivo decreased both spontaneous firing rates and firing evoked by amplitude-modulated sounds.
Molecular mechanism of complement inhibition by the trypanosome receptor ISG65
Authors: Cook Alexander D. , Carrington Mark , Higgins Matthew K. 
Published: April 2023

AbstractAfrican trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.Impact StatementA structure derived from cryogenic electron microscopy shows how ISG65, an African trypanosome receptor that aids virulence, binds C3b and suggests mechanisms through which ISG65 might aid complement resistance.
Flexing fish: cell surface plasticity in response to shape change in the whole organism
Authors: Hall TE , Ariotti N , Lo HP , Ferguson C , Martel N , Lim Y-W , Giacomotto J , Parton RG 
Published: April 2023

SUMMARYPlasma membrane rupture can result in catastrophic cell death. The skeletal muscle fibre plasma membrane, the sarcolemma, provides an extreme example of a membrane subject to mechanical stress since these cells specifically evolved to generate contraction and movement. A quantitative model correlating ultrastructural remodelling of surface architecture with tissue changesin vivois required to understand how membrane domains contribute to the shape changes associated with tissue deformation in whole animals. We and others have shown that loss of caveolae, small invaginations of the plasma membrane particularly prevalent in the muscle sarcolemma, renders the plasma membrane more susceptible to rupture during stretch1–3. While it is thought that caveolae are able to flatten and be absorbed into the bulk membrane to buffer local membrane expansion, a direct demonstration of this modelin vivohas been unachievable since it would require measurement of caveolae at the nanoscale combined with detailed whole animal morphometrics under conditions of perturbation. Here, we describe the development and application of the “active trapping model” where embryonic zebrafish are immobilised in a curved state that mimics natural body axis curvature during an escape response. The model is amenable to multiscale, multimodal imaging including high-resolution whole animal three-dimensional quantitative electron microscopy. Using the active trapping model, we demonstrate the essential role of caveolae in maintaining sarcolemmal integrity and quantify the specific contribution of caveolar-derived membrane to surface expansion. We show that caveolae directly contribute to an increase in plasma membrane surface area under physiologically relevant membrane deformation conditions.
Advergames for children's health education and communication practices
Authors: Lee Pui Yuen , Lau Kung Wong 
Published: April 2023

PurposeAppropriate and deliberate use of drug prevention methods is the key to educating children about the dangers of addiction and the way of prevention. With the growing prevalence of digital games among youngsters, health education and communication among children can try adopting advergames on digital television instead of traditional media, which has also been supported by prior research. It is, therefore, this research attempts to apply digital games as a means of health promotion and carry drug prevention messages through digital gameplay. Based on behavioral models, this research investigated the communication design and effectiveness of advergames for children's health promotion.Design/methodology/approachTwo studies were conducted in this research. In Study 1, the research team investigated how public health message was assimilated into advergames, which affect the health behaviors of children, they are (1) Knowledge about Drug, (2) Attitude Toward Drug and (3) Perceived Severity toward Drug-abuse. In Study 2, this research investigated the effects of the advergames on children through a between-group experiment. A pre-test/post-test for the control group and experimental group with 180 primary school children in Hong Kong was conducted.FindingsThe finding showed the potential use of advergames in health communication among children. The result proved that the anti-drug advergame is a more successful intervention among the participating children in the experimental group than the control group. The result triggers further investigations in academic, professional and educational values for advergames design, health education and communication areas.Research limitations/implicationsBecause of the chosen small sampling locally in Hong Kong, the research results may lack generalizability for other countries or practices.Practical implicationsThe study evokes children's awareness of drug prevention, encourages their physical and emotional wellness, and finally advocates a healthy lifestyle for them, through the deployment of health game communication.Originality/valueDespite this research studied the use of advergames, instead of digital games in general, for health promotion and delivering drug prevention messages. The research design distinctively allowed the primary students to participate in the design of the advergames instead of being passive players and/or in the information delivery process. This approach is indeed a pioneer attempt in that limited practice has been found academically. The study expands academic and practical knowledge on health game communication.