bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Variability and Hotspots of Methane Concentrations in a Large Temperate River
Authors: Bussmann Ingeborg , Koedel Uta , Schütze Claudia , Kamjunke Norbert , Koschorreck Matthias
Published: March 2022

Rivers are significant sources of greenhouse gases (GHGs; e.g., CH4 and CO2); however, our understanding of the large-scale longitudinal patterns of GHG emissions from rivers remains incomplete, representing a major challenge in upscaling. Local hotspots and moderate heterogeneities may be overlooked by conventional sampling schemes. In August 2020 and for the first time, we performed continuous (once per minute) CH4 measurements of surface water during a 584-km-long river cruise along the German Elbe to explore heterogeneities in CH4 concentration at different spatial scales and identify CH4 hotspots along the river. The median concentration of dissolved CH4 in the Elbe was 112 nmol L−1, ranging from 40 to 1,456 nmol L−1 The highest CH4 concentrations were recorded at known potential hotspots, such as weirs and harbors. These hotspots were also notable in terms of atmospheric CH4 concentrations, indicating that measurements in the atmosphere above the water are useful for hotspot detection. The median atmospheric CH4 concentration was 2,033 ppb, ranging from 1,821 to 2,796 ppb. We observed only moderate changes and fluctuations in values along the river. Tributaries did not obviously affect CH4 concentrations in the main river. The median CH4 emission was 251 μmol m−2 d−1, resulting in a total of 28,640 mol d−1 from the entire German Elbe. Similar numbers were obtained using a conventional sampling approach, indicating that continuous measurements are not essential for a large-scale budget. However, we observed considerable lateral heterogeneity, with significantly higher concentrations near the shore only in reaches with groins. Sedimentation and organic matter mineralization in groin fields evidently increase CH4 concentrations in the river, leading to considerable lateral heterogeneity. Thus, river morphology and structures determine the variability of dissolved CH4 in large rivers, resulting in smooth concentrations at the beginning of the Elbe versus a strong variability in its lower parts. In conclusion, groin construction is an additional anthropogenic modification following dam building that can significantly increase GHG emissions from rivers.
Research on the Impact of Deleveraging Policy on Enterprise Green Innovation: An Empirical Study in China
Authors: Shen Dongyang , He Wenjian
Published: March 2022

By optimizing enterprises’ capital structure, the deleveraging policy has a close relationship with green innovation. Taking the Opinions on Actively and Steadily Reducing Enterprise Leverage issued by the State Council of China in 2016 as an exogenous shock and utilizing the panel date of listed manufacturing enterprises in China from 2010 to 2019, this paper constructs a DID model and conducts a series of robustness tests, which quantitatively confirm that the deleveraging policy can play a positive role in improving enterprise green innovation. Furthermore, heterogeneity analysis reveals that the deleveraging policy can promote the application of green invention patents to a greater extent and has a greater effect on green innovation in state-owned enterprises, large-scale enterprises, technology-intensive enterprises, and enterprises in financially developed regions. Ultimately, the mechanism test confirms that the deleveraging policy provides long-term funds for enterprise green innovation by promoting enterprise equity financing. And with the strengthening of shareholders’ supervision and management, it also effectively ensures the stable development of green innovation.
Promoterless Gene Targeting Approach Combined to CRISPR/Cas9 Efficiently Corrects Hemophilia B Phenotype in Neonatal Mice
Authors: Lisjak Michela , De Caneva Alessia , Marais Thibaut , Barbon Elena , Biferi Maria Grazia , Porro Fabiola , Barzel Adi , Zentilin Lorena , Kay Mark A. , Mingozzi Federico , Muro Andrés F.
Published: March 2022

Many inborn errors of metabolism require life-long treatments and, in severe conditions involving the liver, organ transplantation remains the only curative treatment. Non-integrative AAV-mediated gene therapy has shown efficacy in adult patients. However, treatment in pediatric or juvenile settings, or in conditions associated with hepatocyte proliferation, may result in rapid loss of episomal viral DNA and thus therapeutic efficacy. Re-administration of the therapeutic vector later in time may not be possible due to the presence of anti-AAV neutralizing antibodies. We have previously shown the permanent rescue of the neonatal lethality of a Crigler-Najjar mouse model by applying an integrative gene-therapy based approach. Here, we targeted the human coagulation factor IX (hFIX) cDNA into a hemophilia B mouse model. Two AAV8 vectors were used: a promoterless vector with two arms of homology for the albumin locus, and a vector carrying the CRISPR/SaCas9 and the sgRNA. Treatment of neonatal P2 wild-type mice resulted in supraphysiological levels of hFIX being stable 10 months after dosing. A single injection of the AAV vectors into neonatal FIX KO mice also resulted in the stable expression of above-normal levels of hFIX, reaching up to 150% of the human levels. Mice subjected to tail clip analysis showed a clotting capacity comparable to wild-type animals, thus demonstrating the rescue of the disease phenotype. Immunohistological analysis revealed clusters of hFIX-positive hepatocytes. When we tested the approach in adult FIX KO mice, we detected hFIX in plasma by ELISA and in the liver by western blot. However, the hFIX levels were not sufficient to significantly ameliorate the bleeding phenotype upon tail clip assay. Experiments conducted using a AAV donor vectors containing the eGFP or the hFIX cDNAs showed a higher recombination rate in P2 mice compared to adult animals. With this study, we demonstrate an alternative gene targeting strategy exploiting the use of the CRISPR/SaCas9 platform that can be potentially applied in the treatment of pediatric patients suffering from hemophilia, also supporting its application to other liver monogenic diseases. For the treatment of adult patients, further studies for the improvement of targeting efficiency are still required.
Identification of an Iron Metabolism-Related lncRNA Signature for Predicting Osteosarcoma Survival and Immune Landscape
Authors: Hong-bin Shao , Wan-jun Yang , Chen-hui Dong , Xiao-jie Yang , Shen-song Li , Peng Zhou
Published: March 2022

Background: Long noncoding RNAs (lncRNAs) act as epigenetic regulators in the process of ferroptosis and iron metabolism. This study aimed to identify an iron metabolism-related lncRNA signature to predict osteosarcoma (OS) survival and the immune landscape.

Methods: RNA-sequencing data and clinical information were obtained from the TARGET dataset. Univariate Cox regression and LASSO Cox analysis were used to develop an iron metabolism-related lncRNA signature. Consensus clustering analysis was applied to identify subtype-based prognosis-related lncRNAs. CIBERSORT was used to analyze the difference in immune infiltration and the immune microenvironment in the two clusters.

Results: We identified 302 iron metabolism-related lncRNAs based on 515 iron metabolism-related genes. The results of consensus clustering showed the differences in immune infiltration and the immune microenvironment in the two clusters. Through univariate Cox regression and LASSO Cox regression analysis, we constructed an iron metabolism-related lncRNA signature that included seven iron metabolism-related lncRNAs. The signature was verified to have good performance in predicting the overall survival, immune-related functions, and immunotherapy response of OS patients between the high- and low-risk groups.

Conclusion: We identified an iron metabolism-related lncRNA signature that had good performance in predicting survival outcomes and showing the immune landscape for OS patients. Furthermore, our study will provide valuable information to further develop immunotherapies of OS.
Regulation of SIRT1 and Its Roles in Inflammation
Authors: Yang Yunshu , Liu Yang , Wang Yunwei , Chao Yongyi , Zhang Jinxin , Jia Yanhui , Tie Jun , Hu Dahai
Published: March 2022

The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD+-dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional and post-transcriptional levels. We also summarize factors that influence SIRT1 activity including the NAD+/NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases.
Natural Human Immunity Against Staphylococcal Protein A Relies on Effector Functions Triggered by IgG3
Authors: Boero Elena , Cruz Ana Rita , Pansegrau Werner , Giovani Cinzia , Rooijakkers Suzan H. M. , van Kessel Kok P. M. , van Strijp Jos A. G. , Bagnoli Fabio , Manetti Andrea G. O.
Published: March 2022

Staphylococcal protein A (SpA) is a multifunctional, highly conserved virulence factor ofStaphylococcus aureus. By binding the Fc portion of all human IgG subclasses apart from IgG3, SpA interferes with antibody and complement deposition on the bacterial surface, impairing staphylococcal clearance by phagocytosis. Because of its anti-opsonic properties, SpA is not investigated as a surface antigen to mediate bacterial phagocytosis. Herein we investigate human sera for the presence of SpA-opsonizing antibodies. The screening revealed that sera containing IgG3 against SpA were able to correctly opsonize the target and drive Fcγ receptor-mediated interactions and phagocytosis. We demonstrated that IgG3 Fc is significantly more efficient in inducing phagocytosis of SpA-expressingS. aureusas compared to IgG1 Fc in an assay resembling physiological conditions. Furthermore, we show that the capacity of SpA antibodies to induce phagocytosis depends on the specific epitope recognized by the IgGs on SpA molecules. Overall, our results suggest that anti-SpA IgG3 antibodies could favor the anti-staphylococcal response in humans, paving the way towards the identification of a correlate of protection against staphylococcal infections.
Disease Severity in Moderate-to-Severe COVID-19 Is Associated With Platelet Hyperreactivity and Innate Immune Activation
Authors: Jakobs Kai , Reinshagen Leander , Puccini Marianna , Friebel Julian , Wilde Anne-Christin Beatrice , Alsheik Ayman , Rroku Andi , Landmesser Ulf , Haghikia Arash , Kränkel Nicolle , Rauch-Kröhnert Ursula
Published: March 2022

Background

Hemostasis and inflammation are both dysregulated in patients with moderate-to-severe coronavirus disease 2019 (COVID-19). Yet, both processes can also be disturbed in patients with other respiratory diseases, and the interactions between coagulation, inflammation, and disease severity specific to COVID-19 are still vague.

Methods

Hospitalized patients with acute respiratory symptoms and with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-positive (COVpos) and SARS-CoV2-negative (COVneg) status were included. We assessed adenosine diphosphate (ADP)-, thrombin receptor activator peptide 6 (TRAP)-, and arachidonic acid (AA)-induced platelet reactivity by impedance aggregometry, as well as leukocyte subtype spectrum and platelet-leukocyte aggregates by flow cytometry and inflammatory cytokines by cytometric bead array.

Results

ADP-, TRAP-, and AA-induced platelet reactivity was significantly higher in COVpos than in COVneg patients. Disease severity, assessed by sequential organ failure assessment (SOFA) score, was higher in COVpos than in COVneg patients and again higher in deceased COVpos patients than in surviving COVpos. The SOFA score correlated significantly with the mean platelet volume and TRAP-induced platelet aggregability. A larger percentage of classical and intermediate monocytes, and of CD4pos T cells (TH) aggregated with platelets in COVpos than in COVneg patients. Interleukin (IL)-1 receptor antagonist (RA) and IL-6 levels were higher in COVpos than in COVneg patients and again higher in deceased COVpos patients than in surviving COVpos. IL-1RA and IL-6 levels correlated with the SOFA score in COVpos but not in COVneg patients. In both respiratory disease groups, absolute levels of B-cell-platelet aggregates and NK-cell-platelet aggregates were correlated with ex vivo platelet aggegation upon stimulation with AA and ADP, respectively, indicating a universal, but not a COVID-19-specific mechanism.

Conclusion

In moderate-to-severe COVID-19, but not in other respiratory diseases, disease severity was associated with platelet hyperreactivity and a typical inflammatory signature. In addition to a severe inflammatory response, platelet hyperreactivity associated to a worse clinical outcome in patients with COVID-19, pointing to the importance of antithrombotic therapy for reducing disease severity.
Characterization of Monoclonal Antibodies Recognizing Citrulline-Modified Residues
Authors: Chen Yaqiong , Weng Lin , Liu Wei , Deng Chenxi , Xuan Jinxiu , Ma Yuan , Li Cao , Jiang Jinlu , Chen Juan , Ge Shengxiang
Published: March 2022

Background

Citrullination is a post-translational protein modification linked to the occurrence and development of a variety of diseases. The detection of citrullinated proteins is predominately based on antibody detection although currently available reagents demonstrate detection bias according to the environmental context of the citrullinated residues. This study aimed to develop improved antibody reagents capable of detecting citrullinated residues in proteins in an unbiased manner.

Methods

BALB/c mice were sequentially immunized using citrulline conjugates with different carrier proteins, and specific monoclonal antibodies (mAbs) identified by primary screening using citrulline-conjugated proteins unrelated to the immunogen. Secondary screening was performed to identify mAbs whose reactivity could be specifically blocked by free citrulline, followed by identification and performance assessment.

Results

Two mAbs, 22F1 and 30G2, specifically recognizing a single citrulline residue were screened from 22 mAbs reacting with citrulline conjugates. Compared with commercially available anti-citrulline antibodies (AB6464, AB100932 and MABN328), 22F1 and 30G2 demonstrated significantly higher reactivity as well as a broader detection spectrum against different citrullinated proteins. 22F1 and 30G2 also had higher specificity than commercial antibodies and overall better applicability to a range of different immunoassays.

Conclusion

Two mAbs specifically recognizing a single citrulline residue were successfully produced, each possessing good specificity against different citrullinated proteins. The improved utility of these reagents is expected to make a strong contribution to protein citrullination-related research.
A Systematic Review of the Progression of Cutaneous Lupus to Systemic Lupus Erythematosus
Authors: Curtiss Paul , Walker Amanda M. , Chong Benjamin F.
Published: March 2022

Lupus erythematosus is an autoimmune disease that may manifest in a variety of organs and tissues including the skin, kidney, brain, heart and lung. Many patients present with cutaneous lupus, where disease is often limited to the skin, but are at risk for developing systemic lupus. The objective of our present study is to perform a systematic review of studies that investigated patient cohorts and populations for the occurrence of cutaneous lupus progressing to systemic lupus. Inclusion criteria required that studies present longitudinal data of patients with limited cutaneous lupus erythematosus who were followed for development of systemic lupus erythematosus. Studies were excluded if patients had concurrent diagnosis of SLE, or if they failed to present longitudinal data. Medline and Embase were searched for English language studies using the Ovid platform. A total of 25 adult studies were identified, as well as 8 pediatric studies. The rate of cutaneous to systemic lupus progression ranged between 0% to 42% in the adult studies and 0% to 31% in the pediatric groups. The variability in these rates were due to differences in patient populations, study design, criteria used to diagnose systemic lupus, and follow-up time. Common risk factors associated with systemic lupus erythematosus development including having positive anti-nuclear antibodies, hematologic abnormalities, and higher number of lupus classification criteria at baseline. This study emphasizes the importance for providers to routinely monitor for systemic lupus in patients with cutaneous lupus.
Therapeutic Effects of Topical Application of Lycium barbarum Polysaccharide in a Murine Model of Dry Eye
Authors: Qin Danyi , Deng Yingping , Wang Lixiang , Yin Hongbo
Published: March 2022

Purpose

To evaluate the safety and efficacy of Lycium barbarum polysaccharide (LBP) eye drops in a murine model of dry eye disease (DED).

Methods

Six- to eight-week-old female C57BL/6 mice were subjected to a combination of desiccating stress (DS) and topical benzalkonium chloride (BAC) to induce DED. Five microliters of LBP eye drops (0.625, 2.5, or 12.5 mg/ml) or PBS was applied topically 3 times per day for 10 days to subsequently test their efficacy. Tear secretion, tear breakup time (TBUT), corneal irregularity, and corneal fluorescein staining scores were measured on days 3 and 10 after treatment. The expression of tumor necrosis factor-alpha (TNF-α) in the cornea was assessed by quantitative (q) RT–PCR on days 10. The ocular irritation of LBP eye drops of corresponding concentrations was evaluated on 10- to 12-week-old female Sprague–Dawley rats.

Results

Compared with PBS-treated groups, mice treated with 0.625, 2.5, and 12.5 mg/ml LBP showed a significant improvement in the clinical signs of DED in a dose-dependent manner, including corneal epithelial integrity, corneal regularity, and tear production, as well as significant inhibition of inflammatory cell infiltration and TNF-α expression levels in the cornea. All corresponding concentrations of LBP eye drops revealed no obvious ocular irritation.

Conclusion

Topical application of LBP could ameliorate dry eye in a murine model of DED without obvious ocular irritation.
Dynamic Changes of Ocular Surface in First-Time Contact Lens Wearers and the Effective Factors of Contact Lens Discomfort
Authors: Xu Yangyang , Xu Zhiqiang , Shu Xupeng , Liu Qiaoli , Wang Yuzhou , Xia Jiahui , Li Yong , Qu Jia , Hu Liang
Published: March 2022

Purpose

The purpose of the study is to investigate the dynamic changes in ocular surface indicators in first-time contact lens (CL) wearers and identify the most influential factors in CL discomfort (CLD).

Methods

A total of 26 healthy non-CL wearers (26 eyes) were recruited and fitted monthly with disposable hydrogel CLs. Each participant underwent a full ocular surface evaluation, which include Efron grading, tear film breakup time, Schirmer's I test, corneal dendritic cell (DCs) imaging by in vivo confocal microscopy (IVCM), and conjunctival microvasculature evaluation by functional slit-lamp biomicroscopy. CLD was assessed using the Ocular Surface Disease Index questionnaire at baseline, 1 week, 1, 3, and 6 months after wearing it and another 6 months after discontinuing it.

Results

Clinical signs and CLD were significantly increased in the first week (p < 0.05). The microvascular response and DC activation peaked at the 1-month interval (p < 0.05). During CL wear, CLD is positively correlated with corneal staining (B = 0.238, p = 0.002), papillary conjunctivitis (B = 0.245, p < 0.001), and microvascular blood flow velocity (B = 0.353, p < 0.001). After discontinuation, only DC activation remained elevated at 6 months, whereas the other signs recovered.

Conclusions

The first week of CL wear was the main period for the appearance of ocular surface clinical signs, and the first month was the main period for the activation of subclinical inflammation. Corneal staining and conjunctival microvascular response are the main factors affecting CLD. Even if the clinical signs recover after discontinuing wear, subclinical inflammation may persist.
A Combined Procedure of Intrastromal Corneal Rings Explantation and Penetrating Keratoplasty in a Patient With Keratoconus: A Case Report
Authors: Nuzzi Raffaele , Tripoli Flavia , Rossi Alessandro , Ghilardi Andrea
Published: March 2022

Keratoconus is a non-inflammatory and degenerative corneal ectasia that determinate progressive steepening of paracentral cornea with development of irregular astigmatism and visual function deterioration. According to the stage of the pathology, different methods of correction can be used: rigid contact lenses may be used to alter corneal shape and partially correct astigmatism, corneal collagen cross-linking (CXL) and intrastromal corneal ring segment (ICRS) implantation can reinforce corneal stroma to slow disease progression. Late-stage treatment comprehend anterior lamellar keratoplasty or penetrating keratoplasty. We evaluated a 31-year-old patient who was subjected to bilateral ICRS implantation combined with CXL due to keratoconus. This led, after 9 months, to ring extrusion in his left eye, corneal thinning and microperforation into the aqueous chamber with residual irregular astigmatism of 4.50 D. cyl. 10°. The patient underwent ICRS explantation and PKP during the same surgical session. After 15 months of follow-up, the BCVA was 0.2 LogMAR with a residual astigmatism of 6.3 dpt.
Microbial Community and Function-Based Synthetic Bioinoculants: A Perspective for Sustainable Agriculture
Authors: Suman Archna , Govindasamy Venkadasamy , Ramakrishnan Balasubramanian , Aswini K. , SaiPrasad J. , Sharma Pushpendra , Pathak Devashish , Annapurna Kannepalli
Published: March 2022

Interactions among the plant microbiome and its host are dynamic, both spatially and temporally, leading to beneficial or pathogenic relationships in the rhizosphere, phyllosphere, and endosphere. These interactions range from cellular to molecular and genomic levels, exemplified by many complementing and coevolutionary relationships. The host plants acquire many metabolic and developmental traits such as alteration in their exudation pattern, acquisition of systemic tolerance, and coordination of signaling metabolites to interact with the microbial partners including bacteria, fungi, archaea, protists, and viruses. The microbiome responds by gaining or losing its traits to various molecular signals from the host plants and the environment. Such adaptive traits in the host and microbial partners make way for their coexistence, living together on, around, or inside the plants. The beneficial plant microbiome interactions have been exploited using traditional culturable approaches by isolating microbes with target functions, clearly contributing toward the host plants’ growth, fitness, and stress resilience. The new knowledge gained on the unculturable members of the plant microbiome using metagenome research has clearly indicated the predominance of particular phyla/genera with presumptive functions. Practically, the culturable approach gives beneficial microbes in hand for direct use, whereas the unculturable approach gives the perfect theoretical information about the taxonomy and metabolic potential of well-colonized major microbial groups associated with the plants. To capitalize on such beneficial, endemic, and functionally diverse microbiome, the strategic approach of concomitant use of culture-dependent and culture-independent techniques would help in designing novel “biologicals” for various crops. The designed biologicals (or bioinoculants) should ensure the community’s persistence due to their genomic and functional abilities. Here, we discuss the current paradigm on plant-microbiome-induced adaptive functions for the host and the strategies for synthesizing novel bioinoculants based on functions or phylum predominance of microbial communities using culturable and unculturable approaches. The effective crop-specific inclusive microbial community bioinoculants may lead to reduction in the cost of cultivation and improvement in soil and plant health for sustainable agriculture.
Molecular Mechanisms Underlying Bacterial Uranium Resistance
Authors: Rogiers Tom , Van Houdt Rob , Williamson Adam , Leys Natalie , Boon Nico , Mijnendonckx Kristel
Published: March 2022

Environmental uranium pollution due to industries producing naturally occurring radioactive material or nuclear accidents and releases is a global concern. Uranium is hazardous for ecosystems as well as for humans when accumulated through the food chain, through contaminated groundwater and potable water sources, or through inhalation. In particular, uranium pollution pressures microbial communities, which are essential for healthy ecosystems. In turn, microorganisms can influence the mobility and toxicity of uranium through processes like biosorption, bioreduction, biomineralization, and bioaccumulation. These processes were characterized by studying the interaction of different bacteria with uranium. However, most studies unraveling the underlying molecular mechanisms originate from the last decade. Molecular mechanisms help to understand how bacteria interact with radionuclides in the environment. Furthermore, knowledge on these underlying mechanisms could be exploited to improve bioremediation technologies. Here, we review the current knowledge on bacterial uranium resistance and how this could be used for bioremediation applications.
Diagnostic Accuracy of Blood-Based Biomarker Panels: A Systematic Review
Authors: Hardy-Sosa Anette , León-Arcia Karen , Llibre-Guerra Jorge J. , Berlanga-Acosta Jorge , Baez Saiyet de la C. , Guillen-Nieto Gerardo , Valdes-Sosa Pedro A.
Published: March 2022

Background

Because of high prevalence of Alzheimer’s disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD, especially in LMICs. Furthermore, it has been suggested that panels of markers may perform better than single protein candidates.

Methods

Medline/Pubmed was searched to identify current relevant studies published from January 2016 to December 2020. We included all full-text articles examining blood-based biomarkers as a set of protein markers or panels to aid in AD’s early diagnosis, prognosis, and characterization.

Results

Seventy-six articles met the inclusion criteria for systematic review. Majority of the studies reported plasma and serum as the main source for biomarker determination in blood. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis with better accuracy than individual biomarkers. Conventional (amyloid-beta and tau) and neuroinflammatory biomarkers, such as amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, and other tau isoforms, were the most represented. We found the combination of amyloid beta-42/amyloid beta-40 ratio and APOEε4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status.

Conclusion

Assessment of Alzheimer’s disease biomarkers in blood as a non-invasive and cost-effective alternative will potentially contribute to early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, combination of markers seems to perform better in the diagnosis and prognosis of the disease than individual biomarkers.
The Effects of Aging and Time of Day on Inhibitory Control: An Event-Related Potential Study
Authors: Rabi Rahel , Chow Ricky , Paracha Shahier , Hasher Lynn , Gardner Sandra , Anderson Nicole D. , Alain Claude
Published: March 2022

Time of day (TOD) influences on executive functions have been widely reported, with greater efficiency demonstrated at optimal relative to non-optimal TOD according to one’s chronotype (i.e., synchrony effect). Older adults (OAs) show declines in inhibitory control and are more sensitive to the effects of circadian variation on executive functioning. To date, no studies have investigated the effects of TOD and aging on executive functioning using electrophysiological measures. The present study investigated the effects of aging and TOD on the neural correlates of inhibitory processing (N2 and P3) using event-related potentials (ERPs). Go-NoGo and Flanker tasks were administered to 52 OAs of morning chronotype and 51 younger adults (YAs) of afternoon-to-evening chronotype who were randomly assigned to morning or afternoon test sessions, with the optimal TOD for OAs in the morning and for YAs in the afternoon/evening. While behavioral results demonstrated no TOD effects, ERPs indicated synchrony effects. Both YAs and OAs showed greater modulation of Go-NoGo N2 and greater P3 amplitude during the non-optimal than optimal TOD, consistent with the synchrony effect. For the Flanker task, age differences in P3 amplitude were only apparent during the non-optimal TOD. These results suggest that processes associated with inhibitory control are differentially affected by TOD and aging, with age-related reductions in inhibitory efficiency during off-peak test times on measures of interference control. These findings highlight the sensitivity of ERPs to detect TOD effects in the absence of behavioral differences, confirm more pronounced TOD effects in OAs relative to YAs on ERP measures of interference control, and reinforce the need to assess and control for circadian typology in research studies.
Aging-Related Alterations to Persistent Firing in the Lateral Entorhinal Cortex Contribute to Deficits in Temporal Associative Memory
Authors: Lin Carmen , Oh M. Matthew , Disterhoft John F.
Published: March 2022

With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.
Affective Valence Regulates Associative Competition in Pavlovian Conditioning
Authors: Laurent Vincent , Westbrook R. Frederick , Balleine Bernard W.
Published: March 2022

Evidence suggests that, in Pavlovian conditioning, associations form between conditioned stimuli and multiple components of the unconditioned stimulus (US). It is common, for example, to regard USs as composed of sensory and affective components, the latter being either appetitive (e.g., food or water) or aversive (e.g., shock or illness) and, therefore, to suppose different USs of the same affective class activate a common affective system. Furthermore, evidence is growing for the suggestion that, in competitive learning situations, competition between predictive stimuli is primarily for association with the affective system activated by the US. Thus, a conditioned stimulus (CS) previously paired with one US will block conditioning to another CS when both are presented together and paired with a different US of the same affective class, a phenomenon called transreinforcer blocking. Importantly, similar effects have been reported when steps are taken to turn the pretrained CS into a conditioned inhibitor, which activates the opposing affective state to the excitor that it inhibits. Thus, an appetitive inhibitor can block conditioning to a second CS when they are presented together and paired with foot shock. Here we show that the same is true of an aversive inhibitor. In two experiments conducted in rats, we found evidence that an aversive inhibitor blocked conditioning to a second CS when presented in a compound and paired with food. Such findings demonstrate that affective processes and their opponency organize appetitive-aversive interactions and establish the valences on which they are based, consistent with incentive theories of Pavlovian conditioning.
The GummiArm Project: A Replicable and Variable-Stiffness Robot Arm for Experiments on Embodied AI
Authors: Stoelen Martin F. , de Azambuja Ricardo , López Rodríguez Beatriz , Bonsignorio Fabio , Cangelosi Angelo
Published: March 2022

Robots used in research on Embodied AI often need to physically explore the world, to fail in the process, and to develop from such experiences. Most research robots are unfortunately too stiff to safely absorb impacts, too expensive to repair if broken repeatedly, and are never operated without the red kill-switch prominently displayed. The GummiArm Project was intended to be an open-source “soft” robot arm with human-inspired tendon actuation, sufficient dexterity for simple manipulation tasks, and with an eye on enabling easy replication of robotics experiments. The arm offers variable-stiffness and damped actuation, which lowers the potential for damage, and which enables new research opportunities in Embodied AI. The arm structure is printable on hobby-grade 3D printers for ease of manufacture, exploits stretchable composite tendons for robustness to impacts, and has a repair-cycle of minutes when something does break. The material cost of the arm is less than $6000, while the full set of structural parts, the ones most likely to break, can be printed with less than $20 worth of plastic filament. All this promotes a concurrent approach to the design of “brain” and “body,” and can help increase productivity and reproducibility in Embodied AI research. In this work we describe the motivation for, and the development and application of, this 6 year project.
Decoding Digital Visual Stimulation From Neural Manifold With Fuzzy Leaning on Cortical Oscillatory Dynamics
Authors: Yu Haitao , Zhao Quanfa , Li Shanshan , Li Kai , Liu Chen , Wang Jiang
Published: March 2022

A crucial point in neuroscience is how to correctly decode cognitive information from brain dynamics for motion control and neural rehabilitation. However, due to the instability and high dimensions of electroencephalogram (EEG) recordings, it is difficult to directly obtain information from original data. Thus, in this work, we design visual experiments and propose a novel decoding method based on the neural manifold of cortical activity to find critical visual information. First, we studied four major frequency bands divided from EEG and found that the responses of the EEG alpha band (8–15 Hz) in the frontal and occipital lobes to visual stimuli occupy a prominent place. Besides, the essential features of EEG data in the alpha band are further mined via two manifold learning methods. We connect temporally consecutive brain states in the t distribution random adjacency embedded (t-SNE) map on the trial-by-trial level and find the brain state dynamics to form a cyclic manifold, with the different tasks forming distinct loops. Meanwhile, it is proved that the latent factors of brain activities estimated by t-SNE can be used for more accurate decoding and the stable neural manifold is found. Taking the latent factors of the manifold as independent inputs, a fuzzy system-based Takagi-Sugeno-Kang model is established and further trained to identify visual EEG signals. The combination of t-SNE and fuzzy learning can highly improve the accuracy of visual cognitive decoding to 81.98%. Moreover, by optimizing the features, it is found that the combination of the frontal lobe, the parietal lobe, and the occipital lobe is the most effective factor for visual decoding with 83.05% accuracy. This work provides a potential tool for decoding visual EEG signals with the help of low-dimensional manifold dynamics, especially contributing to the brain–computer interface (BCI) control, brain function research, and neural rehabilitation.
Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications
Authors: Costagliola Giorgio , Depietri Greta , Michev Alexandre , Riva Antonella , Foiadelli Thomas , Savasta Salvatore , Bonuccelli Alice , Peroni Diego , Consolini Rita , Marseglia Gian Luigi , Orsini Alessandro , Striano Pasquale
Published: March 2022

Introduction

Recent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field.

Methods

A systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms “status epilepticus,” “epilepsy,” and “seizure.” The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis.

Results

Our search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants.

Conclusion

The experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.
Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview
Authors: Simonati Alessandro , Williams Ruth E.
Published: March 2022

The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.
Aging With Multiple Sclerosis: Age-Related Factors and Socioeconomic Risks
Authors: Wandall-Holm Malthe Faurschou , Andersen Mads Albrecht , Buron Mathias Due , Magyari Melinda
Published: March 2022

Background

Studies have demonstrated an increasing mean age of the population with multiple sclerosis (MS). The association between increased age and socioeconomic outcomes has been investigated sparsely.

Objective

The purpose of this study is to describe the demographic and socioeconomic status of the current Danish population of patients with MS according to age and to assess the age-related risks of no income or losing all income from earnings or receiving disability pension.

Methods

The nationwide population-based Danish Multiple Sclerosis Registry provided data linked with the Danish Income Statistics Register and the Danish Rational Economic Agents Model (DREAM) database. The prevalence of socioeconomic milestones of the current MS population was compared with healthy controls and the risks of reaching socioeconomic milestones were assessed using cause-specific Cox models and cumulative incidence functions compared to healthy controls.

Results

The current Danish population of patients with MS of working age (18–65 years of age) consists of 11,287 patients, of which 29.3% was older than 55 years. In 2018, 38.0% of all patients and 18.9% of controls had no income from earnings, whereas 30.5% of all patients and 7.7% of controls received disability pension. The risk of losing all income from earnings was higher for patients with MS with a hazard ratio (HR) peaking at of 4.0 (95% CI, 3.8–4.2) for the ages of 45–54 years. The risk of receiving disability pension was much higher for patients with MS peaking at a HR of 22.6 (95% CI, 20.9–24.4) for the ages of 25–34 years. Likewise, the absolute risks of both outcomes were higher for the patients with MS at all ages.

Conclusion

Danish patients with MS are at a higher risk of losing all income from earnings and at a much higher risk of receiving disability pension compared with healthy controls.
Alterations of the miR-126-3p/POU2AF1/Spi-B Axis and JCPyV Reactivation in Multiple Sclerosis Patients Receiving Natalizumab
Authors: Mancuso Roberta , Agostini Simone , Hernis Ambra , Caputo Domenico , Galimberti Daniela , Scarpini Elio , Clerici Mario
Published: March 2022

Natalizumab (NTZ) can reactivate human polyomavirus John Cunningham polyomavirus (JCPyV) latent infection and lead to progressive multifocal leukoencephalopathy (PML). NTZ modulates the expression of microRNA-126-3p (miR-126-3p) and its target genes, Spi-B, POU2AF1, and vascular cell adhesion molecule-1 (VCAM-1); Spi-B protein binds the JCPyV regulatory region, initiating early gene transcription. This paper is aimed to evaluate the miR-126-3p and soluble (s)VCAM-1 concentration, Spi-B/POU2AF1 gene expression, and JCPyV activity in patients with multiple sclerosis (MS) before and during 2-years NTZ. Serum miR-126-3p and sVCAM-1 concentration was measured before NTZ and after 1, 12, and 24 months of treatment in 22 MS subjects, 1 patient who developed PML, and 29 healthy controls (HCs). The Spi-B and POU2AF1 expression in blood was analyzed at baseline and at month 24 in 13 patients with MS; results were clusterized based on JCPyV activity. miR-126-3p was significantly downregulated in MS before and during NTZ but was greatly increased in the PML patient. sVCAM-1 concentration was comparable in MS and HCs, and was reduced by NTZ in MS and PML. Spi-B/POU2AF1 expression was significantly increased in MS at baseline and was upregulated by NTZ, particularly in JCPyV-infected patients in whom JCPyV reactivation was detected. Taken together, the results suggest that the modulation of the miR-126-3p/POU2AF1/Spi-B axis associates with JCPyV activity in NTZ-treated patients with MS.
Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes
Authors: Ding Jiangwei , Wang Lei , Jin Zhe , Qiang Yuanyuan , Li Wenchao , Wang Yangyang , Zhu Changliang , Jiang Shucai , Xiao Lifei , Hao Xiaoyan , Hu Xulei , Li Xinxiao , Wang Feng , Sun Tao
Published: March 2022

Background

Dravet syndrome (DS) is a severe epileptic encephalopathy mainly caused by haploinsufficiency of the gene SCN1A, which encodes the voltage-gated sodium channel NaV1. 1 in the brain. While SCN1A mutations are known to be the primary cause of DS, other genes that may cause DS are poorly understood. Several genes with pathogenic mutations result in DS or DS-like phenotypes, which may require different drug treatment approaches. Therefore, it is urgent for clinicians, especially epilepsy specialists to fully understand these genes involved in DS in addition to SCN1A. Particularly for healthcare providers, a deep understanding of these pathogenic genes is useful in properly selecting and adjusting drugs in a more effective and timely manner.

Objective

The purpose of this study was to identify genes other than SCN1A that may also cause DS or DS-like phenotypes.

Methods

A comprehensive search of relevant Dravet syndrome and severe myoclonic epilepsy in infancy was performed in PubMed, until December 1, 2021. Two independent authors performed the screening for potentially eligible studies. Disagreements were decided by a third, more professional researcher or by all three. The results reported by each study were narratively summarized.

Results

A PubMed search yielded 5,064 items, and other sources search 12 records. A total of 29 studies published between 2009 and 2021 met the inclusion criteria. Regarding the included articles, seven studies on PCDH19, three on SCN2A, two on SCN8A, five on SCN1B, two on GABRA1, three on GABRB3, three on GABRG2, and three on STXBP1 were included. Only one study was recorded for CHD2, CPLX1, HCN1 and KCNA2, respectively. It is worth noting that a few articles reported on more than one epilepsy gene.

Conclusion

DS is not only identified in variants of SCN1A, but other genes such as PCDH19, SCN2A, SCN8A, SCN1B, GABRA1, GABRB3, GABRG2, KCNA2, CHD2, CPLX1, HCN1A, STXBP1 can also be involved in DS or DS-like phenotypes. As genetic testing becomes more widely available, more genes associated with DS and DS-like phenotypes may be identified and gene-based diagnosis of subtypes of phenotypes in this spectrum may improve the management of these diseases in the future.