bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantization and sparsity-aware processing for energy-efficient NVM-based convolutional neural networks
Authors: Bao Han , Qin Yifan , Chen Jia , Yang Ling , Li Jiancong , Zhou Houji , Li Yi , Miao Xiangshui
Published: August 2022

Nonvolatile memory (NVM)-based convolutional neural networks (NvCNNs) have received widespread attention as a promising solution for hardware edge intelligence. However, there still exist many challenges in the resource-constrained conditions, such as the limitations of the hardware precision and cost and, especially, the large overhead of the analog-to-digital converters (ADCs). In this study, we systematically analyze the performance of NvCNNs and the hardware restrictions with quantization in both weight and activation and propose the corresponding requirements of NVM devices and peripheral circuits for multiply–accumulate (MAC) units. In addition, we put forward an in situ sparsity-aware processing method that exploits the sparsity of the network and the device array characteristics to further improve the energy efficiency of quantized NvCNNs. Our results suggest that the 4-bit-weight and 3-bit-activation (W4A3) design demonstrates the optimal compromise between the network performance and hardware overhead, achieving 98.82% accuracy for the Modified National Institute of Standards and Technology database (MNIST) classification task. Moreover, higher-precision designs will claim more restrictive requirements for hardware nonidealities including the variations of NVM devices and the nonlinearities of the converters. Moreover, the sparsity-aware processing method can obtain 79%/53% ADC energy reduction and 2.98×/1.15× energy efficiency improvement based on the W8A8/W4A3 quantization design with an array size of 128 × 128.
Youth’s perception toward ecotourism as a possible model for sustainable use of local tourism resources
Authors: Stanciu Mirela , Popescu Agatha , Sava Camelia , Moise George , Nistoreanu Bogdan Gabriel , Rodzik Jarosław , Bratu Iulian Alexandru
Published: August 2022

The knowledge, perception, and behavior of young people toward ecotourism are important for the sustainable development of this sector. The purpose of this research is to evaluate and analyze the knowledge of young Romanian students about ecotourism and the main ecotourism destinations in Romania, their behavior in relation to the practice of this form of sustainable tourism at the local level in the last 2 years (2020 and 2021), and people’s use of the Internet for planning holidays and digital applications while traveling in nature. A quantitative research was conducted based on a self-administered questionnaire, structured in 13 sections on ecotourism, to which were added the sociodemographic data of the respondents. The conclusions of the research are that young people know well the main ecotourism destinations in Romania; they choose them according to the beauty of the landscape, multitude of outdoor activities, and the hospitality of the hosts. In the last 2 years of the pandemic, young people have visited several times the main existing ecotourism destinations locally, with an average vacation duration of 1–3 days. The Internet remains the main source of information, and in the field, they use mobile applications that allow the download of digital maps and recognize different plant species. By integrating various activities in nature, in close connection with the local culture, ecotourism can contribute to the sustainable use of local tourism resources. This study provides a detailed and realistic picture of the knowledge and the type of ecotourism experience that young people want. The implications are theoretical and managerial, highlighting the importance of assessing the preferences of young ecotourists, as a basis for developing ecotourism strategies, sustainable use of local tourism resources, and management of protected areas.
Urea hydrolysis in different farmland soils as affected by long-term biochar application
Authors: Zhao Rui , Liu Juying , Xu Na , He Tianyi , Meng Jun , Liu Zunqi
Published: August 2022

Urea is a commonly used nitrogen (N) fertilizer that contributes to world food production, and there have been increasing concerns about relatively low urea-N use efficiency. Biochar has shown the potential to mitigate N loss, but how biochar influences urea hydrolysis and the underlying mechanisms are still unclear. In this study, long-term biochar-amended upland, paddy and greenhouse soils were sampled at depths of 0–20 and 20–40 cm in Haicheng City, Northeast China. Soil N contents, urea hydrolysis rates (UHRs), and total, intracellular and extracellular urease activities were determined, as well as the total bacterial and ureolytic microbial gene abundance were quantified. The results showed that biochar increased total urease activity by 32.64–66.39% in upland soil and by 2.90–2.13-fold in paddy soil. Both intracellular and extracellular ureases contributed to the increase in total urease activity. However, in greenhouse soil, extracellular (+35.07–74.22%) and intracellular (−40.14–77.68%) urease activities responded inconsistently to biochar incorporation. Increases in ureC gene copy numbers (2.15- to 4.47-fold) in upland and greenhouse (20.93%) soil implied that biochar stimulated microorganisms capable of producing urease, and the biochar liming effect increased the soil pH (0.11–0.60 units), which optimized the ureolytic reaction, together explained the increases in urease activity. We found that the decreased soil N content was accompanied by a higher UHR in upland and greenhouse soils, suggesting that the accelerated UHR exerted a negative effect on the soil N content, possibly caused by excessive NH3 volatilization. In paddy soil, where the UHR was not increased, biochar was an effective amendment for simultaneously improving soil urease activity and N content.
Genetic Predisposition to Severe COVID-19 Might Increase the Risk of Stroke: A Two-Sample Mendelian Randomization Study
Authors: Zhang Jinji , Wu Fayong , Chen Shenge , Zhu Ying , Luo Xian , Qiu Xiaolin
Published: August 2022

Aims: The causal relationship between COVID-19 infection and stroke has not yet been fully established. This study aimed to explore this causality using two-sample Mendelian randomization (MR).

Materials and Methods: Genetic variants associated with COVID-19 infection and stroke were both obtained from genome-wide association study (GWAS) summary data. The single nucleotide polymorphisms (SNPs) were selected as instrumental variables. The standard inverse variance weighted (IVW) was primarily used to assess this causality. Finally, sensitivity analysis was performed to evaluate the reliability and stability.

Results: The results showed that being hospitalized due to COVID-19 had a positive effect on stroke [OR = 1.05; 95% CI= (1.01, 1.10); p = 2.34 × 10−5] and ischemic stroke [OR = 1.06; 95% CI= (1.02, 1.11); p = 2.28 × 10−6] analyzed by inverse variance weighted. Moreover, the results revealed that severe respiratory symptoms due to COVID-19 had a positive effect on stroke [OR = 1.04; 95% CI= (1.00, 1.06); p = 0.04] and that the causal effect of severe respiratory symptoms due to COVID-19 on ischemic stroke estimated by IVW suggested a positive effect [OR = 1.06; 95% CI= (1.02, 1.09); p = 0.0068], too.

Conclusion: In summary, this study showed that severe COVID-19 might increase the risk of stroke, thus much more attention should be paid to patients with severe COVID-19.
Bioinformatic analysis of circular RNA expression profiles in a rat lumbosacral spinal root avulsion model
Authors: Zhou Zhibin , Ma Jun , Cai Jiao , Chen Aimin , Zhu Lei
Published: August 2022

Lumbosacral spinal root avulsion (LSRA) is a severe nerve injury that results in devastating dysfunction in the lower limb. Circular ribonucleic acids (circRNAs) have been reported to be implicated in a variety of diseases. However, the role of circRNAs in LSRA remains unclear. Here, we performed RNA sequencing (RNA-seq) to determine circRNA expression profiles in a rat LSRA model and further investigated their potential functions and the underlying mechanisms by bioinformatic analyses and in vitro experiments. In all, 1708 circRNAs were found to be differentially expressed in spinal cord tissues after LSRA (|fold change| ≥ 2 and p < 0.05), with 591 up-regulated 1117 down-regulated. Meanwhile, 2263 mRNAs were also indentified to be differentially expressed, of which 1471 were upregulated and 792 were downregulated. Eight randomly selected circRNAs and mRNA were successfully verified to be consistent the RNA-seq results by quantitative real-time polymerase chain reaction. Functional analyses based on gene ontology and Kyoto Encyclopedia of Genes and Genomes predicted the potential roles of differentially expressed circRNAs and mRNAs in LSRA, and circRNA/miRNA/mRNA interaction networks revealed that circRNA_7025, a down-regulated circRNA in LSRA, was targeted by two neuronal apoptosis-related miRNAs, rno-miR-1224 and rno-miR-326-5p. Further in vitro experiments revealed that circRNA_7025 protected against oxygen-glucose deprivation induced neuronal apoptosis via the circRNA_7025/miR-1224/miR-326-5p axis. In summary, our results revealed circRNA expression profiles and their potential functions in LSRA. These findings improve our understanding of the pathogenic mechanisms involved in LSRA and might enable us to identify new molecular targets for LSRA.
APAview: A web-based platform for alternative polyadenylation analyses in hematological cancers
Authors: Hu Xi , Song Jialin , Chyr Jacqueline , Wan Jinping , Wang Xiaoyan , Du Jianqiang , Duan Junbo , Zhang Huqin , Zhou Xiaobo , Wu Xiaoming
Published: August 2022

Background: Hematologic malignancies, such as acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML), are cancers that start in blood-forming tissues and can affect the blood, bone marrow, and lymph nodes. They are often caused by genetic and molecular alterations such as mutations and gene expression changes. Alternative polyadenylation (APA) is a post-transcriptional process that regulates gene expression, and dysregulation of APA contributes to hematological malignancies. RNA-sequencing-based bioinformatic methods can identify APA sites and quantify APA usages as molecular indexes to study APA roles in disease development, diagnosis, and treatment. Unfortunately, APA data pre-processing, analysis, and visualization are time-consuming, inconsistent, and laborious. A comprehensive, user-friendly tool will greatly simplify processes for APA feature screening and mining.

Results: Here, we present APAview, a web-based platform to explore APA features in hematological cancers and perform APA statistical analysis. APAview server runs on Python3 with a Flask framework and a Jinja2 templating engine. For visualization, APAview client is built on Bootstrap and Plotly. Multimodal data, such as APA quantified by QAPA/DaPars, gene expression data, and clinical information, can be uploaded to APAview and analyzed interactively. Correlation, survival, and differential analyses among user-defined groups can be performed via the web interface. Using APAview, we explored APA features in two hematological cancers, APL and AML. APAview can also be applied to other diseases by uploading different experimental data.
Concurrent functional gastrointestinal disorders in patients with inflammatory bowel disease
Authors: Walker Caroline , Boland Anna , Carroll Andrew , O’Connor Anthony
Published: August 2022

Approximately 25% of people with quiescent inflammatory bowel disease (IBD) have symptoms caused by a functional gastrointestinal disorder (FGID). The pathophysiology of FGIDs in IBD is multifactorial. The gut–brain axis plays an important role as a bidirectional pathway with reciprocal gastrointestinal and psychological symptoms. Other factors include altered gastrointestinal motility, microbiome dysbiosis, medication use, prior surgery, impaired intestinal permeability, immune-system activation, and visceral hypersensitivity. As both IBD and certain FGIDs can have similar symptoms, it can be difficult to determine which disorder is the precipitant of symptoms. However, a prompt diagnosis of an overlapping FGID helps avoid unnecessary corticosteroid use and escalations of IBD treatment. Despite their prevalence, there have been very few randomized controlled trials conducted on therapeutic interventions for overlapping FGIDs in IBD. Therefore, management usually follows those interventions recommended for FGIDs, with certain adaptations made to allow for an altered gastrointestinal anatomy and functioning, caused by IBD.
Community-led research for reproductive justice: Exploring the SisterLove Georgia Medication Abortion project
Authors: Mosley Elizabeth A. , Ayala Sequoia , Jah Zainab , Hailstorks Tiffany , Dixon Diallo Dázon , Hernandez Natalie , Jackson Kwajelyn , Hairston Indya , Hall Kelli S.
Published: August 2022

Introduction

While reproductive injustice indicators are improving globally, they are worsening in the United States particularly for Black and other marginalized communities. Eugenics and obstetric violence against low-income and communities of color create well-founded distrust of sexual and reproductive health (SRH). Transformational, reparative ways of conducting SRH research are needed.

Proposed principles of community-led research for reproductive justice

Drawing on our collective experience as reproductive justice leaders, SRH researchers, and clinicians, we propose the following principles of community-led research for reproductive justice: 1) Center the marginalized community members most affected by SRH inequities as leaders of research; 2) Facilitate equitable, collaborative partnership through all phases of SRH research; 3) Honor multiple ways of knowing (experiential, cultural, empirical) for knowledge justice and cross-directional learning across the team; 4) Build on strengths (not deficits) within the community; 5) Implement the tenets of reproductive justice including structural-level analysis and the human rights framework; 6) Prioritize disseminating useful findings to community members first then to other audiences; 7) Take action to address social and reproductive injustices.

SisterLove's community-led georgia medication abortion project

We offer the community-led Georgia Medication Abortion (GAMA) Project by reproductive justice organization SisterLove from 2018–2022 as a case study to demonstrate these principles along with the strengths and challenges of reproductive justice research.

Discussion

Community-led reproductive justice research offers innovative and transformational methods for truly advancing SRH in an era of increasing policy restrictions and decreasing access to care. Yet existing funding, research administrative, and publishing systems will require structural change.
Glucocorticoid induced group 2 innate lymphoid cell overactivation exacerbates experimental colitis
Authors: Feng Bingcheng , Lin Lin , Li Lixiang , Long Xin , Liu Chao , Zhao Zixiao , Li Shiyang , Li Yanqing
Published: August 2022

Abnormal activation of the innate and adaptive immune systems has been observed in inflammatory bowel disease (IBD) patients. Anxiety and depression increase the risk of IBD by activating the adaptive immune system. However, whether anxiety affects innate immunity and its impact on IBD severity remains elusive. This study investigated the mechanism by which anxiety contributes to IBD development in a murine model of acute wrap restraint stress (WRS). Here, we found that anxiety-induced overactivation of group 2 innate lymphoid cells (ILC2) aggravated colonic inflammation. Overactivation of the hypothalamic–pituitary–adrenal (HPA) axis is a hallmark of the physiological change of anxiety. Corticosterone (CORT), a stress hormone, is a marker of HPA axis activation and is mainly secreted by HPA activation. We hypothesized that the overproduction of CORT stimulated by anxiety exacerbated colonic inflammation due to the abnormally elevated function of ILC2. The results showed that ILC2 secreted more IL-5 and IL-13 in the WRS mice than in the control mice. Meanwhile, WRS mice experienced more body weight loss, shorter colon length, higher concentrations of IL-6 and TNF-α, more severely impaired barrier function, and more severe inflammatory cell infiltration. As expected, the serum corticosterone levels were elevated after restraint stress. Dexamethasone (DEX) was then injected to mimic HPA axis activation induced CORT secretion. DEX injection can also stimulate ILC2 to secrete more type II cytokines and exacerbate oxazolone (OXA) induced colitis. Blocking the IL-13/STAT6 signaling pathway alleviated colitis in WRS and DEX-injected mice. In conclusion, the overactivation of ILC2 induced by CORT contributed to the development of OXA-induced colitis in mice.
TNF-α enhances sensory DRG neuron excitability through modulation of P2X3 receptors in an acute colitis model
Authors: Valdez-Morales Eduardo E. , Sánchez-Navarro Carlos A. , Reyes-Pavón Diana , Barrios-Garcia Tonatiuh , Ochoa-Cortes Fernando , Barajas-Espinosa Alma , Barragán-Iglesias Paulino , Guerrero-Alba Raquel
Published: August 2022

Previous studies have demonstrated that acute colonic inflammation leads to an increase in dorsal root ganglia (DRG) neuronal excitability. However, the signaling elements implicated in this hyperexcitability have yet to be fully unraveled. Extracellular adenosine 5’-triphosphate (ATP) is a well-recognized sensory signaling molecule that enhances the nociceptive response after inflammation through activation of P2X3 receptors, which are expressed mainly by peripheral sensory neurons. The aim of this study is to continue investigating how P2X3 affects neuronal hypersensitivity in an acute colitis animal model. To achieve this, DNBS (Dinitrobenzene sulfonic acid; 200 mg/kg) was intrarectally administered to C57BL/6 mice, and inflammation severity was assessed according to the following parameters: weight loss, macroscopic and microscopic scores. Perforated patch clamp technique was used to evaluate neuronal excitability via measuring changes in rheobase and action potential firing in T8-L1 DRG neurons. A-317491, a well-established potent and selective P2X3 receptor antagonist, served to dissect their contribution to recorded responses. Protein expression of P2X3 receptors in DRG was evaluated by western blotting and immunofluorescence. Four days post-DNBS administration, colons were processed for histological analyses of ulceration, crypt morphology, goblet cell density, and immune cell infiltration. DRG neurons from DNBS-treated mice were significantly more excitable compared with controls; these changes correlated with increased P2X3 receptor expression. Furthermore, TNF-α mRNA expression was also significantly higher in inflamed colons compared to controls. Incubation of control DRG neurons with TNF-α resulted in similar cell hyperexcitability as measured in DNBS-derived neurons. The selective P2X3 receptor antagonist, A-317491, blocked the TNF-α-induced effect. These results support the hypothesis that TNF-α enhances colon-innervating DRG neuron excitability via modulation of P2X3 receptor activity.
Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies
Authors: Seliger Barbara , Koehl Ulrike
Published: August 2022

Natural killer (NK) cells belong to the family of innate immune cells with the capacity to recognize and kill tumor cells. Different phenotypes and functional properties of NK cells have been described in tumor patients, which could be shaped by the tumor microenvironment. The discovery of HLA class I-specific inhibitory receptors controlling NK cell activity paved the way to the fundamental concept of modulating immune responses that are regulated by an array of inhibitory receptors, and emphasized the importance to explore the potential of NK cells in cancer therapy. Although a whole range of NK cell-based approaches are currently being developed, there are still major challenges that need to be overcome for improved efficacy of these therapies. These include escape of tumor cells from NK cell recognition due to their expression of inhibitory molecules, immune suppressive signals of NK cells, reduced NK cell infiltration of tumors, an immune suppressive micromilieu and limited in vivo persistence of NK cells. Therefore, this review provides an overview about the NK cell biology, alterations of NK cell activities, changes in tumor cells and the tumor microenvironment contributing to immune escape or immune surveillance by NK cells and their underlying molecular mechanisms as well as the current status and novel aspects of NK cell-based therapeutic strategies including their genetic engineering and their combination with conventional treatment options to overcome tumor-mediated evasion strategies and improve therapy efficacy.
Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response
Authors: Chen Ziyu , Wang Gaorui , Xie Xueqing , Liu Heng , Liao Jun , Shi Hailian , Chen Min , Lai Shusheng , Wang Zhengtao , Wu Xiaojun
Published: August 2022

Background

Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could alleviate DVT and its underlying mechanism has not been elucidated.

Methods

The interaction between Rg5 and P2RY12 was studied by molecular docking, molecular dynamics, surface plasmon resonance (SPR), and molecular biology assays. The preventive effect of Rg5 on DVT was evaluated in inferior vena cava stasis–induced mice, and immunocytochemistry, Western blot, and calcium flux assay were performed in neutrophils from bone marrow to explore the mechanism of Rg5 in NETosis via P2RY12.

Results

Rg5 allosterically interacted with P2RY12, formed stable complex, and antagonized its activity via residue E188 and R265. Rg5 ameliorated the formation of thrombus in DVT mice; accompanied by decreased release of Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in plasma; and suppressed neutrophil infiltration and neutrophil extracellular trap (NET) release. In lipopolysaccharide- and platelet-activating factor–induced neutrophils, Rg5 reduced inflammatory responses via inhibiting the activation of ERK/NF-κB signaling pathway while decreasing cellular Ca2+ concentration, thus reducing the activity and expression of peptidyl arginine deiminase 4 to prevent NETosis. The inhibitory effect on neutrophil activity was dependent on P2RY12.

Conclusions

Rg5 could attenuate experimental DVT by counteracting NETosis and inflammatory response in neutrophils via P2RY12, which may pave the road for its clinical application in the prevention of DVT-related disorders.
Immunogenicity and immune-persistence of the CoronaVac or Covilo inactivated COVID-19 Vaccine: a 6-month population-based cohort study
Authors: Hua Qianhui , Zhang Hangjie , Yao Pingping , Xu Nani , Sun Yisheng , Lu Hangjing , Xu Fang , Liao Yuting , Yang Juan , Mao Haiyan , Zhang Yanjun , Zhu Hanping , Hu Xiaowei , Lv Huakun , Jiang Jianmin
Published: August 2022

Background

Owing to the coronavirus disease 2019 (COVID-19) pandemic and the emergency use of different types of COVID-19 vaccines, there is an urgent need to consider the effectiveness and persistence of different COVID-19 vaccines.

Methods

We investigated the immunogenicity of CoronaVac and Covilo, two inactivated vaccines against COVID-19 that each contain inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The levels of neutralizing antibodies to live SARS-CoV-2 and the inhibition rates of neutralizing antibodies to pseudovirus, as well as the immunoglobulin (Ig)G and IgM responses towards the spike (S) and nucleocapsid (N) protein of SARS-CoV-2 at 180 days after two-dose vaccination were detected.

Results

The CoronaVac and Covilo vaccines induced similar antibody responses. Regarding neutralizing antibodies to live SARS-CoV-2, 77.9% of the CoronaVac vaccine recipients and 78.3% of the Covilo vaccine recipients (aged 18–59 years) seroconverted by 28 days after the second vaccine dose. Regarding SARS-CoV-2-specific antibodies, 97.1% of the CoronaVac vaccine recipients and 95.7% of the Covilo vaccine recipients seroconverted by 28 days after the second vaccine dose. The inhibition rates of neutralizing antibody against a pseudovirus of the SARS-CoV-2 Delta variant were significantly lower compared with those against a pseudovirus of wildtype SARS-CoV-2. Associated with participant characteristics and antibody levels, persons in the older age group and with basic disease, especially a chronic respiratory disease, tended to have lower anti-SARS-CoV-2 antibody seroconversion rates.

Conclusion

Antibodies that were elicited by these two inactivated COVID-19 vaccines appeared to wane following their peak after the second vaccine dose, but they persisted at detectable levels through 6 months after the second vaccine dose, and the effectiveness of these antibodies against the Delta variant of SARS-CoV-2 was lower than their effectiveness against wildtype SARS-CoV-2, which suggests that attention must be paid to the protective effectiveness, and its persistence, of COVID-19 vaccines on SARS-CoV-2 variants.
Innate lymphoid cells in early tumor development
Authors: Warner Kathrin , Ghaedi Maryam , Chung Douglas C. , Jacquelot Nicolas , Ohashi Pamela S.
Published: August 2022

Innate and adaptive immune cells monitor, recognize, and eliminate transformed cells. Innate lymphoid cells (ILCs) are innate counterparts of T cells that play a key role in many facets of the immune response and have a profound impact on disease states, including cancer. ILCs regulate immune responses by responding and integrating a wide range of signals within the local microenvironment. As primarily tissue-resident cells, ILCs are ideally suited to sense malignant transformation and initiate anti-tumor immunity. However, as ILCs have been associated with anti-tumor and pro-tumor activities in established tumors, they could potentially have dual functions during carcinogenesis by promoting or suppressing the malignant outgrowth of premalignant lesions. Here we discuss emerging evidence that shows that ILCs can impact early tumor development by regulating immune responses against transformed cells, as well as the environmental cues that potentially induce ILC activation in premalignant lesions.
Lacticaseibacillus rhamnosus alleviates intestinal inflammation and promotes microbiota-mediated protection against Salmonella fatal infections
Authors: Peng Xianqi , Ed-Dra Abdelaziz , Song Yan , Elbediwi Mohammed , Nambiar Reshma B. , Zhou Xiao , Yue Min
Published: August 2022

The fatal impairment of the intestinal mucosal barrier of chicks caused by Salmonella significantly resulting economic losses in the modern poultry industry. Probiotics are recognized for beneficially influencing host immune responses, promoting maintenance of intestinal epithelial integrity, antagonistic activity against pathogenic microorganisms and health-promoting properties. Some basic studies attest to probiotic capabilities and show that Lacticaseibacillus rhamnosus could protect intestinal mucosa from injury in animals infected with Salmonella Typhimurium. However, the mechanisms underlying its protective effects in chicks are still not fully understood. Here, we used the chick infection model combined with histological, immunological, and molecular approaches to address this question. The results indicated that L. rhamnosus significantly reduced the diarrhea rate and increased the daily weight gain and survival rate of chicks infected with S. Typhimurium. Furthermore, we found that L. rhamnosus markedly improved the immunity of gut mucosa by reducing apoptotic cells, hence effectively inhibiting intestinal inflammation. Notably, pre-treatment chicks with L. rhamnosus balanced the expression of interleukin-1β and interleukin-18, moderated endotoxin and D-lactic acid levels, and expanded tight junction protein levels (Zonula occluden-1 and Claudin-1), enhanced the function of the intestinal mucosal epithelial cells. Additionally, investigations using full-length 16S rRNA sequencing also demonstrated that L. rhamnosus greatly weakened the adhesion of Salmonella, the mainly manifestation is the improvement of the diversity of intestinal microbiota in infected chicks. Collectively, these results showed the application of L. rhamnosus against Salmonella fatal infection by enhancing barrier integrity and the stability of the gut microbiota and reducing inflammation in new hatch chicks, offering new antibiotic alternatives for farming animals.
Immunogenicity and toxicity of AAV gene therapy
Authors: Ertl Hildegund C. J.
Published: August 2022

Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.
Archives of short-term fluid flow dynamics and possible influence of human activities at methane seeps: Evidence from high-resolution element geochemistry of chemosynthetic bivalve shells
Authors: Wang Xudong , Fan Danling , Kiel Steffen , Gong Shanggui , Liang Qiangyong , Tao Jun , Chen Duofu , Feng Dong
Published: August 2022

The natural dynamics of fluid flow at methane seeps and increasingly human activities influence the biogeochemistry of the microenvironment and further determine the activity of the chemosynthetic communities within these ecosystems. However, ways to reconstruct short-term fluid flow dynamics and to decipher the influence of scientific exploration at seeps are limited. In this study, we present high-resolution trace elements/Ca ratios (Li/Ca, Mg/Ca, Ti/Ca, Mn/Ca, Co/Ca, Cu/Ca, Zn/Ca, Sr/Ca, Zr/Ca, Mo/Ca, Ba/Ca, Th/Ca and U/Ca ratios) from the shells of two species of chemosymbiotic bivalves (the thiotrophic vesicomyid clam Archivesica marissinica and the methanotrophic mussel Gigantidas haimaensis) from the Haima cold seeps of the South China Sea. We found that the complex distribution patterns of some trace elements (Mg/Ca, Sr/Ca, Mo/Ca and U/Ca ratios) in G. haimaensis are largely controlled by mineral composition or age. The observation of Co/Ca and Ba/Ca ratios in both species indicate strong physiological and environmental control on the incorporation of trace elements during the biomineralization process. Besides, the distribution patterns of other trace elements provide information that can be used to discuss open issues such as the loss of trace elements after death of the bivalves, and the possible influence of human activities such as sediment disturbance. Overall, this study emphasizes the potential for using high-resolution element geochemistry of seep bivalve shells to reveal the physiological and environmental factors that control the growth of bivalves, and to elucidate the potential history of fluid discharge at cold seeps.
Ecological risk assessment of metallic nanoparticles on the marine environments: Species sensitivity distributions analysis
Authors: Feng Sulan , Zhu Lin , Zhao Xinguo , Sui Qi , Sun Xuemei , Chen Bijuan , Qu Keming , Xia Bin
Published: August 2022

Metallic nanoparticles (NPs) are increasingly being used and inevitably entering the marine environment. Therefore, the adverse effects of NPs on individual marine species have attracted increasing attentions. However, to date, the ecological risks of NPs on the marine ecosystem remain poorly understood. In this study, species sensitivity distributions (SSDs) were constructed for Ag, ZnO, CuO, and TiO2 NPs to understand their ecotoxicity to the marine ecosystem and the contribution of size effect and ion effect to the nanotoxicity. Furthermore, a case study on the assessment of marine ecological risk and marine environment carrying capacity of metallic NPs was performed in Jiaozhou Bay, China. The results showed the toxicity of metallic NPs to marine species following the order of Ag > ZnO > CuO > TiO2. Both size effect and ion effect contributed to the toxicity of NPs. Environmental concentrations of Ag, ZnO, CuO, and TiO2 NPs are much lower than the predicted no-effect concentrations, indicating that these metallic NPs have not yet posed risks to the marine ecosystem based on currently limited measured environmental concentrations of metallic NPs in seawater. And the marine environment carrying capacity of Ag, ZnO, CuO, and TiO2 NPs in Jiaozhou Bay seawater were determined to be 5.03, 8.72, 93.06, and 629.79 t, respectively. The results help us understand the ecological risk of NPs in marine environments and provide a scientific basis for the sustainable development of nanotechnology.
Delayed payment schemes in Central-Eastern Europe and Middle-East
Authors: Ádám Ildikó , Callenbach Marcelien , Németh Bertalan , Vreman Rick A. , Pontén Johan , Strbad Tea , Dawoud Dalia , Kostyuk Alexander , Seyam Ahmed , Nagy László , Goettsch Wim G. , Kaló Zoltán
Published: August 2022

The need for innovative payment models for health technologies with high upfront costs has emerged due to affordability concerns across the world. Early technology adopter countries have been experimenting with delayed payment schemes. Our objective included listing potential barriers for implementing delayed payment models and recommendations on how to address these barriers in lower income countries of Central and Eastern Europe (CEE) and the Middle East (ME). We conducted a survey, an exploratory literature review and an iterative brainstorming about potential barriers and solutions to implement delayed payment models in these two regions. A draft list of recommendations was validated in a virtual workshop with payer experts from the two regions. Eight barriers were identified in 4 areas, including transaction costs and administrative burden, payment schedule, information technology and data infrastructure, and governance. Fifteen practical recommendations were prepared to address these barriers, including recommendations that are specific to lower income countries, and recommendations that can be applied more universally, but are more crucial in countries with severe budget constraints. Conclusions of this policy research can be considered as an initial step in a multistakeholder dialogue about implementing delayed payment schemes in CEE and ME countries.
The top 100 most-cited articles on exercise therapy for sarcopenia: A bibliometric analysis
Authors: Guo Zhao-jing , Xie Wen-qing , Cai Zi-jun , Zhang Yue-yao , Ding Yi-lan , Naranmandakh Shinen , Li Yu-sheng , Xiao Wen-feng
Published: August 2022

Objective

Vast quantities of literature regarding the applications of exercise therapy for sarcopenia have been published. The main objective of this study is to determine the top 100 most-cited articles and analyze their bibliometric characteristics.

Design

This study reports a bibliometric analysis via a systematic search of the academic literature regarding the applications of exercise therapy for sarcopenia.

Methods

All databases in the Web of Science were searched with the following strategy: term search (TS) = (exercise* OR training OR “physical activit*”) AND TS = (sarcopenia) on 25 February 2022. The results were presented in descending order by their total citations. The list of the top 100 articles was finally determined by negotiation of two independent researchers.

Results

The top 100 articles were published between 1993 and 2020. More than half of the articles (n = 54) were published during the decade 2006–2015. Total citations of the top 100 articles ranged from 155 to 1,131 with a median of 211.5. The average of annual citations was constantly increasing with year (P < 0.05). The most studied exercise therapy is strength/resistance training, with about 71% articles had discussed about it. The top 100 articles were from 54 different journals, and the Journal of Applied Physiology was the journal that contributed the most articles (n = 8). A total of 75 different first corresponding authors from 15 countries made contributions to the top 100 list. Luc J.C. van Loon from the Maastricht University in the Netherlands published the most articles (n = 5) as the first corresponding author. Most articles (87%) were from North America (58%) and Europe (29%), while the United States as a country contributed over half of the articles (51%).

Conclusion

Our study determined the top 100 most-cited articles on exercise therapy for sarcopenia and analyzed their bibliometric characteristics, which may provide a recommended list for researchers in this field and pave the way for further research.
A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020
Authors: Teixeira Maria Manuel , Borges Fábio Cardoso , Ferreira Paula Sousa , Rocha João , Sepodes Bruno , Torre Carla
Published: August 2022

Introduction

Cancer and corresponding available treatments are associated with substantial symptoms and functional limitations. In this context, collection of patient-reported outcomes (PRO) in clinical trials gained special interest and is recommended by regulatory authorities. Within clinical trials framework, PRO may provide evidence to support medicines approval, labeling and marketing claims. This study aims to analyze the existing evidence based on PRO as part of new oncology indications receiving positive opinions issued by the European Medicines Agency (EMA) between 2017 and 2020 and to identify PRO related label claims granted.

Methodology

Oncology medicinal products and indications approved by the European Commission following a positive opinion from the EMA between 2017 and 2020 were identified. European Public Assessment Report (EPAR) and Summary of Product Characteristics (SmPC) were reviewed for each medicinal product to identify use of PRO and PRO label claims.

Results

A total of 128 oncology indications, corresponding to 76 medicines, were approved; of those, 100 (78.1%) included PRO in the confirmatory clinical trials. Thirty-seven indications were supported by double-blind randomized trials and the remainder 63 by open-label trials. Out of the 104 confirmatory trials analyzed, PRO were defined as a secondary endpoint in 60 studies (57.7%), exploratory in 31 (29.8%) and as both in 13 (12.5%). In total, 54 different PRO measures (PROM) were used, of those 41 (75.9%) were disease-specific measures. Nevertheless, PROM selected relied on the EORTC (41.3%), FACIT (17.1%) and EQ-5D (29.2%) measures. A total of 76 indications (59.4%) had PRO reviewers comments included in the EPAR, however only 22 indications (17.8%) included label claims in the SmPC. The reasons identified in the EMA assessment supporting the exclusion of PRO claims were described for 34 indications (44.7%).

Conclusions

Despite growing recognition of the value of PRO data for the development of improved cancer therapies, PRO implementation remains challenging. The main reasons identified in our study are related with study design, missing data, study conduct and PROM selection.
Residual reserve index modifies the effect of amyloid pathology on fluorodeoxyglucose metabolism: Implications for efficiency and capacity in cognitive reserve
Authors: McKenzie Cathryn , Bucks Romola S. , Weinborn Michael , Bourgeat Pierrick , Salvado Olivier , Gavett Brandon E.
Published: August 2022

Background

The residual approach to measuring cognitive reserve (using the residual reserve index) aims to capture cognitive resilience conferred by cognitive reserve, but may be confounded by factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing interactions between the residual reserve index and amyloid, tau, and neurodegeneration [“AT(N)”] biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience).

Methods

Participants (N = 332) were from the Alzheimer’s Disease Neuroimaging Initiative. The residual reserve index represented the difference between observed and predicted memory performance (a positive residual reserve index suggests higher cognitive reserve). AT(N) biomarkers were: CSF β-amyloid1–42/β-amyloid1–40 (A), plasma phosphorylated tau-181 (T), and FDG metabolism in AD-specific regions ([N]). AT(N) biomarkers (measured at consecutive time points) were entered in a sequential mediation model testing the indirect effects from baseline amyloid to executive function intercept (third annual follow-up) and slope (baseline to seventh follow-up), via tau and/or FDG metabolism. The baseline residual reserve index was entered as a moderator of paths between AT(N) biomarkers (e.g., amyloid-tau), and paths between AT(N) biomarkers and executive function.

Results

The residual reserve index interacted with amyloid pathology when predicting FDG metabolism: the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, executive function performance was comparable at different levels of the residual reserve index, but a higher residual reserve index was associated with lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism.

Conclusion

The effect of the residual reserve index on executive function performance via FDG metabolism was consistent with cognitive resilience. This suggests the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency, and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of greater amyloid pathology. Implications for future research include the potential bidirectionality between neural efficiency and amyloid accumulation.
Cerebral small vessel disease: Pathological mechanisms and potential therapeutic targets
Authors: Gao Yue , Li Di , Lin Jianwen , Thomas Aline M. , Miao Jianyu , Chen Dong , Li Shen , Chu Chengyan
Published: August 2022

Cerebral small vessel disease (CSVD) represents a diverse cluster of cerebrovascular diseases primarily affecting small arteries, capillaries, arterioles and venules. The diagnosis of CSVD relies on the identification of small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, and microbleeds using neuroimaging. CSVD is observed in 25% of strokes worldwide and is the most common pathology of cognitive decline and dementia in the elderly. Still, due to the poor understanding of pathophysiology in CSVD, there is not an effective preventative or therapeutic approach for CSVD. The most widely accepted approach to CSVD treatment is to mitigate vascular risk factors and adopt a healthier lifestyle. Thus, a deeper understanding of pathogenesis may foster more specific therapies. Here, we review the underlying mechanisms of pathological characteristics in CSVD development, with a focus on endothelial dysfunction, blood-brain barrier impairment and white matter change. We also describe inflammation in CSVD, whose role in contributing to CSVD pathology is gaining interest. Finally, we update the current treatments and preventative measures of CSVD, as well as discuss potential targets and novel strategies for CSVD treatment.
Non-coding RNAs: The Neuroinflammatory Regulators in Neurodegenerative Diseases
Authors: Jiang Hao , Zhang Ying , Yue Juan , Shi Yuchen , Xiao Bo , Xiao Wenbiao , Luo Zhaohui
Published: August 2022

As a common indication of nervous system diseases, neuroinflammation has attracted more and more attention, especially in the process of a variety of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Two types of non-coding RNAs (ncRNAs) are widely involved in the process of neuroinflammation in neurodegenerative diseases, namely long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). However, no research has systematically summarized that lncRNAs and miRNAs regulate neurodegenerative diseases through neuroinflammatory mechanisms. In this study, we summarize four main mechanisms of lncRNAs and miRNAs involved in neuroinflammation in neurodegenerative diseases, including the imbalance between proinflammatory and neuroprotective cells in microglia and astrocytes, NLRP3 inflammasome, oxidative stress, and mitochondrial dysfunction, and inflammatory mediators. We hope to clarify the regulatory mechanism of lncRNAs and miRNAs in neurodegenerative diseases and provide new insights into the etiological treatment of neurodegenerative diseases from the perspective of neuroinflammation.
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
Authors: Smith Laura J. , Lee Chiao-Yin , Menozzi Elisa , Schapira Anthony H. V.
Published: August 2022

Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.