bluuebunny/crossref_metadata_2025 huggingface dataset:
Tribochemistry, Mechanical Alloying, Mechanochemistry: What is in a Name?
Authors: Michalchuk Adam A. L. , Boldyreva Elena V. , Belenguer Ana M. , Emmerling Franziska , Boldyrev Vladimir V.
Published: May 2021

Over the decades, the application of mechanical force to influence chemical reactions has been called by various names: mechanochemistry, tribochemistry, mechanical alloying, to name but a few. The evolution of these terms has largely mirrored the understanding of the field. But what is meant by these terms, why have they evolved, and does it really matter how a process is called? Which parameters should be defined to describe unambiguously the experimental conditions such that others can reproduce the results, or to allow a meaningful comparison between processes explored under different conditions? Can the information on the process be encoded in a clear, concise, and self-explanatory way? We address these questions in this Opinion contribution, which we hope will spark timely and constructive discussion across the international mechanochemical community.
Sex-Disaggregated Data on Clinical Characteristics and Outcomes of Hospitalized Patients With COVID-19: A Retrospective Study
Authors: Wang Mengdie , Jiang Nan , Li Changjun , Wang Jing , Yang Heping , Liu Li , Tan Xiangping , Chen Zhenyuan , Gong Yanhong , Yin Xiaoxv , Zong Qiao , Xiong Nian , Zhang Guopeng
Published: May 2021

Background

Sex and gender are crucial variables in coronavirus disease 2019 (COVID-19). We sought to provide information on differences in clinical characteristics and outcomes between male and female patients and to explore the effect of estrogen in disease outcomes in patients with COVID-19.

Method

In this retrospective, multi-center study, we included all confirmed cases of COVID-19 admitted to four hospitals in Hubei province, China from Dec 31, 2019 to Mar 31, 2020. Cases were confirmed by real-time RT-PCR and were analyzed for demographic, clinical, laboratory and radiographic parameters. Random-effect logistic regression analysis was used to assess the association between sex and disease outcomes.

Results

A total of 2501 hospitalized patients with COVID-19 were included in the present study. The clinical manifestations of male and female patients with COVID-19 were similar, while male patients have more comorbidities than female patients. In terms of laboratory findings, compared with female patients, male patients were more likely to have lymphopenia, thrombocytopenia, inflammatory response, hypoproteinemia, and extrapulmonary organ damage. Random-effect logistic regression analysis indicated that male patients were more likely to progress into severe type, and prone to ARDS, secondary bacterial infection, and death than females. However, there was no significant difference in disease outcomes between postmenopausal and premenopausal females after propensity score matching (PSM) by age.

Conclusions

Male patients, especially those age-matched with postmenopausal females, are more likely to have poor outcomes. Sex-specific differences in clinical characteristics and outcomes do exist in patients with COVID-19, but estrogen may not be the primary cause. Further studies are needed to explore the causes of the differences in disease outcomes between the sexes.
Routing of Electric Vehicles With Intermediary Charging Stations: A Reinforcement Learning Approach
Authors: Dorokhova Marina , Ballif Christophe , Wyrsch Nicolas
Published: May 2021

In the past few years, the importance of electric mobility has increased in response to growing concerns about climate change. However, limited cruising range and sparse charging infrastructure could restrain a massive deployment of electric vehicles (EVs). To mitigate the problem, the need for optimal route planning algorithms emerged. In this paper, we propose a mathematical formulation of the EV-specific routing problem in a graph-theoretical context, which incorporates the ability of EVs to recuperate energy. Furthermore, we consider a possibility to recharge on the way using intermediary charging stations. As a possible solution method, we present an off-policy model-free reinforcement learning approach that aims to generate energy feasible paths for EV from source to target. The algorithm was implemented and tested on a case study of a road network in Switzerland. The training procedure requires low computing and memory demands and is suitable for online applications. The results achieved demonstrate the algorithm’s capability to take recharging decisions and produce desired energy feasible paths.
Focal Mechanism and Seismogenic Structure of the MS 5.1 Qingbaijiang Earthquake on February 3, 2020, Southwestern China
Authors: Zhao Min , Long Feng , Yi Guixi , Liang MingJian , Xie Jiangtao , Wang Siwei
Published: May 2021

The 3 February 2020 MS 5.1 Qingbaijiang earthquake, southwestern China, is the closest recorded MS ≥ 5.0 event to downtown Chengdu City to date, with an epicentral distance of only 38 km. Here we analyze seismic data from the Sichuan and Chengdu regional seismic networks, and employ a multi-stage location method to relocate the earthquakes that have occurred along the central and northern segments of the Longquanshan fault zone since 2009, including the MS 5.1 Qingbaijiang earthquake sequence, to investigate the seismogenic structure of the region. The relocation results indicate that the seismicity along the central and northern segments of the Longquanshan fault zone has occurred mainly along the eastern branch since 2009, with the hypocentral distribution along a vertical cross-section illustrating a steep, NW-dipping parallel imbricate structure. The terminating depth of the eastern branch is about 12 km. The distribution of the MS 5.1 Qingbaijiang earthquake sequence is along the NE–SW-striking Longquanshan fault zone. The aftershock focal depths are in the 3–6 km range, with the mainshock located at 104.475°E, 30.73°N. Its initial rupture depth of 5.2 km indicates that the earthquake occurred above the shallow decollement layer of the upper crust in this region. The hypocentral distribution along the long axis of the aftershock area highlights that this earthquake sequence occurred along a fault dipping at 56° to the NW. Our surface projection of the inferred fault plane places it near the eastern branch of the Longquanshan fault zone. We infer the MS 5.1 mainshock to be a thrust faulting event based on the focal mechanism solution via the cut-and-paste waveform inversion method, with strike/dip/rake parameters of 22°/36°/91° and 200°/54°/89° obtained for nodal planes I and II, respectively. We identify that the seismogenic fault of the MS 5.1 Qingbaijiang earthquake lies along the eastern branch of the Longquanshan fault zone, and nodal plane II represents the coseismic rupture plane, based on a joint analysis of the event relocation results, mainshock focal mechanism, and regional geological information. Our study provides vital information for assessing the seismic hazard of the Longquanshan fault zone near Chengdu City.
Lessons Learned: Teaching In-Person During the COVID-19 Pandemic
Authors: Tran Alvin , Kerkstra Robin L. , Gardocki Sarah Logan , Papuga Savannah C.
Published: May 2021

For the Fall 2020 semester, the University of New Haven (UNewHaven) joined over a third of colleges and universities across the country in offering in-person courses and reopening its campus. Allowing the campus community to safely return was a challenging endeavor, particularly for those at the University’s School of Health Sciences, which offers both non-clinical and clinical courses. In order to create learning environments that adhered to continuously-changing guidelines, our team at the School of Health Sciences was forced to develop and implement innovative strategies. In this article, we share our experiences in fulfilling our roles as faculty, staff, and students at a School of Health Sciences offering in-person, non-clinical and clinical courses during the COVID-19 pandemic. We reflect upon our challenges and share the lessons learned, which we hope will serve as guidance for our collective community in higher education, including those working within schools of public health and health sciences. Our lessons learned are presented in following three themes: 1) preparation for in-person classes; 2) the emotional state of faculty, staff, and students; and 3) innovative practices. Should colleges and universities ever find themselves in similar, yet unprecedented times, our lessons and recommendations may serve as a starting point to assist them in navigating through such tumultuous moments.
Decreased Expression of Ileal Thyroid Hormone Transporters in a Hypothyroid Patient: A Case Report
Authors: Chung Chae Won , Mo Eun Young , Jung Gyung Seo , Kim Yoo Hyung , Cho Sun Wook , Park Do Joon , Bae Jeong Mo , Park Young Joo
Published: May 2021

Background

Malabsorption of levothyroxine (LT4) is a common problem faced in clinical practice. It is usually solved, if there are no complexities including gastrointestinal absorption disorder, by taking medicines on an empty stomach and avoiding foods interfering with LT4. Herein we present a rare case of a patient exhibiting malabsorption of LT4 with decreased membranous expression of ileal transporters.

Case

The 22-Year-old female presented with sustained hypothyroid status despite medication of 7.8 μg/kg LT4. Medical history and LT4 absorption test (the absorption rate 8.4%) excluded pseudomalabsorption. No organic gastrointestinal disorder was found in the patient by blood chemistry, endoscopies, and abdominal computed tomography scan. The immunohistochemical analysis showed decreased membranous expression of LAT1 and LAT2 in distal ileum and ascending colon in the patient compared to 20 controls who have no thyroid disease. The expression of MCT8 in colon appeared at both nucleus and brush border in the patient, while it was limited to brush border in controls. The expression of other transporters was similar between the patient and controls.

Conclusion

The changes of the expression of LAT1 and LAT2 in this patient showing LT4 malabsorption might help to understand the role of intestinal transporters in the absorption of LT4 in humans. The functional relevance of the decrement of LAT1 and LAT2 in this patient remains to be elucidated.
Adverse Effects of Selected Markers on the Metabolic and Endocrine Profiles of Obese Women With and Without PCOS
Authors: Daghestani Mazin H. , Daghestani Maha H. , Warsy Arjumand , El-Ansary Afaf , Omair Mohammed A. , Omair Maha A. , Hassen Lena M. , Alhumaidhi Eman MH. , Al Qahtani Bashaer , Harrath Abdel Halim
Published: May 2021

The aim of the present study, is to investigate the influence of obesity, with and without polycystic ovarian syndrome (PCOS), on the levels of kisspeptin, vitamin D (Vit D), and vascular endothelial growth factor (VEGF) and to explore the relationship between these parameters and endocrine and metabolic variables. The study group included 126 obese Saudi females. Of these 63 were suffering from PCOS while the rest were normo-ovulatory obese women (non-PCOS obese). In the obese PCOS, VEGF was almost four times as high as in the non-PCOS obese, while kisspeptin and Vit D did not differ. A highly significant elevation was recorded in the waist/hip (WHR), cholesterol, LDL-C, fasting glucose, LH, LH/FSH ratio, estradiol (E2), and testosterone, while hip circumference, leptin, progesterone, and sex hormone binding globulin (SHBG) were lower in the obese PCOS subjects. BMI, HDL-C, ghrelin, insulin, and FSH levels did not differ significantly between the two groups. The obese PCOS had the same level of insulin resistance as the non-PCOS group, as judged by QUICK Index. Correlation studies showed a significant negative correlation between kisspeptin and glucose and LH levels, and a positive correlation with LH/FSH ratio in obese PCOS while in the non-PCOS obese, the kisspeptin correlated positively with glucose, and there was no correlation with LH or LH/FSH. VEGF negatively correlated with FSH and positively with LH/FSH ratio in the non-PCOS obese but this was lost in the obese PCOS. PCOS had no effect on the correlation between Vit D and all studied parameters. Multiple regression analysis showed triglyceride as predictor variable for kisspeptin as a dependent variable, while, leptin is a predictor variable for VEGF as a dependent variable. ROC studies showed the highest sensitivity and specificity for VEGF (AOC=1.00), followed by LH/FSH ratio (AOC=0.979). In conclusion, our study shows that PCOS results in significant elevation of VEGF in obese females, while kisspeptin and Vit D levels are not affected. It also leads to elevation in several of the lipid and hormonal abnormalities in the obese females. In addition, PCOS influences relationship between Kisspeptin and VEGF and some parameters such as glucose, LH or FSH and LH/FSH ratio in obese females, but does not affect Vit D relationship with other parameter.
Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy
Authors: Carmichael Josie , Fadavi Hassan , Ishibashi Fukashi , Shore Angela C. , Tavakoli Mitra
Published: May 2021

The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN’s sensitivity and performance.
Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study
Authors: Chen Songzan , Yang Fangkun , Xu Tian , Wang Yao , Zhang Kaijie , Fu Guosheng , Zhang Wenbin
Published: May 2021

Background

Although several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.

Methods

A two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10–8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.

Results

In total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.

Conclusions

This two-sample MR analysis found no evidence to support causal association of Hcy with AF.
Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer
Authors: Zhang Facai , Wang Xiaoming , Bai Yunjin , Hu Huan , Yang Yubo , Wang Jiahao , Tang Yin , Ma Honggui , Feng Dechao , Li Dengxiong , Han Ping
Published: May 2021

Objectives

This study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer.

Methods

We downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer.

Results

Eight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets.

Conclusion

We successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients’ prognosis.
The Gender-Based Violence and Precarity Nexus: Asylum-Seeking Women in the Eastern Mediterranean
Authors: Tastsoglou Evangelia , Petrinioti Xanthi , Karagiannopoulou Chara
Published: May 2021

This paper derives from a larger research on gender-based violence and precarity in the forced migration journeys of asylum-seeking women transiting through the Eastern Mediterranean route and arriving in Greece, in the tumultuous, second decade of the 21st century. In this paper we present the findings from the first phase of the research. We analyze and discuss the opinions and information gathered through semi-structured interviews with twenty key informants: service providers, staff of international and national NGOs, local government staff and public officials. Our findings locate the five points/loci in irregular cross-border movements and arrival at an EU member-state where precarity interweaves with gender-based violence. The first locus, is in transit and EU and Greek border crossing; second, during the asylum determination process; third, in their everyday life when they must deal with homelessness and harsh living conditions; fourth, in the deficiency of care services further aggravated by intersectional discrimination; finally, by being trapped in abusive settings and relationships due to the ineffective state response, a sluggish criminal justice system, and the victim’s financial dependence on the perpetrator. Adopting a feminist and intersectional approach our analysis shows that violence and precarity are co-constituted and reinforce each other through the undermining of the citizenship status of asylum seekers and the inscription, on their bodies and lives, of unequal gendered social and institutional power relations.
Nanoparticles Engineered as Artificial Antigen-Presenting Cells Induce Human CD4+ and CD8+ Tregs That Are Functional in Humanized Mice
Authors: Giang Sophia , Horwitz David A. , Bickerton Sean , La Cava Antonio
Published: May 2021

Artificial antigen-presenting cells (aAPCs) are synthetic versions of naturally occurring antigen-presenting cells (APCs) that, similar to natural APCs, promote efficient T effector cell responses in vitro. This report describes a method to produce acellular tolerogenic aAPCs made of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and encapsulating IL-2 and TGF-β for a paracrine release to T cells. We document that these aAPCs can induce both human CD4+ and CD8+ T cells to become FoxP3+ T regulatory cells (Tregs). The aAPC NP-expanded human Tregs are functional in vitro and can modulate systemic autoimmunity in vivo in humanized NSG mice. These findings establish a proof-of-concept to use PLGA NPs as aAPCs for the induction of human Tregs in vitro and in vivo, highlighting the immunotherapeutic potential of this targeted approach to repair IL-2 and/or TGF-β defects documented in certain autoimmune diseases such as systemic lupus erythematosus.
Macrophages and Dendritic Cells Are Not the Major Source of Pro-Inflammatory Cytokines Upon SARS-CoV-2 Infection
Authors: Niles Marc A. , Gogesch Patricia , Kronhart Stefanie , Ortega Iannazzo Samira , Kochs Georg , Waibler Zoe , Anzaghe Martina
Published: May 2021

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)−6, tumor necrosis factor (TNF)-α, or interferon (IFN)−α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.
The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease
Authors: Zheng Hengqi B. , de la Morena M. Teresa , Suskind David L.
Published: May 2021

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) represents a cohort of inflammatory bowel disease (IBD) patients diagnosed before 6 years of age. Unlike IBD diagnosed at older ages, VEO-IBD can be associated with underlying primary immunodeficiencies. VEO-IBD has been linked to monogenic variations in over 70 genes involved in multiple pathways of immunity. As sequencing technologies and platforms evolve and become readily available, an increasing number of genes linked to VEO-IBD have emerged. Although monogenic defects are rare in VEO-IBD, diagnosis of these variants can often dictate specific treatment. In this mini-review, we set out to describe monogenic variants previously characterized in multiple patients in the literature that contribute to VEO-IBD, diagnostic tools, unique treatment modalities for specific genetic diagnoses, and future directions in the field of VEO-IBD. Although this mini-review is by no means comprehensive of all the novel monogenic variants linked to VEO-IBD, we hope to provide relevant information that is readily accessible to clinicians and educators.
Proteomic Analysis of Humoral Immune Components in Bronchoalveolar Lavage of Patients Infected or Colonized by Aspergillus fumigatus
Authors: Dellière Sarah , Duchateau Magalie , Wong Sarah Sze Wah , Giai Gianetto Quentin , Guegan Hélène , Matondo Mariette , Gangneux Jean-Pierre , Aimanianda Vishukumar
Published: May 2021

Humoral immune components have been individually studied in the context of interaction of host with Aspergillus fumigatus, a major airborne fungal pathogen. However, a global view of the multitude and complex nature of humoral immune components is needed to bring new insight into host-Aspergillus interaction. Therefore, we undertook comparative proteomic analysis of the bronchoalveolar lavage fluid collected from individuals infected or colonized with A. fumigatus versus controls, to identify those alveolar humoral components affected upon A. fumigatus infection. Complement proteins C1q, C8 beta-chain, factor-H, ficolin-1, ficolin-2, mannan binding lectin serine peptidase 2, pentraxin-3 and the surfactant protein-D were identified as the major humoral immune components affected by A. fumigatus infection and colonization. Based on this observation, we hypothesize that crosstalk between these humoral components is essential during host-Aspergillus interaction giving new specific leads to study for better understanding the pathogenesis. Furthermore, the affected humoral components could be potential diagnostic markers of A. fumigatus infection or colonization.
Social Sensors for Wildlife: Ecological Opportunities in the Era of Camera Ubiquity
Authors: Borowicz Alex , Lynch Heather J. , Estro Tyler , Foley Catherine , Gonçalves Bento , Herman Katelyn B. , Adamczak Stephanie K. , Stirling Ian , Thorne Lesley
Published: May 2021

Expansive study areas, such as those used by highly-mobile species, provide numerous logistical challenges for researchers. Community science initiatives have been proposed as a means of overcoming some of these challenges but often suffer from low uptake or limited long-term participation rates. Nevertheless, there are many places where the public has a much higher visitation rate than do field researchers. Here we demonstrate a passive means of collecting community science data by sourcing ecological image data from the digital public, who act as “eco-social sensors,” via a public photo-sharing platform—Flickr. To achieve this, we use freely-available Python packages and simple applications of convolutional neural networks. Using the Weddell seal (Leptonychotes weddellii) on the Antarctic Peninsula as an example, we use these data with field survey data to demonstrate the viability of photo-identification for this species, supplement traditional field studies to better understand patterns of habitat use, describe spatial and sex-specific signals in molt phenology, and examine behavioral differences between the Antarctic Peninsula’s Weddell seal population and better-studied populations in the species’ more southerly fast-ice habitat. While our analyses are unavoidably limited by the relatively small volume of imagery currently available, this pilot study demonstrates the utility an eco-social sensors approach, the value of ad hoc wildlife photography, the role of geographic metadata for the incorporation of such imagery into ecological analyses, the remaining challenges of computer vision for ecological applications, and the viability of pelage patterns for use in individual recognition for this species.
Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach
Authors: Granata Simona , Bruschi Maurizio , Deiana Michela , Petretto Andrea , Lombardi Gianmarco , Verlato Alberto , Elia Rossella , Candiano Giovanni , Malerba Giovanni , Gambaro Giovanni , Zaza Gianluigi
Published: May 2021

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.

Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.

Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: −1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.

Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.
Transcriptome-Wide N6-Methyladenosine (m6A) Profiling of Susceptible and Resistant Wheat Varieties Reveals the Involvement of Variety-Specific m6A Modification Involved in Virus-Host Interaction Pathways
Authors: Zhang Tian-ye , Wang Zi-qiong , Hu Hai-chao , Chen Zhi-qing , Liu Peng , Gao Shi-qi , Zhang Fan , He Long , Jin Peng , Xu Miao-ze , Chen Jian-ping , Yang Jian
Published: May 2021

N6-methyladenosine (m6A) methylation is the most prevalent internal modification of post-transcriptional modifications in mRNA, tRNA, miRNA, and long non-coding RNA in eukaryotes. m6A methylation has been proven to be involved in plant resistance to pathogens. However, there are no reports on wheat (Triticum aestivum) m6A transcriptome-wide map and its potential biological function in wheat resistance to wheat yellow mosaic virus (WYMV). To the best of our knowledge, this study is the first to determine the transcriptome-wide m6A profile of two wheat varieties with different resistances to WYMV. By analyzing m6A-sequencing (m6A-seq) data, we identified 25,752 common m6A peaks and 30,582 common m6A genes in two groups [WYMV-infected resistant wheat variety (WRV) and WYMV-infected sensitive wheat variety (WSV)], and all these peaks were mainly enriched in 3′ untranslated regions and stop codons of coding sequences. Gene Ontology analysis of m6A-seq and RNA-sequencing data revealed that genes that showed significant changes in both m6A and mRNA levels were associated with plant defense responses. Kyoto Encyclopedia of Genes and Genomes analysis revealed that these selected genes were enriched in the plant–pathogen interaction pathway. We further verified these changes in m6A and mRNA levels through gene-specific m6A real-time quantitative PCR (RT-qPCR) and normal RT-qPCR. This study highlights the role of m6A methylation in wheat resistance to WYMV, providing a solid basis for the potential functional role of m6A RNA methylation in wheat resistance to infection by RNA viruses.
Melatonin Is a Promising Silage Additive: Evidence From Microbiota and Metabolites
Authors: Li Mao , Lv Renlong , Zhang Lidong , Zi Xuejuan , Zhou Hanlin , Tang Jun
Published: May 2021

The safe and effective storage of forage are very important. As an important storage method, ensiling can keep fresh forage for a long time with less nutritional loss. Melatonin has antioxidant and bacteriostasis, usually used as a natural preservative. The influence of melatonin on silage microbial or fermentation quality has not been clarified. In the present study, we aimed to clarify whether melatonin affected stylo (Stylosanthes guianensis) silage quality via microbiota and metabolites. Melatonin addition significantly improved the silage fermentation quality, including the increased contents of lactic acid and total acid (244.18–255.81% and 63.95–78.97%, respectively), as well as the decreased in pH and butyric acid content compare with control group. Moreover, 16S rRNA sequencing indicated that melatonin addition enhanced the silage microbial diversity indices (such as increase in Shannon indices but decrease in Simpson indices), and significantly shaped the composition of silage microbiota (such as increased abundances of Pantoea, Stenotrophomonas, Sphingobacterium, and Pseudomonas, and decreased abundance of Weissella). Melatonin addition also dramatically affected the metabolites of sylo silage, such as raised malonic acid and some amino acid metabolism(glycine, threonine, methionine and ornithine), while reduced nucleic acid metabolism(2-deoxyuridine and thymine) and carbon metabolism(allose and 2-deoxy-D-glucose). Collectively, our results confirmed that the lowest melatonin addition (5 mg/kg) could improve the fermentation quality, and the potential mechanisms might be associated with the microbiota and metabolites in stylo.
Increasing the Ascomycin Yield by Relieving the Inhibition of Acetyl/Propionyl-CoA Carboxylase by the Signal Transduction Protein GlnB
Authors: Wang Pan , Wang Xin , Yin Ying , He Mingliang , Tan Wei , Gao Wenting , Wen Jianping
Published: May 2021

Ascomycin (FK520) is a multifunctional antibiotic produced by Streptomyces hygroscopicus var. ascomyceticus. In this study, we demonstrated that the inactivation of GlnB, a signal transduction protein belonging to the PII family, can increase the production of ascomycin by strengthening the supply of the precursors malonyl-CoA and methylmalonyl-CoA, which are produced by acetyl-CoA carboxylase and propionyl-CoA carboxylase, respectively. Bioinformatics analysis showed that Streptomyces hygroscopicus var. ascomyceticus contains two PII family signal transduction proteins, GlnB and GlnK. Protein co-precipitation experiments demonstrated that GlnB protein could bind to the α subunit of acetyl-CoA carboxylase, and this binding could be disassociated by a sufficient concentration of 2-oxoglutarate. Coupled enzyme activity assays further revealed that the interaction between GlnB protein and the α subunit inhibited both the activity of acetyl-CoA carboxylase and propionyl-CoA carboxylase, and this inhibition could be relieved by 2-oxoglutarate in a concentration-dependent manner. Because GlnK protein can act redundantly to maintain metabolic homeostasis under the control of the global nitrogen regulator GlnR, the deletion of GlnB protein enhanced the supply of malonyl-CoA and methylmalonyl-CoA by restoring the activity of acetyl-CoA carboxylase and propionyl-CoA carboxylase, thereby improving the production of ascomycin to 390 ± 10 mg/L. On this basis, the co-overexpression of the β and ε subunits of propionyl-CoA carboxylase further increased the ascomycin yield to 550 ± 20 mg/L, which was 1.9-fold higher than that of the parent strain FS35 (287 ± 9 mg/L). Taken together, this study provides a novel strategy to increase the production of ascomycin, providing a reference for improving the yield of other antibiotics.
Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma
Authors: Xu Qianhui , Hu Yuanbo , Chen Shaohuai , Zhu Yulun , Li Siwei , Shen Feng , Guo Yifan , Sun Tao , Chen Xiaoyu , Jiang Jinpeng , Huang Wen
Published: May 2021

Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer.

Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan–Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the “maftools” package to delineate the tumor mutation burden (TMB).

Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5′-cytosine-phosphate-guanine-3′ (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)–related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status.

Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.
Grasping Embodiment: Haptic Feedback for Artificial Limbs
Authors: Moore Charles H. , Corbin Sierra F. , Mayr Riley , Shockley Kevin , Silva Paula L. , Lorenz Tamara
Published: May 2021

Upper-limb prostheses are subject to high rates of abandonment. Prosthesis abandonment is related to a reduced sense of embodiment, the sense of self-location, agency, and ownership that humans feel in relation to their bodies and body parts. If a prosthesis does not evoke a sense of embodiment, users are less likely to view them as useful and integrated with their bodies. Currently, visual feedback is the only option for most prosthesis users to account for their augmented activities. However, for activities of daily living, such as grasping actions, haptic feedback is critically important and may improve sense of embodiment. Therefore, we are investigating how converting natural haptic feedback from the prosthetic fingertips into vibrotactile feedback administered to another location on the body may allow participants to experience haptic feedback and if and how this experience affects embodiment. While we found no differences between our experimental manipulations of feedback type, we found evidence that embodiment was not negatively impacted when switching from natural feedback to proximal vibrotactile feedback. Proximal vibrotactile feedback should be further studied and considered when designing prostheses.
Repetitive Transcranial Magnetic Stimulation at Different Sites for Dysphagia After Stroke: A Randomized, Observer-Blind Clinical Trial
Authors: Zhong Lida , Rao Jinzhu , Wang Jing , Li Fang , Peng Yang , Liu Huiyu , Zhang Yan , Wang Pu
Published: May 2021

Background: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) protocols on patients with poststroke dysphagia is still unclear.

Objective: This trial aimed to explore and analyze the effectiveness of 5 Hz rTMS on the unaffected hemisphere, affected hemisphere, and cerebellum in stroke patients with dysphagia.

Methods: This observer-blind and randomized controlled trial included a total of 147 patients with stroke. Patients were divided into four treatment groups: the unaffected hemispheric group, the affected hemispheric group, the cerebellum group and the control group. Each group received traditional dysphagia treatment 5 days a week for 2 weeks. All recruited patients except for those in the control group underwent 10 consecutive rTMS sessions for 2 weeks. For the affected hemispheric group and unaffected hemispheric group, 5 Hz rTMS was applied to the affected mylohyoid cortical region or to the unaffected mylohyoid cortical region. For the cerebellum group, 5 Hz rTMS was applied to the mylohyoid cortical representation of the cerebellum (4.3 cm lateral and 2.4 cm below the inion). The Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS), Penetration/Aspiration Scale (PAS), Gugging Swallowing Screen (GUSS), and Standardized Swallowing Assessment (SSA) were used to evaluate clinical swallowing function before the intervention (baseline), immediately after the intervention and 2 weeks after the intervention.

Results: There were significant time and intervention interaction effects on the FEDSS, PAS, SSA, and GUSS scores (p < 0.05). In a direct comparison of the swallowing parameters of the four groups, the changes in FEDSS, PAS, SSA, and GUSS scores showed a significantly greater improvement in the unaffected hemispheric group, the affected hemispheric group and cerebellum group than in the control group (p < 0.05).

Conclusions: Whether stimulating the unaffected hemisphere or the affected hemisphere, 5 Hz high-frequency rTMS on mylohyoid cortical tissue might have a positive effect on poststroke patients with dysphagia. In addition, cerebellar rTMS is a safe method that represents a potential treatment for poststroke dysphagia, and more clinical trials are needed to develop this technique further.

Clinical Trial Registration:chictr.org.cn, identifier: ChiCTR2000032255.
Perspectives: Evaluation of Older Adult Cochlear Implant Candidates for Fall Risk in a Developing Country Setting
Authors: Rogers Christine
Published: May 2021

Dizziness, vertigo, and falls are common in older adults. Data suggest that cochlear implant candidates are no different and could be argued to be at elevated risk due to the presence of hearing loss and likely vestibular involvement. Perspectives contextualizes current testing and screening paradigms for vestibular deficits and fall risk and suggests a protocol suitable for use in developing country settings.
Case Report: Deep Brain Stimulation of the Nucleus Basalis of Meynert for Advanced Alzheimer's Disease
Authors: Zhang Wei , Liu Wei , Patel Bhavana , Chen Yingchuan , Wang Kailiang , Yang Anchao , Meng Fangang , Wagle Shukla Aparna , Cen Shanshan , Yu John , Ramirez-Zamora Adolfo , Zhang Jianguo
Published: May 2021

Patients with advanced Alzheimer's disease (AD) experience cognitive impairment and physical disabilities in daily life. Currently, there are no treatments available to slow down the course of the disease, and limited treatments exist only to treat symptoms. However, deep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) has been reported to improve cognitive function in individuals with AD. Here, we report the effects of NBM-DBS on cognitive function in a subject with severe AD. An 80-year-old male with severe AD (Clinical Dementia Rating scale: 3.0 points) underwent surgery for bilateral NBM-DBS electrode placement. After 10 weeks of stimulation, Mini-Mental State Examination (MMSE) assessment improved from a score of 5 to 9 points, and assessment using the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-cog) showed a marked reduction in total score from 43 to 33 points, suggesting cognitive benefits from NBM-DBS. The patient's postoperative course was complicated by a subdural effusion that occurred several days after surgery, with complete recovery. Interestingly, the subject also displayed abnormal thermoregulation with stimulation initiation and stimulation parameter modifications. NBM-DBS may serve as a potential therapy for severe AD patients.

Clinical Trial Registration: ChiCTR1900022324.
Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?
Authors: Hersey Melinda , Bacon Amanda K. , Bailey Lydia G. , Coggiano Mark A. , Newman Amy H. , Leggio Lorenzo , Tanda Gianluigi
Published: May 2021

The number of individuals affected by psychostimulant use disorder (PSUD) has increased rapidly over the last few decades resulting in economic, emotional, and physical burdens on our society. Further compounding this issue is the current lack of clinically approved medications to treat this disorder. The dopamine transporter (DAT) is a common target of psychostimulant actions related to their use and dependence, and the recent availability of atypical DAT inhibitors as a potential therapeutic option has garnered popularity in this research field. Modafinil (MOD), which is approved for clinical use for the treatment of narcolepsy and sleep disorders, blocks DAT just like commonly abused psychostimulants. However, preclinical and clinical studies have shown that it lacks the addictive properties (in both behavioral and neurochemical studies) associated with other abused DAT inhibitors. Clinical availability of MOD has facilitated its off-label use for several psychiatric disorders related to alteration of brain dopamine (DA) systems, including PSUD. In this review, we highlight clinical and preclinical research on MOD and its R-enantiomer, R-MOD, as potential medications for PSUD. Given the complexity of PSUD, we have also reported the effects of MOD on psychostimulant-induced appearance of several symptoms that could intensify the severity of the disease (i.e., sleep disorders and impairment of cognitive functions), besides the potential therapeutic effects of MOD on PSUD.