bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity of Skill Score Metric to Validate Lagrangian Simulations in Coastal Areas: Recommendations for Search and Rescue Applications
Authors: Révelard Adèle , Reyes Emma , Mourre Baptiste , Hernández-Carrasco Ismael , Rubio Anna , Lorente Pablo , Fernández Christian De Lera , Mader Julien , Álvarez-Fanjul Enrique , Tintoré Joaquín
Published: March 2021

Search and rescue (SAR) modeling applications, mostly based on Lagrangian tracking particle algorithms, rely on the accuracy of met-ocean forecast models. Skill assessment methods are therefore required to evaluate the performance of ocean models in predicting particle trajectories. The Skill Score (SS), based on the Normalized Cumulative Lagrangian Separation (NCLS) distance between simulated and satellite-tracked drifter trajectories, is a commonly used metric. However, its applicability in coastal areas, where most of the SAR incidents occur, is difficult and sometimes unfeasible, because of the high variability that characterizes the coastal dynamics and the lack of drifter observations. In this study, we assess the performance of four models available in the Ibiza Channel (Western Mediterranean Sea) and evaluate the applicability of the SS in such coastal risk-prone regions seeking for a functional implementation in the context of SAR operations. We analyze the SS sensitivity to different forecast horizons and examine the best way to quantify the average model performance, to avoid biased conclusions. Our results show that the SS increases with forecast time in most cases. At short forecast times (i.e., 6 h), the SS exhibits a much higher variability due to the short trajectory lengths observed compared to the separation distance obtained at timescales not properly resolved by the models. However, longer forecast times lead to the overestimation of the SS due to the high variability of the surface currents. Findings also show that the averaged SS, as originally defined, can be misleading because of the imposition of a lower limit value of zero. To properly evaluate the averaged skill of the models, a revision of its definition, the so-called SS∗, is recommended. Furthermore, whereas drifters only provide assessment along their drifting paths, we show that trajectories derived from high-frequency radar (HFR) effectively provide information about the spatial distribution of the model performance inside the HFR coverage. HFR-derived trajectories could therefore be used for complementing drifter observations. The SS is, on average, more favorable to coarser-resolution models because of the double-penalty error, whereas higher-resolution models show both very low and very high performance during the experiments.
Improved Magnetorheological Properties by Using Ionic Liquid as Carrier Liquid of Magnetorheological Fluids
Authors: Tong Yu , Li Xiaoguang , Zhao Penghui , Dong Xufeng , Wu Zhanjun , Qi Min
Published: March 2021

The interface between the particles and the carrier fluids has an important influence on the performance of magnetorheological fluid (MRF). In this study, ionic liquids and silicone oils with the same viscosity and different surface tensions were used as carrier fluids to prepare two different carbonyl iron powder (CIP) magnetorheological fluids. The rheological properties of the two magnetorheological fluids were evaluated by the MCR301 rotating rheometer. The experimental results indicate that ionic liquid-based MRF showed higher shear yield strength and more significant MR effect than silicone oil-based ones in higher magnetic field strength. A possible explanation was proposed and proved through experimental data analysis.
Sarcopenic Obesity Is Significantly Associated With Coronary Artery Calcification
Authors: Chung Goh Eun , Park Hyo Eun , Lee Heesun , Kim Min Joo , Choi Su-Yeon , Yim Jeong Yoon , Yoon Ji Won
Published: March 2021

Background: An association between sarcopenic obesity and cardiovascular disease has been suggested. We investigated the relationship between sarcopenia and coronary atherosclerosis, taking into account the presence or absence of obesity in a health check-up population.

Methods: Data were reviewed for subjects who underwent bioelectrical impedance analysis (BIA) and coronary calcium scoring (CAC) computed tomography between January 2017 and December 2018. Appendicular skeletal muscle mass (ASM) was assessed using BIA. Sarcopenia was defined as reduction of muscle mass and calculated as ASM% (ASM/body weight) more than two standard deviations below the sex-specific mean for healthy young adults. CAC scores were dichotomized as low (<100) or high (≥100).

Results: Among 1,282 subjects (mean age, 58.1 years; 75.5% male), the prevalence of high CAC was 21%. When the study population was divided into four groups according to their obesity and sarcopenia status, the prevalence of high CAC in the sarcopenic-obesity (SO) group was significantly higher than in the other groups (40.7%, P < 0.001). After adjusting for age, sex, hypertension, diabetes, dyslipidemia, and creatinine, subjects with SO exhibited a significantly higher odds of a high CAC score, compared with the non-sarcopenic, non-obese group (odds ratio, 1.92; 95% confidence interval, 1.16–3.18, P = 0.011).

Conclusion: SO was significantly associated with CAC, independent of known risk factors for coronary artery disease. These findings suggest that sarcopenia and obesity may potentiate each other to increase atherosclerotic burden in coronary arteries, which may eventually lead to adverse cardiovascular events.
Analysis of Selection Methods to Develop Novel Phage Therapy Cocktails Against Antimicrobial Resistant Clinical Isolates of Bacteria
Authors: Haines Melissa E. K. , Hodges Francesca E. , Nale Janet Y. , Mahony Jennifer , van Sinderen Douwe , Kaczorowska Joanna , Alrashid Bandar , Akter Mahmuda , Brown Nathan , Sauvageau Dominic , Sicheritz-Pontén Thomas , Thanki Anisha M. , Millard Andrew D. , Galyov Edouard E. , Clokie Martha R. J.
Published: March 2021

Antimicrobial resistance (AMR) is a major problem globally. The main bacterial organisms associated with urinary tract infection (UTI) associated sepsis are E. coli and Klebsiella along with Enterobacter species. These all have AMR strains known as ESBL (Extended Spectrum Beta-Lactamase), which are featured on the WHO priority pathogens list as “critical” for research. Bacteriophages (phages), as viruses that can infect and kill bacteria, could provide an effective tool to tackle these AMR strains. There is currently no “gold standard” for developing a phage cocktail. Here we describe a novel approach to develop an effective phage cocktail against a set of ESBL-producing E. coli and Klebsiella largely isolated from patients in United Kingdom hospitals. By comparing different measures of phage efficacy, we show which are the most robust, and suggest an efficient screening cascade that could be used to develop phage cocktails to target other AMR bacterial species. A target panel of 38 ESBL-producing clinical strains isolated from urine samples was collated and used to test phage efficacy. After an initial screening of 68 phages, six were identified and tested against these 38 strains to determine their clinical coverage and killing efficiency. To achieve this, we assessed four different methods to assess phage virulence across these bacterial isolates. These were the Direct Spot Test (DST), the Efficiency of Plating (EOP) assay, the planktonic killing assay (PKA) and the biofilm assay. The final ESBL cocktail of six phages could effectively kill 23/38 strains (61%), for Klebsiella 13/19 (68%) and for E. coli 10/19 (53%) based on the PKA data. The ESBL E. coli collection had six isolates from the prevalent UTI-associated ST131 sequence type, five of which were targeted effectively by the final cocktail. Of the four methods used to assess phage virulence, the data suggests that PKAs are as effective as the much more time-consuming EOPs and data for the two assays correlates well. This suggests that planktonic killing is a good proxy to determine which phages should be used in a cocktail. This assay when combined with the virulence index also allows “phage synergy” to inform cocktail design.
Perspectives on High-Throughput Ligand/Protein Docking With Martini MD Simulations
Authors: Souza Paulo C. T. , Limongelli Vittorio , Wu Sangwook , Marrink Siewert J. , Monticelli Luca
Published: March 2021

Molecular docking is central to rational drug design. Current docking techniques suffer, however, from limitations in protein flexibility and solvation models and by the use of simplified scoring functions. All-atom molecular dynamics simulations, on the other hand, feature a realistic representation of protein flexibility and solvent, but require knowledge of the binding site. Recently we showed that coarse-grained molecular dynamics simulations, based on the most recent version of the Martini force field, can be used to predict protein/ligand binding sites and pathways, without requiring any a priori information, and offer a level of accuracy approaching all-atom simulations. Given the excellent computational efficiency of Martini, this opens the way to high-throughput drug screening based on dynamic docking pipelines. In this opinion article, we sketch the roadmap to achieve this goal.
Integrated 18F-T807 Tau PET, Structural MRI, and Plasma Tau in Tauopathy Neurodegenerative Disorders
Authors: Li Cheng-Hsuan , Chen Ta-Fu , Chiu Ming-Jang , Yen Ruoh-Fang , Shih Ming-Chieh , Lin Chin-Hsien
Published: March 2021

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy.

Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18F-T807 tau PET, brain MRI, and plasma tau assay.

Results: The global cortical standard uptake value ratio (SUVR) of 18F-T807 PET was comparable between PD and control (p = 0.088). The cortical SUVR was significantly higher in AD group (p = 0.002) but was modestly increased in PSP group compared to the PD group (p = 0.044), especially in parietal and pallidal regions. Asymmetric 18F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level (p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = −0.092, p = 0.025; PSP: r = −0.114, p = 0.015).

Conclusions: The 18F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.
Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells
Authors: Iyer Amrita A. , Groves Andrew K.
Published: March 2021

Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.
Regional Neurodegeneration in vitro: The Protective Role of Neural Activity
Authors: Mott Rosalind E. , von Reyn Catherine R. , Firestein Bonnie L. , Meaney David F.
Published: March 2021

Traumatic brain injury is a devastating public health problem, the eighth leading cause of death across the world. To improve our understanding of how injury at the cellular scale affects neural circuit function, we developed a protocol to precisely injure individual neurons within an in vitro neural network. We used high speed calcium imaging to estimate alterations in neural activity and connectivity that occur followed targeted microtrauma. Our studies show that mechanically injured neurons inactivate following microtrauma and eventually re-integrate into the network. Single neuron re-integration is dependent on its activity prior to injury and initial connections in the network: more active and integrated neurons are more resistant to microtrauma and more likely to re-integrate into the network. Micromechanical injury leads to neuronal death 6 h post-injury in a subset of both injured and uninjured neurons. Interestingly, neural activity and network participation after injury were associated with survival in linear discriminate analysis (77.3% correct prediction, Wilks' Lambda = 0.838). Based on this observation, we modulated neuronal activity to rescue neurons after microtrauma. Inhibition of neuronal activity provided much greater survivability than did activation of neurons (ANOVA, p < 0.01 with post-hoc Tukey HSD, p < 0.01). Rescue of neurons by blocking activity in the post-acute period is partially mediated by mitochondrial energetics, as we observed silencing neurons after micromechanical injury led to a significant reduction in mitochondrial calcium accumulation. Overall, the present study provides deeper insight into the propagation of injury within networks, demonstrating that together the initial activity, network structure, and post-injury activity levels contribute to the progressive changes in a neural circuit after mechanical trauma.
Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?
Authors: Savini Giovanni , Asteggiano Carlo , Paoletti Matteo , Parravicini Stefano , Pezzotti Elena , Solazzo Francesca , Muzic Shaun I. , Santini Francesco , Deligianni Xeni , Gardani Alice , Germani Giancarlo , Farina Lisa M. , Bergsland Niels , Gandini Wheeler-Kingshott Claudia A. M. , Berardinelli Angela , Bastianello Stefano , Pichiecchio Anna
Published: March 2021

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA.

Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally.

Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content.

Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.
Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States
Authors: Tabuchi Masashi , Coates Kaylynn E. , Bautista Oscar B. , Zukowski Lauren H.
Published: March 2021

The circadian rhythm is a fundamental process that regulates the sleep–wake cycle. This rhythm is regulated by core clock genes that oscillate to create a physiological rhythm of circadian neuronal activity. However, we do not know much about the mechanism by which circadian inputs influence neurons involved in sleep–wake architecture. One possible mechanism involves the photoreceptor cryptochrome (CRY). In Drosophila, CRY is receptive to blue light and resets the circadian rhythm. CRY also influences membrane potential dynamics that regulate neural activity of circadian clock neurons in Drosophila, including the temporal structure in sequences of spikes, by interacting with subunits of the voltage-dependent potassium channel. Moreover, several core clock molecules interact with voltage-dependent/independent channels, channel-binding protein, and subunits of the electrogenic ion pump. These components cooperatively regulate mechanisms that translate circadian photoreception and the timing of clock genes into changes in membrane excitability, such as neural firing activity and polarization sensitivity. In clock neurons expressing CRY, these mechanisms also influence synaptic plasticity. In this review, we propose that membrane potential dynamics created by circadian photoreception and core clock molecules are critical for generating the set point of synaptic plasticity that depend on neural coding. In this way, membrane potential dynamics drive formation of baseline sleep architecture, light-driven arousal, and memory processing. We also discuss the machinery that coordinates membrane excitability in circadian networks found in Drosophila, and we compare this machinery to that found in mammalian systems. Based on this body of work, we propose future studies that can better delineate how neural codes impact molecular/cellular signaling and contribute to sleep, memory processing, and neurological disorders.
Progression of Visual Pathway Degeneration in Primary Open-Angle Glaucoma: A Longitudinal Study
Authors: Haykal Shereif , Jansonius Nomdo M. , Cornelissen Frans W.
Published: March 2021

Background: Primary open-angle glaucoma (POAG) patients exhibit widespread white matter (WM) degeneration throughout their visual pathways. Whether this degeneration starts at the pre- or post-geniculate pathways remains unclear. In this longitudinal study, we assess the progression of WM degeneration exhibited by the pre-geniculate optic tracts (OTs) and the post-geniculate optic radiations (ORs) of POAG patients over time, aiming to determine the source and pattern of spread of this degeneration.

Methods: Diffusion-weighted MRI scans were acquired for 12 POAG patients and 14 controls at two time-points 5.4 ± 2.1 years apart. Fiber density (FD), an estimate of WM axonal density, was computed for the OTs and ORs of all participants in an unbiased longitudinal population template space. First, FD was compared between POAG patients and the controls at time-point 1 (TP1) and time-point 2 (TP2) independently. Secondly, repeated measures analysis was performed for FD change in POAG patients between the two time-points. Finally, we compared the rate of FD change over time between the two groups.

Results: Compared to the controls, POAG patients exhibited significantly lower FD in the left OT at TP1 and in both OTs and the left OR at TP2. POAG patients showed a significant loss of FD between the time-points in the right OT and both ORs, while the left OR showed a significantly higher rate of FD loss in POAG patients compared to the controls.

Conclusions: We find longitudinal progression of neurodegenerative WM changes in both the pre- and post-geniculate visual pathways of POAG patients. The pattern of changes suggests that glaucomatous WM degeneration starts at the pre-geniculate pathways and then spreads to the post-geniculate pathways. Furthermore, we find evidence that the trans-synaptic spread of glaucomatous degeneration to the post-geniculate pathways is a prolonged process which continues in the absence of detectable pre-geniculate degenerative progression. This suggests the presence of a time window for salvaging intact post-geniculate pathways, which could prove to be a viable therapeutic target in the future.
Advancements in the Protocol for Rate of Force Development/Relaxation Scaling Factor Evaluation
Authors: Smajla Darjan , Žitnik Jure , Šarabon Nejc
Published: March 2021

Brief submaximal actions are important for wide range of functional movements. Until now, rate of force development and relaxation scaling factor (RFD-SF and RFR-SF) have been used for neuromuscular assessment using 100–120 isometric pulses which requires a high level of attention from the participant and may be influenced by physiological and/or psychological fatigue. All previous studies have been conducted on a smaller number of participants which calls into question the eligibility of some of the outcome measures reported to date. Our aims were: (1) to find the smallest number of rapid isometric force pulses at different force amplitudes is still valid and reliable for RFD-SF slope (kRFD–SF) and RFR-SF slope (kRFR–SF) calculation, (2) to introduce a new outcome measure – theoretical peak of rate of force development/relaxation (TPRFD and TPRFR) and (3) to investigate differences and associations between kRFD–SF and kRFR–SF. A cross-sectional study was conducted on a group of young healthy participants; 40 in the reliability study and 336 in the comparison/association study. We investigated the smallest number of rapid isometric pulses for knee extensors that still provides excellent reliability of the calculated kRFD–SF and kRFR–SF (ICC2,1 ≥ 0.95, CV < 5%). Our results showed excellent reliability of the reduced protocol when 36 pulses (nine for each of the four intensity ranges) were used for the calculations of kRFD–SF and kRFR–SF. We confirmed the negligibility of the y-intercepts and confirmed the reliability of the newly introduced TPRFD and TPRFR. Large negative associations were found between kRFD–SF and kRFR–SF (r = 0.502, p < 0.001), while comparison of the absolute values showed a significantly higher kRFD–SF (8.86 ± 1.0/s) compared to kRFR–SF (8.03 ± 1.3/s) (p < 0.001). The advantage of the reduced protocol (4 intensities × 9 pulses = 36 pulses) is the shorter assessment time and the reduction of possible influence of fatigue. In addition, the introduction of TPRFD and TPRFR as an outcome measure provides valuable information about the participant’s maximal theoretical RFD/RFR capacity. This can be useful for the assessment of maximal capacity in people with various impairments or pain problems.
Video-Oculography During Free Visual Exploration to Detect Right Spatial Neglect in Left-Hemispheric Stroke Patients With Aphasia: A Feasibility Study
Authors: Kaufmann Brigitte C. , Cazzoli Dario , Koenig-Bruhin Monica , Müri René M. , Nef Tobias , Nyffeler Thomas
Published: March 2021

Spatial neglect has been shown to occur in 17–65% of patients after acute left-hemispheric stroke. One reason for this varying incidence values might be that left-hemispheric stroke is often accompanied by aphasia, which raises difficulties in assessing attention deficits with conventional neuropsychological tests entailing verbal instructions. Video-oculography during free visual exploration (FVE) requires only little understanding of simple non-verbal instruction and has been shown to be a sensitive and reliable tool to detect spatial neglect in patients with right-hemispheric stroke. In the present study, we aimed to investigate the feasibility of FVE to detect neglect in 10 left-hemispheric stroke patients with mild to severe aphasia as assessed by means of the Token Test, Boston Naming Test and Aachener Aphasie Test. The patient’s individual deviation between eye movement calibration and validation was recorded and compared to 20 age-matched healthy controls. Furthermore, typical FVE parameters such as the landing point of the first fixation, the mean gaze position (in ° of visual angle), the number and duration of visual fixations and the mean visual exploration area were compared between groups. In addition, to evaluate for neglect, the Bells cancellation test was performed and neglect severity in daily living was measured by means of the Catherine Bergego Scale (CBS). Our results showed that the deviation between calibration and validation did not differ between aphasia patients and healthy controls highlighting its feasibility. Furthermore, FVE revealed the typical neglect pattern with a significant leftward shift in visual exploration bahaviour, which highly correlated with neglect severity as assessed with CBS. The present study provides evidence that FVE has the potential to be used as a neglect screening tool in left-hemispheric stroke patients with aphasia in which compliance with verbal test instructions may be compromised by language deficits.
Polygenic Score Models for Alzheimer’s Disease: From Research to Clinical Applications
Authors: Zhou Xiaopu , Li Yolanda Y. T. , Fu Amy K. Y. , Ip Nancy Y.
Published: March 2021

The high prevalence of Alzheimer’s disease (AD) among the elderly population and its lack of effective treatments make this disease a critical threat to human health. Recent epidemiological and genetics studies have revealed the polygenic nature of the disease, which is possibly explainable by a polygenic score model that considers multiple genetic risks. Here, we systemically review the rationale and methods used to construct polygenic score models for studying AD. We also discuss the associations of polygenic risk scores (PRSs) with clinical outcomes, brain imaging findings, and biochemical biomarkers from both the brain and peripheral system. Finally, we discuss the possibility of incorporating polygenic score models into research and clinical practice along with potential challenges.
Lateral Habenula Regulates Cardiovascular Autonomic Responses via the Serotonergic System in Rats
Authors: Doan Tri Huu , Sato Yuma , Matsumoto Masayuki , Koganezawa Tadachika
Published: March 2021

The lateral habenula (LHb) plays essential roles in behavioral responses to stressful events. Stress is tightly linked to autonomic responses such as cardiovascular responses, yet how the LHb regulates these responses is not well understood. To address this issue, we electrically stimulated the LHb in rats, measured its effects on heart rate (HR) and mean arterial pressure (MAP), and investigated the neural circuits that mediate these LHb-induced cardiovascular responsesviathe autonomic nervous system. We observed that stimulation of the LHb induced bradycardia and pressor responses, whereas stimulation of the adjacent areas changed neither the HR nor the MAP. Bilateral vagotomy and administration of a muscarinic receptor antagonist suppressed the LHb stimulation effect on the HR but not on the MAP, whereas administration of a β-adrenoceptor antagonist partly attenuated the effect on the MAP but not on the HR. Thus, the LHb-induced cardiovascular responses of the HR and the MAP were likely caused by activations of the cardiac parasympathetic nerves and the cardiovascular sympathetic nerves, respectively. Furthermore, administration of a non-selective 5-HT receptor antagonist significantly attenuated the LHb stimulation effects on both the MAP and the HR. A 5-HT2receptor antagonist also attenuated the LHb stimulation effects. A low dose of a 5-HT1Areceptor antagonist enhanced the LHb stimulation effects, but a high dose of the drug attenuated them. 5-HT1Band 5-HT1Dreceptor antagonists as well as a 5-HT7receptor antagonist did not affect the LHb stimulation effects. Taken together, our findings suggest that the LHb regulates autonomic cardiovascular responses at least partly through the serotonergic system, particularlyviathe 5-HT1Aand 5-HT2receptors.
Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders
Authors: Jung Yoo Jin , Tweedie David , Scerba Michael T. , Kim Dong Seok , Palmas Maria Francesca , Pisanu Augusta , Carta Anna R. , Greig Nigel H.
Published: March 2021

Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001;GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.
Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming
Authors: Adeshakin Funmilayo O. , Adeshakin Adeleye O. , Afolabi Lukman O. , Yan Dehong , Zhang Guizhong , Wan Xiaochun
Published: March 2021

The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure–function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis. Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through “anoikis.” However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis. Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis. Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis. Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis. This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis. In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis.
MiR-450a-5p Inhibits Gastric Cancer Cell Proliferation, Migration, and Invasion and Promotes Apoptosis via Targeting CREB1 and Inhibiting AKT/GSK-3β Signaling Pathway
Authors: Zhao Ya-Jun , Zhang Jun , Wang Yong-Cang , Wang Liang , He Xin-Yang
Published: March 2021

Gastric cancer seriously affects human health and research on gastric cancer is attracting more and more attentions. In recent years, molecular targets have become the research focus. Accumulating evidence indicates that miR-450a-5p plays a critical role in cancer progression. However, the biological role of miR-450a-5p in gastric carcinogenesis remains largely unknown. In this study, we explore the effects and mechanisms of miR-450a-5p on the development and progression of gastric cancer. We used gain-of-function approaches to investigate the role of miR-450a-5p on gastric cancer cell proliferation, migration, invasion, and apoptosis using biological and molecular techniques including real-time quantitative PCR (RT-qPCR), CCK-8, colony formation, flow cytometry, Western blot, wound healing, transwell chamber, dual luciferase reporter, and tumor xenograft mouse model. We found that gastric cancer cells have low expression of miR-450a-5p and overexpression of miR-450a-5p inhibited gastric cancer cell proliferation, migration and invasion, and induced apoptosis in vitro. Moreover, we demonstrated that ectopic expression of miR-450a-5p inhibited gastric cancer growth in vivo. At the molecular level, overexpression of miR-450a-5p significantly increased the expression of pro-apoptotic proteins, including caspase-3, caspase-9, and Bax, and inhibited the expression of anti-apoptotic protein Bcl-2. Luciferase reporter experiment suggested that camp response element binding protein 1 (CREB1) had a negative correlation with miR-450a-5p expression, and knockdown of CREB1 alleviated gastric cancer growth. Furthermore, we also found that miR-450a-5p inhibited the activation of AKT/GSK-3β signaling pathway to inhibit the progression of gastric cancer. Collectively, miR-450a-5p repressed gastric cancer cell proliferation, migration and invasion and induced apoptosis through targeting CREB1 by inhibiting AKT/GSK-3β signaling pathway. MiR-450a-5p could be a novel molecular target for the treatment of gastric cancer.
Multiplexed Immunohistochemistry and Digital Pathology as the Foundation for Next-Generation Pathology in Melanoma: Methodological Comparison and Future Clinical Applications
Authors: Van Herck Yannick , Antoranz Asier , Andhari Madhavi Dipak , Milli Giorgia , Bechter Oliver , De Smet Frederik , Bosisio Francesca Maria
Published: March 2021

The state-of-the-art for melanoma treatment has recently witnessed an enormous revolution, evolving from a chemotherapeutic, “one-drug-for-all” approach, to a tailored molecular- and immunological-based approach with the potential to make personalized therapy a reality. Nevertheless, methods still have to improve a lot before these can reliably characterize all the tumoral features that make each patient unique. While the clinical introduction of next-generation sequencing has made it possible to match mutational profiles to specific targeted therapies, improving response rates to immunotherapy will similarly require a deep understanding of the immune microenvironment and the specific contribution of each component in a patient-specific way. Recent advancements in artificial intelligence and single-cell profiling of resected tumor samples are paving the way for this challenging task. In this review, we provide an overview of the state-of-the-art in artificial intelligence and multiplexed immunohistochemistry in pathology, and how these bear the potential to improve diagnostics and therapy matching in melanoma. A major asset of in-situ single-cell profiling methods is that these preserve the spatial distribution of the cells in the tissue, allowing researchers to not only determine the cellular composition of the tumoral microenvironment, but also study tissue sociology, making inferences about specific cell-cell interactions and visualizing distinctive cellular architectures - all features that have an impact on anti-tumoral response rates. Despite the many advantages, the introduction of these approaches requires the digitization of tissue slides and the development of standardized analysis pipelines which pose substantial challenges that need to be addressed before these can enter clinical routine.
Optimal Therapies for Recurrent Glioblastoma: A Bayesian Network Meta-Analysis
Authors: Chen Wenlin , Wang Yuekun , Zhao Binghao , Liu Penghao , Liu Lei , Wang Yu , Ma Wenbin
Published: March 2021

The optimal treatment of recurrent glioblastoma (GBM) remains controversial. Therefore, our study aimed to compare and rank active therapies in recurrent GBM. We performed a systematic review and a Bayesian network meta-analysis. We obtained a treatment hierarchy using the surface under the cumulative ranking curve and mean ranks. A cluster analysis was conducted to aggregate the separated results of three outcomes. The protocol was registered in PROSPERO (CRD42019146794). A total of 1,667 citations were identified, and 15 eligible articles with 17 treatments remained in the final network meta-analysis. Pairwise comparison showed no significant difference on the 6-month progression-free survival (6-m PFS) rate, objective response rate (ORR), and overall survival (OS). Among the reports, cediranib plus lomustine (CCNU) corresponded to the highest rates of grade 3-4 adverse events. Ranking and cluster analysis indicated that bevacizumab (BEV) plus CCNU and regorafenib had a higher efficacy on the ORR, 6-m PFS rate and OS, and that BEV monotherapy or BEV combined with active drug therapies was advantageous for the ORR and 6-m PFS rate. Additionally, tumor treatment fields (TTF) plus BEV showed a relatively higher SUCRA value in OS. According to ranking and cluster analysis, BEV plus CCNU and regorafenib are the primary recommendations for treatment. BEV monotherapy alone or combined with active drug therapies are recommended in patients with severe neurological symptoms. Advanced therapy, such as TTF and immunotherapy, remain to be investigated in future studies.
Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen?
Authors: Faviana Pinuccia , Boldrini Laura , Erba Paola Anna , Di Stefano Iosè , Manassero Francesca , Bartoletti Riccardo , Galli Luca , Gentile Carlo , Bardi Massimo
Published: March 2021

The aim of the present study was to evaluate whether prostate cancer (PC) patients can be accurately classified on the bases of tissue expression of gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA). This retrospective study included 28 patients with PC. Formalin-fixed paraffin-embedded samples were used for diagnosis. Immunohistochemistry staining techniques were used to evaluate PSMA and GRPR expression (both number of cells expressed and % of area stained). To assess the independent associations among selected variables, a multi-dimensional scaling (MDS) analysis was used. It was found that the PSMA expression was inversely correlated with GRPR expression. Only the number of cells expressing GRPR was significantly related to the Gleason score. Both the percentage of area expressing GRPR and the number of cells expressing PSMA were close to reaching significance at the 0.05 level. MDS provided a map of the overall, independent association confirming that GRPR and PSMA represent inversely correlated measures of the same dimension. In conclusion, our data showed that GRPR expression should be evaluated in prostate biopsy specimens to improve our ability to detect PC with low grades at the earliest phases of development. Considering that GRPRs appear to be directly involved in the mechanisms of tumor proliferation, advancements in nuclear medicine radiotherapy can focus on this receptor to improve the therapeutic approach to PC. Further studies in our laboratory will investigate the molecular mechanisms of activation based on GRPR.
Angiotensin Receptor Blockers for COVID-19: Pathophysiological and Pharmacological Considerations About Ongoing and Future Prospective Clinical Trials
Authors: Rothlin Rodolfo Pedro , Duarte Mariano , Pelorosso Facundo Germán , Nicolosi Liliana , Salgado M. Victoria , Vetulli Héctor Miguel , Spitzer Eduardo
Published: March 2021

COVID-19 pandemic demands a swift response to find therapeutic tools that effectively reduce morbidity and mortality. Despite initial fears, evidence from retrospective observational studies supports the inhibition of the renin-angiotensin system as an emerging pathway to delay or moderate angiotensin II-driven lung inflammation. This has triggered several prospective clinical trials. In this commentary we provide an overview and analysis of current ongoing clinical trials aimed at evaluating the therapeutic efficacy of angiotensin receptor blocker (ARB) use in COVID-19. The relevance of the results of these trials will have to be interpreted depending on the stage and severity of the disease and in light of the start time of their prescription related to the time of diagnosis of COVID-19 as well as the administered doses.
Jasmonates Alleviate the Harm of High-Temperature Stress During Anthesis to Stigma Vitality of Photothermosensitive Genetic Male Sterile Rice Lines
Authors: Chen Jing , Miao Wenqian , Fei Keqi , Shen Hongli , Zhou Yujiao , Shen Yan , Li Chaoqing , He Jiang , Zhu Kuanyu , Wang Zhiqin , Yang Jianchang
Published: March 2021

Using photothermosensitive genic male sterile (PTSGMS) rice (Oryza sativa L.) lines to produce hybrids can obtain great heterosis. However, PTSGMS rice lines exhibit low stigma vitality when high-temperature (HT) stress happens during anthesis. Jasmonates (JAs) are novel phytohormones and play vital roles in mediating biotic and abiotic stresses. Little is known, however, if and how JAs could alleviate the harm of HT stress during anthesis to the stigma vitality of PTSGMS lines. This study investigated the question. Two PTSGMS lines and one restorer line of rice were pot-grown and subjected to normal temperature and HT stress during anthesis. The stigma exertion rate, sigma fresh weight, stigma area, contents of JAs, hydrogen peroxide (H2O2), and ascorbic acid (AsA), activity of catalase in stigmas, and the number of pollens germinated on the stigma of PTSGMS lines were determined. The results showed that a rice line with higher JAs content in the stigma under HT stress showed lower H2O2 content, higher AsA content and catalase activity in stigmas, larger stigma area, heavier stigma fresh weight, more pollens germinated on the stigma, and higher fertilization and seed-setting and rates. Applying methyl JAs during anthesis to rice panicles decreased the accumulation of reactive oxygen species and enhanced stigma vitality, thereby increasing fertilization and seed-setting rates of the hybrids of PTSGMS rice lines under HT stress. The results demonstrate that JAs attenuate the injury of HT stress to the stigma vitality of PTSGMS rice lines through enhancing antioxidant ability.
The WtmsDW Locus on Wheat Chromosome 2B Controls Major Natural Variation for Floret Sterility Responses to Heat Stress at Booting Stage
Authors: Erena Million F. , Lohraseb Iman , Munoz-Santa Isabel , Taylor Julian D. , Emebiri Livinus C. , Collins Nicholas C.
Published: March 2021

Heat stress at booting stage causes significant losses to floret fertility (grain set) and hence yield in wheat (Triticum aestivum L.); however, there is a lack of well-characterized sources of tolerance to this type of stress. Here, we describe the genetic analysis of booting stage heat tolerance in a cross between the Australian cultivars Drysdale (intolerant) and Waagan (tolerant), leading to the definition of a major-effect tolerance locus on the short arm of chromosome 2B, Wheat thermosensitive male sterile Drysdale/Waagan (WtmsDW). WtmsDW offsets between 44 and 65% of the losses in grain set due to heat, suggesting that it offers significant value for marker-assisted tolerance breeding. In lines lacking the WtmsDW tolerance allele, peaks in sensitivity were defined with reference to auricle distance, for various floret positions along the spike. Other (relatively minor) floret fertility response effects, including at the Rht-D1 dwarfing locus, were considered likely escape artifacts, due to their association with height and flowering time effects that might interfere with correct staging of stems for heat treatment. Heat stress increased grain set at distal floret positions in spikelets located at the top of the spike and increased the size of spikelets at the base of the spike, but these effects were offset by greater reductions in grain set at other floret positions. Potentially orthologous loci on chromosomes 1A and 1B were identified for heat response of flowering time. The potential significance of these findings for tolerance breeding and further tolerance screening is discussed.