bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria–ER Contacts: A Cancer Perspective
Authors: Amodio Giuseppina , Pagliara Valentina , Moltedo Ornella , Remondelli Paolo
Published: March 2021

In the last decades, the endoplasmic reticulum (ER) has emerged as a key coordinator of cellular homeostasis, thanks to its physical interconnection to almost all intracellular organelles. In particular, an intense and mutual crosstalk between the ER and mitochondria occurs at the mitochondria–ER contacts (MERCs). MERCs ensure a fine-tuned regulation of fundamental cellular processes, involving cell fate decision, mitochondria dynamics, metabolism, and proteostasis, which plays a pivotal role in the tumorigenesis and therapeutic response of cancer cells. Intriguingly, recent studies have shown that different components of the unfolded protein response (UPR) machinery, including PERK, IRE1α, and ER chaperones, localize at MERCs. These proteins appear to exhibit multifaceted roles that expand beyond protein folding and UPR transduction and are often related to the control of calcium fluxes to the mitochondria, thus acquiring relevance to cell survival and death. In this review, we highlight the novel functions played by PERK, IRE1α, and ER chaperones at MERCs focusing on their impact on tumor development.
Biological Significance of NOTCH Signaling Strength
Authors: Shen Wei , Huang Jiaxin , Wang Yan
Published: March 2021

The evolutionarily conserved NOTCH signaling displays pleotropic functions in almost every organ system with a simple signaling axis. Different from many other signaling pathways that can be amplified via kinase cascades, NOTCH signaling does not contain any intermediate to amplify signal. Thus, NOTCH signaling can be activated at distinct signaling strength levels, disruption of which leads to various developmental disorders. Here, we reviewed mechanisms establishing different NOTCH signaling strengths, developmental processes sensitive to NOTCH signaling strength perturbation, and transcriptional regulations influenced by NOTCH signaling strength changes. We hope this could add a new layer of diversity to explain the pleotropic functions of NOTCH signaling pathway.
Supramolecular Copolymerization of Bichromophoric Chiral and Achiral Perylenediimide Dyes
Authors: Yonezawa Shumpei , Kawai Tsuyoshi , Nakashima Takuya
Published: March 2021

Propagation and amplification of chirality are considered to play an important role in the chemical evolution of biological homochirality. Stereochemical communications have been demonstrated to have a significant effect on the formation of chiral hierarchical structures in helical polymers, surface assemblies and supramolecular polymers. The formation of supramolecular copolymers based on chiral and achiral bichromophoric perylenediimide (PDI) dyes having a binaphtyl- and biphenyl-core-bridging unit, respectively, was investigated in terms of chiral amplification and propagation. The biphenyl-bridged PDI dye was expected to perform as a prochiral component to adopt both right- and left-handed twisting structures with the free rotation over the phenyl-phenyl linkage upon partnered with the chiral binaphtly PDI dye in the coassemblies. The coassemblies between the chiral and achiral PDI dyes with dissimilar core units demonstrated the composition dependent control in the length of supramolecular nanofibers as well as amplification of optical activity.
Identifying Drivers Behind Spatial Variability of Methane Concentrations in East Siberian Ponds
Authors: Rehder Zoé , Zaplavnova Anna , Kutzbach Lars
Published: March 2021

Waterbody methane emissions per area are negatively correlated with the size of the emitting waterbody. Thus, ponds, defined here as having an area smaller than 8 · 104m2, contribute out of proportion to the aquatic methane budget compared to the total area they cover and compared to other waterbodies. However, methane concentrations in and methane emissions from ponds show more spatial variability than larger waterbodies. We need to better understand this variability to improve upscaling estimates of freshwater methane emissions. In this regard, the Arctic permafrost landscape is an important region, which, besides carbon-rich soils, features a high pond density and is exposed to above-average climatic warming. We studied 41 polygonal-tundra ponds in the Lena River Delta, northeast Siberia. We collected water samples at different locations and depths in each pond and determined methane concentrations using gas chromatography. Additionally, we collected information on the key properties of the ponds to identify drivers of surface water methane concentrations. The ponds can be categorized into three geomorphological types with distinct differences in drivers of methane concentrations: polygonal-center ponds, ice-wedge ponds and larger merged polygonal ponds. All ponds are supersaturated in methane, but ice-wedge ponds exhibit the highest surface water concentrations. We find that ice-wedge ponds feature a strong stratification due to consistently low bottom temperatures. This causes surface concentrations to mainly depend on wind speed and on the amount of methane that has accumulated in the hypolimnion. In polygonal-center ponds, high methane surface concentrations are mostly determined by a small water depth. Apart from the influence of water depth on mixing speed, water depth controls the overgrown fraction, the fraction of the pond covered by vascular plants. The plants provide labile substrate to the methane-producing microbes. This link can also be seen in merged polygonal ponds, which furthermore show the strongest dependence on area as well as an anticorrelation to energy input indicating that stratification influences the surface water methane concentrations in larger ponds. Overall, our findings underpin the strong variability of methane concentrations in ponds. No single driver could explain a significant part of the variability over all pond types suggesting that more complex upscaling methods such as process-based modeling are needed.
Seismicity of the Northern Volcanic Zone of Iceland
Authors: Einarsson Páll , Brandsdóttir Bryndís
Published: March 2021

A half century of monitoring of the Northern Volcanic Zone of Iceland, a branch of the North America—Eurasia plate boundary, shows that the seismicity is very unevenly distributed, both in time and space. The four central volcanoes at the boundary, Þeistareykir, Krafla, Fremrinámar, and Askja, show persistent but very low-level seismicity, spatially coinciding with their high-temperature geothermal systems. On their rift structures, on the other hand, seismicity is almost absent, except during rifting episodes. Krafla went through a rifting episode in 1975–1984 with inflation, interrupted by 20 diking events with extensive rifting, eruptive activity, and intense seismicity along an 80 km long section of the rift. During inflation periods, the seismicity was contained within the caldera of the volcano, reflecting the inflation level of the magma chamber. Diking events were marked by seismicity propagating away from the volcano into the fissure swarms to the south or north of the volcano, accompanied by rapid deflation of the caldera magma chamber. These events lasted from 1 day to 3 months, and the dike length varied between 1 and 60 km. The area around the Askja volcano is the only section of the Northern Volcanic Zone that shows persistent moderate seismicity. The largest events are located between fissure swarms of adjacent volcanic systems. Detailed relative locations of hypocenters reveal a system of vertical strike-slip faults, forming a conjugate system consistent with minimum principal stress in the direction of spreading across the plate boundary. A diking event into the lower crust was identified in the adjacent fissure swarm at Upptyppingar in 2007–2008. Four nests of anomalously deep earthquakes (10–34 km) have been identified in the Askja region, apparently associated with the movements of magma well below the brittle-ductile transition. Several processes have been pointed out as possible causes of earthquakes in the deformation zone around the plate boundary. These include inflation and deflation of central volcanoes, intrusion of propagating dikes, both laterally and vertically, strike-slip faulting on conjugate fault systems between overlapping fissure swarms, migration of magma in the lower, ductile crust, and geothermal heat mining.
Permafrost Carbon and CO2 Pathways Differ at Contrasting Coastal Erosion Sites in the Canadian Arctic
Authors: Tanski George , Bröder Lisa , Wagner Dirk , Knoblauch Christian , Lantuit Hugues , Beer Christian , Sachs Torsten , Fritz Michael , Tesi Tommaso , Koch Boris P. , Haghipour Negar , Eglinton Timothy I. , Strauss Jens , Vonk Jorien E.
Published: March 2021

Warming air and sea temperatures, longer open-water seasons and sea-level rise collectively promote the erosion of permafrost coasts in the Arctic, which profoundly impacts organic matter pathways. Although estimates on organic carbon (OC) fluxes from erosion exist for some parts of the Arctic, little is known about how much OC is transformed into greenhouse gases (GHGs). In this study we investigated two different coastal erosion scenarios on Qikiqtaruk – Herschel Island (Canada) and estimate the potential for GHG formation. We distinguished between adelayedrelease represented bymud debrisdraining a coastal thermoerosional feature and adirectrelease represented bycliff debrisat a low collapsing bluff. Carbon dioxide (CO2) production was measured during incubations at 4°C under aerobic conditions for two months and were modeled for four months and a full year. Our incubation results show thatmud debrisandcliff debrislost a considerable amount of OC as CO2(2.5 ± 0.2 and 1.6 ± 0.3% of OC, respectively). Although relative OC losses were highest in mineralmud debris, higher initial OC content and fresh organic matter incliff debrisresulted in a ∼three times higher cumulative CO2release (4.0 ± 0.9 compared to 1.4 ± 0.1 mg CO2gdw–1), which was further increased by the addition of seawater. After four months, modeled OC losses were 4.9 ± 0.1 and 3.2 ± 0.3% in set-ups without seawater and 14.3 ± 0.1 and 7.3 ± 0.8% in set-ups with seawater. The results indicate that adelayedrelease may support substantial cycling of OC at relatively low CO2production rates during long transit timesonshoreduring the Arctic warm season. By contrast,directerosion may result in a single CO2pulse and less substantial OC cyclingonshoreas transfer times are short. Once eroded sediments are deposited in thenearshore, highest OC losses can be expected. We conclude that the release of CO2from eroding permafrost coasts varies considerably between erosion types and residence timeonshore. We emphasize the importance of a more comprehensive understanding of OC degradation during the coastal erosion process to improve thawed carbon trajectories and models.
Spatial Heterogeneity of eDNA Transport Improves Stream Assessment of Threatened Salmon Presence, Abundance, and Location
Authors: Wood Zachary T. , Lacoursière-Roussel Anaïs , LeBlanc Francis , Trudel Marc , Kinnison Michael T. , Garry McBrine Colton , Pavey Scott A. , Gagné Nellie
Published: March 2021

The integration of environmental DNA (eDNA) within management strategies for lotic organisms requires translating eDNA detection and quantification data into inferences of the locations and abundances of target species. Understanding how eDNA is distributed in space and time within the complex environments of rivers and streams is a major factor in achieving this translation. Here we study bidimensional eDNA signals in streams to predict the position and abundance of Atlantic salmon (Salmo salar) juveniles. We use data from sentinel cages with a range of abundances (3–63 juveniles) that were deployed in three coastal streams in New Brunswick, Canada. We evaluate the spatial patterns of eDNA dispersal and determine the effect of discharge on the dilution rate of eDNA. Our results show that eDNA exhibits predictable plume dynamics downstream from sources, with eDNA being initially concentrated and transported in the midstream, but eventually accumulating in stream margins with time and distance. From these findings we developed a fish detection and distribution prediction model based on the eDNA ratio in midstream versus bankside sites for a variety of fish distribution scenarios. Finally, we advise that sampling midstream at every 400 m is sufficient to detect a single fish at low velocity, but sampling efforts need to be increased at higher water velocity (every 100 m in the systems surveyed in this study). Studying salmon eDNA spatio-temporal patterns in lotic environments is essential to developing strong quantitative population assessment models that successfully leverage eDNA as a tool to protect salmon populations.
Exploring the Imbalance of Periodontitis Immune System From the Cellular to Molecular Level
Authors: He Longfei , Liu Lijuan , Li Ti , Zhuang Deshu , Dai Jiayin , Wang Bo , Bi Liangjia
Published: March 2021

Periodontitis is a common chronic inflammatory disease of periodontal tissue, mostly concentrated in people over 30 years old. Statistics show that compared with foreign countries, the prevalence of periodontitis in China is as high as 40%, and the prevalence of periodontal disease is more than 90%, which must arouse our great attention. Diagnosis and treatment of periodontitis currently rely mainly on clinical criteria, and the exploration of the etiologic criteria is relatively lacking. We, therefore, have explored the pathogenesis of periodontitis from the perspective of immune imbalance. By predicting the fraction of 22 immune cells in periodontitis tissues and comparing them with normal tissues, we found that multiple immune cell infiltration in periodontitis tissues was inhibited and this feature can clearly distinguish periodontitis from normal tissues. Further, protein interaction network (PPI) and transcription regulation network have been constructed based on differentially expressed genes (DEGs) to explore the interaction function modules and regulation pathways. Three functional modules have been revealed and top TFs such as EGR1 and ETS1 have been shown to regulate the expression of periodontitis-related immune genes that play an important role in the formation of the immunosuppressive microenvironment. The classifier was also used to verify the reliability of periodontitis features obtained at the cellular and molecular levels. In conclusion, we have revealed the immune microenvironment and molecular characteristics of periodontitis, which will help to better understand the mechanism of periodontitis and its application in clinical diagnosis and treatment.
Predicting HIV-1 Protease Cleavage Sites With Positive-Unlabeled Learning
Authors: Li Zhenfeng , Hu Lun , Tang Zehai , Zhao Cheng
Published: March 2021

Understanding the substrate specificity of HIV-1 protease plays an essential role in the prevention of HIV infection. A variety of computational models have thus been developed to predict substrate sites that are cleaved by HIV-1 protease, but most of them normally follow a supervised learning scheme to build classifiers by considering experimentally verified cleavable sites as positive samples and unknown sites as negative samples. However, certain noisy can be contained in the negative set, as false negative samples are possibly existed. Hence, the performance of the classifiers is not as accurate as they could be due to the biased prediction results. In this work, unknown substrate sites are regarded as unlabeled samples instead of negative ones. We propose a novel positive-unlabeled learning algorithm, namely PU-HIV, for an effective prediction of HIV-1 protease cleavage sites. Features used by PU-HIV are encoded from different perspectives of substrate sequences, including amino acid identities, coevolutionary patterns and chemical properties. By adjusting the weights of errors generated by positive and unlabeled samples, a biased support vector machine classifier can be built to complete the prediction task. In comparison with state-of-the-art prediction models, benchmarking experiments using cross-validation and independent tests demonstrated the superior performance of PU-HIV in terms of AUC, PR-AUC, and F-measure. Thus, with PU-HIV, it is possible to identify previously unknown, but physiologically existed substrate sites that are able to be cleaved by HIV-1 protease, thus providing valuable insights into designing novel HIV-1 protease inhibitors for HIV treatment.
The Anti-Inflammatory Properties of Phytochemicals and Their Effects on Epigenetic Mechanisms Involved in TLR4/NF-κB-Mediated Inflammation
Authors: Saleh Haidy A. , Yousef Mohamed H. , Abdelnaser Anwar
Published: March 2021

Innate immune response induces positive inflammatory transducers and regulators in order to attack pathogens, while simultaneously negative signaling regulators are transcribed to maintain innate immune homeostasis and to avoid persistent inflammatory immune responses. The gene expression of many of these regulators is controlled by different epigenetic modifications. The remarkable impact of epigenetic changes in inducing or suppressing inflammatory signaling is being increasingly recognized. Several studies have highlighted the interplay of histone modification, DNA methylation, and post-transcriptional miRNA-mediated modifications in inflammatory diseases, and inflammation-mediated tumorigenesis. Targeting these epigenetic alterations affords the opportunity of attenuating different inflammatory dysregulations. In this regard, many studies have identified the significant anti-inflammatory properties of distinct naturally-derived phytochemicals, and revealed their regulatory capacity. In the current review, we demonstrate the signaling cascade during the immune response and the epigenetic modifications that take place during inflammation. Moreover, we also provide an updated overview of phytochemicals that target these mechanisms in macrophages and other experimental models, and go on to illustrate the effects of these phytochemicals in regulating epigenetic mechanisms and attenuating aberrant inflammation.
Histone Deacetylases in the Inflamed Intestinal Epithelium—Promises of New Therapeutic Strategies
Authors: Gerbeth Lorenz , Glauben Rainer
Published: March 2021

The intestinal epithelium is a complex, dynamic barrier that separates luminal contents from the immune compartment while mediating nutrient absorption and controlled passage of antigens to convey oral tolerance. A compromised epithelial barrier often leads to inflammation because immune cells in the lamina propria come into direct contact with luminal antigens. Defects in epithelial cell function were also shown to be involved in the etiology of inflammatory bowel diseases. These are severe, chronically relapsing inflammatory conditions of the gastrointestinal tract that also increase the risk of developing colorectal cancer. Despite major efforts of the scientific community, the precise causes and drivers of these conditions still remain largely obscured impeding the development of a permanent cure. Current therapeutic approaches mostly focus on alleviating symptoms by targeting immune cell signaling. The protein family of histone deacetylases (HDACs) has gained increasing attention over the last years, as HDAC inhibitors were shown to be potent tumor cell suppressors and also alleviate morbid inflammatory responses. Recent research continuously identifies new roles for specific HDACs suggesting that HDACs influence the cell signaling network from many different angles. This makes HDACs very interesting targets for therapeutic approaches but predicting effects after system manipulations can be difficult. In this review, we want to provide a comprehensive overview of current knowledge about the individual roles of HDACs in the intestinal epithelium to evaluate their therapeutic potential for inflammatory conditions of the gut.
Specialized Plant Growth Chamber Designs to Study Complex Rhizosphere Interactions
Authors: Yee Mon Oo , Kim Peter , Li Yifan , Singh Anup K. , Northen Trent R. , Chakraborty Romy
Published: March 2021

The rhizosphere is a dynamic ecosystem shaped by complex interactions between plant roots, soil, microbial communities and other micro- and macro-fauna. Although studied for decades, critical gaps exist in the study of plant roots, the rhizosphere microbiome and the soil system surrounding roots, partly due to the challenges associated with measuring and parsing these spatiotemporal interactions in complex heterogeneous systems such as soil. To overcome the challenges associated with in situ study of rhizosphere interactions, specialized plant growth chamber systems have been developed that mimic the natural growth environment. This review discusses the currently available lab-based systems ranging from widely known rhizotrons to other emerging devices designed to allow continuous monitoring and non-destructive sampling of the rhizosphere ecosystems in real-time throughout the developmental stages of a plant. We categorize them based on the major rhizosphere processes it addresses and identify their unique challenges as well as advantages. We find that while some design elements are shared among different systems (e.g., size exclusion membranes), most of the systems are bespoke and speaks to the intricacies and specialization involved in unraveling the details of rhizosphere processes. We also discuss what we describe as the next generation of growth chamber employing the latest technology as well as the current barriers they face. We conclude with a perspective on the current knowledge gaps in the rhizosphere which can be filled by innovative chamber designs.
Reliable 2D Phase Transitions for Low-Noise and Long-Life Memory Programming
Authors: Ding Keyuan , Li Tianci , Chen Bin , Rao Feng
Published: March 2021

Extending cycling endurance and suppressing programming noise of phase-change random-access memory (PCRAM) are the key challenges with respect to the development of nonvolatile working memory and high-accuracy neuromorphic computing devices. However, the large-scale atomic migration along electrical pulse direction in the unconstrained three-dimensional phase transitions of the phase-change materials (PCMs) induces big resistance fluctuations upon repeated programming and renders the classic PCRAM devices into premature failure with limited cycling endurance. Previous efforts of superlattice-like and superlattice PCM schemes cannot effectively resolve such issues. In this work, we demonstrated that, through fine-tuning the sputtering techniques, a phase-change heterostructure (PCH) of Sb2Te3/TiTe2 can be successfully constructed. In contrast to its superlattice-like counterpart with inferior crystal quality, the well-textured PCH architecture ensures the reliable (well-confined) two-dimensional phase transitions, promoting an ultralow-noise and long-life operation of the PCRAM devices. Our study thus provides a useful reference for better manufacturing the PCH architecture and further exploring the excellent device performances and other new physics.
Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration
Authors: Ernest James Phillips Thomas , Maguire Emily
Published: March 2021

Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identifiedviagenetic studies are expressed in microglia and are involved in phospholipid metabolism. One of these, the enzyme PLCγ2 that hydrolyzes the PIP species PI(4,5)P2, displays altered expression in AD and PD and is currently being investigated as a potential therapeutic target.Perhaps unsurprisingly, neurodegenerative conditions exhibiting PIP dyshomeostasis also tend to show alterations in aspects of microglial function regulated by these lipids. In particular, phosphoinositides regulate the activities of proteins and enzymes required for endocytosis, toll-like receptor signaling, purinergic signaling, chemotaxis, and migration, all of which are affected in a variety of neurodegenerative conditions. These functions are crucial to allow microglia to adequately survey the brain and respond appropriately to invading pathogens and other abnormalities, including misfolded proteins. AD and PD therapies are being developed to target many of the above pathways, and although not yet investigated, simultaneous PIP manipulation might enhance the beneficial effects observed. Currently, only limited therapeutics are available for dementia, and although these show some benefits for symptom severity and progression, they are far from curative. Given the importance of microglia and PIPs in dementia development, this review summarizes current research and asks whether we can exploit this information to design more targeted, or perhaps combined, dementia therapeutics. More work is needed to fully characterize the pathways discussed in this review, but given the strength of the current literature, insights in this area could be invaluable for the future of neurodegenerative disease research.
Case Report: Improvement Following Immunotherapy in an Individual With Seronegative Down Syndrome Disintegrative Disorder
Authors: Hart Sarah J. , Worley Gordon , Kishnani Priya S. , Van Mater Heather
Published: March 2021

Down syndrome disintegrative disorder (DSDD) is a condition of unknown etiology characterized by acute cognitive decline, catatonia, insomnia, and autistic features in individuals with Down syndrome. A prior report of four patients with DSDD suggested a potential autoimmune etiology based on the presence of autoantibodies and on successful treatment with immunotherapy that included intravenous immunoglobulin (IVIG). Herein, we present the case of an 8-year old girl who developed acute cognitive decline to a dementia-like state, insomnia, catatonia, and autistic features. In contrast to the four patients with DSDD above, she had no evidence of autoimmunity and presented at a younger age. Given the gravity of her acute deterioration and the exclusion of other etiologies, she was treated with immunotherapy presumptively. She responded with near complete resolution of symptoms, but demonstrated a pattern of mild decline as she approached each monthly dosing of IVIG and steroids, reversed by treatment. Mycophenolate mofetil (MMF) was therefore added, with stability throughout the month and the ability to taper off IVIG. After stopping IVIG, she had a mild recurrence of symptoms that again resolved with repeat IVIG followed by tapering off. Outcome was assessed at 2.5 years after presentation, at which time she was back to her premorbid condition, except for persistent tics off immunotherapy. This case supports the contention that patients with a rapid onset of severe symptoms consistent with DSDD, who have a thorough evaluation with the exclusion of other etiologies, may warrant a trial of immunotherapy with steroids, IVIG and/or other agents like MMF even in the absence of evidence of autoimmunity on standard evaluation.
BPPV Simulation: A Powerful Tool to Understand and Optimize the Diagnostics and Treatment of all Possible Variants of BPPV
Authors: Bhandari Anita , Kingma Herman , Bhandari Rajneesh
Published: March 2021

BPPV is a mechanical disorder caused by the displacement of otolith debris into the semicircular canals. The treatment involves different repositioning maneuvers to bring the debris back into the utricle. This study aims to show how dynamic simulation models based on fluid dynamics and MRI, can help to visualize and understand the movement of the debris within the canals during head movement in 3D as a function of time. The user can define the rotation angle and plane at each step of the maneuver and then the model visualizes the canal and the otoconial movement in 3D. The simulation developed also allows alteration of various parameters like the rotational head acceleration, the duration of each step of the maneuver, the initial position of the otoconial debris in the canal, the size and the number of the particles and fluid dynamics of endolymph. The clod movement is visualized in such a way that it allows a better understanding of the impact and efficacy of various liberation maneuvers and why certain maneuvers might fail when not applied properly in the clinic. The model allows simulation of multi-canal BPPV. In this paper we demonstrate the power of the model applied on the maneuvers of Semont and Yacovino when executed in different ways. The model aims to provide a visual explanation for the need of specific maneuvers for each type of BPPV. The simulator presented here can be used to test the efficacy of existing maneuvers and help in the development of new maneuvers to treat different BPPV variants.
CXCL13 and CXCL9 CSF Levels in Central Nervous System Lymphoma—Diagnostic, Therapeutic, and Prognostic Relevance
Authors: Masouris Ilias , Manz Kirsi , Pfirrmann Markus , Dreyling Martin , Angele Barbara , Straube Andreas , Langer Sigrid , Huber Marion , Koedel Uwe , Von Baumgarten Louisa
Published: March 2021

Background: Diagnostic delay and neurologic deterioration are still a problem for the treatment of rapidly progressing CNS lymphoma (CNSL); there is an unmet need for a diagnostic test with a high diagnostic yield and limited risk, minimizing the time to the initiation of effective treatment.

Methods: In this prospective monocentric study, we analyzed the utility of CXCL13 and CXCL9 as diagnostic, therapeutic and prognostic biomarkers for CNSL. Cerebrospinal fluid (CSF) from 155 consecutive patients admitted with brain lesions of various origins was collected. Levels of CXCL13 and CXCL9 were analyzed by ELISA. Additionally, CSF was analyzed during CNSL disease course (relapse, remission, progress) in 17 patients.

Results: CXCL13 and CXCL9 CSF levels were significantly increased in patients with CNSL compared to control patients with lesions of other origin. Using logistic regression and a minimal-p-value approach, a cut-off value of 80 pg/ml for CXCL13 shows high sensitivity (90.7%) and specificity (90.1%) for the diagnosis of active CNSL. CXCL9 at a cut-off value of 84 pg/ml is less sensitive (61.5%) and specific (87.1%). Both cytokines correlate with the clinical course and response to therapy.

Conclusions: Our results confirm the excellent diagnostic potential of CXCL13 and introduce CXCL9 as a novel albeit less powerful marker for PCNSL.
Nitric Oxide in the Spinal Cord Is Involved in the Hyperalgesia Induced by Tetrahydrobiopterin in Chronic Restraint Stress Rats
Authors: Huang Ying , Jiao Bo , Zhu Bo , Xiong Bingrui , Lu Pei , Ai Ling , Yang Ning , Zhao Yilin , Xu Hui
Published: March 2021

It has been well recognized that exposure to chronic stress could increase pain responding and exacerbate pain symptoms, resulting in stress-induced hyperalgesia. However, the mechanisms underlying stress-induced hyperalgesia are not yet fully elucidated. To this end, we observed that restraint as a stressful event exacerbated mechanical and thermal hyperalgesia, accompanied with up-regulation of nitric oxide (NO) (P < 0.001), GTP cyclohydrolase 1 (GCH1) (GCH1 mRNA: P = 0.001; GCH1 protein: P = 0.001), and tetrahydrobiopterin (BH4) concentration (plasma BH4: P < 0.001; spinal BH4: P < 0.001) on Day 7 in restraint stress (RS) rats. Intrathecal injection of Nω-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase inhibitor, or N-([3-(aminomethyl)phenyl]methyl) ethanimidamide, a special inhibitor of inducible NO synthase (iNOS), for seven consecutive days attenuated stress-induced hyperalgesia and decreased the production of NO (P < 0.001). Interestingly, 7-nitro indazole, a special inhibitor of neuronal NO synthase, alleviated stress-induced hyperalgesia but did not affect spinal NO synthesis. Furthermore, intrathecal injection of BH4 not only aggravated stress-induced hyperalgesia but also up-regulated the expression of spinal iNOS (iNOS mRNA: P = 0.015; iNOS protein: P < 0.001) and NO production (P < 0.001). These findings suggest that hyperalgesia induced by RS is associated with the modulation of the GCH1–BH4 system and constitutively expressed spinal iNOS. Thus, the GCH1–BH4–iNOS signaling pathway may be a new novel therapeutic target for pain relief in the spinal cord.
Defining Surgical Terminology and Risk for Brain Computer Interface Technologies
Authors: Leuthardt Eric C. , Moran Daniel W. , Mullen Tim R.
Published: March 2021

With the emergence of numerous brain computer interfaces (BCI), their form factors, and clinical applications the terminology to describe their clinical deployment and the associated risk has been vague. The terms “minimally invasive” or “non-invasive” have been commonly used, but the risk can vary widely based on the form factor and anatomic location. Thus, taken together, there needs to be a terminology that best accommodates the surgical footprint of a BCI and their attendant risks. This work presents a semantic framework that describes the BCI from a procedural standpoint and its attendant clinical risk profile. We propose extending the common invasive/non-invasive distinction for BCI systems to accommodate three categories in which the BCI anatomically interfaces with the patient and whether or not a surgical procedure is required for deployment: (1)Non-invasive—BCI components do not penetrate the body, (2)Embedded—components are penetrative, but not deeper than the inner table of the skull, and (3)Intracranial–components are located within the inner table of the skull and possibly within the brain volume. Each class has a separate risk profile that should be considered when being applied to a given clinical population. Optimally, balancing this risk profile with clinical need provides the most ethical deployment of these emerging classes of devices. As BCIs gain larger adoption, and terminology becomes standardized, having an improved, more precise language will better serve clinicians, patients, and consumers in discussing these technologies, particularly within the context of surgical procedures.
Comparative Effects of Event Detection Methods on the Analysis and Interpretation of Ca2+ Imaging Data
Authors: Neugornet Austin , O’Donovan Bernadette , Ortinski Pavel Ivanovich
Published: March 2021

Calcium imaging has gained substantial popularity as a tool to profile the activity of multiple simultaneously active cells at high spatiotemporal resolution. Among the diverse approaches to processing of Ca2+ imaging data is an often subjective decision of how to quantify baseline fluorescence or F0. We examine the effect of popular F0 determination methods on the interpretation of neuronal and astrocyte activity in a single dataset of rats trained to self-administer intravenous infusions of cocaine and compare them with an F0-independent wavelet ridgewalking event detection approach. We find that the choice of the processing method has a profound impact on the interpretation of widefield imaging results. All of the dF/F0 thresholding methods tended to introduce spurious events and fragment individual transients, leading to smaller calculated event durations and larger event frequencies. Analysis of simulated datasets confirmed these observations and indicated substantial intermethod variability as to the events classified as significant. Additionally, most dF/F0 methods on their own were unable to adequately account for bleaching of fluorescence, although the F0 smooth approach and the wavelet ridgewalking algorithm both did so. In general, the choice of the processing method led to dramatically different quantitative and sometimes opposing qualitative interpretations of the effects of cocaine self-administration both at the level of individual cells and at the level of cell networks. Significantly different distributions of event duration, amplitude, frequency, and network measures were found across the majority of dF/F0 approaches. The wavelet ridgewalking algorithm broadly outperformed dF/F0-based methods for both neuron and astrocyte recordings. These results indicate the need for heightened awareness of the limitations and tendencies associated with decisions to use particular Ca2+ image processing pipelines. Both quantification and interpretation of the effects of experimental manipulations are strongly sensitive to such decisions.
Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior
Authors: Oliveira Tadeu P. D. , Gonçalves Bruno D. C. , Oliveira Bruna S. , de Oliveira Antonio Carlos P. , Reis Helton J. , Ferreira Claudia N. , Aguiar Daniele C. , de Miranda Aline S. , Ribeiro Fabiola M. , Vieira Erica M. L. , Palotás András , Vieira Luciene B.
Published: March 2021

Graphical Abstract

Diet-induced obese (DIO) C57BL/6 mice were treated for 14 days with VU0409106, a negative allosteric modulator of mGluR5. Food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in DIO mice after chronic treatment with VU0409106.
Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior
Authors: Eckert Philipp , Marchetta Philine , Manthey Marie K. , Walter Michael H. , Jovanovic Sasa , Savitska Daria , Singer Wibke , Jacob Michele H. , Rüttiger Lukas , Schimmang Thomas , Milenkovic Ivan , Pilz Peter K. D. , Knipper Marlies
Published: March 2021

Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants ofBdnfPax2KOs causes severe cognitive disabilities. InBdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here:Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearingBdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.
Review of Analytical Methods and Reporting of the Polyphenol Content of Tart Cherry Supplements in Human Supplementation Studies Investigating Health and Exercise Performance Effects: Recommendations for Good Practice
Authors: Sabou Vlad R. , O'Leary Mary F. , Liu Ying , Brown Paula N. , Murch Susan , Bowtell Joanna L.
Published: March 2021

Tart cherries (TC) are a rich source of polyphenols that elicit antioxidant and anti-inflammatory effects. As a consequence, the effects of TC derived supplements on markers of human health, exercise performance and sleep have been investigated. Supplementation protocols have been highly variable across studies and the dose of bioactive compounds used has often been poorly characterized. Specific and non-specific analytical methods were employed for measuring the total polyphenol and anthocyanin content in TC supplements. This review critically analyses the supplementation protocols and the analytical methods used for the characterization of TC supplements, culminating in recommendations for good practice in the analysis and reporting of the polyphenol content and profile of TC products. A literature search was conducted using PubMed/Medline and Web of Science up to May 4th, 2020, including studies published in all years prior. Only articles written in English that provided a TC dietary supplement as opposed to fresh whole TC were included in this review. Forty-three studies were identified as eligible and included for analysis in this review. The studies investigated the effects of TC supplementation on various aspects of human health, exercise recovery and performance and sleep. Twenty studies conducted an analysis of TC supplement and reported total polyphenol/anthocyanin content. Six studies did not report the polyphenol content of the TC supplement used. Seventeen studies reported the TC supplement polyphenol content but this was derived from previously published studies and presumably different supplement batches. The duration of the supplementation protocol ranged from acute supplementation to 84 days, meanwhile the total polyphenol and anthocyanin dose ranged from 143 to 2,140 mg/day and 15 to 547 mg/day, respectively. Due to the variety of specific and non-specific analytical methods used, the relative efficacy of different doses and polyphenol blends cannot reliably be extrapolated from critical analysis of the literature. Future studies should conduct an analysis of the study supplement batch. In addition to analysis and reporting of total polyphenol content, specific analytical methods such as HPLC UV/MS should be used to quantify total and individual anthocyanin contents.
Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers
Authors: Liu Ling , Feng Jinghua , Polimeni Julian , Zhang Manli , Nguyen Hai , Das Urmi , Zhang Xu , Singh Harminder , Yao Xiao-Jian , Leygue Etienne , Kung Sam K. P. , Xie Jiuyong
Published: March 2021

Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination.
Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma
Authors: Fan Zhongru , Zhang Zhe , Piao Chiyuan , Liu Zhuona , Wang Zeshu , Kong Chuize
Published: March 2021

Background

Alternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level.

Methods

We adopted a gap analysis to screen for significant differential AS events (DASEs) associated with BLCA. DASEs with prognostic value for OS and the disease-free interval (DFI) were identified by Cox analysis. In addition, a differential AS network and AS clusters were identified using unsupervised cluster analysis. We examined differences in the sensitivity to chemotherapy and immunotherapy between BLCA patients with high and low overall survival (OS) risk.

Results

An extensive number of DASEs (296) were found to be clinically relevant in BLCA. A prognosis model was established based prognostic value of OS and DFI. CUGBP elav-like family member 2 (CELF2) was identified as a hub splicing factor for AS networks. We also identified AS clusters associated with OS using unsupervised cluster analysis, and we predicted that the effects of cisplatin and gemcitabine chemotherapy would be different between high- and low-risk groups based on OS prognosis.

Conclusion

We completed a comprehensive analysis of AS events in BLCA at the genome-wide level. The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.