bluuebunny/crossref_metadata_2025 huggingface dataset:
Prebiotic Supplementation During Gestation Induces a Tolerogenic Environment and a Protective Microbiota in Offspring Mitigating Food Allergy
Authors: Selle Amandine , Brosseau Carole , Dijk Wieneke , Duval Angéline , Bouchaud Grégory , Rousseaux Anais , Bruneau Aurélia , Cherbuy Claire , Mariadassou Mahendra , Cariou Véronique , Barbarot Sebastien , Bodinier Marie
Published: January 2022

Food allergy is associated with alterations in the gut microbiota, epithelial barrier, and immune tolerance. These dysfunctions are observed within the first months of life, indicating that early intervention is crucial for disease prevention. Preventive nutritional strategies with prebiotics are an attractive option, as prebiotics such as galacto-oligosaccharides and inulin can promote tolerance, epithelial barrier reinforcement, and gut microbiota modulation. Nonetheless, the ideal period for intervention remains unknown. Here, we investigated whether galacto-oligosaccharide/inulin supplementation during gestation could protect offspring from wheat allergy development in BALB/cJRj mice. We demonstrated that gestational prebiotic supplementation promoted the presence of beneficial strains in the fecal microbiota of dams during gestation and partially during mid-lactation. This specific microbiota was transferred to their offspring and maintained to adulthood. The presence of B and T regulatory immune cell subsets was also increased in the lymph nodes of offspring born from supplemented mothers, suggestive of a more tolerogenic immune environment. Indeed, antenatal prebiotic supplementation reduced the development of wheat allergy symptoms in offspring. Our study thus demonstrates that prebiotic supplementation during pregnancy induces, in the offspring, a tolerogenic environment and a microbial imprint that mitigates food allergy development.
Functional Analysis of Variants in Complement Factor I Identified in Age-Related Macular Degeneration and Atypical Hemolytic Uremic Syndrome
Authors: de Jong Sarah , de Breuk Anita , Bakker Bjorn , Katti Suresh , Hoyng Carel B. , Nilsson Sara C. , Blom Anna M. , van den Heuvel Lambert P. , den Hollander Anneke I. , Volokhina Elena B.
Published: January 2022

Complement factor I (FI) is a central inhibitor of the complement system, and impaired FI function increases complement activation, contributing to diseases such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS). Genetic variation in complement factor I (CFI) has been identified in both AMD and aHUS, with more than half of these variants leading to reduced FI secretion levels. For many of the variants with normal FI secretion, however, functional implications are not yet known. Here we studied 11 rare missense variants, with FI secretion levels comparable to wildtype, but a predicted damaging effects based on the Combined Annotation Dependent Depletion (CADD) score. Three variants (p.Pro50Ala, p.Arg339Gln, and p.Ser570Thr) were analyzed in plasma and serum samples of carriers affected by AMD. All 11 variants (nine for the first time in this study) were recombinantly expressed and the ability to degrade C3b was studied with the C3b degradation assay. The amount of degradation was determined by measuring the degradation product iC3b with ELISA. Eight of 11 (73%) mutant proteins (p.Pro50Ala, p.Arg339Gln, p.Ile340Thr, p.Gly342Glu, p.Gly349Arg, p.Arg474Gln, p.Gly487Cys, and p.Gly512Ser) showed significantly impaired C3b degradation, and were therefore classified as likely pathogenic. Our data indicate that genetic variants in CFI with a CADD score >20 are likely to affect FI function, and that monitoring iC3b in a degradation assay is a useful tool to establish the pathogenicity of CFI variants in functional studies.
Ranging Patterns and Site Fidelity of Snubfin Dolphins in Yawuru Nagulagun/Roebuck Bay, Western Australia
Authors: D’Cruz Alexandra , Salgado Kent Chandra , Waples Kelly , Brown Alexander M. , Marley Sarah A. , Thiele Deborah ,   Yawuru PBC, Raudino Holly C.
Published: January 2022

For long-lived species such as marine mammals, having sufficient data on ranging patterns and space use in a timescale suitable for population management and conservation can be difficult. Yawuru Nagulagun/Roebuck Bay in the northwest of Western Australia supports one of the largest known populations of Australian snubfin dolphins (Orcaella heinsohni)—a species with a limited distribution, vulnerable conservation status, and high cultural value. Understanding the species’ use of this area will inform management for the long-term conservation of this species. We combined 11 years of data collected from a variety of sources between 2007 and 2020 to assess the ranging patterns and site fidelity of this population. Ranging patterns were estimated using minimum convex polygons (MCPs) and fixed kernel densities (weighted to account for survey effort) to estimate core and representative areas of use for both the population and for individuals. We estimated the population to range over a small area within the bay (103.05 km2). The Mean individual representative area of use (95% Kernel density contour) was estimated as 39.88 km2 (± 32.65 SD) and the Mean individual core area of use (50% Kernel density contour) was estimated as 21.66 km2 (±18.85 SD) with the majority of sightings located in the northern part of the bay less than 10 km from the coastline. Most individuals (56%) showed moderate to high levels of site fidelity (i.e., part-time or long-term residency) when individual re-sight rates were classified using agglomerative hierarchical clustering (AHC). These results emphasize the importance of the area to this vulnerable species, particularly the area within the Port of Broome that has been identified within the population’s core range. The pressures associated with coastal development and exposure to vessel traffic, noise, and humans will need to be considered in ongoing management efforts. Analyzing datasets from multiple studies and across time could be beneficial for threatened species where little is known on their ranging patterns and site fidelity. Combined datasets can provide larger sample sizes over an extended period of time, fill knowledge gaps, highlight data limitations, and identify future research needs to be considered with dedicated studies.
Regime Shifts in Future Shoreline Dynamics of Saudi Arabia
Authors: Luijendijk Arjen Pieter , Kras Etiënne , Dagalaki Vasiliki , Morelissen Robin , Hoteit Ibrahim , Ranasinghe Roshanka
Published: January 2022

The Saudi Arabian tourism sector is growing, and its economy has flourished over the last decades. This has resulted in numerous coastal developments close to large economic centers, while many more are proposed or planned. The coastal developments have influenced the behavior of the shoreline in the past. Here we undertake a national assessment on the state of the coast of Saudi Arabia based on recent data sets on historic and future shoreline positions. While at national scale the shoreline is found to be stable over the last three decades, the Red Sea coast shows a regional-mean retreat rate while the Gulf coast shows a regional-mean prograding behavior. Detailed analysis of the temporal evolution of shoreline position at selected locations show that human interventions may have accelerated shoreline retreat along adjacent shorelines, some of which are Marine Protected Areas. Furthermore, reef-fronted coastal sections have a mean accretive shoreline change rate, while the open coast shows a mean retreat rate. Future shoreline projections under RCP 4.5 and RCP 8.5 show that large parts of the shoreline may experience an accelerated retreat or a change in its regime from either stable or sprograding to retreating. Under the high emission RCP 8.5 scenario, the length of coastline projected to retreat more than doubles along the Red Sea coast, and approximately triples along the Gulf coast in 2100. At national scale, the Saudi Arabian coastline is projected to experience regional-mean retreats of ~30 m and of ~130 m by 2050 and 2100 under both RCPs considered in this study. These results indicate that effective adaptation strategies will be required to protect areas of ecological and economic value, and that climate resilience should be a key consideration in planned or proposed coastal interventions.
Role of Aluminum and Lithium in Mitigating Alkali-Silica Reaction—A Review
Authors: Shi Zhenguo , Lothenbach Barbara
Published: January 2022

Effective mitigation of alkali-silica reaction (ASR) is critical for producing durable concrete. The use of alumina-rich supplementary cementitious materials (SCMs) and chemical admixtures such as lithium salts to prevent expansion caused by ASR was first reported 70 years ago, shortly after the discovery of ASR in 1940s. Despite numerous investigations, the understanding of the mechanisms of Al and Li for mitigating ASR remain partially inexplicit in the case of Al, and hardly understood in the case of Li. This paper reviews the available information on the effect of Al and Li on ASR expansion, the influencing factors, possible mechanisms and limitations. The role of Al in mitigating ASR is likely related to the reduction of dissolution rate of reactive silica. Moreover, the presence of Al may alter the structure of crystalline ASR products to zeolite or its precursor, but such effect seems to be not that significant at ambient conditions due to the slow kinetics of zeolite formation. Several mechanisms for the lithium salts in mitigating ASR have been proposed, but most of them are not conclusive primarily due to the lack of knowledge about the formed reaction products. Combination of Al-rich SCMs and lithium salts may be used as an economic solution for ASR mitigation, although systematic studies are necessary prior to the applications.
Incidence, Risk Factors and Prognosis of T4a Gastric Cancer: A Population-Based Study
Authors: Hu Zhiya , Zuo Ziyi , Miao Han , Ning Zhijie , Deng Youyuan
Published: January 2022

Background: T4a gastric cancer (GC) is a subtype of advanced GC (AGC), which urgently needs a comprehensive grade method for better treatment strategy choosing. The purpose of this study was to develop two nomograms for predicting the prognosis of patients with T4a GC.

Methods: A total of 1,129 patients diagnosed as T4a GC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Result (SEER) program database. Univariate and multivariate Cox analyses were performed to explore the independent predictors and to establish nomogram for overall survival (OS) of the patients, whereas competing risk analyses were performed to find the independent predictors and to establish nomogram for cancer-specific survival (CSS) of the patients. The area under the curve (AUC), calibration curve, decision curve analysis (DCA), and Kaplan–Meier analysis were performed to evaluate the nomograms.

Results: Older age, larger tumor size, black race, signet ring cell carcinoma (SRCC), more lymph node involvement, the absence of surgery, the absence of radiotherapy, and the absence of chemotherapy were identified as independent prognostic factors for both OS and CSS. In the training cohort, the AUCs of the OS nomogram were 0.760, 0.743, and 0.723 for 1-, 3-, and 5-year OS, whereas the AUCs of the CSS nomogram were 0.724, 0.703, and 0.713 for 1-, 3-, and 5-year CSS, respectively. The calibration curve and DCA indicated that both nomograms can effectively predict OS and CSS, respectively. The abovementioned results were also confirmed in the validation cohort. Stratification of the patients into high- and low-risk groups highlighted the differences in prognosis between the two groups both in training and in validation cohorts.

Conclusions: Age, tumor size, race, histologic type, N stage, surgery status, radiotherapy, and chemotherapy were confirmed as independent prognostic factors for both OS and CSS in patients with T4a GC. Two nomograms based on the abovementioned variables were constructed to provide more accurate individual survival predictions for them.
Abnormal Static and Dynamic Functional Network Connectivity in Patients With Presbycusis
Authors: Xing Chunhua , Chen Yu-Chen , Shang Song’an , Xu Jin-Jing , Chen Huiyou , Yin Xindao , Wu Yuanqing , Zheng Jin-Xia
Published: January 2022

Aim: This study aimed to investigate abnormal static and dynamic functional network connectivity (FNC) and its association with cognitive function in patients with presbycusis.

Methods: In total, 60 patients with presbycusis and 60 age-, sex-, and education-matched healthy controls (HCs) underwent resting-state functional MRI (rs-fMRI) and cognitive assessments. Group independent component analysis (ICA) was carried out on the rs-fMRI data, and eight resting-state networks (RSNs) were identified. Static and dynamic FNCs (sFNC and dFNC) were then constructed to evaluate differences in RSN connectivity between the patients with presbycusis and the HCs. Furthermore, the correlations between these differences and cognitive scores were analyzed.

Results: Patients with presbycusis had differences in sFNC compared with HCs, mainly reflected in decreased sFNC in the default mode network (DMN)-left frontoparietal network (LFPN) and attention network (AN)-cerebellum network (CN) pairs, but they had increased sFNC in the auditory network (AUN) between DMN domains. The decreased sFNC in the DMN-LFPN pair was negatively correlated with their TMT-B score (r = –0.441, p = 0.002). Patients with presbycusis exhibited aberrant dFNCs in State 2 and decreased dFNCs between the CN and AN and the visual network (VN). Moreover, the presbycusis group had a shorter mean dwell time (MDT) and fraction time (FT) in State 3 (p = 0.0027; p = 0.0031, respectively).

Conclusion: This study highlighted differences in static and dynamic functional connectivity in patients with presbycusis and suggested that FNC may serve as an important biomarker of cognitive performance since abnormal alterations can better track cognitive impairment in presbycusis.
Effects of Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 on the Reinstatement of Cocaine-Mediated Conditioned Place Preference in Mice
Authors: Zhu Changliang , Wang Lei , Ding Jiangwei , Li Hailiang , Wan Din , Sun Yangyang , Guo Baorui , He Zhenquan , Ren Xiaofan , Jiang Shucai , Gao Caibing , Guo Hua , Sun Tao , Wang Feng
Published: January 2022

A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.
GABAA/Benzodiazepine Receptor Complex in the Dorsal Hippocampus Mediates the Effects of Chrysin on Anxiety-Like Behaviour in Female Rats
Authors: Rodríguez-Landa Juan Francisco , Hernández-López Fabiola , Martínez-Mota Lucía , Scuteri Damiana , Bernal-Morales Blandina , Rivadeneyra-Domínguez Eduardo
Published: January 2022

Systemic injections of the flavonoid chrysin (5,7-dihydroxyflavone) exert anxiolytic-like effects in ovariectomised and cycling female rats through actions on gamma-aminobutyric acid-A (GABAA) receptors; however, it is unknown if chrysin directly acts on brain structures that are involved in regulating emotional processes, such as the hippocampus. The present study evaluated the effects of intrahippocampal microinjections of 0.25, 0.5, and 1 μg of chrysin on anxiety-like behaviour in the elevated plus maze (EPM) and locomotor activity test (LAT) in female rats in proestrus and dioestrus. Similar doses of the neurosteroid allopregnanolone were used as a reference GABAergic anxiolytic drug. The participation of the GABAA/benzodiazepine receptor complex was evaluated by administering the antagonists picrotoxin, bicuculline and flumazenil. In proestrus, 0.5 and 1 μg of chrysin and allopregnanolone induced anxiogenic-like behaviour. In dioestrus, chrysin, and allopregnanolone (0.5 μg) induced anxiolytic-like effects. Picrotoxin, bicuculline and flumazenil prevented the effects of chrysin and allopregnanolone in both proestrus and dioestrus. None of the treatments significantly affected locomotor activity. These results indicate that the GABAA/benzodiazepine receptor complex in the dorsal hippocampus regulates the effects of chrysin on anxiety-like behaviour, similar to the actions of allopregnanolone. The divergent effects of treatments across the oestrous cycle phases suggest complex interactions between GABAA receptors and compounds with an anxiolytic potential.
Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study
Authors: Li Jie , Yan Wen-Jie , Wu Yan , Tian Xin-Xin , Zhang Yi-Wen
Published: January 2022

Methylphenidate (MPH) is the first-line drug for the treatment of children with attention-deficit hyperactivity disorder (ADHD); however, individual curative effects of MPH vary. Many studies have demonstrated that synaptosomal-associated protein 25 (SNAP-25) gene MnlI polymorphisms may be related to the efficacy of MPH. However, the association between SNAP-25MnlI polymorphisms and changes in brain hemodynamic responses after MPH treatment is still unclear. This study used functional near-infrared spectroscopy (fNIRS) to preliminarily investigate the interaction of MPH treatment-related prefrontal inhibitory functional changes with the genotype status of the SNAP-25 gene in children with ADHD. In total, 38 children with ADHD aged 6.76–12.08 years were enrolled in this study and divided into the following two groups based on SNAP-25 gene MnlI polymorphisms: T/T genotype group (wild-type group, 27 children) and G allele carrier group (mutation group, 11 children). The averaged oxygenated hemoglobin concentration changes [Δavg oxy-Hb] and deoxyhemoglobin concentration changes [Δavg deoxy-Hb] in the frontal cortex before MPH treatment and after 1.5 h (post-MPH1.5h) and 4 weeks (post-MPH4w) of MPH treatments were monitored using fNIRS during the go/no-go task. SNAP-IV scores were evaluated both pre-MPH and post-MPH4w treatments. In the T/T genotype group, [Δavg oxy-Hb] in the dorsolateral prefrontal cortex was significantly higher after 4 weeks of MPH (post-MPH4W) treatment than pre-treatment; however, in the G allele group, no significant differences in [Δavg oxy-Hb] were observed between pre- and post-treatments. In the go/no-go task, the accuracy was significantly increased post-MPH4w treatment in the T/T genotype group, while no significant differences were observed in response time and accuracy of the “go” sand no-go task in the G allele group for pre-MPH, post-MPH1.5h, and post-MPH4w treatments. The T/T genotype group exhibited a significant decrease in SNAP-IV scores after MPH treatment, while the G allele group showed no significant difference. In conclusion, fNIRS data combined with SNAP-25 MnlI polymorphism analysis may be a useful biomarker for evaluating the effects of MPH in children with ADHD.
Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance
Authors: Cherubini Enrico , Di Cristo Graziella , Avoli Massimo
Published: January 2022

The construction of the brain relies on a series of well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt to the external environment. Disruption of these processes leads to neurological and psychiatric disorders, which in many cases are manifest already early in postnatal life. GABA, the main inhibitory neurotransmitter in the adult brain is one of the major players in the early assembly and formation of neuronal circuits. In the prenatal and immediate postnatal period GABA, acting on GABAA receptors, depolarizes and excites targeted cells via an outwardly directed flux of chloride. In this way it activates NMDA receptors and voltage-dependent calcium channels contributing, through intracellular calcium rise, to shape neuronal activity and to establish, through the formation of new synapses and elimination of others, adult neuronal circuits. The direction of GABAA-mediated neurotransmission (depolarizing or hyperpolarizing) depends on the intracellular levels of chloride [Cl−]i, which in turn are maintained by the activity of the cation-chloride importer and exporter KCC2 and NKCC1, respectively. Thus, the premature hyperpolarizing action of GABA or its persistent depolarizing effect beyond the postnatal period, leads to behavioral deficits associated with morphological alterations and an excitatory (E)/inhibitory (I) imbalance in selective brain areas. The aim of this review is to summarize recent data concerning the functional role of GABAergic transmission in building up and refining neuronal circuits early in development and its dysfunction in neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia and epilepsy. In particular, we focus on novel information concerning the mechanisms by which alterations in cation-chloride co-transporters (CCC) generate behavioral and cognitive impairment in these diseases. We discuss also the possibility to re-establish a proper GABAA-mediated neurotransmission and excitatory (E)/inhibitory (I) balance within selective brain areas acting on CCC.
Mechanism and Prevention of Spiral Ganglion Neuron Degeneration in the Cochlea
Authors: Zhang Li , Chen Sen , Sun Yu
Published: January 2022

Sensorineural hearing loss (SNHL) is one of the most prevalent sensory deficits in humans, and approximately 360 million people worldwide are affected. The current treatment option for severe to profound hearing loss is cochlear implantation (CI), but its treatment efficacy is related to the survival of spiral ganglion neurons (SGNs). SGNs are the primary sensory neurons, transmitting complex acoustic information from hair cells to second-order sensory neurons in the cochlear nucleus. In mammals, SGNs have very limited regeneration ability, and SGN loss causes irreversible hearing loss. In most cases of SNHL, SGN damage is the dominant pathogenesis, and it could be caused by noise exposure, ototoxic drugs, hereditary defects, presbycusis, etc. Tremendous efforts have been made to identify novel treatments to prevent or reverse the damage to SGNs, including gene therapy and stem cell therapy. This review summarizes the major causes and the corresponding mechanisms of SGN loss and the current protection strategies, especially gene therapy and stem cell therapy, to promote the development of new therapeutic methods.
Linking Multi-Modal MRI to Clinical Measures of Visual Field Loss After Stroke
Authors: Beh Anthony , McGraw Paul V. , Webb Ben S. , Schluppeck Denis
Published: January 2022

Loss of vision across large parts of the visual field is a common and devastating complication of cerebral strokes. In the clinic, this loss is quantified by measuring the sensitivity threshold across the field of vision using static perimetry. These methods rely on the ability of the patient to report the presence of lights in particular locations. While perimetry provides important information about the intactness of the visual field, the approach has some shortcomings. For example, it cannot distinguish where in the visual pathway the key processing deficit is located. In contrast, brain imaging can provide important information about anatomy, connectivity, and function of the visual pathway following stroke. In particular, functional magnetic resonance imaging (fMRI) and analysis of population receptive fields (pRF) can reveal mismatches between clinical perimetry and maps of cortical areas that still respond to visual stimuli after stroke. Here, we demonstrate how information from different brain imaging modalities—visual field maps derived from fMRI, lesion definitions from anatomical scans, and white matter tracts from diffusion weighted MRI data—provides a more complete picture of vision loss. For any given location in the visual field, the combination of anatomical and functional information can help identify whether vision loss is due to absence of gray matter tissue or likely due to white matter disconnection from other cortical areas. We present a combined imaging acquisition and visual stimulus protocol, together with a description of the analysis methodology, and apply it to datasets from four stroke survivors with homonymous field loss (two with hemianopia, two with quadrantanopia). For researchers trying to understand recovery of vision after stroke and clinicians seeking to stratify patients into different treatment pathways, this approach combines multiple, convergent sources of data to characterize the extent of the stroke damage. We show that such an approach gives a more comprehensive measure of residual visual capacity—in two particular respects: which locations in the visual field should be targeted and what kind of visual attributes are most suited for rehabilitation.
Speech-Driven Facial Animations Improve Speech-in-Noise Comprehension of Humans
Authors: Varano Enrico , Vougioukas Konstantinos , Ma Pingchuan , Petridis Stavros , Pantic Maja , Reichenbach Tobias
Published: January 2022

Understanding speech becomes a demanding task when the environment is noisy. Comprehension of speech in noise can be substantially improved by looking at the speaker’s face, and this audiovisual benefit is even more pronounced in people with hearing impairment. Recent advances in AI have allowed to synthesize photorealistic talking faces from a speech recording and a still image of a person’s face in an end-to-end manner. However, it has remained unknown whether such facial animations improve speech-in-noise comprehension. Here we consider facial animations produced by a recently introduced generative adversarial network (GAN), and show that humans cannot distinguish between the synthesized and the natural videos. Importantly, we then show that the end-to-end synthesized videos significantly aid humans in understanding speech in noise, although the natural facial motions yield a yet higher audiovisual benefit. We further find that an audiovisual speech recognizer (AVSR) benefits from the synthesized facial animations as well. Our results suggest that synthesizing facial motions from speech can be used to aid speech comprehension in difficult listening environments.
Hardware-Efficient Stochastic Binary CNN Architectures for Near-Sensor Computing
Authors: Parmar Vivek , Penkovsky Bogdan , Querlioz Damien , Suri Manan
Published: January 2022

With recent advances in the field of artificial intelligence (AI) such as binarized neural networks (BNNs), a wide variety of vision applications with energy-optimized implementations have become possible at the edge. Such networks have the first layer implemented with high precision, which poses a challenge in deploying a uniform hardware mapping for the network implementation. Stochastic computing can allow conversion of such high-precision computations to a sequence of binarized operations while maintaining equivalent accuracy. In this work, we propose a fully binarized hardware-friendly computation engine based on stochastic computing as a proof of concept for vision applications involving multi-channel inputs. Stochastic sampling is performed by sampling from a non-uniform (normal) distribution based on analog hardware sources. We first validate the benefits of the proposed pipeline on the CIFAR-10 dataset. To further demonstrate its application for real-world scenarios, we present a case-study of microscopy image diagnostics for pathogen detection. We then evaluate benefits of implementing such a pipeline using OxRAM-based circuits for stochastic sampling as well as in-memory computing-based binarized multiplication. The proposed implementation is about 1,000 times more energy efficient compared to conventional floating-precision-based digital implementations, with memory savings of a factor of 45.
Engineering Spiking Neurons Using Threshold Switching Devices for High-Efficient Neuromorphic Computing
Authors: Ding Yanting , Zhang Yajun , Zhang Xumeng , Chen Pei , Zhang Zefeng , Yang Yue , Cheng Lingli , Mu Chen , Wang Ming , Xiang Du , Wu Guangjian , Zhou Keji , Yuan Zhe , Liu Qi
Published: January 2022

Inspired by the human brain, the spike-based neuromorphic system has attracted strong research enthusiasm because of the high energy efficiency and powerful computational capability, in which the spiking neurons and plastic synapses are two fundamental building blocks. Recently, two-terminal threshold switching (TS) devices have been regarded as promising candidates for building spiking neurons in hardware. However, how circuit parameters affect the spiking behavior of TS-based neurons is still an open question. Here, based on a leaky integrate-and-fire (LIF) neuron circuit, we systematically study the effect of both the extrinsic and intrinsic factors of NbOx -based TS neurons on their spiking behaviors. The extrinsic influence factors contain input intensities, connected synaptic weights, and parallel capacitances. To illustrate the effect of intrinsic factors, including the threshold voltage, holding voltage, and high/low resistance states of NbOx devices, we propose an empirical model of the fabricated NbOx devices, fitting well with the experimental results. The results indicate that with enhancing the input intensity, the spiking frequency increases first then decreases after reaching a peak value. Except for the connected synaptic weights, all other parameters can modulate the spiking peak frequency under high enough input intensity. Also, the relationship between energy consumption per spike and frequency of the neuron cell is further studied, leading guidance to design neuron circuits in a system to obtain the lowest energy consumption. At last, to demonstrate the practical applications of TS-based neurons, we construct a spiking neural network (SNN) to control the cart-pole using reinforcement learning, obtaining a reward score up to 450. This work provides valuable guidance on building compact LIF neurons based on TS devices and further bolsters the construction of high-efficiency neuromorphic systems.
Integrated Analysis to Obtain Potential Prognostic Signature in Glioblastoma
Authors: Chen Jia-Qi , Zhang Nuo , Su Zhi-Lin , Qiu Hui-Guo , Zhuang Xin-Guo , Tao Zhi-hua
Published: January 2022

Glioblastoma multiforme (GBM) is the most malignant and multiple tumors of the central nervous system. The survival rate for GBM patients is less than 15 months. We aimed to uncover the potential mechanism of GBM in tumor microenvironment and provide several candidate biomarkers for GBM prognosis. In this study, ESTIMATE analysis was used to divide the GBM patients into high and low immune or stromal score groups. Microenvironment associated genes were filtered through differential analysis. Weighted gene co-expression network analysis (WGCNA) was performed to correlate the genes and clinical traits. The candidate genes’ functions were annotated by enrichment analyses. The potential prognostic biomarkers were assessed by survival analysis. We obtained 81 immune associated differentially expressed genes (DEGs) for subsequent WGCNA analysis. Ten out of these DEGs were significantly associated with targeted molecular therapy of GBM patients. Three genes (S100A4, FCGR2B, and BIRC3) out of these genes were associated with overall survival and the independent test set testified the result. Here, we obtained three crucial genes that had good prognostic efficacy of GBM and may help to improve the prognostic prediction of GBM.
Association of ADHD and Obesity in Hispanic Children on the US-Mexico Border: A Retrospective Analysis
Authors: Salcido Alyssa , Robles Eden Hernandez , Chaudhary Kiran , Alvarado Luis , Iñiguez Sergio D. , Vargas-Medrano Javier , Diaz-Pacheco Valeria , Villanos Maria Theresa , Gadad Bharathi S. , Martin Sarah L.
Published: January 2022

Pediatric obesity and Attention Deficit Hyperactivity Disorder (ADHD) are rising health concerns in the United States, especially among Hispanic children and adolescents. Research on Hispanic children and adolescents indicates disproportionately higher prevalence rates of obesity in this community but scant data on ADHD prevalence rates. In contrast, a plethora of research studies across the general population examines the relationship between childhood obesity and ADHD. In addition, there is a lack of research that examines the role of ethnicity and sub-ethnic group correlations in ADHD, particularly in the Hispanic population. Existing studies in the general population indicate ADHD may be a risk factor for being overweight compared to normal controls. The objective of the present study is to examine the prevalence of obesity in children with ADHD compared to children in the general population in a predominately Hispanic sample on the US-Mexico border. A total of 7,270 pediatric medical records were evaluated. The retrospective analysis included Body Mass Index (BMI) and related health variables, and ethnicity and showed that children with ADHD are more likely to be underweight. In conclusion, no significant relationship existed between obesity and ADHD among Hispanic children on the US-Mexico Border, and instead we found the opposite correlation.
CircWHSC1 Promotes Breast Cancer Progression by Regulating the FASN/AMPK/mTOR Axis Through Sponging miR-195-5p
Authors: Chen Qian , Yang Zhen , Ding Hongjian , Li Huaqing , Wang Weiyu , Pan Zhiyu
Published: January 2022

Numerous studies reveal that circular RNAs (circRNAs) affect cancer progression. CircWHSC1 is a novel circRNA that accelerates ovarian cancer progression. Nevertheless, the function of circWHSC1 in regulating breast cancer (BC) is elusive. Here, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out to detect the profiles of circWHSC1 and miR-195-5p in BC tissues and corresponding non-tumor tissues. Gain- and loss-of-function assays were implemented both in vivo and ex vivo to verify the significance of circWHSC1 in BC development. BC cell proliferation was estimated by the cell counting kit-8 (CCK-8) and BrdU assays. Transwell assay was implemented to test BC cell migration and invasion. The protein levels of FASN, AMPK and mTOR were determined by Western blot. Moreover, immunohistochemistry was performed to examine Ki67 and FASN expression. As shown by the result, circWHSC1 was up-regulated in BC tissues versus adjacent non-tumor tissues. circWHSC1 overexpression was correlated with higher tumor stages, lymphatic metastasis and worse survival of BC patients. Functionally, overexpressing circWHSC1 amplified proliferation, migration and invasion of BC cell lines and boosted xenograft tumor growth in nude mice. Bioinformatics uncovered that circWHSC1 functioned as a competitive endogenous RNA by sponging miR-195-5p, which was further corroborated by the dual-luciferase reporter assay and RNA immunoprecipitation. miR-195-5p delayed BC progression, which was dampened by circWHSC1 up-regulation. Fatty acid synthase (FASN) was affirmed as a direct target of miR-195-5p. miR-195-5p overexpression curbed FASN expression and activated its downstream AMPK pathway. Inhibition of FASN or activation of the AMPK pathway reversed circWHSC1-mediated oncogenic effects. Collectively, CircWHSC1 acted as an oncogene to expedite BC evolvement by modulating the miR-195-5p/FASN/AMPK/mTOR pathway.
Case Report: Differential Genomics and Evolution of a Meningeal Melanoma Treated With Ipilimumab and Nivolumab
Authors: Burgos Remberto , Cardona Andrés F. , Santoyo Nicolas , Ruiz-Patiño Alejandro , Cure-Casilimas Juanita , Rojas Leonardo , Ricaurte Luisa , Muñoz Álvaro , Garcia-Robledo Juan Esteban , Ordoñez Camila , Sotelo Carolina , Rodríguez July , Zatarain-Barrón Zyanya Lucia , Pineda Diego , Arrieta Oscar
Published: January 2022

Primary melanocytic tumors of the CNS are extremely rare conditions, encompassing different disease processes including meningeal melanoma and meningeal melanocytosis. Its incidence range between 3-5%, with approximately 0.005 cases per 100,000 people. Tumor biological behavior is commonly aggressive, with poor prognosis and very low survivability, and a high recurrence rate, even after disease remission with multimodal treatments. Specific genetic alterations involving gene transcription, alternative splicing, RNA translation, and cell proliferation are usually seen, affecting genes like BRAF, TERT, GNAQ, SF3B1, and EIF1AX. Here we present an interesting case of a 59-year-old male presenting with neurologic symptoms and a further confirmed diagnosis of primary meningeal melanoma. Multiple therapy lines were used, including radiosurgery, immunotherapy, and chemotherapy. The patient developed two relapses and an evolving genetic makeup that confirmed the disease’s clonal origin. We also provide a review of the literature on the genetic basis of primary melanocytic tumors of the CNS.
CXCR4 Mediates Enhanced Cell Migration in CALM-AF10 Leukemia
Authors: Fertal Shelby A. , Zaidi Sayyed K. , Stein Janet L. , Stein Gary S. , Heath Jessica L.
Published: January 2022

Leukemia transformed by the CALM-AF10 chromosomal translocation is characterized by a high incidence of extramedullary disease, central nervous system (CNS) relapse, and a poor prognosis. Invasion of the extramedullary compartment and CNS requires leukemia cell migration out of the marrow and adherence to the cells of the local tissue. Cell adhesion and migration are increasingly recognized as contributors to leukemia development and therapeutic response. These processes are mediated by a variety of cytokines, chemokines, and their receptors, forming networks of both secreted and cell surface factors. The cytokines and cytokine receptors that play key roles in CALM-AF10 driven leukemia are unknown. We find high cell surface expression of the cytokine receptor CXCR4 on leukemia cells expressing the CALM-AF10 oncogenic protein, contributing to the migratory nature of this leukemia. Our discovery of altered cytokine receptor expression and function provides valuable insight into the propagation and persistence of CALM-AF10 driven leukemia.
Immunotherapy for Cutaneous Squamous Cell Carcinoma: Results and Perspectives
Authors: Alberti Andrea , Bossi Paolo
Published: January 2022

Although initial surgical excision cures 95% of patients, a minority of cutaneous squamous cell carcinomas (cSCCs) are judged to be unresectable, either locally advanced or with unresectable regional lymph nodes or distant metastases. These patients are offered systemic treatments. Response rate to chemotherapy is relatively low and not durable, as well as the results obtained with epidermal growth factor inhibitors (EGFRi). Like other cutaneous tumors, cSCCs have high immunogenicity, driven by the high mutational burden, the ultraviolet signature, and the overexpressed tumor antigens. Two checkpoint inhibitors, cemiplimab and pembrolizumab, achieved high response rate and survival with fewer toxicities than other available systemic agents. These promising results prompted to investigate new combination strategies of systemic therapy and surgery or radiotherapy. Subgroup analysis showed promising role of immunotherapy to facilitate surgery in locally advanced cSCC and, in a small group of patients, long-term survivals without resection. However, some cSCCs treated with immunotherapy develop either early or late resistance, so new drugs and new combinations are in a clinical study to overcome the mechanism underpinning these resistances. The present review focuses on the progress with immunotherapy to date and on new therapeutic strategies for cSCC.
Aberrant Expression of miR-1301 in Human Cancer
Authors: Zhong Chenming , Dong Yiyao , Zhang Qiudan , Yuan Chunhui , Duan Shiwei
Published: January 2022

miR-1301 is a newly discovered miRNA, which is abnormally expressed in 14 types of tumors. miR-1301 inhibits 23 target genes, forms a ceRNA network with 2 circRNAs and 8 lncRNAs, and participates in 6 signaling pathways, thereby affecting tumor cell proliferation, invasion, metastasis, apoptosis, angiogenesis, etc. Abnormal expression of miR-1301 is often associated with poor prognosis of cancer patients. In addition, miR-1301 is related to the anti-tumor effect of epirubicin on osteosarcoma and imatinib on chronic myeloid leukemia(CML) and can enhance the cisplatin sensitivity of ovarian cancer. This work systematically summarizes the abnormal expression and prognostic value of miR-1301 in a variety of cancers, depicts the miR-1301-related signaling pathways and ceRNA network, and provides potential clues for future miR-1301 research.
The Organization of Diagnosis, Care and Funding for Specific Learning and Developmental Disorders (SLDD): A French Regional Experimental Protocol
Authors: Willig Thiébaut-Noël , Henry Vincent , Netter Jean-Claude , Contis Patrick , Castro-Gutierrez Cécile , Oget-Gendre Claire , Bonnier Christophe , Cabarrou Emilie , Raffier Laurent , Kabantchenko Agnès
Published: January 2022

Introduction: Access in France to early diagnosis and care for the most severe, but infrequent, Neurodevelopmental Disorders (NDD), autism spectrum disorder and global developmental delay, in children aged 0–7 was improved through measures implemented in 2019. However, there are no such measures for specific learning disorders (SLD), attention, motricity and language disorders (SLDD), despite their annual incidence of between 5 and 8%.

Method: We describe the design of a new type of organization and financing of care for SLDD including evaluation procedure, as well as other factors, mainly at the prevention level that will contribute to local and national policy for this frequent health problem. This in response to a national call for projects, commonly called Article 51, targeted innovation in healthcare delivery and funding in the context of medium-term national reform. This provides project stakeholders with the opportunity to set up and implement “bottom-up” projects, mainly using local professionals. A joint initiative by the regional Health Authorities of the Occitanie region, the French Social Security system and a non-profit Association (Occitadys) proposed an experimental new structure of NDD care and funding.

Discussion: We here discuss the design of this experiment that aims, over two to three years, to alleviate families' financial burden of care and establish a regional three-tier care system with respect to evaluation, re-education and rehabilitation care. Our approach may benefit SLDD health-care planning, and addresses the questions of prevention, early detection and care-design for families, taking local and socioeconomic disparities into account.
Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!
Authors: André Pascal , Diezi Léonore , Dao Kim , Crisinel Pierre Alex , Rothuizen Laura E. , Chtioui Haithem , Decosterd Laurent Arthur , Diezi Manuel , Asner Sandra , Buclin Thierry
Published: January 2022

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.

Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.

Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.

Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.
A Diagnostic Model for Kawasaki Disease Based on Immune Cell Characterization From Blood Samples
Authors: Du Shangming , Mansmann Ulrich , Geisler Benjamin P. , Li Yingxia , Hornung Roman
Published: January 2022

Background: Kawasaki disease (KD) is the leading cause of acquired heart disease in children. However, distinguishing KD from febrile infections early in the disease course remains difficult. Our goal was to estimate the immune cell composition in KD patients and febrile controls (FC), and to develop a tool for KD diagnosis.

Methods: We used a machine-learning algorithm, CIBERSORT, to estimate the proportions of 22 immune cell types based on blood samples from children with KD and FC. Using these immune cell compositions, a diagnostic score for predicting KD was then constructed based on LASSO regression for binary outcomes.

Results: In the training set (n = 496), a model was fit which consisted of eight types of immune cells. The area under the curve (AUC) values for diagnosing KD in a held-out test set (n = 212) and an external validation set (n = 36) were 0.80 and 0.77, respectively. The most common cell types in KD blood samples were monocytes, neutrophils, CD4+-naïve and CD8+ T cells, and M0 macrophages. The diagnostic score was highly correlated to genes that had been previously reported as associated with KD, such as interleukins and chemokine receptors, and enriched in reported pathways, such as IL-6/JAK/STAT3 and TNFα signaling pathways.

Conclusion: Altogether, the diagnostic score for predicting KD could potentially serve as a biomarker. Prospective studies could evaluate how incorporating the diagnostic score into a clinical algorithm would improve diagnostic accuracy further.