bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Liver and Spleen With Shear Wave Elastography in Adult Patients With Familial Mediterranean Fever
Authors: Akti Serdar , Albayrak Eda 
Published: September 2022

Abstract
Familial Mediterranean fever (FMF) is an autoinflammatory disease and an important health problem in countries bordering the eastern Mediterranean, including Turkey. In this study, we aimed to evaluate possible tissue stiffness changes that may develop in the liver and spleen in adult FMF patients with shear wave elastography (SWE), and its usability as an auxiliary imaging method that will be able to provide additional advantage in clinical follow-up. Seventy-five adult FMF patients and 73 adult volunteer were included in the study. Examination was performed through an intercostal space where the liver and spleen were clearly visible. The parenchymal stiffness degrees of the liver and spleen were quantified by shear modulus values in kilopascals. Differences in stiffness values of the liver and spleen between the 2 groups were examined. Liver stiffness value (LSV) was found to be statistically significantly higher in the FMF group. Although the spleen stiffness value (SSV) was found higher in the FMF group, the difference between the groups was not statistically significant. Increased LSVs in patients with FMF can be quantitatively demonstrated by the 2-dimensional SWE method, and SWE may be useful as an auxiliary imaging method in the follow-up of patients with FMF for this purpose. The LSV and SSV obtained in this study may be useful as reference stiffness values for both healthy individuals and those with FMF.
Investigation of Molecular Weights and Pharmacokinetic Characteristics of Older and Modern Small Drugs
Authors: Fagerholm Urban 
Published: September 2022

AbstractBackgroundA shift towards higher molecular weight (MW) of drug candidates is anticipated to lead to changed pharmacokinetics (PK), including deteriorated absorption.MethodsThe objective of the study was to investigate changes in MW and PK of drugs over time by comparing MW and measured PK of small drugs (here MW<1500 g/mole) marketed before 2010 (n=277) and MW andin silicopredicted (data produced using the ANDROMEDA by Prosilico software) and of small drugs marketed in 2021 (n=28).ResultsApparently, there has been a shift towards higher MW (from 355 to 551 g/mole on average). This has influenced PK-parameters such as unbound fraction (on average approximately halved), fraction excreted renally (on average approximately halved; markedly decreased contribution by active secretion), bile excretion (almost 4-fold increased appearance; now for more than every other drug) and intrinsic metabolic clearance (increased). The very high percentage of modern drugs with (according toin silicopredictions) significant renal and biliary excretion and gut-wall extraction, metabolic stability, limited passive intestinal permeability+efflux, limited gastrointestinal dissolution/solubility potential and/or a very low fuincreases complexity in predictions and places demands on predictive laboratory and computational methods.ConclusionIncreased MW and changed PK-profiles (increased complexity) with time were observed. This shows the need for updating method set-ups for quantification and prediction of PK-parameters. ANDROMEDA has the capability to predict and optimize human clinical PK-characteristics of modern drug candidates with high accuracy.
A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta
Authors: Carter Brandon , Huang Pinghan , Liu Ge , Liang Yuejin , Lin Paulo J.C. , Peng Bi-Hung , McKay Lindsay , Dimitrakakis Alexander , Hsu Jason , Tat Vivian , Saenkham-Huntsinger Panatda , Chen Jinjin , Kaseke Clarety , Gaiha Gaurav D. , Xu Qiaobing , Griffiths Anthony , Tam Ying K. , Tseng Chien-Te K. , Gifford David K. 
Published: September 2022

AbstractClinically licensed COVID-19 vaccines ameliorate viral infection by inducing vaccinee production of neutralizing antibodies that bind to the SARS-CoV-2 Spike protein to inhibit viral cellular entry (Walsh et al., 2020; Baden et al., 2021), however the clinical effectiveness of these vaccines is transitory as viral variants arise that escape antibody neutralization (Tregoning et al., 2021; Willett et al., 2022). Vaccines that solely rely upon a T cell response to combat viral infection could be transformational because they can be based on highly conserved short peptide epitopes that hold the potential for pan-variant immunity, but a mRNA-LNP T cell vaccine has not been shown to be sufficient for effective antiviral prophylaxis. Here we show that a mRNA-LNP vaccine based on highly conserved short peptide epitopes activates a CD8+and CD4+T cell response that prevents mortality in HLA-A*02:01 transgenic mice infected with the SARS-CoV-2 Beta variant of concern (B.1.351). In mice vaccinated with the T cell vaccine, 24% of the nucleated cells in lung were CD8+T cells on day 7 post infection. This was 5.5 times more CD8+T cell infiltration of the lungs in response to infection compared to the Pfizer-BioNTech Comirnaty® vaccine. Between days 2 and 7 post infection, the number of CD8+T cells in the lung increased in mice vaccinated with the T cell vaccine and decreased in mice vaccinated with Comirnaty®. The T cell vaccine did not produce neutralizing antibodies, and thus our results demonstrate that SARS-CoV-2 viral infection can be controlled by a T cell response alone. Our results suggest that further study is merited for pan-variant T cell vaccines, and that T cell vaccines may be relevant for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.
High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike
Authors: Tan Timothy J.C. , Mou Zongjun , Lei Ruipeng , Ouyang Wenhao O. , Yuan Meng , Song Ge , Andrabi Raiees , Wilson Ian A. , Kieffer Collin , Dai Xinghong , Matreyek Kenneth A. , Wu Nicholas C. 
Published: September 2022

ABSTRACTDesigning prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we established a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrated a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, this method was applied to a region in the S2 domain that includes the first heptad repeat and central helix. Our results revealed that besides K986P and V987P, several mutations simultaneously improved expression and significantly lowered the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.
Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
Authors: Zhang Danyang , Lape Remigijus , Shaikh Saher A. , Kohegyi Bianka K. , Watson Jake F. , Cais Ondrej , Nakagawa Terunaga , Greger Ingo H. 
Published: September 2022

AbstractAMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse drugs. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
Taxon cycles in Neotropical mangroves
Authors: Rull Valentí 
Published: September 2022

AbstractThe concept of taxon cycle involves successive range expansions and contractions over time through which a species can indefinitely maintain its core distribution. Otherwise, it becomes extinct. Taxon cycles have been defined mostly for tropical island faunas, examples from continental areas are scarce and similar case studies for plants remain unknown. Most taxon cycles have been identified on the basis of phylogeographic studies, and straightforward empirical evidence from fossils is lacking. Here, empirical fossil evidence is provided for recurrent Eocene to present expansion/contraction cycles in a mangrove taxon (Pelliciera), after a Neotropical-wide study of the available pollen records. This recurrent behavior is compatible with the concept of taxon cycle from biogeographical, chronological and ecological perspectives. The biotic and abiotic drivers potentially involved in the initiation and maintenance of thePellicieraexpansion/contraction cycles are analyzed, and the ecological and evolutionary implications are discussed. Whether this could be a trend toward extinction is considered under the predictions of the taxon cycle theory. The recurrent expansion and contraction cycles identified forPellicierahave strong potential for being the first empirically and unequivocally documented taxon cycles and likely the only taxon cycles documented to date for plants.
Associations of maternal prenatal emotional complaints and cortisol with neonatal meconium microbiota: A cross-sectional study
Authors: Deflorin Nadia , Ehlert Ulrike , Amiel Castro Rita T. 
Published: September 2022

AbstractThe gut microbiome is a complex microbial ecosystem considered as a key modulator of human health and disease. Alterations in the diversity and relative abundances of the gut microbiome have been associated with a broad spectrum of medical conditions. Maternal emotional complaints during pregnancy can impact on offspring development by altering the maternal and the foetal gut microbiome. We aimed to investigate whether self-reported maternal anxiety, depressive symptoms, and distress as well as biological stress in late pregnancy alter the bacterial composition of the infant’s meconium.MethodsA total ofN=100 mother-infant pairs were included. Maternal emotional complaints were measured using standardised questionnaires (EPDS, PSS-10, STAI) at 34-36 weeks gestation and salivary cortisol was measured at 34-36 and 38 weeks gestation. Infant meconium samples were collected in the first five days postpartum and analysed using 16S rRNA amplicon sequencing.ResultsCorrelations showed that lower alpha diversity of the meconium microbiome was significantly associated with increased maternal prenatal depressive symptoms in late gestation (τ = -0.149,p= 0.041). Increased cortisol AUCg at T2 was significantly related to higher beta diversity of the meconium samples (Pr(>F) = 0.003*).Proteobacteriawas the most abundant phylum and was associated with maternal cortisol total decline. No other associations were found.ConclusionsMaternal prenatal depressive symptoms are associated with infant faecal microbiota alpha diversity, whereas maternal cortisol AUCg is linked to increased beta diversity and total decline related to increasedProteobacteria. Future studies are warranted to understand how these microbiota community alterations are linked to child health outcomes.HighlightsMaternal prenatal depressive symptoms alter the meconium microbiome.Increased biological stress during pregnancy alters the beta diversity of the meconium microbiome.Proteobacteriais the most abundant phylum in the meconium samples.
Phase of firing does not reflect temporal order in sequence memory of humans and recurrent neural networks
Authors: Liebe Stefanie , Niediek Johannes , Pals Matthijs , Reber Thomas P. , Faber Jenny , Bostroem Jan , Elger Christian E. , Macke Jakob H. , Mormann Florian 
Published: September 2022

AbstractA prominent theory proposes that the temporal order of a sequence of items held in memory is reflected in ordered firing of neurons at different phases of theta oscillations 1. We probe this theory by directly measuring single neuron activity (1420 neurons) and local field potentials (LFP, 921 channels) in the medial temporal lobe of 16 epilepsy patients performing a working memory task for temporal order. We observe theta oscillations and preferential firing of single neurons at theta phase during memory maintenance. We find that - depending on memory performance - phase of firing is related to item position within a sequence. However, in contrast to the theory, phase order did not match item order. To investigate underlying mechanisms, we subsequently trained recurrent neural networks (RNNs) to perform an analogous task. Similar to recorded neural activity, we show that RNNs generate theta oscillations during memory maintenance. Importantly, model neurons exhibit theta phase-dependent firing related to item position, where phase of firing again did not match item order. Instead, we observed a mechanistic link between phase order, stimulus timing and oscillation frequency - a relationship we subsequently confirmed in our neural recordings. Taken together, in both biological and artificial neural networks we provide validating evidence for the role of phase-of-firing in memory processing while at the same time challenging a long-held theory about the functional role of spiking and oscillations in sequence memory.
From Correlation to Communication: disentangling hidden factors from functional connectivity changes
Authors: Yu Yuhua , Gratton Caterina , Smith Derek M. 
Published: September 2022

AbstractWhile correlations in the BOLD fMRI signal are widely used to capture functional connectivity (FC) and its changes across contexts, its interpretation is often ambiguous. The entanglement of multiple factors including local coupling of two neighbors and non-local inputs from the rest of the network (affecting one or both regions) limits the scope of the conclusions that can be drawn from correlation measures alone. Here we present a method of estimating the contribution of non-local network input to FC changes across different contexts. To disentangle the effect of task-induced coupling change from the network input change, we propose a new metric, “communication change”, utilizing BOLD signal correlation and variance. With a combination of simulation and empirical analysis, we demonstrate that 1) input from the rest of the network accounts for a moderate but significant amount of task-induced FC change; 2) the proposed “communication change” is a promising candidate for tracking the local coupling in task context-induced change. Additionally, when compared to FC change across three different tasks, communication change can better discriminate specific task types. Taken together, this novel index of local coupling may have many applications in improving our understanding of local and widespread interactions across large-scale functional networks.
Adaptive mechanisms facilitate robust performance in noise and in reverberation in an auditory categorization model
Authors: Parida Satyabrata , Liu Shi Tong , Sadagopan Srivatsun 
Published: September 2022

AbstractFor robust vocalization perception, the auditory system must generalize over variability in vocalization production as well as variability arising from the listening environment (e.g., noise and reverberation). We previously demonstrated that a hierarchical model generalized over production variability by detecting sparse intermediate-complexity features that are maximally informative about vocalization category from a dense spectrotemporal input representation. Here, we explore three biologically feasible model extensions to generalize over environmental variability: (1) training in degraded conditions, (2) adaptation to sound statistics in the spectrotemporal stage and (3) sensitivity adjustment at the feature detection stage. All mechanisms improved vocalization categorization performance, but improvement trends varied across degradation type and vocalization type. One or both adaptive mechanisms were required for model performance to approach the behavioral performance of guinea pigs on a vocalization categorization task. These results highlight the contributions of adaptive mechanisms at multiple auditory processing stages to achieve robust auditory categorization.
The Micromechanical Environment of the Impinged Achilles Tendon Insertion
Authors: Mora Keshia E. , Mlawer Samuel J. , Loiselle Alayna E. , Buckley Mark R. 
Published: September 2022

AbstractMechanical deformation applied to tendon at the tissue-scale is transferred to the microscale — including the extracellular matrix (ECM), the pericellular matrix (PCM), the cell and the nucleus — through a process known as strain transfer. Microscale strains, in turn, trigger biological activity that plays an important role in the maintenance of tendon phenotype and homeostasis. Although tendon predominantly experiences longitudinal tensile forces, transverse forces due to bony impingement have been implicated in both physiological (e.g., maintenance of the tendon insertion) and pathophysiological (e.g. insertional Achilles tendinopathy) processes. However, to our knowledge, prior studies have not characterized the micromechanical strain environment in the context of tendon impingement. Therefore, the objective of this study was to characterize the micromechanical strain environment in the impinged Achilles tendon insertion using a novel mouse hindlimb explant model in combination with finite element (FE) modeling. We hypothesized that impingement would generate large magnitudes of transverse compressive strain at the local matrix, PCM, and cell scales. Mouse hindlimb explants were imaged on a multiphoton microscope, and image stacks of the same population of tendon cells were obtained at the Achilles tendon insertion before and after dorsiflexion-induced impingement. Using an innovative multiphoton elastography approach, three-dimensional Green-Lagrange and principal strains were measured at the matrix scale, while longitudinal strain and aspect ratio were measured at the PCM and cell scales. Our results demonstrate that impingement generated substantial transverse compression at the matrix-scale, which led to longitudinal stretching of cells, an increase in cell aspect ratio, and — surprisingly — longitudinal compression of the tendon PCM. These experimental results were corroborated by an FE model developed to simulate the micromechanical environment in impinged regions of the Achilles tendon. Moreover, in both experiments and simulations, impingement-generated microscale stresses and strains were highly dependent on initial cell-cell gap spacing. Understanding the factors that influence the microscale strain environment generated by impingement could contribute to a more mechanistic understanding of impingement-induced tendinopathies and inform the development of approaches that disrupt the progression of pathology.
Gene panel design for spatial transcriptomics with prioritized gene sets
Authors: Yafi Mashrur Ahmed , Husain Hisham Md. Hasibul , Grisanti Francisco , Rahman Atif , Samee Md. Abul Hassan 
Published: September 2022

ABSTRACTA fundamental limitation of the emerging single-cell spatial transcriptomics (sc-ST) technologies is their panel size. Being based on fluorescence in situ hybridization, an sc-ST dataset can profile only a pre-determined panel of a few hundred genes. This often forces biologists to build panels from only the marker genes of different cell types and forgo other genes of interest, e.g., genes encoding ligand-receptor complexes or genes in specific pathways. We propose scGIST– a deep neural network that designs sc-ST panels through constrained feature selection. On four datasets, scGIST outperformed alternative methods in terms of cell type detection accuracy. Moreover, unlike other methods, scGIST allows genes of interest to be prioritized for inclusion in the panel while staying within the its size constraint. We demonstrate through diverse use cases that scGIST includes large fractions of prioritized genes without compromising cell type prediction efficacy making it a valuable addition to sc-ST’s algorithmic toolbox.
Hippocampo-cortical circuits for selective memory encoding, routing, and replay
Authors: Harvey Ryan E. , Robinson Heath L. , Liu Can , Oliva Azahara , Fernandez-Ruiz Antonio 
Published: September 2022

AbstractTraditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We discovered that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and selectively routed these representations to different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.
Gut bacteria-derived serotonin promotes immune tolerance in early life
Authors: Sanidad Katherine Z. , Rager Stephanie L. , Carrow Hannah C. , Ananthanarayanan Aparna , Callaghan Ryann , Hart Lucy R. , Li Tingting , Ravisankar Purnima , Brown Julia A. , Amir Mohammed , Jin Jenny C. , Savage Alexandria Rose , Luo Ryan , Mardorsky Rowdo Florencia , Martin M. Laura , Silver Randi B. , Guo Chun-Jun , Krumsiek Jan , Inohara Naohiro , Zeng Melody Y. 
Published: September 2022

AbstractThe gut microbiome promotes immune system development in early life, but the neonatal gut metabolome remains undefined. Here, we demonstrate that, distinct from adults, the neonatal mouse gut is enriched with neurotransmitters, and specific bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin inhibits mTOR activation to promote regulatory T cells and suppress T cell responses bothex vivoandin vivoin the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term immune tolerance toward both dietary antigens and commensal bacteria as well as alterations of the gut microbiome. Together, our study has uncovered unique microbiome-dependent mechanisms to maximize serotonin in the neonatal gut and a novel role for intestinal serotonin to promote immune tolerance in early life.