bluuebunny/crossref_metadata_2025_split huggingface dataset:
Out of rhythm: Compromised precision of theta-gamma coupling impairs associative memory in old age
Authors: Karlsson Anna E. , Lindenberger Ulman , Sander Myriam C. 
Published: July 2021

AbstractEpisodic memory declines with advancing adult age. This decline is particularly pronounced when associations between items and their contexts need to be formed. According to theories of neural communication, the precise coupling of gamma power to the phase of the theta rhythm supports associative memory formation. To investigate whether age differences in associative memory are related to compromised theta–gamma coupling, we took electroencephalographic (EEG) recordings during the encoding phase of an item-context association task. Fifty-eight younger and 55 older adults studied pictures of objects superimposed on background scenes. In a recognition test, objects were presented on old or new backgrounds, and participants responded if they had seen (1) the object and (2) the object–scene pair. Theta–gamma coupling supported pair memory formation in both age groups. Whereas pair memory was associated with coupling closer to the peak of the theta rhythm, item-only memory was associated with a deviation in phase angle relative to pair memory. Furthermore, a stable relation between coupling phase and pair memory performance demonstrated that coupling closer to the peak is beneficial for associative memory. Critically, older adults’ lower pair memory was accompanied by a shift in coupling phase relative to younger adults. In concert, the present results are consistent with the hypothesis that decrements in the precision with which gamma power is coupled to the theta phase underlie the decline of associative memory in normal cognitive aging.Significance StatementAccording to prominent theories of neural communication, the precise coordination of oscillatory activity enables the formation of associative memories. We propose that normal cognitive aging impairs associative memory formation by compromising the precision of neural communication. We show that the coupling of high-frequency gamma power to low-frequency theta phase supports associative memory formation in both younger and older adults, with coupling closer to the theta peak benefitting memory performance. However, compared to younger adults, the coupling phase angle is shifted and more variable in older adults. We conclude that alterations in the precision of theta–gamma coupling contribute to adult age differences in associative memory.
Signatures of rapid synaptic learning in the hippocampus during novel experiences
Authors: Priestley James B. , Bowler John C. , Rolotti Sebi V. , Fusi Stefano , Losonczy Attila 
Published: July 2021

SummaryNeurons in the hippocampus exhibit striking selectivity for specific combinations of sensory features, forming representations which are thought to subserve episodic memory. Even during a completely novel experience, ensembles of hippocampal “place cells” are rapidly configured such that the population sparsely encodes visited locations, stabilizing within minutes of the first exposure to a new environment. What cellular mechanisms enable this fast encoding of experience? Here we leverage virtual reality and large scale neural recordings to dissect the effects of novelty and experience on the dynamics of place field formation. We show that the place fields of many CA1 neurons transiently shift locations and modulate the amplitude of their activity immediately after place field formation, consistent with rapid plasticity mechanisms driven by plateau potentials and somatic burst spiking. These motifs were particularly enriched during initial exploration of a novel context and decayed with experience. Our data suggest that novelty modulates the effective learning rate in CA1, favoring burst-driven field formation to support fast synaptic updating during new experience.
Using Progressive Context Encoders for Anomaly Detection in Digital Pathology Images
Authors: Gillard Ryan , Meroueh Chady , Gu Qiangqiang , Prodduturi Naresh , Patil Sandhya , Flotte Thomas J , Hart Steven N 
Published: July 2021

ABSTRACTWhole slide imaging (WSI) is transforming the practice of pathology, converting a qualitative discipline into a quantitative one. However, one must exercise caution in interpreting algorithm assertions, particularly in pathology where an incorrect classification could have profound impacts on a patient, and rare classes exist that may not have been seen by the algorithm during training. A more robust approach would be to identify areas of an image for which the pathologist should concentrate their effort to make a final diagnosis. This anomaly detection strategy would be ideal for WSI, but given the extremely high resolution and large file sizes, such an approach is difficult. Here, we combine progressive generative adversarial networks with a flexible adversarial autoencoder architecture capable of learning the “normal distribution” of WSIs of normal skin tissue at extremely high resolution and demonstrate its anomaly detection performance. Our approach yielded pixel-level accuracy of 89% for identifying melanoma, suggesting that our label-free anomaly detection pipeline is a viable strategy for generating high quality annotations - without tedious manual segmentation by pathologists. The code is publicly available athttps://github.com/Steven-N-Hart/P-CEAD.
SARS-CoV-2 Lambda Variant Remains Susceptible to Neutralization by mRNA Vaccine-elicited Antibodies and Convalescent Serum
Authors: Tada Takuya , Zhou Hao , Dcosta Belinda M. , Samanovic Marie I. , Mulligan Mark J. , Landau Nathaniel R. 
Published: July 2021

AbstractThe SARS-CoV-2 lambda variant (lineage C.37) was designated by the World Health Organization as a variant of interest and is currently increasing in prevalence in South American and other countries. The lambda spike protein contains novel mutations within the receptor binding domain (L452Q and F490S) that may contribute to its increased transmissibility and could result in susceptibility to re-infection or a reduction in protection provided by current vaccines. In this study, the infectivity and susceptibility of viruses with the lambda variant spike protein to neutralization by convalescent sera and vaccine-elicited antibodies was tested. Virus with the lambda spike had higher infectivity and was neutralized by convalescent sera and vaccine-elicited antibodies with a relatively minor 2.3-3.3-fold decrease in titer on average. The virus was neutralized by the Regeneron therapeutic monoclonal antibody cocktail with no loss of titer. The results suggest that vaccines in current use will remain protective against the lambda variant and that monoclonal antibody therapy will remain effective.
Pharmacokinetics and Central Accumulation of Delta-9-Tetrahydrocannabinol (THC) and its Bioactive Metabolites Are Influenced by Route of Administration and Sex
Authors: Baglot Samantha L. , Hume Catherine , Petrie Gavin N. , Aukema Robert J. , Lightfoot Savannah H.M. , Grace Laine M. , Zhou Ruokun , Parker Linda , Rho Jong M. , Borgland Stephanie L. , McLaughlin Ryan J. , Brechenmacher Laurent , Hill Matthew N. 
Published: July 2021

AbstractUp to a third of North Americans over 16 years old report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human cannabis consumption are critical to study its impacts on brain and behaviour. Nevertheless, most animal studies to date examine effects of cannabis through injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics of each administration route. The current study directly examined if administration route (injection versus inhalation), with dosing being matched on peak THC blood levels, alters the metabolism of THC, and the central accumulation of THC and its metabolites over time. Adult male and female Sprague-Dawley rats received either a single intraperitoneal injection of THC (2.5 mg/kg) or a single (15 min) session of inhaled exposure to THC distillate (100 mg/mL) vapour. Blood and brains were collected at 15, 30, 60, 90 and 240 minutes post-exposure for analysis of THC and metabolites through mass spectrometry-liquid chromatography. Inhalation results in immediate hypothermia, whereas injection results in delayed hypothermia. Despite achieving comparable peak concentrations of blood THC in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentrations, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence that THC and its metabolites exhibit different pharmacokinetic profiles following inhalation versus injection, which could have significant impacts for data interpretation and generalizability. Accordingly, we suggest that translational work in the realm of THC and cannabis strongly consider using inhalation models over those that employ injection.HighlightsBody temperature as well as blood and brain levels of THC and metabolites differ based on administration routeTHC inhalation results in immediate hypothermia, whereas THC injection results in delayed hypothermiaTHC inhalation results in higher initial brain THC levels than injectionTHC injection results in higher blood & brain 11-OH-THC levels than inhalationTranslational cannabis work should strongly consider using inhalation over injection
Kinetic Properties of Microbial Exoenzymes Vary with Soil Depth but Have Similar Temperature Sensitivities Through the Soil Profile
Authors: Alves Ricardo J. Eloy , Callejas Ileana A. , Marschmann Gianna L. , Mooshammer Maria , Singh Hans W. , Whitney Bizuayehu , Torn Margaret S. , Brodie Eoin L. 
Published: July 2021

AbstractCurrent knowledge of the mechanisms and responses of soil organic matter (SOM) turnover to warming is mainly limited to surface soils, although over 50% of global soil carbon is contained in subsoils. Deep soils have different physicochemical properties, nutrient inputs and microbiomes, which may harbor distinct functional traits and lead to different SOM dynamics and temperature responses. We hypothesized that kinetic and thermal properties of microbial exoenzymes, which mediate SOM depolymerization, vary with soil depth, reflecting microbial adaptation to distinct substrate and temperature regimes. We determined the Michaelis-Menten (MM) kinetics of three ubiquitous enzymes involved in carbon (C), nitrogen (N) and phosphorus (P) acquisition at six soil depths down to 90 cm at a temperate coniferous forest, and their temperature sensitivity based on Arrhenius and Macromolecular Rate Theory (MMRT) models over six temperatures between 4-50°C. Maximal enzyme velocity (Vmax) decreased strongly with depth for all enzymes, both on a dry soil mass and a microbial biomass C basis, whereas their affinities increased, indicating adaptation to lower substrate availability. Surprisingly, microbial biomass-specific catalytic efficiencies also decreased with depth, except for the P-acquiring enzyme, indicating distinct nutrient demands at depth relative to microbial abundance. These results indicated that deep soil microbiomes encode enzymes with intrinsically lower turnover and/or produce less enzymes per cell, likely reflecting distinct life strategies. The relative kinetics between different enzymes also varied with depth, suggesting an increase in relative P demand with depth, or that phosphatases may be involved in C acquisition. Warming consistently led to increasedVmaxand catalytic efficiency of all enzymes, and thus to overall higher SOM-decomposition potential, but enzyme temperature sensitivity was similar through the soil profile based on both Arrhenius/Q10and MMRT models. Nevertheless, temperature directly affected the kinetic properties of different enzyme types in a depth-dependent manner, and thus the relative depolymerization potential of different compounds. Our results indicate that kinetic and thermal properties of exoenzymes are intrinsic traits of soil microbiomes adapted to distinct physicochemical conditions associated with different soil depths, and improve our conceptual understanding of critical mechanisms underlying SOM dynamics and responses to warming through the soil profile.
The blood vasculature instructs lymphatics patterning in a SOX7 dependent manner
Authors: Chiang Ivy Kim-Ni , Luu Winnie , Jiang Key , Kirschnick Nils , Moustaqil Mehdi , Davidson Tara , Lesieur Emmanuelle , Skoczylas Renae , Kouskoff Valerie , Kazenwadel Jan , Arriola-Martinez Luis , Sierecki Emma , Gambin Yann , Alitalo Kari , Kiefer Friedmann , Harvey Natasha L. , Francois Mathias 
Published: July 2021

AbstractDespite a growing catalogue of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in lymphatic vessel patterning by modulating the transcription of lymphangiocrine signals. While SOX7 is not expressed in lymphatic endothelial cells (LECs), loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signalling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.
Fatty acid binding proteins shape the cellular response to activation of the glucocorticoid receptor
Authors: Liu Bonan , Chandrashekaran Indu R. , Ilyichova Olga , Valour Damien , Melchiore Fabien , Bourrier Chantal , Giganti Adeline , Stephan Jean-Philippe , Dacquet Catherine , Genissel Patrick , Gosgnach Willy , Weaver Richard J. , Porter Christopher J.H. , Scanlon Martin J. , Halls Michelle L. 
Published: July 2021

AbstractGlucocorticoids are steroid hormones that are essential for life in mammals. Therapeutically, they are some of the most cost-effective drugs for the treatment of inflammatory diseases ranging from skin rashes to COVID-19, but their use is limited by adverse effects. Glucocorticoids exert their effects via the glucocorticoid receptor, a type I nuclear hormone receptor which modulates gene expression. The transcriptional activity of some related, but nuclear restricted, type II nuclear hormone receptors can be enhanced by a family of intracellular transport proteins, the fatty acid binding proteins (FABPs). We find that the transcriptional activity of the GR can be altered by a sub-set of FABP family members dependent on the GR-ligand. The ability of some FABPs to selectively promote or limit the transcriptional activity of the GR in a ligand-dependent manner could facilitate the discovery of drugs that narrow GR activity to only the desired subset of therapeutically relevant genes.
A scalable, multi-wavelength, broad bandwidth frequency-domain near-infrared spectroscopy platform for real-time quantitative tissue optical imaging
Authors: Stillwell Roy A. , Kitsmiller Vincent J. , Wei Alicia Y. , Chong Alyssa , Senn Lyla , O’Sullivan Thomas D. 
Published: July 2021

AbstractFrequency-domain near-infrared spectroscopy (FD-NIRS) provides quantitative noninvasive measurements of tissue optical absorption and scattering, and provides a safe and accurate method for characterizing tissue composition and metabolism. However, the poor scalability and high complexity of most FD-NIRS systems assembled to date have contributed to its limited clinical impact. To address these shortcomings, we present a scalable, digital-based FD-NIRS platform capable of measuring optical properties and tissue chromophore concentrations in real-time. The system provides single-channel FD-NIRS amplitude/phase, optical property, and chromophore data at a maximum display rate of 36.6 kHz, 17.9 kHz, and 10.2 kHz, respectively, and can be scaled to multiple channels as well as integrated into a handheld format. The entire system is enabled by several innovations including an ultra-high-speed k-nearest neighbor lookup table method (maximum of 250,000 inversions/s for large 2500×700 table of absorption and reduced scattering coefficients), embedded FPGA and CPU high-speed co-processing, and high-speed data transfer (due to on-board processing). We show that our 6-wavelength, broad modulation bandwidth (1-400 MHz) system can be used to perform 2D high-density spatial mapping of optical properties.
MAGI2-AS3 modulates proliferation, apoptosis and glycolysis in acute lymphoblastic leukemia via miR-452-5p/FOXN3 axis
Authors: Chen Xiao-Guang , Dou Bing-Hua , An Jin-Dou , Feng Song , Liu Na , Sheng Guang-Yao 
Published: July 2021

AbstractBackgroundLong non-coding RNA MAGI2 antisense RNA 3 (MAGI2-AS3) has been identified as a tumor suppressor in various cancers. Acute lymphoblastic leukemia (ALL) is a prevalent kind of leukemia among children. In this study, we aimed at evaluate the role of MAGI2-AS3 in ALL and its underlying mechanisms.MethodsqPCR was adopted to determine MAGI2-AS3, miR-452-5p, and FOXN3 expression. The malignant properties of ALL cells were assessed by CCK8 assay and flow cytometry analysis. The glucose uptake, lactate production, and ATP level were measured to evaluate glycolysis. Western blotting was performed to detect PCNA, Bcl-2, Bax, and HK2 protein levels. The interaction between MAGI2-AS3/FOXN3 and miR-452-5p was validated by luciferase reporter assay. The in vivo growth of ALL cells was determined in xenograft model.ResultsMAGI2-AS3 was strikingly down-regulated in ALL samples and cells. Overexpression of MAGI2-AS3 restrained growth, glycolysis and triggered apoptosis of ALL cells. Mechanistically, MAGI2-AS3 could sponge miR-452-5p to up-regulate FOXN3. Silencing of FOXN3 abolished the anti-tumor effect of MAGI2-AS3. Finally, MAGI2-AS3 suppressed the in vivo growth of ALL cells via modulating miR-452-5p/FOXN3 axis.ConclusionOur findings demonstrate that MAGI2-AS3 delays the progression of ALL by regulating miR-452-5p/FOXN3 signaling pathway.
Single-orientation Quantitative Susceptibility Mapping identifies the Ventral Intermediate Nucleus of the Thalamus
Authors: Yu Fang Frank , Lee Dongyoung , Achilleos Michael , Feltrin Fabricio , Shah Bhavya R. 
Published: July 2021

AbstractIntroductionThe ventral intermediate nucleus (VIM) represents the primary target in the treatment of tremor. Accurate localization is extremely important given its proximity to other thalamic nuclei. We utilized single orientation quantitative susceptibility mapping (QSM) at 3T to directly visualize the VIM.MethodsFour adult volunteers, one adult cadaver, and an essential tremor patient were scanned on a 3T MRI using a multi-echo gradient echo sequence. QSM images were generated using the improved sparse linear equation and least-squares (iLSQR) algorithm. Two adult subjects underwent multiple head orientation imaging for multi-orientation QSM reconstruction. The VIM was prospectively identified with direct visualization as well as indirect landmark-based localization.ResultsThe bilateral VIM was consistently identified as a hypointense structure within the lateral thalamus, appearing similar on multi-orientation and single-orientation QSM, corresponding to the myelinated dentatorubrothalamic tract (DRTT). The indirect method resulted in a comparatively inferomedial localization, at times missing the VIM and DRTT.ConclusionSingle-orientation QSM offers a clinically feasible, non-invasive imaging-based approach to directly localize the VIM.
A multimodal AI system for out-of-distribution generalization of seizure detection
Authors: Yang Yikai , Truong Nhan Duy , Eshraghian Jason K. , Maher Christina , Nikpour Armin , Kavehei Omid 
Published: July 2021

AbstractEpilepsy is one of the most common severe neurological disorders worldwide. The International League Against Epilepsy (ILAE) define epilepsy as a brain disorder that generates (1) two unprovoked seizures more than 24 hrs apart, or (2) one unprovoked seizure with at least 60% risk of recurrence over the next ten years. Complete remission has been defined as ten years seizure free with the last five years medication free. This requires a cost-effective ambulatory ultra-long term out-patient monitoring solution. The common practice of self-reporting is inaccurate. Applying artificial intelligence (AI) to scalp electroencephalogram (EEG) interpretation is becoming increasingly common, but other data modalities such as electrocardiograms (ECGs) are simpler to collect and often recorded simultaneously with EEG. Both recordings contain biomarkers in the detection of seizures.Here, we propose a state-of-the-art performing AI system that combines EEG and ECG for seizure detection, tested on clinical data with early evidence demonstrating generalization across hospitals. The model was trained and validated on the publicly available Temple University Hospital (TUH) dataset. To evaluate performance in a clinical setting, we conducted nonpatient-specific inference-only tests on three out-of-distribution datasets, including EPILEPSIAE (30 patients) and the Royal Prince Alfred Hospital (RPAH) in Sydney, Australia (31 patients shortlisted by neurologists and 30 randomly selected). Across all datasets, our multimodal approach improves the area under the receiver operating characteristic curve (AUC-ROC) by an average margin of 6.71% and 14.42% for prior state-of-the-art approaches using EEG and ECG alone, respectively. Our model’s state-of-the-art performance and robustness to out-ofdistribution datasets can improve the accuracy and efficiency of epilepsy diagnoses.
ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium
Authors: Bi Youkun , Yang Zhiguang , Jin Meng , Zhai Kui , Wang Jun , Mao Yang , Liu Yang , Ding Mingqin , Wang Huiwen , Wang Fengchao , Ji Guangju 
Published: July 2021

AbstractRationale: Endocardial cushions are precursors of the valvoseptal complex that separates the four heart chambers and control blood flow through the heart. Abnormalities in endocardial cushion development lead to atrioventricular septal defects (AVSDs), which affect 1 in 2,100 live births. Several genes have been implicated in the development of endocardial cushions. Specifically, endoplasmic reticulum-resident protein 44 (ERp44) has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. Objective: The goal of this study was to investigate the role of ERp44 in heart development in mice. Approach and Results: Using conventional and tissue-specific knockout mouse models, we demonstrated that ERp44 plays a specific role in heart development. ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes as well as severe septal and valvular defects. Similar phenotypes were found in cTnt-cre+/−; Erp44fl/fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 directly bound to VEGFA and controlled its release. Conclusions: ERp44 contributes to the development of the endocardial cushion by affecting the EndMT of cushion cells by regulating VEGFA release in myocardial cells.