bluuebunny/crossref_metadata_2025 huggingface dataset:
Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome—Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network
Authors: Vitale Antonio , Obici Laura , Cattalini Marco , Lopalco Giuseppe , Merlini Giampaolo , Ricco Nicola , Soriano Alessandra , La Torre Francesco , Verrecchia Elena , Insalaco Antonella , Dagna Lorenzo , Jaber Masen Abdel , Montin Davide , Emmi Giacomo , Ciarcia Luisa , Barneschi Sara , Parronchi Paola , Ruscitti Piero , Maggio Maria Cristina , Viapiana Ombretta , Sota Jurgen , Gaggiano Carla , Giacomelli Roberto , Sicignano Ludovico Luca , Manna Raffaele , Renieri Alessandra , Lo Rizzo Caterina , Frediani Bruno , Rigante Donato , Cantarini Luca
Published: July 2021

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response.

Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers.

Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001–0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301–0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed.

Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.
Response of Root-Associated Bacterial Communities to Different Degrees of Soft Rot Damage in Amorphophallus konjac Under a Robinia pseudoacacia Plantation
Authors: He Fei
Published: July 2021

Bacterial soft rot is a destructive disease that restricts the development of the konjac (Amorphophallus konjacK. Koch ex N.E.Br) industry. The objective of this study was to investigate how soft rot disease affects bacterial communities associated with the roots of konjac plants growing under a pureRobinia pseudoacaciaplantation. Three sampling sites affected by different degrees of soft rot damage were selected based on the disease incidence [0%, non-diseased (ND); 4.2%, moderately diseased (MD); and 18.6%, highly diseased (HD)]. The variation in soil and root bacterial diversity and community composition among the sampling sites was determined by Illumina HiSeq sequencing of the V3–V4 hypervariable regions of the bacterial 16S rRNA gene. The results showed that the contents of soil organic matter and available nutrients (N, P, and K) increased with increasing damage degree, whereas higher damage degree resulted in lower soil pH and enzymatic activity (sucrase, urease, catalase, and polyphenol oxidase). The composition of root-associated bacterial communities differed among the three sampling sites. Proteobacteria was the most dominant bacterial phylum in all soil and root samples.Pseudomonas,Bacillus,Rhizobium, andStreptomyceswere the most abundant in all samples from the ND sites, whereasPectobacterium carotovorumandSerratiawere predominant in the samples from the MD and HD sites. The abundance and alpha diversity of root-associated bacteria were significantly higher (p< 0.05) in the ND sites than in the diseased sites. The results suggested pronounced differences in the abundance, alpha diversity, and community composition of bacteria associated with the roots of konjac plants affected by different degrees of soft rot damage. Such differences in bacterial community structure were related to dynamic changes in soil variables, especially soil available potassium content, sucrase activity, and urease activity. Analysis of the dominant root-associated bacterial taxa offers an approach to predict the damage degree due to soft rot in konjac and provides evidence for the prevention of this soil-borne disease via microecological regulation.
Disentangling the Complexity of the Rumen Microbial Diversity Through Fractionation Using a Sucrose Density Gradient
Authors: Hernández Ruth , Jimenez Hugo , Vargas-Garcia Cesar , Caro-Quintero Alejandro , Reyes Alejandro
Published: July 2021

The ruminal microbial community is an important element in health, nutrition, livestock productivity, and climate impact. Despite the historic and current efforts to characterize this microbial diversity, many of its members remain unidentified, making it challenging to associate microbial groups with functions. Here we present a low-cost methodology for rumen sample treatment that separates the microbial community based on cell size, allowing for the identification of subtle compositional changes. In brief, the sample is centrifuged through a series of sucrose density gradients, and cells migrate to their corresponding density fraction. From each fraction, DNA is extracted and 16S rRNA gene amplicons are sequenced. We tested our methodology on four animals under two different conditions, fasting, and post-feeding. Each fraction was examined by confocal microscopy showing that the same sucrose fraction consistently separated similar cell-sized microorganisms independent of the animal or treatment. Microbial composition analysis using metabarcoding showed that our methodology detected low abundance bacterial families and population changes between fasting and post-feeding treatments that could not be observed by bulk DNA analysis. In conclusion, the sucrose-based method is a powerful low-cost approximation to untwine, enrich, and potentially isolate uncharacterized members of the ruminal microbiome.
CRISPR-Based Isothermal Next-Generation Diagnostic Method for Virus Detection in Sugarbeet
Authors: Ramachandran Vanitharani , Weiland John J. , Bolton Melvin D.
Published: July 2021

Rhizomania is a disease of sugarbeet caused by beet necrotic yellow vein virus (BNYVV) that significantly affects sugarbeet yield globally. Accurate and sensitive detection methods for BNYVV in plants and field soil are necessary for growers to make informed decisions on variety selection to manage this disease. A recently developed CRISPR-Cas-based detection method has proven highly sensitive and accurate in human virus diagnostics. Here, we report the development of a CRISPR-Cas12a-based method for detecting BNYVV in the roots of sugarbeet. A critical aspect of this technique is the identification of conditions for isothermal amplification of viral fragments. Toward this end, we have developed a reverse transcription (RT) recombinase polymerase amplification (RPA) for detecting BNYVV in sugarbeet roots. The RT-RPA product was visualized, and its sequence was confirmed. Subsequently, we designed and validated the cutting efficiency of guide RNA targeting BNYVV via in vitro activity assay in the presence of Cas12a. The sensitivity of CRISPR-Cas12a trans reporter-based detection for BNYVV was determined using a serially diluted synthetic BNYVV target sequence. Further, we have validated the developed CRISPR-Cas12a assay for detecting BNYVV in the root-tissue of sugarbeet bait plants reared in BNYVV-infested field soil. The results revealed that BNYVV detection is highly sensitive and specific to the infected roots relative to healthy control roots as measured quantitatively through the reporter signal. To our knowledge, this is the first report establishing isothermal RT-RPA- and CRISPR-based methods for virus diagnostic approaches for detecting BNYVV from rhizomania diseased sugarbeet roots.
Diverse ATPase Proteins in Mobilomes Constitute a Large Potential Sink for Prokaryotic Host ATP
Authors: Shim Hyunjin , Shivram Haridha , Lei Shufei , Doudna Jennifer A. , Banfield Jillian F.
Published: July 2021

Prokaryote mobilome genomes rely on host machineries for survival and replication. Given that mobile genetic elements (MGEs) derive their energy from host cells, we investigated the diversity of ATP-utilizing proteins in MGE genomes to determine whether they might be associated with proteins that could suppress related host proteins that consume energy. A comprehensive search of 353 huge phage genomes revealed that up to 9% of the proteins have ATPase domains. For example, ATPase proteins constitute ∼3% of the genomes of Lak phages with ∼550 kbp genomes that occur in the microbiomes of humans and other animals. Statistical analysis shows the number of ATPase proteins increases linearly with genome length, consistent with a large sink for host ATP during replication of megaphages. Using metagenomic data from diverse environments, we found 505 mobilome proteins with ATPase domains fused to diverse functional domains. Among these composite ATPase proteins, 61.6% have known functional domains that could contribute to host energy diversion during the mobilome infection cycle. As many have domains that are known to interact with nucleic acids and proteins, we infer that numerous ATPase proteins are used during replication and for protection from host immune systems. We found a set of uncharacterized ATPase proteins with nuclease and protease activities, displaying unique domain architectures that are energy intensive based on the presence of multiple ATPase domains. In many cases, these composite ATPase proteins genomically co-localize with small proteins in genomic contexts that are reminiscent of toxin-antitoxin systems and phage helicase-antibacterial helicase systems. Small proteins that function as inhibitors may be a common strategy for control of cellular processes, thus could inspire future biochemical experiments for the development of new nucleic acid and protein manipulation tools, with diverse biotechnological applications.
PsGRASP, a Golgi Reassembly Stacking Protein in Phytophthora sojae, Is Required for Mycelial Growth, Stress Responses, and Plant Infection
Authors: Si Jierui , Pei Yong , Ji Peiyun , Zhang Xiong , Xu Ruofei , Qiao Huijun , Shen Danyu , Peng Hao , Dou Daolong
Published: July 2021

Golgi reassembly stacking proteins (GRASPs) play important roles in Golgi structure formation, ER stress response, and unconventional secretion in eukaryotic cells. However, GRASP functions in oomycetes haven’t been adequately characterized. Here, we report the identification and functional analysis of PsGRASP, a GRASP-encoding gene from the soybean-infecting oomycete Phytophthora sojae. Transcriptional profiling showed that PsGRASP expression is up-regulated at the infection stages. PsGRASP knockout mutants were created using the CRISPR/Cas9 system. These mutants exhibited impaired vegetative growth, zoospore release and virulence. PsGRASP was involved ER stress responses and altered laccase activity. Our work suggests that PsGRASP is crucial for P. sojae development and pathogenicity.
A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity
Authors: Hopkins Eleanor L. , Gu Weixi , Kobe Bostjan , Coleman Michael P.
Published: July 2021

Axon degeneration represents a pathological feature of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease where axons die before the neuronal soma, and axonopathies, such as Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Over the last two decades, it has slowly emerged that a central signaling pathway forms the basis of this process in many circumstances. This is an axonal NAD-related signaling mechanism mainly regulated by the two key proteins with opposing roles: the NAD-synthesizing enzyme NMNAT2, and SARM1, a protein with NADase and related activities. The crosstalk between the axon survival factor NMNAT2 and pro-degenerative factor SARM1 has been extensively characterized and plays an essential role in maintaining the axon integrity. This pathway can be activated in necroptosis and in genetic, toxic or metabolic disorders, physical injury and neuroinflammation, all leading to axon pathology. SARM1 is also known to be involved in regulating innate immunity, potentially linking axon degeneration to the response to pathogens and intercellular signaling. Understanding this NAD-related signaling mechanism enhances our understanding of the process of axon degeneration and enables a path to the development of drugs for a wide range of neurodegenerative diseases.
Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification
Authors: Osaka Natsuki , Hirota Yoshihisa , Ito Doshun , Ikeda Yoshiki , Kamata Ryo , Fujii Yuki , Chirasani Venkat R. , Campbell Sharon L. , Takeuchi Koh , Senda Toshiya , Sasaki Atsuo T.
Published: July 2021

RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) accelerate GTP loading and hydrolysis, respectively. These accessory proteins play a fundamental role in regulating activities of RAS superfamily small GTPase via a conserved guanine binding (G)-domain, which consists of five G motifs. The Switch regions lie within or proximal to the G2 and G3 motifs, and undergo dynamic conformational changes between the GDP-bound “OFF” state and GTP-bound “ON” state. They play an important role in the recognition of regulatory factors (GEFs and GAPs) and effectors. The G4 and G5 motifs are the focus of the present work and lie outside Switch regions. These motifs are responsible for the recognition of the guanine moiety in GTP and GDP, and contain residues that undergo post-translational modifications that underlie new mechanisms of RAS regulation. Post-translational modification within the G4 and G5 motifs activates RAS by populating the GTP-bound “ON” state, either through enhancement of intrinsic guanine nucleotide exchange or impairing GAP-mediated down-regulation. Here, we provide a comprehensive review of post-translational modifications in the RAS G4 and G5 motifs, and describe the role of these modifications in RAS activation as well as potential applications for cancer therapy.
The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases
Authors: Yang Chen , Qi Yan , Sun Zhitang
Published: July 2021

The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.
The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies
Authors: Takeuchi Yuichi , Nagy Anett J. , Barcsai Lívia , Li Qun , Ohsawa Masahiro , Mizuseki Kenji , Berényi Antal
Published: July 2021

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer’s disease, anxiety/fear, schizophrenia, and depression, as well as pain.
Longitudinal Study of Cognitive and Emotional Alterations in Amyotrophic Lateral Sclerosis: Clinical and Imaging Data
Authors: Benbrika Soumia , Doidy Franck , Carluer Laurence , Mondou Audrey , Pélerin Alice , Eustache Francis , Viader Fausto , Desgranges Béatrice
Published: July 2021

Objectives: Extra-motor manifestations occur in 50% of patients with amyotrophic lateral sclerosis (ALS). These mainly concern cognition, emotional processing and behavior. Depression and anxiety are less frequent. Little is known about how these manifestations change as the disease progresses. Similarly, although cortical thinning has been well-documented at disease onset, there are scant data about cortical thinning over time and how this correlates with extra-motor manifestations. The present study therefore assessed cognitive, emotional and psychological state and cortical thinning in a group of patients with ALS at baseline and after a follow-up period.

Methods: We assessed executive functions, facial emotion recognition, depressive and anxious symptoms, and cortical thinning in 43 patients with ALS at baseline, comparing them with 28 healthy controls, and 21 of them 9 months later. We looked for links among the extra-motor manifestations and correlations with cortical thickness.

Results: At baseline, patients had poor executive function and recognition of complex emotions from the eyes, and more anxious and depressive symptoms than controls. At follow-up, only inhibition abilities had worsened. Cortical thinning was observed in bilateral pre-central regions and other parts of the cerebral cortex at baseline. Over time, it worsened in motor and extra-motor areas. Executive functions correlated with thinning in the middle and inferior frontal gyrus and orbitofrontal cortex.

Conclusions: During follow-up, there was little deterioration in extra-motor manifestations and psychological state, despite continuing cortical thinning. Patients with affective Theory of Mind (ToM) changes seemed less depressed than the others. Impaired mental flexibility was subtended by prefrontal regions with cortical thinning.
Past Trauma Is Associated With a Higher Risk of Experiencing an Epileptic Seizure as Traumatic in Patients With Pharmacoresistant Focal Epilepsy
Authors: Mariotti Sara , Valentin Damien , Ertan Deniz , Maillard Louis , Tarrada Alexis , Chrusciel Jan , Sanchez Stéphane , Schwan Raymund , Vignal Jean-Pierre , Tyvaert Louise , El-Hage Wissam , Hingray Coraline
Published: July 2021

Objective: The present study aimed to evaluate the prevalence of traumatic experienced seizures (TES) and of postepileptic seizure PTSD (PS-PTSD) in patients with pharmacoresistant focal epilepsy and to explore the determining factors of TES.

Methods: We conducted an observational study enrolling 107 adult refractory epilepsy patients. We used the DSM-5 criteria of traumatic events and PTSD to define TES and PS-PTSD. We assessed all traumatic life events unrelated to epilepsy, general and specific psychiatric comorbidities, and quality of life.

Results: Nearly half (n = 48) of the 107 participants reported at least one TES (44.85%). Among these, one-third (n = 16) developed PS-PTSD. The TES group was more likely to experience traumatic events unrelated to epilepsy (p < 0.001), to have generalized anxiety disorder (p = 0.019), and to have specific psychiatric comorbidities [e.g., interictal dysphoric disorder (p = 0.024) or anticipatory anxiety of seizures (p = 0.005)]. They reported a severe impact of epilepsy on their life (p = 0.01). The determining factors of TES according to the multifactorial model were the experience of trauma (p = 0.008), a history of at least one psychiatric disorder (p = 0.03), and a strong tendency toward dissociation (p = 0.03).

Significance: Epileptic seizures may be a traumatic experience in some patients who suffer from pharmacoresistant epilepsy and may be the source of the development of PS-PTSD. Previous trauma unrelated to epilepsy and psychiatric history are determining factors of TES. These clinical entities should be explored systematically.
A Lightweight Multi-Scale Convolutional Neural Network for P300 Decoding: Analysis of Training Strategies and Uncovering of Network Decision
Authors: Borra Davide , Fantozzi Silvia , Magosso Elisa
Published: July 2021

Convolutional neural networks (CNNs), which automatically learn features from raw data to approximate functions, are being increasingly applied to the end-to-end analysis of electroencephalographic (EEG) signals, especially for decoding brain states in brain-computer interfaces (BCIs). Nevertheless, CNNs introduce a large number of trainable parameters, may require long training times, and lack in interpretability of learned features. The aim of this study is to propose a CNN design for P300 decoding with emphasis on its lightweight design while guaranteeing high performance, on the effects of different training strategies, and on the use of post-hoc techniques to explain network decisions. The proposed design, named MS-EEGNet, learned temporal features in two different timescales (i.e., multi-scale, MS) in an efficient and optimized (in terms of trainable parameters) way, and was validated on three P300 datasets. The CNN was trained using different strategies (within-participant and within-session, within-participant and cross-session, leave-one-subject-out, transfer learning) and was compared with several state-of-the-art (SOA) algorithms. Furthermore, variants of the baseline MS-EEGNet were analyzed to evaluate the impact of different hyper-parameters on performance. Lastly, saliency maps were used to derive representations of the relevant spatio-temporal features that drove CNN decisions. MS-EEGNet was the lightest CNN compared with the tested SOA CNNs, despite its multiple timescales, and significantly outperformed the SOA algorithms. Post-hoc hyper-parameter analysis confirmed the benefits of the innovative aspects of MS-EEGNet. Furthermore, MS-EEGNet did benefit from transfer learning, especially using a low number of training examples, suggesting that the proposed approach could be used in BCIs to accurately decode the P300 event while reducing calibration times. Representations derived from the saliency maps matched the P300 spatio-temporal distribution, further validating the proposed decoding approach. This study, by specifically addressing the aspects of lightweight design, transfer learning, and interpretability, can contribute to advance the development of deep learning algorithms for P300-based BCIs.
Intermodal Priming of Cognitive Conflict? A Failed Replication of Mager et al. (2009)
Authors: Wiswede Daniel , Rüsseler Jascha
Published: July 2021

Introduction: The present study was conducted to verify a promising experimental setup which demonstrated an inversed Stroop-effect (much faster responses for incongruent relative to congruent Stroop trials) following a mismatching tone. In the matching condition, which was an almost exact replication of the original study, participants were required to indicate whether word color and word meaning were matching, whereas in the response conflict condition, instruction was the same as in a classical Stroop task and required the participants to respond to the word color. As in the original study, each trial was preceded by a sine tone which was deviant in pitch in 20% of the trials.

Results: The main result was that the Stroop effect was not inversed after deviant tones, neither under the matching task instruction nor under the response conflict task instruction. The Stroop effect was unaffected by the previous “conceptual mismatch.”

Conclusion: The current study failed to replicate the astonishing concept of “conflict priming” reported in previous work and does not open the doors for a new window on sequences of conflicts. Nevertheless, the failed replication is valuable for future research, since it demonstrated that “Conflict Priming” as a facilitation of processing of conflict trials following deviant tones, is not an confirmed finding.
Overfitting the Literature to One Set of Stimuli and Data
Authors: Grootswagers Tijl , Robinson Amanda K.
Published: July 2021

A large number of papers in Computational Cognitive Neuroscience are developing and testing novel analysis methods using one specific neuroimaging dataset and problematic experimental stimuli. Publication bias and confirmatory exploration will result in overfitting to the limited available data. We highlight the problems with this specific dataset and argue for the need to collect more good quality open neuroimaging data using a variety of experimental stimuli, in order to test the generalisability of current published results, and allow for more robust results in future work.
Characterization and Stage-Dependent Lineage Analysis of Intermediate Progenitors of Cortical GABAergic Interneurons
Authors: Esumi Shigeyuki , Nasu Makoto , Kawauchi Takeshi , Miike Koichiro , Morooka Kento , Yanagawa Yuchio , Seki Tatsunori , Sakimura Kenji , Fukuda Takaichi , Tamamaki Nobuaki
Published: July 2021

Intermediate progenitors of both excitatory and inhibitory neurons, which can replenish neurons in the adult brain, were recently identified. However, the generation of intermediate progenitors of GABAergic inhibitory neurons (IPGNs) has not been studied in detail. Here, we characterized the spatiotemporal distribution of IPGNs in mouse cerebral cortex. IPGNs generated neurons during both embryonic and postnatal stages, but the embryonic IPGNs were more proliferative. Our lineage tracing analyses showed that the embryonically proliferating IPGNs tended to localize to the superficial layers rather than the deep cortical layers at 3 weeks after birth. We also found that embryonic IPGNs derived from the medial and caudal ganglionic eminence (CGE) but more than half of the embryonic IPGNs were derived from the CGE and broadly distributed in the cerebral cortex. Taken together, our data indicate that the broadly located IPGNs during embryonic and postnatal stages exhibit a different proliferative property and layer distribution.
Bundle-Specific Axon Diameter Index as a New Contrast to Differentiate White Matter Tracts
Authors: Barakovic Muhamed , Girard Gabriel , Schiavi Simona , Romascano David , Descoteaux Maxime , Granziera Cristina , Jones Derek K. , Innocenti Giorgio M. , Thiran Jean-Philippe , Daducci Alessandro
Published: July 2021

In the central nervous system of primates, several pathways are characterized by different spectra of axon diameters.In vivomethods, based on diffusion-weighted magnetic resonance imaging, can provide axon diameter index estimates non-invasively. However, such methods report voxel-wise estimates, which vary from voxel-to-voxel for the same white matter bundle due to partial volume contributions from other pathways having different microstructure properties. Here, we propose a novel microstructure-informed tractography approach, COMMITAxSize, to resolve axon diameter index estimates at the streamline level, thus making the estimates invariant along trajectories. Compared to previously proposed voxel-wise methods, our formulation allows the estimation of a distinct axon diameter index value for each streamline, directly, furnishing a complementary measure to the existing calculation of the mean value along the bundle. We demonstrate the favourable performance of our approach comparing our estimates with existing histologically-derived measurements performed in the corpus callosum and the posterior limb of the internal capsule. Overall, our method provides a more robust estimation of the axon diameter index of pathways by jointly estimating the microstructure properties of the tissue and the macroscopic organisation of the white matter connectivity.
The Intestinal Microbiome Predicts Weight Loss on a Calorie-Restricted Diet and Is Associated With Improved Hepatic Steatosis
Authors: Dong Tien S. , Luu Kayti , Lagishetty Venu , Sedighian Farzaneh , Woo Shih-Lung , Dreskin Benjamin W. , Katzka William , Chang Candace , Zhou Yi , Arias-Jayo Nerea , Yang Julianne , Ahdoot Aaron I. , Ye Jason , Li Zhaoping , Pisegna Joseph R. , Jacobs Jonathan P.
Published: July 2021

Background: The microbiome has been shown in pre-clinical and epidemiological studies to be important in both the development and treatment of obesity and metabolic associated fatty liver disease (MAFLD). However, few studies have examined the role of the microbiome in the clinical response to calorie restriction. To explore this area, we performed a prospective study examining the association of the intestinal microbiome with weight loss and change in hepatic steatosis on a calorie-restricted diet.

Methods: A prospective dietary intervention study of 80 overweight and obese participants was performed at the Greater West Los Angeles Veterans Affair Hospital. Patients were placed on a macronutrient standardized diet for 16 weeks, including 14 weeks of calorie restriction (500 calorie deficit). Body composition analysis by impedance, plasma lipid measurements, and ultrasound elastography to measure hepatic steatosis were performed at baseline and week 16. Intestinal microbiome composition was assessed using 16S rRNA gene sequencing. A per protocol analysis was performed on all subjects completing the trial (n = 46).

Results: Study completers showed significant reduction in weight, body mass index, total cholesterol, low density lipoprotein, and triglyceride. Subjects who lost at least 5% of their body weight had significantly greater reduction in serum triglyceride and hepatic steatosis than those with <5% body weight loss. Enterococcus and Klebsiella were reduced at the end of the trial while Coprococcus and Collinsella were increased. There were also significant baseline microbiome differences between patients who had at least 5% weight loss as compared to those that did not. Lachnoclostridium was positively associated with hepatic steatosis and Actinomyces was positively associated with hepatic steatosis and weight. Baseline microbiome profiles were able to predict which patients lost at least 5% of their body weight with an AUROC of 0.80.

Conclusion: Calorie restriction alters the intestinal microbiome and improves hepatic steatosis in those who experience significant weight loss. Baseline microbiome differences predict weight loss on a calorie–restricted diet and are associated with improvement in hepatic steatosis, suggesting a role of the gut microbiome in mediating the clinical response to calorie restriction.
Comparison of a Tumor-Ratio–Metastasis Staging System and the 8th AJCC TNM Staging System for Gastric Cancer
Authors: Zhang Miaoquan , Ding Chao , Xu Lin , Ou Biyi , Feng Shoucheng , Wang Guoqiang , Wang Wei , Liang Yao , Chen Yingbo , Zhou Zhiwei , Qiu Haibo
Published: July 2021

Background

Despite the implementation of the 8th American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer (GC) in 2017, it still holds a significant level of stage migration which affects patients’ proper classification and accurate prognosis. Here, to reduce this effect, we evaluated the prognostic value of a lymph node ratio (LNR) and established a novel tumor–ratio–metastasis (TRM) staging system.

Method

The data of 15,206 GC patients from the Sun Yat-sen University Cancer Center (Training set; n=2,032) and the US Surveillance, Epidemiology, and End Results (SEER) database (Validation set; n=13,174) were analyzed. The training set was classified into 5 LNR categories, based on which the novel TRM staging system was constructed. The overall survival (OS) between the TRM and AJCC TNM systems was compared in the training set and validated in the validation set. The likelihood ratio x2, liner trend x2, C-index, and Akaike information criterion (AIC) values were used to measure the discriminatory ability between the two different staging systems. Decision curve analyses (DCAs) were conducted to test the clinical value of the two staging systems.

Result

The patients were classified into the following categories: LNR0: 0%, LNR1: 0%<LNR ≤ 10%, LNR2: 10%<LNR ≤ 25%, LNR 3a: 25%60%. Univariate analyses demonstrated that the log-rank x2 of the LNR stage (Training/Validation set: x2 = 463.1/2880.8) was larger than the AJCC pN stage (Training/Validation set: x2 = 281.5/2240.8). For both the training set and validation set, stratified analyses using the Kaplan-Meier method identified significantly heterogeneous OS in every pN category but only one using the LNR. The TRM staging system had higher likelihood ratio x2, liner trend x2, C-index and smaller AIC values than the TNM system.

Conclusion

The TRM staging system demonstrated improved homogeneity and discriminatory ability in predicting the prognosis of GC patients compared with the AJCC TNM staging system.
Long Noncoding RNA NONHSAT079852.2 Contributes to GBM Recurrence by Functioning as a ceRNA for has-mir-10401-3p to Facilitate HSPA1A Upregulation
Authors: Zhao Ningning , Zhang Jiajie , Zhao Lili , Fu Xiaoni , Zhao Qian , Chao Min , Cao Haiyan , Jiao Yang , Hu Yaqin , Chen Chao , Wang Liang , Wang Huijuan
Published: July 2021

Glioblastoma multiforme (GBM) is the most common brain malignancy and major cause of high mortality in patients with GBM, and its high recurrence rate is its most prominent feature. However, the pathobiological mechanisms involved in recurrent GBM remain largely unknown. Here, whole-transcriptome sequencing (RNA-sequencing, RNA-Seq) was used in characterizing the expression profile of recurrent GBM, and the aim was to identify crucial biomarkers that contribute to GBM relapse. Differentially expressed RNAs in three recurrent GBM tissues compared with three primary GBM tissues were identified through RNA-Seq. The function and mechanism of a candidate long noncoding RNA (lncRNA) in the progression and recurrence of GBM were elucidated by performing comprehensive bioinformatics analyses, such as functional enrichment analysis, protein–protein interaction prediction, and lncRNA–miRNA–mRNA regulatory network construction, and a series of in vitro assays. As the most significantly upregulated gene identified in recurrent GBM, HSPA1A is mainly related to antigen presentation and the MAPK signaling pathway, as indicated by functional enrichment analysis. HSPA1A was predicted as the target gene of the lncRNA NONHSAT079852.2. qRT-PCR revealed that NONHSAT079852.2 was significantly elevated in recurrent GBM relative to that in primary GBM, and high NONHSAT079852.2 expression was associated with the poor overall survival rates of patients with GBM. The knockdown of NONHSAT079852.2 successfully induced tumor cell apoptosis, inhibited the proliferation, migration, invasion and the expression level of HSPA1A in glioma cells. NONHSAT079852.2 was identified to be a sponge for hsa-miR-10401-3p through luciferase reporter assay. Moreover, HSPA1A was targeted and regulated by hsa-miR-10401-3p. Collectively, the results suggested that NONHSAT079852.2 acts as a sponge of hsa-mir-10401-3p and thereby enhances HSPA1A expression, promotes tumor cell proliferation and invasion, and leads to the progression and recurrence of GBM. This study will provide new insight into the regulatory mechanisms of NONHSAT079852.2-mediated competing endogenous RNA in the pathogenesis of recurrent GBM and evidence of the potential of lncRNAs as diagnostic biomarkers or potential therapeutic targets.
Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies
Authors: Zhao Yuming , Zhang Dengyang , Guo Yao , Lu Bo , Zhao Zhizhuang Joe , Xu Xiaojun , Chen Yun
Published: July 2021

Receptor tyrosine kinase ROR1 plays an essential role in embryogenesis and is overexpressed in many types of malignant tumors. Studies have demonstrated that it plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. Antibody-based immunotherapies targeting ROR1 have been developed and evaluated in preclinical and clinical studies with promising outcomes. However, small molecule inhibitors targeting ROR1 are underappreciated because of the initial characterization of ROR1 as a peusdokinase. The function of ROR1 as a tyrosine kinase remains poorly understood, although accumulating evidence have demonstrated its intrinsic tyrosine kinase activity. In this review, we analyzed the structural and functional features of ROR1 and discussed therapeutic strategies targeting this kinase.
Breastfeeding in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Italian Observational Study
Authors: Murciano Manuel , Biancone Davide Maria , De Luca Francesca , Piras Marafon Denise , Guido Cristiana Alessia , Spalice Alberto
Published: July 2021

Objective:Pediatric acute-onset neuropsychiatric syndrome (PANS) is a condition defined by sudden onset of obsessive–compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms. Its pathogenesis is unknown but it seems triggered by infections, metabolic disturbances, and other inflammatory reactions. PANS represents a neurodevelopmental problem and infant feeding can play a role. Breast milk is the ideal food for infants and influences children's brain, cognitive, and socio-emotional development.

Methods:We enrolled 52 children diagnosed with PANS. We interviewed their parents in order to investigate perinatal history, infant feeding, neurologic development, and confounding factors like socio-economic status and region of origin. We subgrouped PANS patients into three subsets: those who only received human milk (HMO), those who only received infant formula, and those who received mixed feeding.

Results:The cohort is composed of 78.9% males, with a median age of 11 years (range 7–17). We found some neurodevelopmental problems (13.5%): walking disorders, ASD, ADHD, oppositional attitude, and delayed psychomotor development. We found scholar performance deficits (25%), including language problems like dysgraphia, dyslexia, and dyscalculia. The achievement of some milestones in the development of the infant is affected in 73.1% of cases. Breastfeeding is not homogeneously practiced in Italy because of social, economic, and cultural phenomena. The richest and the poorest families (100%) in the sample choose breastfeeding, probably with a different approach and for different reasons (awareness or need). In the group of PANS patients fed with HMO, compared to the rest of the patients, we registered fewer cases of growth problems (0 vs. 12.9%;p= 0.14), school performance problems or the need for school support (19.1% vs. 29%;p= 0.42), and a delay in the age of babbling/speaking (range 4–20 vs. 7–36 months;p= 0.066).

Conclusion:This is the first study that investigates the role of breastfeeding in the development of PANS. Promoting breastfeeding is important in the general population and also in PANS patients because it has an important social and global health impact, also during adult life. Further studies with a bigger population are needed to investigate the mechanisms underlying PANS and the role that breastfeeding may play in their short- and long-term neurodevelopment.
Antimetastatic Effects of Ganoderma lucidum Polysaccharide Peptide on B16-F10-luc-G5 Melanoma Mice With Sleep Fragmentation
Authors: Xian Haocheng , Li Jiayi , Zhang Yimeng , Li Ditian , Zhu Yinan , Li Siyan , Tan Zhelun , Lin Zhibin , Li Xuejun , Pan Yan
Published: July 2021

Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.
Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes
Authors: Gallego Mónica , Zayas-Arrabal Julián , Alquiza Amaia , Apellaniz Beatriz , Casis Oscar
Published: July 2021

Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.
Recent Progress in Environmental Toxins-Induced Cardiotoxicity and Protective Potential of Natural Products
Authors: Yang Yuanying , Wei Shanshan , Zhang Bikui , Li Wenqun
Published: July 2021

Humans are unconsciously exposed to environmental toxins including heavy metals as well as various pesticides, which have deleterious effects on human health. Accumulating studies pointed out that exposure to environmental toxins was associated with various cardiopathologic effects. This review summarizes the main mechanisms of cardiotoxicity induced by environmental toxins (cadmium, arsenic and pesticides) and discusses the potential preventive effects of natural products. These findings will provide a theoretical basis and novel agents for the prevention and treatment of environmental toxins-induced cardiotoxicity. Furthermore, the limitations of current studies, future needs and priorities are discussed.
Structured Light Control and Diagnostics Using Optical Crystals
Authors: Angelsky O. V. , Bekshaev A. Y. , Dragan G. S. , Maksimyak P. P. , Zenkova C. Yu. , Zheng Jun
Published: July 2021

We describe experimental results exposing the possibilities of optical crystals, especially anisotropic and birefringent, for creation, control, and diagnostics of structured light fields with singular and extraordinary properties. The efficiency of birefringent media is demonstrated for purposeful generation of optical beams with phase singularities (optical vortices) and desirable patterns of internal energy flows, in both the mono- and polychromatic light. On the other hand, anisotropic micro-objects can be used as probing bodies for investigation of the peculiar features of internal energy flows and corresponding momentum and angular momentum distributions in structured light fields. In particular, the specific mechanical action of light fields, formed under the total-reflection conditions, has been detected that confirms the existence of “extraordinary” dynamical characteristics of evanescent light waves predicted theoretically: the “transverse” momentum and “vertical” spin and their dependence on the incident beam polarization. The results can be useful for the optical trapping and micromanipulation techniques, including the biomedical and pharmaceutical applications.