bluuebunny/crossref_metadata_2025 huggingface dataset:
The Overnight Retention of Novel Metaphors Associates With Slow Oscillation–Spindle Coupling but Not With Respiratory Phase at Encoding
Authors: Halonen Risto , Kuula Liisa , Antila Minea , Pesonen Anu-Katriina
Published: September 2021

Accumulating evidence emphasizes the relevance of oscillatory synchrony in memory consolidation during sleep. Sleep spindles promote memory retention, especially when occurring in the depolarized upstate of slow oscillation (SO). A less studied topic is the inter-spindle synchrony, i.e. the temporal overlap and phasic coherence between spindles perceived in different electroencephalography channels. In this study, we examined how synchrony between SOs and spindles, as well as between simultaneous spindles, is associated with the retention of novel verbal metaphors. Moreover, we combined the encoding of the metaphors with respiratory phase (inhalation/exhalation) with the aim of modulating the strength of memorized items, as previous studies have shown that inhalation entrains neural activity, thereby benefiting memory in a waking condition. In the current study, 27 young adults underwent a two-night mixed-design study with a 12-h delayed memory task during both sleep and waking conditions. As expected, we found better retention over the delay containing sleep, and this outcome was strongly associated with the timing of SO–spindle coupling. However, no associations were observed regarding inter-spindle synchrony or respiratory phase. These findings contribute to a better understanding of the importance of SO–spindle coupling for memory. In contrast, the observed lack of association with inter-spindle synchrony may emphasize the local nature of spindle-related plasticity.
Compensatory Hippocampal Neurogenesis in the Absence of Cognitive Impairment Following Experimental Hippocampectomy in Adult Rats
Authors: Cardoso Giuliana T. M. , Gomes-Leal Walace , Franco Edna C. S. , Pereira Antonio , Gomes Francinaldo L. , Brino Ana Leda F. , Lima Silene M. A.
Published: September 2021

Temporal lobe epilepsy (TLE) is the commonest type of focal epilepsy in adult humans, and hippocampal sclerosis (HS) is the main pathological finding in this type of epilepsy. In refractory TLE, patients are indicated for unilateral resection of the affected hippocampus by a surgical procedure called hippocampectomy which generally does not cause any cognitive impairment. Once adult hippocampus is a region of endogenous neurogenesis, even in elderly people, we have hypothesized that a compensatory increase in hippocampal neurogenesis might occur in the remaining hippocampus after unilateral hippocampectomy. To test this hypothesis, we performed unilateral hippocampectomy in adult Wistar rats, which were perfused at 15 (G15) and 30 (G30) days post-surgery. Eighteen Wistar rats were randomly distributed in the following experimental groups: control (no surgery, N = 6), G15 (N = 6), and G30 (N = 6). Adjacent cortex and hippocampus of the left hemisphere were completely removed. Behavioral procedures were performed to address possible cognitive impairments. Brains were collected and fixed from animals belonging to all experimental groups. Gross histopathology was performed using thionine staining. Neuroblasts and mature neurons were immunolabeled using anti-doublecortin (DCX) and anti-NeuN antibodies, respectively. Numbers of DCX and NeuN positive cells were quantified for all experimental groups. Animals submitted to hippocampectomy did not present any cognitive impairment as evaluated by eight-arm radial maze behavioral test. The remaining hippocampus presented a higher number of DCX positive cells compared to control (p < 0.001, ANOVA-Tukey) at both G15 and G30. A higher number of NeuN positive cells were present in the granular layer of dentate gyrus at G30 compared to control and G15 (p < 0.001, ANOVA-Tukey). The data suggest that unilateral hippocampectomy induces compensatory neurogenic effect in the contralateral hippocampus. This may underlie the reported absence of significant cognitive impairment and parallels the findings in human patients submitted to unilateral hippocampectomy to treat refractory TLE.
The Flow of Axonal Information Among Hippocampal Subregions: 1. Feed-Forward and Feedback Network Spatial Dynamics Underpinning Emergent Information Processing
Authors: Vakilna Yash S. , Tang William C. , Wheeler Bruce C. , Brewer Gregory J.
Published: September 2021

The tri-synaptic pathway in the mammalian hippocampus enables cognitive learning and memory. Despite decades of reports on anatomy and physiology, the functional architecture of the hippocampal network remains poorly understood in terms of the dynamics of axonal information transfer between subregions. Information inputs largely flow from the entorhinal cortex (EC) to the dentate gyrus (DG), and then are processed further in the CA3 and CA1 before returning to the EC. Here, we reconstructed elements of the rat hippocampus in a novel device over an electrode array that allowed for monitoring the directionality of individual axons between the subregions. The direction of spike propagation was determined by the transmission delay of the axons recorded between two electrodes in microfluidic tunnels. The majority of axons from the EC to the DG operated in the feed-forward direction, with other regions developing unexpectedly large proportions of feedback axons to balance excitation. Spike timing in axons between each region followed single exponential log-log distributions over two orders of magnitude from 0.01 to 1 s, indicating that conventional descriptors of mean firing rates are misleading assumptions. Most of the spiking occurred in bursts that required two exponentials to fit the distribution of inter-burst intervals. This suggested the presence of up-states and down-states in every region, with the least up-states in the DG to CA3 feed-forward axons and the CA3 subregion. The peaks of the log-normal distributions of intra-burst spike rates were similar in axons between regions with modes around 95 Hz distributed over an order of magnitude. Burst durations were also log-normally distributed around a peak of 88 ms over two orders of magnitude. Despite the diversity of these spike distributions, spike rates from individual axons were often linearly correlated to subregions. These linear relationships enabled the generation of structural connectivity graphs, not possible previously without the directional flow of axonal information. The rich axonal spike dynamics between subregions of the hippocampus reveal both constraints and broad emergent dynamics of hippocampal architecture. Knowledge of this network architecture may enable more efficient computational artificial intelligence (AI) networks, neuromorphic hardware, and stimulation and decoding from cognitive implants.
Disentangling of Local and Wide-Field Motion Adaptation
Authors: Li Jinglin , Niemeier Miriam , Kern Roland , Egelhaaf Martin
Published: September 2021

Motion adaptation has been attributed in flying insects a pivotal functional role in spatial vision based on optic flow. Ongoing motion enhances in the visual pathway the representation of spatial discontinuities, which manifest themselves as velocity discontinuities in the retinal optic flow pattern during translational locomotion. There is evidence for different spatial scales of motion adaptation at the different visual processing stages. Motion adaptation is supposed to take place, on the one hand, on a retinotopic basis at the level of local motion detecting neurons and, on the other hand, at the level of wide-field neurons pooling the output of many of these local motion detectors. So far, local and wide-field adaptation could not be analyzed separately, since conventional motion stimuli jointly affect both adaptive processes. Therefore, we designed a novel stimulus paradigm based on two types of motion stimuli that had the same overall strength but differed in that one led to local motion adaptation while the other did not. We recorded intracellularly the activity of a particular wide-field motion-sensitive neuron, the horizontal system equatorial cell (HSE) in blowflies. The experimental data were interpreted based on a computational model of the visual motion pathway, which included the spatially pooling HSE-cell. By comparing the difference between the recorded and modeled HSE-cell responses induced by the two types of motion adaptation, the major characteristics of local and wide-field adaptation could be pinpointed. Wide-field adaptation could be shown to strongly depend on the activation level of the cell and, thus, on the direction of motion. In contrast, the response gain is reduced by local motion adaptation to a similar extent independent of the direction of motion. This direction-independent adaptation differs fundamentally from the well-known adaptive adjustment of response gain according to the prevailing overall stimulus level that is considered essential for an efficient signal representation by neurons with a limited operating range. Direction-independent adaptation is discussed to result from the joint activity of local motion-sensitive neurons of different preferred directions and to lead to a representation of the local motion direction that is independent of the overall direction of global motion.
Associations of IRAK1 Gene Polymorphisms and mRNA Expression With NMOSD Risk in the Northern Chinese Han Population
Authors: Yan Hongjing , Guo Ruoyi , Chen Weifeng , Xi Xutao , Wang Lianchang , Ma Jianxun , Li Bin
Published: September 2021

Objectives:Interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) is a very important immunomodulatory gene for autoimmune diseases located on the X chromosome. However, there was little study about the correlation of IRAK1 functional single nucleotide polymorphisms with mRNA expression in neuromyelitis optica spectrum disorder (NMOSD) patients. In this study, we aimed to investigate the plausible association of IRAK1 polymorphism, IRAK1 mRNA expression, and NMOSD risk in the northern Chinese Han population.

Methods:Four loci of IRAK1 gene (rs1059702, rs7061789, rs1059703, and rs3027898) were genotyped using multiplex SNaPshot technique in 102 NMOSD patients and 213 healthy subjects. Allele, genotype, and haplotype frequencies were compared. Stratified analyses were conducted by age, sex, AQP4 status, and age of onset. IRAK1 mRNA levels in the peripheral blood mononuclear cells of 30 NMOSD patients (of active phase) and 15 healthy control subjects were detected using qPCR. The correlations between the SNP polymorphisms and mRNA expression levels of genes were tested using non-parametric tests.

Results:The minor allele frequencies (MAF) of these four locis were significantly lower in NMOSD cases than that of the controls. The frequencies of rs1059703G/G genotype, rs1059702A/A genotype, rs3027898 C/C genotype, and rs7061789G/G genotype were higher in the case group than that of the control group. Haplotype analysis revealed that the major haplotype “G-A-C-G” (alleles in the order of SNPs rs1059703, rs1059702, rs3027898, and rs7061789), containing the risk alleles, conferred an adverse effect on NMOSD. The level of IRAK1mRNA was markedly higher in NMOSD when compared to the healthy control groups. The IRAK1mRNA levels of female patients with the major haplotype were significantly higher compared to those with other haplotypes and to the male patients with the same genotype.

Conclusion:IRAK1 polymorphisms were highly correlated with NMOSD susceptibility. Its haplotype G-A-C-G (rs1059703-rs1059702-rs3027898-rs7061789) confers increasing the risk of NMOSD in female patients. The IRAK1 risk haplotype G-A-C-G upregulated IRAK1 mRNA expression in female NMOSD patients. Our study provides a novel insight into the molecular mechanism of the pathogenesis of NMOSD and reveals that IRAK1 is the potential mechanism-specific druggable target in NMOSD disease.
Case Report: Minimal Neurological Deficit of Two Adult Patients With Weston–Hurst Syndrome Due to Early Craniectomy: Case Series and Review of Literature on Craniectomy
Authors: Loesch-Biffar Anna Mira , Junker Andreas , Linn Jennifer , Thon Niklas , Heck Suzette , Ottomeyer Caroline , Straube Andreas , Pfister Hans Walter
Published: September 2021

Objectives:We describe two new cases of acute hemorrhagic leucoencephalitis (AHLE), who survived with minimal sequelae due to early measures against increased intracranial pressure, particularly craniotomy. The recently published literature review on treatment and outcome of AHLE was further examined for the effect of craniotomy.

Methods:We present two cases from our institution. The outcome of 44 cases from the literature was defined either as good (no deficit, minimal deficit/no daily help) or poor outcome (severe deficit/disabled, death). Patients with purely infratentorial lesions (n= 9) were excluded. Fisher's exact test was applied.

Results:Two cases are presented: A 43-year-old woman with rapidly progressive aphasia and right hemiparesis due to a huge left frontal white matter lesion with rim contrast enhancement. Pathology was consistent with AHLE. The second case was a 56-year-old woman with rapidly progressive aphasia and right hemiparesis. Cranial MRI showed a huge left temporo-occipital white matter lesion with typical morphology for AHLE. Both patients received craniotomy within the first 24 h and consequent immunosuppressive-immunomodulatory treatment and survived with minimal deficits. Out of 35 supratentorial reported AHLE cases, seven patients received decompressive craniotomy. Comparing all supratentorial cases, patients who received craniotomy were more likely to have a good outcome (71 vs. 29%).

Conclusion:Due to early control of the intracranial pressure, particularly due to early craniotomy; diagnosis per biopsy; and immediate start of immunosuppressive-immunomodulatory therapies (cortisone pulse, plasma exchanges), both patients survived with minimal sequelae. Craniotomy plays an important role and should be considered early on in patients with probable AHLE.
Overview of the Complex Figure Test and Its Clinical Application in Neuropsychiatric Disorders, Including Copying and Recall
Authors: Zhang Xiaonan , Lv Liangliang , Min Guowen , Wang Qiuyan , Zhao Yarong , Li Yang
Published: September 2021

The Rey–Osterrieth Complex Figure (ROCF) test is a commonly used neuropsychological assessment tool. It is widely used to assess the visuo-constructional ability and visual memory of neuropsychiatric disorders, including copying and recall tests. By drawing the complex figure, the functional decline of a patient in multiple cognitive dimensions can be assessed, including attention and concentration, fine-motor coordination, visuospatial perception, non-verbal memory, planning and organization, and spatial orientation. This review first describes the different versions and scoring methods of ROCF. It then reviews the application of ROCF in the assessment of visuo-constructional ability in patients with dementia, other brain diseases, and psychiatric disorders. Finally, based on the scoring method of the digital system, future research hopes to develop a new digital ROCF scoring method combined with machine learning algorithms to standardize clinical practice and explore the characteristic neuropsychological structure information of different disorders.
Short-Latency Covert Saccades - The Explanation for Good Dynamic Visual Performance After Unilateral Vestibular Loss?
Authors: Sjögren Julia , Karlberg Mikael , Hickson Craig , Magnusson Måns , Fransson Per-Anders , Tjernström Fredrik
Published: September 2021

Background: Functional head impulse test (fHIT) tests the ability of the vestibulo-ocular reflex (VOR) to allow visual perception during head movements. Our previous study showed that active head movements to the side with a vestibular lesion generated a dynamic visual performance that were as good as during movements to the intact side.

Objective: To examine the differences in eye position during the head impulse test when performed with active and passive head movements, in order to better understand the role of the different saccade properties in improving visual performance.

Method: We recruited 8 subjects with complete unilateral vestibular loss (4 men and 4 women, mean age 47 years) and tested them with video Head Impulse Test (vHIT) and Functional Head Impulse Test (fHIT) during passive and active movements while looking at a target. We assessed the mean absolute position error of the eye during different time frames of the head movement, the peak latency and the peak velocity of the first saccade, as well as the visual performance during the head movement.

Results: Active head impulses to the lesioned side generated dynamic visual performances that were as good as when testing the intact side. Active head impulses resulted in smaller position errors during the visual perception task (p = 0.006) compared to passive head-impulses and the position error during the visual perception time frame correlated with shorter latencies of the first saccade (p < 0.001).

Conclusion: Actively generated head impulses toward the side with a complete vestibular loss resulted in a position error within or close to the margin necessary to obtain visual perception for a brief period of time in patients with chronic unilateral vestibular loss. This seems to be attributed to the appearance of short-latency covert saccades, which position the eyes in a more favorable position during head movements.
Brain Network Integrity Changes in Subjective Cognitive Decline: A Possible Physiological Biomarker of Dementia
Authors: Fogel Hilla , Levy-Lamdan Ofri , Zifman Noa , Hiller Tal , Efrati Shai , Suzin Gil , Hack Dallas C. , Dolev Iftach , Tanne David
Published: September 2021

Objective: The current study seeks to illustrate potential early and objective neurophysiological biomarkers of neurodegenerative cognitive decline by evaluating features of brain network physiological performance and structure utilizing different modalities.

Methods: This study included 17 clinically healthy individuals with self-reported cognitive decline (Subjective Cognitive Decline group, SCD, no objective finding of cognitive decline), 12 individuals diagnosed with amnestic Mild Cognitive Impairment (aMCI), 11 individuals diagnosed with Dementia, and 15 healthy subjects. All subjects underwent computerized cognitive performance testing, MRI scans including T1 for gray matter (GM) volume quantification, DTI for quantification of white matter (WM) microstructure fractional anisotropy (FA) and mean diffusivity (MD), and brain network function evaluation using DELPHI (TMS-EEG) measures of connectivity, excitability, and plasticity.

Results: Both DELPHI analysis of network function and DTI analysis detected a significant decrease in connectivity, excitability, and WM integrity in the SCD group compared to healthy control (HC) subjects; a significant decrease was also noted for aMCI and Dementia groups compared to HC. In contrast, no significant decrease was observed in GM volume in the SCD group compared to healthy norms, a significant GM volume decrease was observed only in objectively cognitively impaired aMCI subjects and in dementia subjects.

Conclusions: This study results suggest that objective direct measures of brain network physiology and WM integrity may provide early-stage biomarkers of neurodegenerative-related changes in subjects that have not yet displayed any other objective measurable cognitive or GM volume deficits which may facilitate early preventive care for neurodegenerative decline and dementia.
Evaluation of Thiol Homeostasis in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders
Authors: Arslan Burak , Arslan Gökçe Ayhan , Tuncer Aslı , Karabudak Rana , Dinçel Aylin Sepici
Published: September 2021

Objectives: The aim of this pilot study was to evaluate dynamic thiol-disulfide homeostasis as a novel oxidative stress parameter in multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) to better understand the role of thiol homeostasis in neuroimmunological diseases.

Methods: A total of 85 participants were included in this study, consisting of 18 healthy controls, 52 patients diagnosed with MS, seven with NMOSD, and eight with MOGAD. We measured total thiol (–SH+-S–S–) and native thiol (–SH) levels in the serum of all the participants, and in a subset of patients (n = 11), these parameters were investigated in paired cerebrospinal fluid (CSF) and serum samples. Dynamic disulfide concentrations were calculated separately. Finally, we determined if there was any relationship between clinical features and dynamic thiol homeostasis.

Results: There was a statistically significant difference between serum and CSF levels of biomarkers of thiol homeostasis. Serum total thiol (317.88 ± 66.04) and native thiol (211.61 ± 44.15) levels were significantly lower in relapsed patients compared to those in remission (368.84 ± 150.36 vs. 222.52 ± 70.59, respectively).

Conclusions: Oxidative stress plays a crucial role in the physiopathology of neuroimmunological diseases. Thiol homeostasis may be useful for monitoring disease activity.
MMP-9 as a Biomarker for Predicting Hemorrhagic Strokes in Moyamoya Disease
Authors: Lu Junlin , Wang Jingyi , Lin Zhidong , Shi Guangchao , Wang Rong , Zhao Yahui , Zhao Yuanli , Zhao Jizong
Published: September 2021

Objective: This study was conducted in order to investigate the association of matrix metalloproteinase (MMP)-9 levels with phenotypes of moyamoya disease (MMD).

Methods: This study included plasma samples from 84 MMD patients. The clinical variables of these patients were reviewed from the medical record. The serum concentration of tight junction, adherens junction proteins, and MMPs (MMP-2 and MMP-9) was determined using the ELISA method. Patients with hemorrhagic-onset MMD were compared with those with ischemic-onset MMD.

Results: Compared with pediatric patients, the expression of MMP-9 was significantly higher, while the MMP-2 and vascular endothelial-cadherin were lower in adult patients. In adult subgroup analysis, hemorrhagic MMD patients exhibited significantly higher serum concentrations of MMP-9 compared with ischemic MMD patients. The ROC curve identified that a baseline serum MMP-9 level >1,011 ng/ml may be associated with spontaneous hemorrhage in adult MMD patients with 70.37% sensitivity and 71.88% specificity [area under curve (AUC), 0.73; 95% CI 0.597–0.864; P = 0.003]. A late Suzuki stage (>4) (OR 4.565, 95% CI 1.028–20.280, P = 0.046) and serum concentrations of MMP-9 >1,011 ng/ml (OR 7.218, 95% CI 1.826–28.533, P = 0.005) are risk predictors of hemorrhages in MMD patients. Hemorrhagic-type MMD patients had higher serum levels of MMP-9 and BBB permeability compared with ischemic-type MMD patients. Adult MMD patients had higher serum levels of MMP-9 and BBB permeability compared with pediatric patients.

Conclusions: MMP-9 might serve as a biomarker for hemorrhage prediction in MMD. Serum MMP-9 level >1,011 ng/ml is an independent risk factor of MMD hemorrhagic strokes.
Audiovisual Interactions Among Near-Threshold Oscillating Stimuli in the Far Periphery Are Phase-Dependent
Authors: Zulfiqar Isma , Moerel Michelle , Lage-Castellanos Agustin , Formisano Elia , De Weerd Peter
Published: September 2021

Recent studies have highlighted the possible contributions of direct connectivity between early sensory cortices to audiovisual integration. Anatomical connections between the early auditory and visual cortices are concentrated in visual sites representing the peripheral field of view. Here, we aimed to engage early sensory interactive pathways with simple, far-peripheral audiovisual stimuli (auditory noise and visual gratings). Using a modulation detection task in one modality performed at an 84% correct threshold level, we investigated multisensory interactions by simultaneously presenting weak stimuli from the other modality in which the temporal modulation was barely-detectable (at 55 and 65% correct detection performance). Furthermore, we manipulated the temporal congruence between the cross-sensory streams. We found evidence for an influence of barely-detectable visual stimuli on the response times for auditory stimuli, but not for the reverse effect. These visual-to-auditory influences only occurred for specific phase-differences (at onset) between the modulated audiovisual stimuli. We discuss our findings in the light of a possible role of direct interactions between early visual and auditory areas, along with contributions from the higher-order association cortex. In sum, our results extend the behavioral evidence of audio-visual processing to the far periphery, and suggest – within this specific experimental setting – an asymmetry between the auditory influence on visual processing and the visual influence on auditory processing.
Oscillatory Pattern of Sympathetic Nerve Bursts Is Associated With Baroreflex Function in Heart Failure Patients With Reduced Ejection Fraction
Authors: Toschi-Dias Edgar , Montano Nicola , Tobaldini Eleonora , Trevizan Patrícia F. , Groehs Raphaela V. , Antunes-Correa Ligia M. , Nobre Thais S. , Lobo Denise M. , Sales Allan R. K. , Ueno-Pardi Linda M. , de Matos Luciana D. N. J. , Oliveira Patrícia A. , Braga Ana Maria F. W. , Alves Maria Janieire N. N. , Negrão Carlos E. , Rondon Maria Urbana P. B.
Published: September 2021

Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LFMSNA/HFMSNA) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LFMSNA/HFMSNA index: (1) Lower LFMSNA/HFMSNA (lower terciles, n = 46, aged 53 ± 1 y) and (2) Higher LFMSNA/HFMSNA (upper terciles, n = 47, aged 52 ± 2 y). Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LFMSNA/HFMSNA, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LFMSNA/HFMSNA had reduced left ventricular ejection fraction (26 ± 1 vs. 29 ± 1%, P = 0.03), gain (0.15 ± 0.03 vs. 0.30 ± 0.04 a.u./mmHg, P < 0.001) and coupling of sympathetic baroreflex function (0.26 ± 0.03 vs. 0.56 ± 0.04%, P < 0.001) and increased muscle sympathetic nerve activity (48 ± 2 vs. 41 ± 2 bursts/min, P < 0.01) and heart rate (71 ± 2 vs. 61 ± 2 bpm, P < 0.001) compared with HFrEF patients with higher LFMSNA/HFMSNA. Further analysis showed an association between the LFMSNA/HFMSNA with coupling of sympathetic baroreflex function (R = 0.56, P < 0.001) and left ventricular ejection fraction (R = 0.23, P = 0.02). In conclusion, there is a direct association between LFMSNA/HFMSNA and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LFMSNA/HFMSNA.
Clinical Strategies Against Early Hematoma Expansion Following Intracerebral Hemorrhage
Authors: Tanaka Kanta , Toyoda Kazunori
Published: September 2021

Hematoma volume is the strongest predictor of morbidity and mortality after intracerebral hemorrhage. Protection against early hematoma growth is therefore the mainstay of therapeutic intervention for acute intracerebral hemorrhage, but the current armamentarium is restricted to early blood pressure lowering and emergent reversal for anticoagulant agents. Although intensive lowering of systolic blood pressure to <140 mmHg appears likely to prevent hematoma growth, two recent randomized trials, INTERACT-2 and ATACH-2, demonstrated non-significant trends of reduced hematoma enlargement by intensive blood pressure control, with only a small magnitude of benefit or no benefit for clinical outcomes. While oral anticoagulants can be immediately reversed by prothrombin complex concentrate, or the newly developed idarucizumab for direct thrombin inhibitor or andexanet for factor Xa inhibitors, the situation regarding reversal of antiplatelet agents is not yet quite as advanced. However, considering at most the approximately 10% rate of anticoagulant use among patients with intracerebral hemorrhage, what is most essential for patients with intracerebral hemorrhage in general is early hemostatic therapy. Tranexamic acid may safely reduce hematoma expansion, but its hemostatic effect was insufficient to be translated into improved functional outcomes in the TICH-2 randomized trial with 2,325 participants. In this context, recombinant activated factor VII (rFVIIa) is a candidate to be added to the armory against hematoma enlargement. The FAST, a phase 3 trial that compared doses of 80 and 20 μg/kg rFVIIa with placebo in 841 patients within 4 h after the stroke onset, showed a significant reduction in hematoma growth with rFVIIa treatment, but demonstrated no significant difference in the proportion of patients with severe disability or death. However, apost hocanalysis of the FAST trial suggested a benefit of rFVIIa in a target subgroup of younger patients without extensive bleeding at baseline when treated earlier after stroke onset. The FASTEST trial is now being prepared to determine this potential benefit of rFVIIa, reflecting the pressing need to develop therapeutic strategies against hematoma enlargement, a powerful but modifiable prognostic factor in patients with intracerebral hemorrhage.
Closed-Loop Identification of Baroreflex Properties in the Frequency Domain
Authors: Kawada Toru , Saku Keita , Miyamoto Tadayoshi
Published: September 2021

The arterial baroreflex system plays a key role in maintaining the homeostasis of arterial pressure (AP). Changes in AP affect autonomic nervous activities through the baroreflex neural arc, whereas changes in the autonomic nervous activities, in turn, alter AP through the baroreflex peripheral arc. This closed-loop negative feedback operation makes it difficult to identify open-loop dynamic characteristics of the neural and peripheral arcs. Regarding sympathetic AP controls, we examined the applicability of a nonparametric frequency-domain closed-loop identification method to the carotid sinus baroreflex system in anesthetized rabbits. This article compares the results of an open-loop analysis applied to open-loop data, an open-loop analysis erroneously applied to closed-loop data, and a closed-loop analysis applied to closed-loop data. To facilitate the understanding of the analytical method, sample data files and sample analytical codes were provided. In the closed-loop identification, properties of the unknown central noise that modulated the sympathetic nerve activity and the unknown peripheral noise that fluctuated AP affected the accuracy of the estimation results. A priori knowledge about the open-loop dynamic characteristics of the arterial baroreflex system may be used to advance the assessment of baroreflex function under closed-loop conditions in the future.
HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy
Authors: English Krystal , Barton Michelle Craig
Published: September 2021

Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.
Discordant Effects of Cannabinoid 2 Receptor Antagonism/Inverse Agonism During Adolescence on Pavlovian and Instrumental Reward Learning in Adult Male Rats
Authors: Ellner Danna , Hallam Bryana , Frie Jude A. , Thorpe Hayley H. A. , Shoaib Muhammad , Kayir Hakan , Jenkins Bryan W. , Khokhar Jibran Y.
Published: September 2021

The endocannabinoid system is responsible for regulating a spectrum of physiological activities and plays a critical role in the developing brain. During adolescence, the endocannabinoid system is particularly sensitive to external insults that may change the brain’s developmental trajectory. Cannabinoid receptor type 2 (CB2R) was initially thought to predominantly function in the peripheral nervous system, but more recent studies have implicated its role in the mesolimbic pathway, a network largely attributed to reward circuitry and reward motivated behavior, which undergoes extensive changes during adolescence. It is therefore important to understand how CB2R modulation during adolescence can impact reward-related behaviors in adulthood. In this study, adolescent male rats (postnatal days 28–41) were exposed to a low or high dose of the CB2R antagonist/inverse agonist SR144528 and Pavlovian autoshaping and instrumental conditional behavioral outcomes were measured in adulthood. SR144528-treated rats had significantly slower acquisition of the autoshaping task, seen by less lever pressing behavior over time [F(2, 19) = 5.964, p = 0.010]. Conversely, there was no effect of adolescent SR144528 exposure on instrumental conditioning. These results suggest that modulation of the CB2R in adolescence differentially impacts reward-learning behaviors in adulthood.
Pulmonary Neuroendocrine Neoplasms Overexpressing Epithelial-Mesenchymal Transition Mechanical Barriers Genes Lack Immune-Suppressive Response and Present an Increased Risk of Metastasis
Authors: Prieto Tabatha Gutierrez , Baldavira Camila Machado , Machado-Rugolo Juliana , Farhat Cecília , Olivieri Eloisa Helena Ribeiro , de Sá Vanessa Karen , da Silva Eduardo Caetano Abilio , Balancin Marcelo Luiz , Ab´Saber Alexandre Muxfeldt , Takagaki Teresa Yae , Cordeiro de Lima Vladmir Cláudio , Capelozzi Vera Luiza
Published: September 2021

Typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC), and small cell lung carcinomas (SCLC) encompass a bimodal spectrum of metastatic tumors with morphological, histological and histogenesis differences, The hierarchical structure reveals high cohesiveness between neoplastic cells by mechanical desmosomes barrier assembly in carcinoid tumors and LCNEC, while SCLC does not present an organoid arrangement in morphology, the neoplastic cells are less cohesive. However, the molecular mechanisms that lead to PNENs metastasis remain largely unknown and require further study. In this work, epithelial to mesenchymal transition (EMT) transcription factors were evaluated using a set of twenty-four patients with surgically resected PNENs, including carcinomas. Twelve EMT transcription factors (BMP1, BMP7, CALD1, CDH1, COL3A1, COL5A2, EGFR, ERBB3, PLEK2, SNAI2, STEAP1, and TCF4) proved to be highly expressed among carcinomas and downregulated in carcinoid tumors, whereas upregulation of BMP1, CDH2, KRT14 and downregulation of CAV2, DSC2, IL1RN occurred in both histological subtypes. These EMT transcription factors identified were involved in proliferative signals, epithelium desmosomes assembly, and cell motility sequential steps that support PNENs invasion and metastasis in localized surgically resected primary tumor. We used a two-stage design where we first examined the candidate EMT transcription factors using a whole-genome screen, and subsequently, confirmed EMT-like changes by transmission electron microscopy and then, the EMT-related genes that were differentially expressed among PNENs subtypes were predicted through a Metascape analysis by in silico approach. A high expression of these EMT transcription factors was significantly associated with lymph node and distant metastasis. The sequential steps for invasion and metastasis were completed by an inverse association between functional barrier created by PD-L1 immunosuppressive molecule and EMT transcriptional factors. Our study implicates upregulation of EMT transcription factors to high proliferation rates, mechanical molecular barriers disassembly and increased cancer cell motility, as a critical molecular event leading to metastasis risk in PNENs thus emerging as a promising tool to select and customize therapy.
Carotenoid-Enriched Fractions From Spondias mombin Demonstrate HER2 ATP Kinase Domain Inhibition: Computational and In Vivo Animal Model of Breast Carcinoma Studies
Authors: Metibemu Damilohun Samuel , Akinloye Oluseyi Adeboye , Omotuyi Idowu Olaposi , Okoye Jude Ogechukwu , Popoola Mustapha Ayodele , Akamo Adio Jamiu
Published: September 2021

Human epidermal growth factor 2 (HER2) is overexpressed in about 20% of breast cancer and is associated with a poor prognosis. We report in this study that carotenoid-enriched fractions from Spondias mombin demonstrate HER2 ATP kinase domain inhibition. HER2 breast carcinoma was modeled in female Wistar rats and authenticated via immunohistochemical studies. Inhibition of HER2 ATP kinase domain by the carotenoid-enriched fractions was investigated by molecular docking, atomistic simulation, and the expression of HER2 mRNA in HER2-positive breast carcinoma model in female Wistar rats. The therapeutic efficacy of the treatments (carotenoid-rich fractions) was determined by biochemical, tumor volume, and histopathological analysis. Immunohistochemical analysis revealed 7,12-dimethylbenz[a]anthracene (DMBA)-induced HER2-positive breast carcinoma. Phytoconstituents of the carotenoid-enriched fractions astaxanthin, 7,7′,8,8′-tetrahydro-β,β-carotene, beta-carotene-15,15′-epoxide, and lapatinib (standard drug) demonstrate inhibition of HER2 with docking scores of −3.0, −8.5, −11.5, and −10.6 kcal/mol, respectively; and during atomistic simulation, the compounds ruptured the canonical active-state K753/E770 salt-bridge interaction. The treatment similarly downregulated HER2 mRNA expression significantly at p < 0.05. It also upregulated the expression of p53 and p27 mRNAs significantly at p < 0.05 and reduced creatinine and urea concentrations in the serum at p < 0.05. The tumor volume was also significantly reduced when compared with that of the untreated group. Carotenoid-enriched fractions from S. mombin demonstrate anti-HER2 positive breast carcinoma potentials via HER2 ATP kinase domain inhibition.
Use of F-18 FDG PET/CT Through Delayed Diuretic Imaging for Preoperative Evaluation of Upper Urinary Tract-Occupying Lesions
Authors: Wang Jun , Zhang Liang , Wu Jian Guo , Chen Ruohua , Shen Jia lin
Published: September 2021

Purpose

To evaluate the value of F-18 FDG PET/CT in the differentiation of malignant and benign upper urinary tract-occupying lesions.

Patients and Methods

64 patients with upper urinary tract-occupying lesions underwent F-18 FDG PET/CT at RenJi Hospital from January 2015 to February 2019 in this retrospective study. Of the 64 patients, 50 patients received nephroureterectomy or partial ureterectomy; 14 patients received ureteroscopy and biopsy. The comparisons of PET/CT parameters and clinical characteristics between malignant and benign upper urinary tract-occupying lesions were investigated.

Results

Of the 64 patients, 49 were found to have malignant tumors. Receiver operating characteristic analysis determined the lesion SUVmax value of 6.75 as the threshold for predicting malignant tumors. There were significant associations between malignant and benign upper urinary tract-occupying lesions and SUVmax of lesion (P<0.001), lesion size (P<0.001), and patient age (P=0.011). Multivariate analysis showed that SUVmax of lesion (P=0.042) and patient age (P=0.009) as independent predictors for differentiation of malignant from benign upper urinary tract-occupying lesions. There was a significant difference in tumor size between the positive (SUVmax >6.75) and negative (SUVmax ≤6.75) PET groups in 38 of the 49 patients with malignant tumors.

Conclusion

The SUVmax of lesion and patient age is associated with the nature of upper urinary tract-occupying lesions. F-18 FDG PET/CT may be useful to distinguish between malignant and benign upper urinary tract-occupying lesions and determine a suitable therapeutic strategy.
A Novel Microfluidic Chip for Fast, Sensitive Quantification of Plasma Extracellular Vesicles as Biomarkers in Patients With Osteosarcoma
Authors: Xu Yi-Qi , Bao Qi-Yuan , Yu Sai-Xi , Liu Qi , Xie Yan , Li Xin , Liu Yan-Jun , Shen Yu-Hui
Published: September 2021

Plasma circulating extracellular vesicle (EV) has emerged as a promising biomarker for diagnosis and prognosis of various epithelial tumors. However, fast and efficient capture of EVs with microfluidic chip in sarcoma remains to be established. Herein, we reported a ZnO-nanorods integrated (ZNI) microfluidic chip, where EV capture antibody was uniformly grafted to the surface of the ZnO-nanorods of the chip to enhance the plasma turbulence formation and the capture efficiency at the micro-scale. Based on osteosarcoma (OS) cell line, we demonstrated that a combination of CD81 and CD63 antibody on ZNI chip yielded the greatest amount of total EVs, with an extra sensitive limit of detection (LOD) of ~104 particles mL-1. Furthermore, the addition of fluorescent labeling of Vimentin (VIM), a previously reported sarcoma cell surface biomarker, could enabled the dual visualization of total plasma EVs and VIM-positive EVs from OS patients’ plasma. Based on our ZNI chip, we found that the amount of plasma total EVs was significantly different between OS and healthy donors (1562 a.u. versus 639 a.u., p< 0.05), but not between metastatic and nonmetastatic OS (p> 0.05). Interestingly, patients with metastatic disease had a significantly greater amount of VIM-positive EVs (1411 a.u. versus 231 a.u.., p< 0.05) and increased VIM-positive/total EVs ratio (0.943 versus 0.211, p< 0.05) in comparison with the nonmetastatic counterpart. Therefore, our ZNI microfluidic chip has great potential for the fast quantification of plasma EVs, and the microfluidic-based quantification of total and VIM-positive EVs might serve as a promising biomarker for the diagnosis and surveillance in OS patients.
Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies
Authors: Harland Abigail , Liu Xia , Ghirardello Mattia , Galan M. Carmen , Perks Claire M. , Kurian Kathreena M.
Published: September 2021

Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.
A Co-Expression Network Reveals the Potential Regulatory Mechanism of lncRNAs in Relapsed Hepatocellular Carcinoma
Authors: Fang Yuan , Yang Yang , Zhang XiaoLi , Li Na , Yuan Bo , Jin Li , Bao Sheng , Li MengGe , Zhao Dan , Li LingRui , Zeng Zhong , Huang HanFei
Published: September 2021

Background

The mechanistic basis for relapsed hepatocellular carcinoma (HCC) remains poorly understood. Recent research has highlighted the important roles of long non-coding RNAs (lncRNAs) in HCC. However, there are only a few studies on the association between lncRNAs and HCC relapse.

Methods

Differentially expressed lncRNAs and mRNAs between a primary HCC group and relapsed HCC group were identified using the edge R package to analyze the GSE101432 dataset. The differentially expressed lncRNAs and mRNAs were used to construct a lncRNA–mRNA co-expression network. Weighted gene co-expression network analysis followed by Gene Ontology (GO) enrichment analyses were conducted on the database. Furthermore, correlation and survival analyses were performed using The Cancer Genome Atlas database, and expression in the clinical samples was verified by qRT-PCR. Thereafter, we inputted the genes from the two groups into the HCC TNM stage and tumor grade database from TCGA. Finally, we performed Kaplan–Meier survival analysis on the lncRNAs related to relapsed HCC.

Results

In this study, lncRNAs and mRNAs associated with HCC relapse were identified. Two gene modules were found to be closely linked to this. The GO terms in the yellow and black modules were related to cell proliferation, differentiation, and survival, as well as some transcription-related biological processes. Through qRT-PCR, we found that the expression levels of LINC00941 and LINC00668 in relapsed HCC were higher than those in primary HCC. Further, mRNA levels of LOX, OTX1, MICB, NDUFA4L2, BAIAP2L2, and KCTD17 were changed in relapsed HCC compared to levels in primary HCC. In addition, we verified that these genes could predict the overall survival and recurrence-free survival of HCC. Moreover, we found that LINC00668 and LINC00941 could affect tumor grade and TNM stages. In total, we identified and validated two lncRNAs (LINC00941 and LINC00668) and six mRNAs (LOX, MICB, OTX1, BAIAP2L2, KCTD17, NDUFA4L2) associated with HCC relapse.

Conclusion

In summary, we identified the key gene modules and central genes associated with relapsed HCC and constructed lncRNA–mRNA networks related to this. These genes are likely to have potential prognostic value for relapsed HCC and might shed new light on novel biomarkers or diagnostic targets for relapsed HCC.