bluuebunny/crossref_metadata_2025_split huggingface dataset:
The transition state for coupled folding and binding of a disordered DNA binding domain resembles the unbound state
Authors: Kuravsky Mikhail , Kelly Conor , Redfield Christina , Shammas Sarah L 
Published: February 2024

ABSTRACTThe basic zippers (bZIPs) are one of two large eukaryotic families of transcription factors whose DNA binding domains are disordered in isolation but fold into stable α-helices upon target DNA binding. Here we systematically disrupt pre-existing helical propensity within the DNA binding region of the homodimeric bZIP domain of cAMP-response element binding protein (CREB) using Ala-Gly scanning and examine the impact on target binding kinetics. We find that the secondary structure of the transition state strongly resembles that of the unbound state. The closest residue to the dimerisation domain that has been examined is largely folded within both unbound and transition states; dimerisation apparently propagates additional helical propensity into the basic region. The results are consistent with electrostatically-enhanced DNA binding, followed by rapid folding from the folded zipper outwards. Interestingly, despite taking the exact experimental approach suggested for testing it, we find no evidence for disorder-mediated rate enhancement predicted by fly-casting theory.
Bifidobacterium longumsubsp. longumBG-L47 boosts growth and activity ofLimosilactobacillus reuteriDSM 17938 and its extracellular membrane vesicles
Authors: Lundberg Ludwig Ermann , Mishra Punya Pallabi , Liu Peidi , Forsberg Manuel Mata , Sverremark-Ekström Eva , Grompone Gianfranco , Håkansson Sebastian , Linninge Caroline , Roos Stefan 
Published: February 2024

AbstractThe aim was to identify aBifidobacteriumstrain that improved the performance ofLimosilactobacillus reuteriDSM 17938. Initial tests showed thatBifidobacterium longumsubsp.longumstrains boosted the growth of DSM 17938 duringin vivo-like conditions. Further characterization revealed that one of the strains, BG-L47, had better bile and acid tolerance compared to BG-L48, as well as mucus adhesion compared to both BG-L48 and the control strain BB536. BG-L47 also had the capacity to metabolize a broad range of carbohydrates and sugar alcohols. Mapping of glycoside hydrolase (GH) genes of BG-L47 and BB536 revealed many GHs associated with plant-fiber utilization. However, BG-L47 had a broader phenotypic fiber utilization capacity. In addition,B. longumsubsp.longumcells boosted the bioactivity of extracellular membrane vesicles (MV) produced byL. reuteriDSM 17938 during cocultivation. Secreted 5’ nucleotidase (5’NT), an enzyme that converts AMP into the signal molecule adenosine, was increased in MV boosted by BG-L47. The MV exerted an improved antagonistic effect on the pain receptor TRPV1 and increased the expression of the immune development markers IL-6 and IL-1ß in a PBMC model. Finally, the safety of BG-L47 was evaluated both by genome safety assessment and in a human safety study. Microbiota analysis showed that the treatment did not induce significant changes in the composition. In conclusion,B. longumsubsp.longumBG-L47 has favorable physiological properties, can boost thein vitroactivity ofL. reuteriDSM 17938, and is safe for consumption, making it a candidate for further evaluation in probiotic studies.ImportanceBy using probiotics that contain a combination of strains with synergistic properties, the likelihood of achieving beneficial interactions with the host can increase. In this study, we first performed a broad screening ofBifidobacterium longumsubsp.longumstrains in terms of synergistic potential and physiological properties. We identified a superior strain, BG-L47, with favorable characteristics and potential to boost the activity of the known probiotic strainLimosilactobacillus reuteriDSM 17938. Further, we demonstrated that BG-L47 is safe for consumption in a human randomized clinical study and by performing a genome safety assessment. This work illustrates that bacteria-bacteria interactions differ at the strain level and further provides a strategy for finding and selecting companion strains of probiotics.
Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs
Authors: Stinson Jordan A. , Barbosa Matheus Moreno P. , Sheen Allison , Momin Noor , Fink Elizabeth , Hampel Jordan , Selting Kimberly , Kamerer Rebecca , Bailey Keith L. , Wittrup K. Dane , Fan Timothy M. 
Published: February 2024

ABSTRACTThe clinical use of interleukin-2 and -12 cytokines against cancer is limited by their narrow therapeutic windows due to on-target, off-tumor activation of immune cells when delivered systemically. Engineering IL-2 and IL-12 to bind to extracellular matrix collagen allows these cytokines to be retained within tumors after intralesional injection, overcoming these clinical safety challenges. While this approach has potentiated responses in syngeneic mouse tumors without toxicity, the complex tumor-immune interactions in human cancers are difficult to recapitulate in mouse models of cancer. This has driven an increased role for comparative oncology clinical trials in companion (pet) dogs with spontaneous cancers that feature analogous tumor and immune biology to human cancers. Here, we report the results from a dose-escalation clinical trial of intratumoral collagen-binding IL-2 and IL-12 cytokines in pet dogs with malignant melanoma, observing encouraging local and regional responses to therapy that may suggest human clinical benefit with this approach.
Trim66’s paternal deficiency causes intrauterine overgrowth
Authors: Mielnicka Monika , Tabaro Francesco , Sureka Rahul , Acurzio Basilia , Paoletti Renata , Scavizzi Ferdinando , Raspa Marcello , Crevenna Alvaro H. , Lapouge Karine , Remans Kim , Boulard Matthieu 
Published: February 2024

AbstractThe tripartite motif-containing protein 66 (TRIM66, also known as TIF1-delta) is a PHD-Bromo containing protein primarily expressed in post-meiotic male germ cells known as spermatids. Biophysical assays showed that TRIM66 PHD-Bromo domain binds to H3 N-terminus only when lysine 4 is unmethylated. We addressed TRIM66’s role in reproduction by loss-of-function genetics in the mouse. Males homozygous forTrim66-nullmutations produced functional spermatozoa. Round spermatids lacking TRIM66 upregulated a network of genes involved in histone acetylation and H3K4 methylation. Profiling of H3K4me3 patterns in the sperm produced byTrim66-null mutant showed minor alterations below statistical significance. Unexpectedly,Trim66-null males, but not females, sired pups overweight at birth, hence revealing thatTrim66mutations cause a paternal effect phenotype.
Mechanism Study on the Effect of Kidney Tonifying and Liver Soothing Methods on Mouse Oocyte Quality by Regulating OSFs and Smads Pathways
Authors: Zhang Ruijuan , Jia Rui , Bai Jing , Du Huilan , Yang Liyun 
Published: February 2024

AbstractObjective: To observe the effects of kidney tonifying and liver soothing methods on the secretion of factor BMP-6, related receptors ALK-2/6, and downstream Smads pathway Smad1/5/844 in oocytes, and to explore the targeted mechanisms of their effects on mouse oocyte quality; Method: Healthy female mice aged 6-7 weeks were randomly divided into 6 groups, namely high and low dose kidney tonifying groups; High – and low-dose liver soothing groups; Control group and normal group. The high-dose and low-dose groups of tonifying the kidney were given oral solution of tonifying the kidney and regulating the meridian at 5.4g/ml and 2.7g/ml, respectively. The high-dose and low-dose groups of soothing the liver were given suspension of Xiaoyao Pill at 0.6g/ml and 0.3g/ml, respectively. The control group and normal group were given distilled water by gavage. Immunohistochemistry and Western blot were used to detect the expression of BMP-6, ALK-2/6, and Smad1/5/8/4 proteins in oocytes, while PCR was used to detect the mRNA expression of these indicators in oocytes; Result: Both methods can increase the expression of BMP-6 in oocytes of mice in the treatment group, activate ALK-2/6, and phosphorylate Smad1/5/8 to bind with Smad4, initiating signal transduction; The high-dose group of kidney tonifying is superior to other groups in regulating BMP-6, ALK-2/6, and Smad1/5/4. Conclusion: Kidney tonifying and liver soothing methods can regulate BMP-6 and its Smads pathway through different mechanisms to improve mouse oocyte quality.
Differential Impact of Biomechanical Constraints on Control Signal Dimensionality for Gravity Support Versus Propulsion
Authors: Korol AS , Gritsenko V 
Published: February 2024

AbstractNeural control of movement has to overcome the problem of redundancy in the multidimensional musculoskeletal system. The problem can be solved by reducing the dimensionality of the control space of motor commands, i.e., through muscle synergies or motor primitives. Evidence for this solution exists, multiple studies have obtained muscle synergies using decomposition methods. These synergies vary across different workspaces and are present in both dominant and non-dominant limbs. Here we explore the dimensionality of control space by examining muscle activity patterns across reaching movements in different directions starting from different postures performed bilaterally by healthy individuals. We further explore the effect of biomechanical constraints on the dimensionality of control space. We are building on top of prior work showing that muscle activity profiles can be explained by applied moments about the limb joints that reflect the biomechanical constraints. These muscle torques derived from motion capture represent the combined actions of muscle contractions that are under the control of the nervous system. Here we test the generalizability of the relationship between muscle torques and muscle activity profiles across different starting positions and between limbs. We also test a hypothesis that the dimensionality of control space is shaped by biomechanical constraints. We used principal component analysis to evaluate the contribution of individual muscles to producing muscle torques across different workspaces and in both dominant and non-dominant limbs. Results generalize and support the hypothesis. We show that the muscle torques that support the limb against gravity are produced by more consistent combinations of muscle co-contraction than those that produce propulsion. This effect was the strongest in the non-dominant arm moving in the lateral workspace on one side of the body.
Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span
Authors: Coleman Colin R. , Pallos Judit , Arreola-Bustos Alicia , Wang Lu , Raftery Daniel , Promislow Daniel E.L. , Martin Ian 
Published: February 2024

SUMMARYAging is the biggest risk factor for Parkinson’s disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varyingDrosophilastrains, we find a strong relationship between life span and age-related dopamine neuron loss. Naturally short-lived strains exhibit a loss of dopamine neurons but not generalized neurodegeneration, while long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress and vulnerability to silencing the familial PD geneparkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (GCL) overexpression is sufficient to normalize ROS levels, extend life span and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is frequently reported in idiopathic PD patient brain. Building on this evidence, we detect reduced levels of GCL catalytic and modulatory subunits in brain from PD patients harboring the LRRK2 G2019S mutation, implicating possible glutathione deficits in familial LRRK2-linked PD. Our study acrossDrosophilaand human PD systems suggests that glutathione plays an important role in the influence of aging on PD neurodegeneration.
Early mechanisms of aortic failure in a zebrafish model for thoracic aortic dissection and rupture
Authors: Vanhooydonck Michiel , Verlee Maxim , Silva Marta Santana , Pottie Lore , Boel Annekatrien , Van Impe Matthias , De Saffel Hanna , Caboor Lisa , Tapaneeyaphan Piyanoot , Bonnin Anne , Segers Patrick , De Clercq Adelbert , Willaert Andy , Syx Delfien , Sips Patrick , Callewaert Bert 
Published: February 2024

ABSTRACTThoracic aortic aneurysm and dissection (TAAD) associates with a high mortality rate. Despite the existence of different mouse models for TAAD, the underlying disease mechanisms remain elusive. Treatment options are limited and mainly consist of surgical repair at critical aortic diameters as current pharmacological interventions are unable to stop disease progression.In humans, loss of function (LOF) ofSMAD3andSMAD6impairs vascular homeostasis, increasing the risk for TAAD. We developed a zebrafish model for thoracic aortic dissection/rupture by targeting both ohnologs ofsmad3andsmad6. At 10 days post fertilization, we found an increased diameter of the ventral aorta insmad3a−/−;smad3b−/−double knockout zebrafish, whilesmad6a−/−;smad6b−/−double knockout zebrafish have a reduced aortic diameter associated with early mortality. We discovered that asmad3a−/−;smad3b−/−;smad6a−/−;smad6b−/−quadruple knockout (qKO) zebrafish model is viable and survives to adulthood, although exposure to stress leads to sudden death. Histological analysis of the adult ventral aorta shows medial elastolysis, aortic dissections and ruptures at sites exposed to high biomechanical stress. RNA-sequencing of 5 days post fertilization qKO zebrafish indicates a profile of reduced negative regulation of proteolysis and upregulation of melanogenesis, a previously unaddressed pathway in this pathology. We confirm that pharmacological modulation of tyrosinase, the enzyme responsible for the production of melanin, influences aortic morphology.Overall, the qKO mutant, thus far the only known zebrafish model of thoracic aortic dissection and rupture, reveals novel SMAD3/6-dependent pathways that impact thoracic aortic homeostasis, in this way opening avenues for the development of novel treatments in TAAD.
Aging disrupts blood-brain and blood-spinal cord barrier homeostasis, but does not increase paracellular permeability
Authors: Cummins Mitchell J , Cresswell Ethan T , Smith Doug W 
Published: February 2024

3SummaryBlood-CNS barriers protect the CNS from circulating immune cells and damaging molecules. It is thought barrier integrity becomes disrupted with aging, contributing to impaired CNS function. Using genome-wide and targeted molecular approaches, we found aging affected expression of predominantly immune invasion and pericyte-related genes in most CNS regions investigated, especially after middle age, with spinal cord being most impacted. We did not find significant perturbation of tight junction genes, nor were vascular density or pericyte coverage affected by aging. We evaluated barrier paracellular permeability using small molecular weight tracers, serum protein extravasation, CNS water content, and iron labelling measures. We found no evidence for age-related increased barrier permeability in any of these tests. We conclude that blood-brain (BBB) and blood-spinal cord barrier (BSCB) paracellular permeability does not increase with normal aging in mouse. Whilst expression changes were not associated with increased permeability, they may represent an age-related primed state whereby additional insults cause increased leakiness.
Characteristics of Cerebrospinal Fluid in Autism Spectrum Disorder - A Systematic Review
Authors: Srivastava Vandana , O’Reilly Christian 
Published: February 2024

AbstractAutism Spectrum Disorder (ASD) is a range of neurodevelopmental conditions characterized by impaired social interaction, learning, and restricted or repetitive behaviors. The underlying causes of ASD are still debated, but researchers have found many physiological traits like gut problems and impaired immune system, to help understand the etiology of ASD. Cerebrospinal fluid (CSF) plays a critical role in maintaining the homeostasis of the neuronal environment and has, therefore, been analyzed in multiple conditions impacting the central nervous system. The study of CSF is crucial to understanding neurological disorders as its composition changes with the disorders, and these changes may indicate various disorder-related physiological mechanisms. For this systematic review, we searched the PubMed database for studies published between 1977 and 2023 and selected 45 studies after manual screening. We took stock of the evidence supporting the hypothesis that ASD alters the properties and composition of CSF. We systematically report on the different attributes of CSF in the ASD population that could be potential biomarkers and assist in understanding the origins and progression of ASD.We found that in CSF, immune markers, proteins, extra-axial CSF, folate, oxytocin, and vasopressin showed changes in ASD compared to the neurotypicals. We observed many gaps in the literature due to variations in the age and sample size, bias in sex-based reporting of results, and a handful of studies on ASD adults. Our review highlights the need for more research on CSF in autism spectrum disorder to improve understanding of the disorder and identify CSF biomarkers.
Causal role of medial superior frontal cortex on enhancing neural information flow and self-agency judgments in the self-agency network
Authors: Jia Yingxin , Kudo Kiwamu , Jariwala Namasvi , Tarapore Phiroz , Nagarajan Srikantan , Subramaniam Karuna 
Published: February 2024

AbstractSelf-agency is being aware of oneself as the agent of one’s thoughts and actions. Self-agency is necessary for successful interactions with the outside world (reality-monitoring). Prior research has shown that the medial superior prefrontal gyri (mPFC/SFG) may represent one neural correlate underlying self-agency judgments. However, the causal relationship remains unknown. Here, we applied high-frequency 10Hz repetitive transcranial magnetic stimulation (rTMS) to modulate the excitability of the mPFC/SFG site that we have previously shown to mediate self-agency. For the first time, we delineatecausalneural mechanisms, revealing precisely how rTMS modulates SFG excitability and impactsdirectionalneural information flow in the self-agency network by implementing innovative magnetoencephalography (MEG) phase-transfer entropy (PTE) metrics, measured from pre-to-post rTMS. We found that, compared to control rTMS, enhancing SFG excitability by rTMS induced significant increases in information flow between SFG and specific cingulate and paracentral regions in the self-agency network in delta-theta, alpha, and gamma bands, which predicted improved self-agency judgments. This is the first multimodal imaging study in which we implement MEG PTE metrics of 5D imaging of space, frequency and time, to provide cutting-edge analyses of thecausalneural mechanisms of how rTMS enhances SFG excitability and improves neural information flow between distinct regions in the self-agency network to potentiate improved self-agency judgments. Our findings provide a novel perspective for investigatingcausalneural mechanisms underlying self-agency and create a path towards developing novel neuromodulation interventions to improve self-agency that will be particularly useful for patients with psychosis who exhibit severe impairments in self-agency.
Pulsatility analysis of the circle of Willis
Authors: Voss Henning U. , Razlighi Qolamreza R. 
Published: February 2024

AbstractPurposeTo evaluate the phenomenological significance of cerebral blood pulsatility imaging in aging research.MethodsN = 38 subjects aged from 20 to 72 years of age (24 females) were imaged with ultrafast MRI with a sampling rate of 100 ms and simultaneous acquisition of pulse oximetry data. Of these, 28 subjects had acceptable MRI and pulse data, with 16 subjects between 20 and 28 years of age, and 12 subjects between 61 and 72 years of age. Pulse amplitude in the circle of Willis was assessed with the recently developed method of analytic phase projection to extract blood volume waveforms with an effective sampling rate of about 0.3 ms.ResultsArteries in the circle of Willis showed pulsatility in the MRI for both the young and old age groups. Pulse amplitude in the circle of Willis significantly increased with age (p = 0.01) but was independent of gender, heart rate, and head motion during MRI.Discussion and conclusionIncreased pulse wave amplitude in the circle of Willis in the elderly suggests a phenomenological significance of cerebral blood pulsatility imaging in aging research. The physiologic origin of increased pulse amplitude (increased pulse pressure vs. change in arterial morphology vs. re-shaping of pulse waveforms caused by the heart) requires further investigation.