bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Accuracy Nodal Staging of Head and Neck Cancer With USPIO-Enhanced MRI
Authors: Driessen Daphne A.J.J. , Zámecnik Patrik , Dijkema Tim , Pegge Sjoert A.H. , van Engen-van Grunsven Adriana C.H. , Takes Robert P. , Kaanders Johannes H.A.M. , Scheenen Tom W.J. 
Published: July 2022

Abstract

Objectives
Ultrasmall superparamagnetic iron oxide (USPIO)–enhanced magnetic resonance imaging (MRI) is a potential diagnostic tool for lymph node assessment in patients with head and neck cancer. Validation by radiologic-pathologic correlation is essential before the method is evaluated in clinical studies. In this study, MRI signal intensity patterns of lymph nodes are correlated to their histopathology to develop a new USPIO-enhanced MRI reading algorithm that can be used for nodal assessment in head and neck cancer patients.

Materials and Methods
Ten head and neck cancer patients underwent in vivo USPIO-enhanced MRI before neck dissection. An ex vivo MRI of the neck dissection specimen was performed for precise coregistration of in vivo MRI with histopathology. Normal clinical histopathological workup was extended with meticulous matching of all lymph nodes regarded as potentially metastatic based on their in vivo MRI signal intensity pattern. On the basis of histopathology of resected nodes, in vivo MRI signal characteristics were defined separating benign from malignant lymph nodes.

Results
Fifteen of 34 node-to-node correlated lymph nodes with remaining signal intensity on T2*-weighted MRI were histopathologically metastatic and 19 were benign. Radiological analysis revealed that metastatic lymph nodes showed equal or higher MRI signal intensity when compared with lipid tissue on T2*-weighted MGRE sequence (15/16 lymph nodes; 94%), whereas healthy lymph nodes showed lower (17/19 lymph nodes; 89%) or complete attenuation of signal intensity (273/279; 98%) when compared with lipid tissue on T2*-weighted MGRE. Histopathology of all resected specimens identified 392 lymph nodes. Six lymph nodes with (micro)metastases were missed with in vivo MRI. Whether these 6 lymph nodes were correlated to a nonmalignant lymph node on in vivo MRI or could not be detected at all is unclear.

Conclusions
We developed a new reading algorithm to differentiate benign from malignant lymph nodes in head and neck cancer patients on the basis of their appearance on high-resolution T2*-weighted USPIO-enhanced MRI. Next steps involve validation of our reading algorithm to further improve the accuracy of neck lymph node staging with USPIO-enhanced MRI in prospective clinical studies with larger number of patients.
Active search signatures in a free-viewing task exploiting concurrent EEG and eye movements recordings
Authors: Care Damián , da Fonseca María , Ison Matias J. , Kamienkowski Juan E. 
Published: July 2022

AbstractTasks we often perform in our everyday lives, such as reading or looking for a friend in the crowd, are seemingly straightforward but they actually require the orchestrated activity of several cognitive processes. Free-viewing visual search requires a plan to move our gaze on the different items, identifying them, and deciding on whether to continue with the search. Little is known about the electrophysiological signatures of these processes in free-viewing since there are technical challenges associated with eye movement artifacts. Here we aimed to study how category information, as well as ecologically-relevant variables such as the task performed, influence brain activity in a free-viewing paradigm. Participants were asked to observe/search from an array of faces and objects embedded in random noise. We concurrently recorded EEG and eye movements and applied a deconvolution analysis approach to estimate the contribution of the different elements embedded in the task. Consistent with classical fixed-gaze experiments and a handful of free-viewing studies, we found a robust categorical effect around 150 ms in occipital and occipitotemporal electrodes. We also report a task effect, more negative in posterior central electrodes in visual search compared to exploration, starting at around 80 ms. We also found significant effects of trial progression, and an interaction with the task effect. Overall, these results generalise the characterisation of early visual face processing to a wider range of experiments and show how a suitable analysis approach allows to discern among multiple neural contributions to the signal, preserving key attributes of real-world tasks.
Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism
Authors: Lim Ryan G. , Al-Dalahmah Osama , Wu Jie , Gold Maxwell P. , Reidling Jack C. , Tang Guomei , Adam Miriam , Dansu David , Park Hye-Jin , Casaccia Patricia , Miramontes Ricardo , Reyes-Ortiz Andrea M. , Lau Alice , Khan Fatima , Paryani Fahad , Tang Alice , Ofori Kenneth , Miyoshi Emily , Michael Neethu , Geller Nicolette , Flowers Xena E. , Vonsattel Jean Paul , Davidson Shawn , Menon Vilas , Swarup Vivek , Fraenkel Ernest , Goldman James E. , Thompson Leslie M. 
Published: July 2022

AbstractThe complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
Prediction of mammalian tissue-specific CLOCK-BMAL1 binding to E-box motifs
Authors: Marri Daniel , Filipovic David , Kana Omar , Tischkau Shelley , Bhattacharya Sudin 
Published: July 2022

ABSTRACTThe mammalian circadian clock is based on a core intracellular gene regulatory network, coordinated by communication between the central nervous system and peripheral tissues like the liver. Transcriptional and translational feedback loops underlie the molecular mechanism of circadian oscillation and generate its 24 h periodicity. The Brain and muscle Arnt-like protein-1 (Bmal1) forms a heterodimer with Circadian Locomotor Output Cycles Kaput (Clock) that binds to E-box gene regulatory elements, activating transcription of clock genes. In this work we aimed to develop a predictive model of genome-wide CLOCK-BMAL1 binding to E-box motifs. We found over-representation of the canonical E-box motif CACGTG in BMAL1-bound regions in accessible chromatin of the mouse liver, heart and kidney. We developed three different tissue-specific machine learning models based on DNA sequence, DNA sequence plus DNA shape, and DNA sequence and shape plus histone modifications. Combining DNA sequence with DNA shape and histone modification features yielded improved transcription factor binding site prediction. Further, we identified the genomic and epigenomic features that best correlate to the binding of BMAL1 to DNA. The DNA shape features Electrostatic Potential, Minor Groove Width and Propeller Twist together with the histone modifications H3K27ac, H3K4me1, H3K36me3, and H3K4me3 were the features most highly predictive of DNA binding by BMAL1 across all three tissues.
Neural Population Dynamics of Computing with Synaptic Modulations
Authors: Aitken Kyle , Mihalas Stefan 
Published: July 2022

AbstractIn addition to long-time scale rewiring, synapses in the brain are subject to significant modulation that occurs at much shorter time scales and allows them to process short-term information. Despite this, models of the brain like recurrent neural networks (RNNs) often have their weights frozen after training, relying on an internal state stored in neuron activity to process temporal information. Although networks with dynamical synapses have been explored previously, often said dynamics are added to networks that also have recurrent connections and thus the short-time scale computational capabilities of synapse modulation alone remain unclear. In this work, we analyze the dynamics of a network that relies solely on synaptic modulations to process short-time scale information, the multi-plasticity network (MPN). We thoroughly examine the neural population dynamics of the MPN trained on integration-based tasks and compare it to known RNN dynamics, findings the two to have fundamentally different behavior and attractor structure. We find said differences in dynamics allow the MPN to outperform its RNN counterparts on several neuroscience-relevant tasks. Of note, the MPN has a significantly simpler attractor structure that allows it to be more flexible in training and sequential-learning settings. Lastly, how the dynamics change for MPNs trained on contextual and continuous integration tasks is also investigated.
Retrieving fMRI data in real-time: difficulties and pitfalls
Authors: Lührs Michael , Poser Benedikt A , Auer Tibor , Goebel Rainer 
Published: July 2022

ABSTRACTOne of the significant challenges in real-time fMRI environments is to ensure that the functional images are exported in real-time. The prerequired ability to reconstruct these images immediately after the acquisition has already been resolved in 2004. Nowadays, more sophisticated sequences allow for higher resolution and faster repetition times and thereby challenging the ability to export this data in real-time. In this article, we tackle the potentially arising problem of sending the reconstructed data from the MRI to an external PC to perform the real-time fMRI analysis. We show that depending on the implementation of the data transfer, long delays can occur that can differ drastically in time and how often they occur. In addition, we propose a solution for SIEMENS MRI devices which was tested and applied already on multiple MRI devices including 3T and 7T machines on different vendor software versions. This new technique can be used as a blueprint that can be directly applied to other manufacturers. We also provide the source code of the described solution and show that the delay in the data transfer can be significantly reduced to a tolerable level using our proposed procedure. Finally, we integrate measurement options for the data transfer times to improve quality measures in real-time fMRI environments (e.g., clinical) that can implement the proposed solution. Efforts should be taken by the real-time community and MRI manufacturers to employ a standardized real-time export e.g., similar to the lab streaming layer which is used as a standard export method in EEG environments.
Quantification of Receptor Binding from Response Data Obtained at Different Receptor Levels: A Simple Individual Sigmoid Fitting and a Unified SABRE Approach
Authors: Buchwald Peter 
Published: July 2022

ABSTRACTMethods that allow quantification of receptor binding (occupancy) by measuring response (effect) data only are of interest as they can be used to allow characterization of binding properties (e.g., dissociation constant, Kd) without having to perform explicit ligand binding experiments that require different setups (e.g., use of labeled ligands). However, since response depends not just on the binding affinity-determined receptor occupancy, but also on receptor activation, which is affected by ligand efficacy (plus constitutive activity, if present), and downstream pathway amplification, this requires the acquisition and fitting of multiple concentration-response data. Here, two alternative methods, which both are straightforward to implement using nonlinear regression software, are described to fit such multiple responses measured at different receptor levels that can be obtained, for example, by partial irreversible receptor inactivation (i.e., Furchgott method) or different expression levels. One is a simple method via straightforward fitting of each response with sigmoid functions and estimation of Kd from the obtained Emax and EC50 values as Kd=(Emax·EC’50−E’max·EC50)/(Emax−E’max). This is less error-prone than the original Furchgott method of double-reciprocal fit and simpler than alternatives that require concentration interpolations, thus, should allow more widespread use of this so-far underutilized approach to estimate binding properties. Relative efficacies can then be compared using Emax·Kd/EC50 values. The other is a complex method that uses the SABRE receptor model to obtain a unified fit of the multiple concentration-response curves with a single set of parameters that include binding affinity Kd, efficacy ε, amplification γ, and Hill coefficient n. Illustrations with simulated and experimental data are presented including with activity data of three muscarinic agonists measured in rabbit myocardium.
Electrical Signaling in Cochlear Efferents is Driven by an Intrinsic Neuronal Oscillator
Authors: Hong Hui , Trussell Laurence O 
Published: July 2022

AbstractEfferent neurons are believed to play essential roles in maintaining auditory function. The lateral olivocochlear (LOC) neurons, which project from the brainstem to the inner ear where they release multiple transmitters including peptides, catecholamines and acetylcholine, are the most numerous yet least understood elements of efferent control of the cochlea. Usingin vitrocalcium imaging and patch-clamp recordings, we found that LOC neurons in juvenile and young adult mice exhibited extremely slow waves of activity (~0.1 Hz). These seconds-long bursts of Na+spikes were driven by an intrinsic oscillator dependent on L-type Ca2+channels, and were not observed in prehearing mice, suggesting an age-dependent mechanism underlying the intrinsic oscillator. Using optogenetic approaches, we identified both ascending (cochlear nucleus) and descending (auditory cortex) sources of synaptic excitation, as well as the synaptic receptors used for such excitation. Additionally, we identified potent inhibition originating in the glycinergic medial nucleus of trapezoid body (MNTB). Conductance-clamp experiments revealed an unusual mechanism of electrical signaling in LOC neurons, in which synaptic excitation and inhibition served to switch on and off the intrinsically generated spike burst mechanism, allowing for prolonged periods of activity or silence controlled by brief synaptic events. Protracted bursts of action potentials may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea.Significance StatementThe lateral olivocochlear (LOC) neurons, being the most abundant auditory efferent control of the ear, remained largely unexplored. Here we reported that LOC neurons displayed patterned electrical activity at an unusually slow pace (~0.1 Hz), mediated by a calcium-dependent intrinsic oscillator. This is surprising given the speed and precision were believed to be the currency of signaling in the lower auditory system. Optogenetic experiments determined the glutamatergic and glycinergic sources of synaptic inputs to these neurons, while conductance-clamp experiments revealed that synaptic activity acts like switches for turning on or off prolonged spike activity driven by the intrinsic oscillator. This extended spike activity may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea.
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
Authors: Abdel-Haq Reem , Schlachetzki Johannes C.M. , Boktor Joseph C. , Cantu-Jungles Thaisa M. , Thron Taren , Zhang Mengying , Bostick John W. , Khazaei Tahmineh , Chilakala Sujatha , Morais Livia H. , Humphrey Greg , Keshavarzian Ali , Katz Jonathan E. , Thomson Matt , Knight Rob , Gradinaru Viviana , Hamaker Bruce R. , Glass Christopher K. , Mazmanian Sarkis K. 
Published: July 2022

AbstractParkinson’s disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, though mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.
Induced CD45 Proximity Potentiates Natural Killer Cell Receptor Antagonism
Authors: Ren Junming , Jo Yeara , Picton Lora K. , Su Leon L. , Raulet David H , Garcia K. Christopher 
Published: July 2022

AbstractNatural Killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus infected cells, limiting their antitumor and antiviral activity. Here, we find that single-chain mouse NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activity to a greater extent than NKR blocking antibodies alone in vitro. We also uncovered crosstalk between mouse NKG2A and Ly49 that collectively inhibit NK cell activation, such that CD45-NKG2A and CD45-Ly49 bispecific molecules show synergistic effects in their ability to enhance NK cell activation. The basis of the activity enhancement by CD45 ligation may reflect greater antagonism of inhibitory signaling from engagement of MHC I on target cells, combined with other mechanisms, including avidity effects, tonic signaling, antagonism of weak inhibition from engagement of MHC I on non-target cells and possibly CD45 segregation within the NK cell-target cell synapse. These engineered ligands uncover a mechanism for enhancing the activity of mouse NK and T cells that merits evaluation in the context of human NKR antagonist cancer immunotherapies.
Modelling of immune response in chronic myeloid leukemia patients suggests potential for treatment reduction prior to cessation
Authors: Karg Elena , Baldow Christoph , Zerjatke Thomas , Clark Richard E , Roeder Ingo , Fassoni Artur C. , Glauche Ingmar 
Published: July 2022

AbstractTyrosine kinase inhibitors (TKI) are highly efficient drugs to combat Chronic Myeloid Leukemia (CML). While long-term drug administration is associated with side effects and high economic costs, current efforts focus on the discontinuation of TKI therapy for well-responding patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Our analysis is based on a cohort of 72 patients from the DESTINY trial for which we obtained individual model fits.Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Applying the model to an unstratified cohort of CML patients in deep remission our results suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.SummaryDiscontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for patients suffering from Chronic Myeloid Leukemia, although it is not clear how dose reduction regimens can improve the achievement of treatment free remission (TFR). Our systematic analysis uses mathematical models of leukemia-immune interaction to show that a stepwise dose reduction prior to TKI cessation can potentially increase the success rate of TFR, while substantially reducing the amount of total administered TKI.