bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune activation state modulates the retrieval of infant engrams
Authors: Power Sarah D. , Stewart Erika , Zielke Louisa G. , Byrne Eric Patrick , Ortega-de San Luis Clara , Lynch Lydia , Ryan Tomás J. 
Published: May 2022

AbstractInfantile amnesia is possibly the most ubiquitous form of memory loss in mammals. Despite its widespread relevance, little is known about the biological conditions for infantile amnesia to occur and its effect on the engram cells that encode a memory. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we discovered a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. We rescued the same apparently forgotten infantile memories in mice by optogenetically reactivating dentate gyrus engram cells labeled during complex infant development experiences. Further, we were able to permanently reinstate lost infantile memories by artificially updating the memory engram, demonstrating that infantile amnesia is a reversible process. Our findings suggest that immune activation during development modulates innate, and reversible, forgetting switches that determine whether infantile amnesia will occur.
The Devil Is In The Details: Landscape Features Are Insufficient To Explain Patterns Of Non-Native Fishes Distribution In North Patagonian Streams
Authors: Lallement Mailén Elizabeth , Rechencq Magalí , Zattara Eduardo Enrique 
Published: May 2022

AbstractEcological communities are structured by combinations of factors known as habitat templates. These templates work as a filter allowing only species with particular traits or phenotypes to establish and persist excluding all others. Defining which habitat variables and spatial scales drive the assembly of freshwater communities is key to effective and efficient management of fluvial ecosystems. We took advantage of the relatively recent and well-studied history of salmonid introductions in Patagonia to evaluate if non-native species show different patterns of association with abiotic factors depending on the spatial scale of the environmental filter. We used a hierarchical approach to characterized environmental variables at the basin and reach scales to assess their influence on the presence, abundance and structure of the salmonid assemblages in breeding streams. We saw no evidence that presence/absence patterns of salmonid distribution were driven by landscape variables, except for those basins with physical environmental barriers to colonization. However, we did find evidence for relative abundances being influenced by climatic and geomorphological variables (e.g., precipitation and relief). Our results do not support a scenario in which any of the salmonid species modulates the distribution of the other species, suggesting that interference has played only a minor role in determining current fish distribution in fluvial systems of the region. Instead, current patterns of presence and abundance of salmonids are best explained as the product of environmental filters. Our findings contribute to our understanding of the ecology of individual species and provide insight into the mechanisms structuring fish assemblages in Southern Hemisphere’s lotic systems.
Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome
Authors: Mykins Michael , Layo-Carris Dana , Dunn Logan Reid , Skinner David Wilson , McBryar Alexandra Hart , Perez Sarah , Shultz Trinity Rose , Willems Andrew , Lau Billy You Bun , Hong Tian , Krishnan Keerthi 
Published: May 2022

AbstractRett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2Heterozygous, Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying similar levels of perineuronal net expression, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincide with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.
First-in-human evaluation of cutaneous innate and adaptive immunomodulation by mosquito bites
Authors: Guerrero David , My Vo Hoa Thi , Lon Chanthap , Bohl Jennifer A. , Nhik Sreynik , Chea Sophana , Man Somnang , Sreng Sokunthea , Pacheco Andrea R. , Ly Sokna , Sath Rathanak , Lay Sokchea , Missé Dorothee , Huy Rekol , Leang Rithea , Kry Hok , Valenzuela Jesus G. , Oliveira Fabiano , Cantaert Tineke , Manning Jessica E. 
Published: May 2022

AbstractMosquito-borne viruses are a growing global threat. Initial viral inoculation occurs in the skin via the mosquito ‘bite’, eliciting immune responses that shape the establishment of infection and pathogenesis. We aimed to cutaneous innate and adaptive immune responses to mosquito bites in individuals from endemic areas. In this single-arm, cross-sectional interventional study, we enrolled 30 healthy adult participants aged 18 to 45 years of age from Cambodia between October 2020 and January 2021. We performed 3-mm skin biopsies at baseline as well as 30 minutes, 4 hours, and 48 hours after a controlled feeding by uninfectedAedes aegyptimosquitos. The primary endpoints were measurement of changes in early and late innate responses in bitten vs unbitten skin by gene expression profiling, immunophenotyping, and cytokine profiling. Results revealed induction of neutrophil degranulation and recruitment of skin-resident dendritic cells and M2-macrophages in ‘bitten’ skin. As the immune reaction progressed over time, T cell priming and regulatory pathways were upregulated along with a shift to a Th2-driven response and CD8+ T cell activation. In accordance, participants’ bitten skin cells produced less pro-inflammatory cytokines when stimulated byAe. aegyptisalivary gland extract. No unexpected adverse events occurred, and one patient was lost to follow-up at Day 14. These results identify key immune genes, cell types, and pathways in the human response to mosquito bites that can be leveraged to develop novel therapeutics and vector-targeted vaccine candidates to arboviral diseases.Graphical AbstractPanel shows evolution of the human skin response toAedes aegyptibites over time.
Spatial patterns of evolutionary diversity in Cactaceae show low ecological representation within protected areas
Authors: Amaral Danilo Trabuco , Bonatelli Isabel A. S. , Romeiro-Brito Monique , Moraes Evandro Marsola , Franco Fernando Faria 
Published: May 2022

AbstractMapping biodiversity patterns across taxa and environments is crucial to address the evolutionary and ecological dimensions of species distribution, suggesting areas of particular importance for conservation purposes. Within Cactaceae, spatial diversity patterns are poorly explored, as well as the abiotic factors that may predict these patterns. We gathered geographic and genetic data from 922 cactus species, which are tightly associated with drylands, to evaluate diversity patterns, such as phylogenetic diversity and endemism, paleo-, neo-, and superendemism, and the environmental predictor variables of such patterns in a global analysis. Hotspot areas of cacti diversity are scattered along the Neotropical and Nearctic regions, mainly in the desertic portion of Mesoamerica, Caribbean Island, and the dry diagonal of South America. The geomorphological features of these regions may create a complexity of areas that work as locally buffered zones over time, which triggers local events of diversification and speciation. Desert and dryland/dry forest areas comprise paleo- and superendemism and may act as both museums and cradles of species, displaying great importance for conservation. Past climates, topography, soil features, and solar irradiance seem to be the main predictors of distinct endemism types. The hotspot areas that encompass a major part of the endemism cells are outside or poorly covered by formal protection units. The current legally protected areas are not able to conserve cactus evolutionary history. Given the rapid anthropogenic disturbance, efforts must be reinforced to monitor biodiversity and the environment and to define/plan current and new protected areas.
Functional metagenomic screening in microfluidic droplets identifies a β-glucuronidase in an unprecedented sequence neighbourhood
Authors: Neun Stefanie , Brear Paul , Campbell Eleanor , Tryfona Theodora , Omari Kamel El , Wagner Armin , Dupree Paul , Hyvönen Marko , Hollfelder Florian 
Published: May 2022

ABSTRACTThe abundance of recorded protein sequence data stands in contrast to the small number of experimentally verified functional annotation. Here we screened a million-membered metagenomic library at ultrahigh throughput in microfluidic droplets for β-glucuronidase activity. We identified SN243, a genuine β-glucuronidase with little homology to previously studied enzymes of this type, as a glycoside hydrolase (GH) 3 family member. This GH family had no recorded evidence of β-glucuronidases at the outset of this study, showing that a functional metagenomic approach can shed light on assignments that are currently ‘unpredictable’ by bioinformatics. Kinetic analyses of SN243 characterised it as a promiscuous catalyst and structural analysis suggests regions of divergence from homologous GH3 members creating a wide-open active site. With a screening throughput of >107 library members per day, picolitre volume microfluidic droplets enable functional assignments that complement current enzyme database dictionaries and provide bridgeheads for the annotation of unexplored sequence space.
Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study
Authors: Kuznetsov Ivan A. , Kuznetsov Andrey V. 
Published: May 2022

AbstractWe report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson’s disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities.
A Feed-forward Pathway Drives LRRK2 kinase Membrane Recruitment and Activation
Authors: Vides Edmundo G. , Adhikari Ayan , Chiang Claire Y. , Lis Pawel , Purlyte Elena , Limouse Charles , Shumate Justin L. , Spínola-Lasso Elena , Dhekne Herschel S. , Alessi Dario R. , Pfeffer Suzanne R. 
Published: May 2022

AbstractActivating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson’s disease and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed “Site #1”, can also bind additional LRRK2 substrates, Rab8A and Rab10. Moreover, we identify a distinct, N-terminal, higher affinity interaction interface between LRRK2 phosphorylated Rab8 and Rab10 termed “Site #2”, that can retain LRRK2 on membranes in cells to catalyze multiple, subsequent phosphorylation events. Kinase inhibitor washout experiments demonstrate that rapid recovery of kinase activity in cells depends on the ability of LRRK2 to associate with phosphorylated Rab proteins, and phosphorylated Rab8A stimulates LRRK2 phosphorylation of Rab10 in vitro. Reconstitution of purified LRRK2 recruitment onto planar lipid bilayers decorated with Rab10 protein demonstrates cooperative association of only active LRRK2 with phospho-Rab10-containing membrane surfaces. These experiments reveal a feed-forward pathway that provides spatial control and membrane activation of LRRK2 kinase activity.
Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors
Authors: Owoloye Afolabi J. , Ligali Funmilayo C. , Enejoh Ojochenemi A. , Musa Adesola Z. , Aina Oluwagbemiga , Idowu Emmanuel T. , Oyebola Kolapo M. 
Published: May 2022

AbstractMalaria chemotherapy has been plagued by parasite resistance. Novel drugs must be continually explored for malaria treatment. Plasmodium falciparum requires host glucose for survival and proliferation. Protein involved in hexose permeation, P. falciparum hexose transporter 1 (PfHT1) is a potential drug target. We performed high throughput virtual screening of 21,352 small-molecule compounds against PfHT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit PfHT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalised Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for PfHT1 over the human glucose transporter (hGLUT1) orthologue. Five important compounds were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the PfHT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for PfHT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against PfHT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.
Lysosomal alterations and decreased electrophysiological activity in CLN3 disease (966 bp deletion, E295K) patient-derived cortical neurons
Authors: Chear Sueanne , Perry Sharn , Wilson Richard , Bindoff Aidan , Talbot Jana , Ware Tyson L , Grubman Alexandra , Vickers James C , Pébay Alice , Ruddle Jonathan B , King Anna E , Hewitt Alex W , Cook Anthony L 
Published: May 2022

ABSTRACTCLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3. Most individuals with CLN3 disease carry at least one allele with a 966 bp deletion in CLN3 which results in the deletion of exons 7 and 8. There is a need for more physiologically relevant human cell-based CLN3 disease models to better understand the cellular changes during the disease process. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human induced pluripotent stem cells (iPSCs) of a compound heterozygous patient (CLN3 Δ 966 bp and E295K). The isogenic deletion-corrected and unedited CLN3 patient iPSCs were used for disease modeling. iPSC-derived neurons carrying this particular CLN3 mutation (CLN3 neurons) had lower functional activity as recorded using microelectrode arrays for most of the culture period. Proteomics analysis showed downregulation of proteins related to axon guidance and endocytosis at day in vitro (DIV) 14 and 42 in CLN3 neurons. This was accompanied by an increase in lysosomal-related proteins in CLN3 neurons. Western blot analysis revealed hyperglycosylation of the lysosomal marker, Lysosome Associated Membrane Protein 1 (LAMP1) in CLN3 neurons at DIV 14, 28 and 42, which was not apparent in control neurons. Ultrastructural analysis of CLN3 neurons showed numerous membrane-bound vacuoles containing diverse types of storage material, ranging from curvilinear deposits, multilamellar structures to osmiophilic deposits. Our findings suggest alterations in lysosomal function and neurodevelopment involving axon guidance and synaptic transmission in CLN3-deficient neuronal derivatives, which could be potential targets for therapy.
Association between zinc deficiency and aorta stiffness in non-diabetic hemodialysis patients
Authors: Ishioka Kunihiro , Hidaka Sumi , Fujiwara Naoki , Yamano Mizuki , Mochida Yasuhiro , Oka Machiko , Maesato Kyoko , Moriya Hidekazu , Ohtake Takayasu , Kobayashi Shuzo 
Published: May 2022

AbstractObjectivesZinc deficiency (Zn < 60 μg/dL) is known to play an important role for vascular calcification. However, little data is available regarding the association between zinc deficiency and aorta stiffness in dialysis patients. Thus, we studied the relationship between zinc deficiency and aorta stiffness in non-diabetic hemodialysis(HD) patients.MethodsOf 150 patients receiving maintenance HD at our hospital, we included 79 non-diabetic HD patients (age: 70±11 years, 49 men) after excluding 71 diabetic HD patients. Zinc deficiency was defined as Zn <60 μg/dL during pre-HD blood sampling. The association between zinc deficiency and aorta stiffness was analyzed. Aorta stiffness was evaluated as brachial-ankle pulse wave velocity (baPWV). Other surrogate markers for cardiovascular complications were also measured.ResultsThe zinc deficiency group (ZD group) included 45 patients (57.0%). Compared to the zinc non-deficiency group (ZND group), patients with ZD group were significantly older, higher levels of CRP and hypoalbuminemia. Moreover, they had significantly higher levels of baPWV, and lower levels of ankle-brachial pressure index (ABI) (p<0.05). After adjusting for hypoalubuminuria, and CRP, multivariate analysis showed that age and zinc level were independent predictors of baPWV.ConclusionThe study suggested that zinc deficiency may be an independent risk factor for aorta stiffness, even after adjusting for malnutrition and inflammation.
APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction
Authors: Wynne Meghan E. , Ogunbona Oluwaseun , Lane Alicia R. , Gokhale Avanti , Zlatic Stephanie , Xu Chongchong , Wen Zhexing , Duong Duc , Rayaprolu Sruti , Ivanova Anna , Ortlund Eric A. , Dammer Eric B. , Seyfried Nicholas T. , Roberts Blaine R. , Crocker Amanda , Shanbhag Vinit , Petris Michael , Senoo Nanami , Kandasamy Selvaraju , Claypool Steven M. , Barrientos Antoni , Wingo Aliza P. , Wingo Thomas S. , Rangaraju Srikant , Levey Allan , Werner Erica , Faundez Victor 
Published: May 2022

AbstractMitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain, elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.