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Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI (dMRI) and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N = 628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (ventral tegmental area) showed stronger connectivity with the anterior versus posterior hippocampus, the ventromedial prefrontal cortex showed stronger connectivity with the posterior hippocampus. The limbic (ventral) striatum demonstrated a more homogeneous connectivity profile along the hippocampal long axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. Management of the pandemic has relied mainly on SARS-CoV-2 vaccines, while alternative approaches such as meditation, shown to improve immunity, have been largely unexplored. Here, we probe the relationship between meditation and COVID-19 disease and directly test the impact of meditation on the induction of a blood environment that modulates viral infection. We found a significant inverse correlation between length of meditation practice and SARS-CoV-2 infection as well as accelerated resolution of symptomology of those infected. A meditation "dosing" effect was also observed. In cultured human lung cells, blood from experienced meditators induced factors that prevented entry of pseudotyped viruses for SARS-CoV-2 spike protein of both the wild-type Wuhan-1 virus and the Delta variant. We identified and validated SERPINA5, a serine protease inhibitor, as one possible protein factor in the blood of meditators that is necessary and sufficient for limiting pseudovirus entry into cells. In summary, we conclude that meditation can enhance resiliency to viral infection and may serve as a possible adjuvant therapy in the management of the COVID-19 pandemic.

Delayed graft function (DGF) after kidney transplantation heralds a worse prognosis. In patients with hyperoxaluria, the incidence of DGF is high. Oxalic acid is a waste product that accumulates when kidney function decreases. We hypothesize that residual diuresis and accumulated waste products influence the DGF incidence. Patients transplanted between 2018–2022 participated in the prospective cohort study. Pre-transplant concentrations of oxalic acid and its precursors were determined. Data on residual diuresis and other recipient, donor or transplant related variables were collected. 496 patients were included, 154 were not on dialysis. Oxalic acid, and glyoxylic acid, were above upper normal concentrations in 98.8%, and 100% of patients. Residual diuresis was ≤150 mL/min in 24% of patients. DGF occurred in 157 patients. Multivariable binary logistic regression analysis demonstrated a significant influence of dialysis type, recipient BMI, donor type, age, and serum creatinine on the DGF risk. Residual diuresis and glycolic acid concentration were inversely proportionally related to this risk, glyoxylic acid directly proportionally. Results in the dialysis population showed the same results, but glyoxylic acid lacked significance. In conclusion, low residual diuresis is associated with increased DGF incidence. Possibly accumulated waste products also play a role. Pre-emptive transplantation may decrease the incidence of DGF.

Many neurodegenerative diseases (NDD) appear to share commonality of origin, chronic ER stress. The endoplasmic reticulum (ER) is a dynamic organelle, functioning as a major site of protein synthesis and protein posttranslational modifications, required for proper folding. ER stress can occur because of external stimuli, such as oxidative stress or neuroinflammatory cytokines, creating the ER luminal environment permissive for the accumulation of aggregated and misfolded proteins. Unresolvable ER stress upregulates a highly conserved pathway, the unfolded protein response (UPR). Maladaptive chronic activation of UPR components leads to apoptotic neuronal death. In addition to other factors, physiological responses to stressors are emerging as a significant risk factor in the etiology and pathogenesis of NDD. Owned cats share a common environment with people, being exposed to many of the same stressors as people and additional pressures due to their “quasi” domesticated status. Feline Cognitive Dysfunction Syndrome (fCDS) presents many of the same disease hallmarks as human NDD. The prevalence of fCDS is rapidly increasing as more people welcome cats as companions. Barely recognized 20 years ago, veterinarians and scientists are in infancy stages in understanding what is a very complex disease. This review will describe how cats may represent an unexplored animal mimetic phenotype for human NDD with stressors as potential triggering mechanisms. We will consider how multiple variations of stressful events over the short-life span of a cat could affect neuronal loss or glial dysfunction and ultimately tip the balance towards dementia.

This article presents an in-depth qualitative case study asking, “How do Norwegian kindergarten teachers conceptualize and negotiate the field of psychosocial support?” This article thoroughly explores how Norwegian kindergarten teachers perceive of the field Mental health and psychosocial support (MHPSS). Recognizing the global imperative to advance mental health and psychosocial support for children, the study highlights the crucial need for interprofessional grounded concepts and logics in developing MHPSS interventions. The study employs a grounded theory approach to actively develop concepts in the MHPSS field in Norway. The six selected Norwegian expert teachers can make up a so-called “unique case”, representing a high-income country with a robust welfare system and child-centered pedagogy. Yet, they reveal challenges in embracing the concept of psychosocial support: The analysis shows that the teachers seem to neglect and even reject the concept of psychosocial support, while also expressing inferiority and lack of agency towards other professions. However, the teachers also express the desire for more knowledge, and with proudness they energetically engage in fostering children’s agency and functioning by their everyday descriptions of «meeting with the child». The study calls for the kindergarten teachers’ increased efforts to actively participate in MHPSS interventions, advocating for the further development of an «educational footprint» that can empower interprofessional work.

People may be more likely to exercise if they have self-efficacy for exercise (SEE). We conducted an exploratory analysis of SEE using data from a clinical trial designed to increase physical activity (N = 340). We evaluated correlates of baseline SEE and the relationship between baseline SEE and physical activity. Low SEE at baseline was correlated with lower well-being, physical activity, and higher depression at baseline. Participants with high (vs. low) baseline SEE had higher physical activity (but no differential change in activity) over time. These data highlight the potential role of SEE in psychological health and physical activity.

The domain wall energy is calculated by the balance between exchange, magnetocrystalline anisotropy and magnetoelastic energy contributions. The described method is theoretical and is based on experimental measurements of neutron inelastic scattering. The domain wall energy is determined by both finding the minimum of energy and deriving the energy and setting it to zero. The determination was undertaken for the discrete case, and this means that the calculation was performed for each plane or atomic layer. This is in contrast with the Bloch wall, which assumes continuum mean. The energy of the Lilley domain wall was discussed. Most of the energy of the Bloch wall was comprised inside the Lilley distance (above 99.9% of the energy). Antiferromagnetic interactions strongly decreased the domain wall energy. The negative terms due to antiferromagnetism must be considered in the Hamiltonian describing the exchange energy terms. The domain wall energy and width of terbium were reassessed. The values varied between 83.7 and 95.2 Kelvin (10.3 to 11.2 ergs/cm2). The domain width was estimated to be 57 Angstroms. It was found that a significant part of the total domain wall energy was concentrated on the planes at the center of the domain wall.

AbstractRepresentation learning is a core component in data-driven modeling of various complex phenomena. Learning a contextually informative representation can especially benefit the analysis of fMRI data because of the complexities and dynamic dependencies present in such datasets. In this work, we propose a framework based on transformer models to learn an embedding of the fMRI data by taking the spatiotemporal contextual information in the data into account. This approach takes the multivariate BOLD time series of the regions of the brain as well as their functional connectivity network simultaneously as the input to create a set of meaningful features that can in turn be used in various downstream tasks such as classification, feature extraction, and statistical analysis. The proposed spatiotemporal framework uses the attention mechanism as well as the graph convolution neural network to jointly inject the contextual information regarding the dynamics in time series data and their connectivity into the representation. We demonstrate the benefits of this framework by applying it to two resting-state fMRI datasets, and provide further discussion on various aspects and advantages of it over a number of other commonly adopted architectures.

To understand the biological relevance and mode of action of artificial protein ligands, crystal structures with their protein targets are essential. Here, we describe and investigate all known crystal structures that contain a so-called “molecular tweezer” or one of its derivatives with an attached natural ligand on the respective target protein. The aromatic ring system of these compounds is able to include lysine and arginine side chains, supported by one or two phosphate groups that are attached to the half-moon-shaped molecule. Due to their marked preference for basic amino acids and the fully reversible binding mode, molecular tweezers are able to counteract pathologic protein aggregation and are currently being developed as disease-modifying therapies against neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. We analyzed the corresponding crystal structures with 14-3-3 proteins in complex with mono- and diphosphate tweezers. Furthermore, we solved crystal structures of two different tweezer variants in complex with the enzyme Δ1-Pyrroline-5-carboxyl-dehydrogenase (P5CDH) and found that the tweezers are bound to a lysine and methionine side chain, respectively. The different binding modes and their implications for affinity and specificity are discussed, as well as the general problems in crystallizing protein complexes with artificial ligands.

Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.

This article presents an in-depth qualitative case study asking, "How do Norwegian kindergarten teachers conceptualize and negotiate the field of psychosocial support?" This article thoroughly explores how Norwegian kindergarten teachers perceive of the field Mental health and psychosocial support (MHPSS). Recognizing the global imperative to advance mental health and psychosocial support for children, the study highlights the crucial need for interprofessional grounded concepts and logics in developing MHPSS interventions. The study employs a grounded theory approach to actively develop concepts in the MHPSS field in Norway. The six selected Norwegian expert teachers can make up a so-called "unique case", representing a high-income country with a robust welfare system and child-centered pedagogy. Yet, they reveal challenges in embracing the concept of psychosocial support: The analysis shows that the teachers seem to neglect and even reject the concept of psychosocial support, while also expressing inferiority and lack of agency towards other professions. However, the teachers also express the desire for more knowledge, and with proudness they energetically engage in fostering children's agency and functioning by their everyday descriptions of «meeting with the child». The study calls for the kindergarten teachers' increased efforts to actively participate in MHPSS interventions, advocating for the further development of an «educational footprint» that can empower interprofessional work. [ABSTRACT FROM AUTHOR]

Statins, which reduce LDL-cholesterol by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin-induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity-dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2T202/Y204, AktSer473, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor, and insulin receptor-β; decreased Ras homolog gene family member A activation; and induced apoptosis. In cardiomyocyte-equivalent HL-1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long-term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size-variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria- and endoplasmic reticulum-related genes; and a 21% increase in mortality in cardiac-specific vinculin-knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long-term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications.-Godoy, J. C., Niesman, I. R., Busija, A. R., Kassan, A., Schilling, J. M., Schwarz, A., Alvarez, E. A., Dalton, N. D., Drummond, J. C., Roth, D. M., Kararigas, G., Patel, H. H., Zemljic-Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

IntroductionThe media’s recent focus on possible negative health outcomes following sports- related concussion has increased awareness as well as anxiety among parents and athletes. However, the literature on concussion outcomes is equivocal and limited by a variety of diagnostic approaches.MethodsThe current study used a rigorous, open- access concussion identification method—the Ohio State University Traumatic Brain Injury Identification method (OSU TBI-ID) to identify concussion and periods of repeated, subclinical head trauma in 108 young adult athletes who also underwent a comprehensive protocol of cognitive tests, mood/anxiety questionnaires, and high-angular-resolution diffusion-weighted brain imaging to evaluate potential changes in white matter microstructure.ResultsAnalyses showed that athletes with a history of repetitive, subclinical impacts to the head performed slightly worse on a measure of inhibitory impulse control and had more anxiety symptoms compared to those who never sustained any type of head injury but were otherwise the same as athletes with no history of concussion. Importantly, there were no group differences in cerebral white matter as measured by tract- based spatial statistics (TBSS), nor were there any associations between OSU TBI-ID measures and whole-brain principal scalars and free-water corrected scalars.DiscussionOur results provide support for the hypothesis that it is not concussion per se, but repetitive head impacts that beget worse outcomes.

A delicate interneuronal communication between pre- and postsynaptic membranes is critical for synaptic plasticity and the formation of memory. Evidence shows that membrane/lipid rafts (MLRs), plasma membrane microdomains enriched in cholesterol and sphingolipids, organize presynaptic proteins and postsynaptic receptors necessary for synaptic formation and signaling. MLRs establish a cell polarity that facilitates transduction of extracellular cues to the intracellular environment. Here we show that neuron-targeted overexpression of an MLR protein, caveolin-1 (SynCav1), in the adult mouse hippocampus increased the number of presynaptic vesicles per bouton, total excitatory type I glutamatergic synapses, number of same-dendrite multiple-synapse boutons, increased myelination, increased long-term potentiation, and increased MLR-localized N-methyl-d-aspartate receptor subunits (GluN1, GluN2A, and GluN2B). Immunogold electron microscopy revealed that Cav-1 localizes to both the pre- and postsynaptic membrane regions as well as in the synaptic cleft. These findings, which are consistent with a significant increase in ultrastructural and functional synaptic plasticity, provide a fundamental framework that underlies previously demonstrated improvements in learning and memory in adult and aged mice by SynCav1. Such observations suggest that Cav-1 and MLRs alter basic aspects of synapse biology that could serve as potential therapeutic targets to promote neuroplasticity and combat neurodegeneration in a number of neurological disorders.

Emerging research in nonhuman animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white matter connectivity in a cohort of men and women using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections between the cerebellum and VTA predominantly originate in the right cerebellar hemisphere, interposed nucleus, and paravermal cortex and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared with other lobules. We discovered a mediolateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socioaffective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socioaffective regulation. [ABSTRACT FROM AUTHOR]

BackgroundStudies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown.MethodsHere, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes.ResultsSynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function.ConclusionsNeuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal-dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.