bluuebunny/crossref_metadata_2025 huggingface dataset:
Speech Pauses and Pronominal Anaphors
Authors: Navarretta Costanza
Published: May 2021

This paper addresses the usefulness of speech pauses for determining whether third person neuter gender singular pronouns refer to individual or abstract entities in Danish spoken language. The annotations of dyadic map task dialogues and spontaneous first encounters are analyzed and used in machine learning experiments act to automatically identify the anaphoric functions of pronouns and the type of abstract reference. The analysis of the data shows that abstract reference is more often performed by marked (stressed or demonstrative pronouns) than by unmarked personal pronouns in Danish speech as in English, and therefore previous studies of abstract reference in the former language are corrected. The data also show that silent and filled pauses precede significantly more often third person singular neuter gender pronouns when they refer to abstract entities than when they refer to individual entities. Since abstract entities are not the most salient ones and referring to them is cognitively more hard than referring to individual entities, pauses signal this complex processes. This is in line with perception studies, which connect pauses with the expression of abstract or complex concepts. We also found that unmarked pronouns referring to an entity type usually referred to by a marked pronoun are significantly more often preceded by a speech pause than marked pronouns with the same referent type. This indicates that speech pauses can also signal that the referent of a pronoun of a certain type is not the most expected one. Finally, language models were produced from the annotated map task and first encounter dialogues in order to train machine learning experiments to predict the function of third person neuter gender singular pronouns as a first step toward the identification of the anaphoric antecedents. The language models from the map task dialogues were also used for training classifiers to determine the referent type (speech act, event, fact or proposition) of abstract anaphors. In all cases, the best results were obtained by a multilayer perceptron with an F1-score between 0.52 and 0.67 for the three-class function prediction task and of 0.73 for the referential type prediction.
The Prognostic Significance of Anemia in Patients With Heart Failure: A Meta-Analysis of Studies From the Last Decade
Authors: Xia Haijiang , Shen Hongfeng , Cha Wei , Lu Qiaoli
Published: May 2021

Background: Anemia is a commonly occurring comorbidity in patients with heart failure (HF). Although there are a few reports of a higher prevalence of mortality and hospitalization-related outcomes due to accompanying anemia, other studies suggest that anemia does not have an adverse impact on the prognostic outcomes of HF. Two meta-analyses in the past decade had reported the adverse impact of anemia on both mortality and hospitalization- related outcomes. However, only one of these studies had evaluated the outcome while using multivariable adjusted hazard ratios. Moreover, several studies since then reported the prognostic influence of anemia in HF. In this present study, we evaluate the prognostic impact of anemia on mortality and hospitalization outcomes in patients with HF.

Methods: We carried out a systematic search of the academic literature in the scientific databases EMBASE, CENTRAL, Scopus, PubMed, Cochrane, ISI Web of Science, clinicaltrial.gov, and MEDLINE based on the PRISMA guidelines. Meta-analysis was then performed to evaluate the effect (presented as risk ratio) of anemia on the overall mortality and hospitalization outcome in patients with HF.

Results: Out of 1,397 studies, 11 eligible studies were included with a total of 53,502 (20,615 Female, 32,887 Male) HF patients (mean age: 71.6 ± 8.3-years, Hemoglobin: 11.9 ± 1.5 g/dL). Among them, 19,794 patients suffered from anemia (Hb: 10.5 ± 1.6), and 33,708 patients did not have anemia (Hb: 13.2 ± 1.7 g/dL). A meta-analysis revealed a high-odds ratio (OR) for the overall mortality in patients with anemia (OR: 1.43, 95% CI: 1.29–1.84). A high-risk ratio was also reported for hospitalization as the outcome in patients with anemia (1.22, 1.0–1.58).

Conclusion: This systematic review and meta-analysis provide evidence of the high risk of mortality and hospitalization-related outcomes in patients with HF and anemia. The study confirms the findings of previously published meta-analyses suggesting anemia as an important and independent risk factor delineating the prognostic outcome of chronic HF.
Albuminuria and Dipstick Proteinuria for Predicting Mortality in Heart Failure: A Systematic Review and Meta-Analysis
Authors: Liang Wei , Liu Qian , Wang Qiong-ying , Yu Heng , Yu Jing
Published: May 2021

Background: Research suggest that albuminuria is not only an independent risk factor for the development of heart failure but may also act as a biomarker for predicting adverse outcomes. To date, no study has synthesized evidence on its role as a prognostic indicator. Thus, the current study aimed to quantitatively assess the prognostic utility of albuminuria as well as dipstick proteinuria in predicting mortality in heart failure patients.

Methods: PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar databases were searched up to October 10, 2020. All studies reporting multivariable-adjusted hazard ratios (HR) for albuminuria or dipstick proteinuria for mortality and/or hospitalization in heart failure patients were included.

Results: Eleven studies were included. Seven assessed albuminuria and five assessed dipstick proteinuria. Our analysis revealed a statistically significant increased risk of all-cause mortality with microalbuminuria (HR: 1.54; 95% CI, 1.23–1.93; I2 = 79%; p = 0.0002) and macroalbuminuria (HR: 1.76; 95% CI, 1.21–2.56; I2 = 88%; p = 0.003) in heart failure patients. The risk of all-cause mortality and hospitalization was also significantly increased with macroalbuminuria. Microalbuminuria was associated with significantly increased cardiovascular mortality and combined cardiovascular mortality and hospitalization. Positive dipstick test for proteinuria was significantly associated with mortality in heart failure (HR: 1.54; 95% CI, 1.28–1.84; I2 = 67%; p < 0.00001).

Conclusion: Both microalbuminuria and macroalbuminuria are predictors of mortality in patients with heart failure. Dipstick proteinuria may be used as a rapid screening test to predict mortality in these patients.
Data Consistency for Data-Driven Smart Energy Assessment
Authors: Chicco Gianfranco
Published: May 2021

In the smart grid era, the number of data available for different applications has increased considerably. However, data could not perfectly represent the phenomenon or process under analysis, so their usability requires a preliminary validation carried out by experts of the specific domain. The process of data gathering and transmission over the communication channels has to be verified to ensure that data are provided in a useful format, and that no external effect has impacted on the correct data to be received. Consistency of the data coming from different sources (in terms of timings and data resolution) has to be ensured and managed appropriately. Suitable procedures are needed for transforming data into knowledge in an effective way. This contribution addresses the previous aspects by highlighting a number of potential issues and the solutions in place in different power and energy system, including the generation, grid and user sides. Recent references, as well as selected historical references, are listed to support the illustration of the conceptual aspects.
A Combined Application of Molecular Microbial Ecology and Elemental Analyses Can Advance the Understanding of Decomposition Dynamics
Authors: Bisker Chawki , Taylor Gillian , Carney Helen , Ralebitso-Senior Theresia Komang
Published: May 2021

Introducing animal carbon-source to soil initiates biochemical and microbial processes that lead to its decomposition and recycling, which subsequently cause successional shifts in soil microbial community. To investigate the use of soil microbial community to inform criminal investigation, this study was designed to mimic clandestine graves. It compared the decomposition of stillborn piglets (Sus scrofa domesticus), as human analogues, to oak (Quercus robur) leaf litter and soil-only controls outdoors for 720 days. Environmental and edaphic parameters were monitored and showed soil microbial community alignment with temperature seasonality, which highlighted the importance of this abiotic factor. Denaturing gradient gel electrophoresis (DGGE) data were used to calculate Hill numbers and diversity indices of the bacterial 16S rRNA community did not distinguish mammalian- from plant-based decomposition consistently during the first or second year of the study. In contrast, the fungal 18S rRNA community allowed clear differentiation between different treatments (beta diversity) throughout the 720-day experiment and suggested the moment of the decomposing mammalian skin rupture. 16S rRNA-based NGS facilitated the identification of e.g., Pirellulaceae, Acidobacteria ii1-15_order and Candidatus xiphinematobacter as Year 2 bacterial markers of gravesoil at family, order and species taxonomic levels, respectively, and confirmed the similarity of the calculated Hill diversity metrics with those derived from DGGE profiling. Parallel soil elemental composition was measured by portable X-ray Fluorescence where calcium profiles for the piglet-associated soils were distinct from those without carrion. Also, soil calcium content and PMI correlated positively during the first year then negatively during the second. This study is one of the first to apply a multidisciplinary approach based on molecular and physicochemical analytical techniques to assess decomposition. It highlights the recognised potential of using soil microbial community in forensic investigations and provides a proof-of-concept for the application of a combined molecular and elemental approach to further understand the dynamics of decomposition. In addition, it sets the scene for further research in different conditions based on Hill numbers metrics instead of the classic ecological indices for soil necrobiome richness, diversity and evenness.
Case Report: Aicardi-Goutières Syndrome and Singleton-Merten Syndrome Caused by a Gain-of-Function Mutation in IFIH1
Authors: Xiao Wei , Feng Jie , Long Hongyu , Xiao Bo , Luo Zhaohui H.
Published: May 2021

The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation.
The Unsupervised Feature Selection Algorithms Based on Standard Deviation and Cosine Similarity for Genomic Data Analysis
Authors: Xie Juanying , Wang Mingzhao , Xu Shengquan , Huang Zhao , Grant Philip W.
Published: May 2021

To tackle the challenges in genomic data analysis caused by their tens of thousands of dimensions while having a small number of examples and unbalanced examples between classes, the technique of unsupervised feature selection based on standard deviation and cosine similarity is proposed in this paper. We refer to this idea as SCFS (Standard deviation and Cosine similarity based Feature Selection). It defines the discernibility and independence of a feature to value its distinguishable capability between classes and its redundancy to other features, respectively. A 2-dimensional space is constructed using discernibility as x-axis and independence as y-axis to represent all features where the upper right corner features have both comparatively high discernibility and independence. The importance of a feature is defined as the product of its discernibility and its independence (i.e., the area of the rectangular enclosed by the feature’s coordinate lines and axes). The upper right corner features are by far the most important, comprising the optimal feature subset. Based on different definitions of independence using cosine similarity, there are three feature selection algorithms derived from SCFS. These are SCEFS (Standard deviation and Exponent Cosine similarity based Feature Selection), SCRFS (Standard deviation and Reciprocal Cosine similarity based Feature Selection) and SCAFS (Standard deviation and Anti-Cosine similarity based Feature Selection), respectively. The KNN and SVM classifiers are built based on the optimal feature subsets detected by these feature selection algorithms, respectively. The experimental results on 18 genomic datasets of cancers demonstrate that the proposed unsupervised feature selection algorithms SCEFS, SCRFS and SCAFS can detect the stable biomarkers with strong classification capability. This shows that the idea proposed in this paper is powerful. The functional analysis of these biomarkers show that the occurrence of the cancer is closely related to the biomarker gene regulation level. This fact will benefit cancer pathology research, drug development, early diagnosis, treatment and prevention.
DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation
Authors: Kienes Ioannis , Bauer Sarah , Gottschild Clarissa , Mirza Nora , Pfannstiel Jens , Schröder Martina , Kufer Thomas A.
Published: May 2021

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.
Maternal-Fetal HLA Compatibility in Uncomplicated and Preeclamptic Naturally Conceived Pregnancies
Authors: van ‘t Hof Liseanne J. , Schotvanger Naomi , Haasnoot Geert W. , van der Keur Carin , Roelen Dave L. , Lashley Lisa E. E. L. O. , Claas Frans H. J. , Eikmans Michael , van der Hoorn Marie-Louise P.
Published: May 2021

Introduction

In pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.

Methods

Genotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).

Results

In uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.

Conclusion

The data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.
Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn
Authors: Kalbermatter Cristina , Fernandez Trigo Nerea , Christensen Sandro , Ganal-Vonarburg Stephanie C.
Published: May 2021

The innate immune system is the oldest protection strategy that is conserved across all organisms. Although having an unspecific action, it is the first and fastest defense mechanism against pathogens. Development of predominantly the adaptive immune system takes place after birth. However, some key components of the innate immune system evolve during the prenatal period of life, which endows the newborn with the ability to mount an immune response against pathogenic invaders directly after birth. Undoubtedly, the crosstalk between maternal immune cells, antibodies, dietary antigens, and microbial metabolites originating from the maternal microbiota are the key players in preparing the neonate’s immunity to the outer world. Birth represents the biggest substantial environmental change in life, where the newborn leaves the protective amniotic sac and is exposed for the first time to a countless variety of microbes. Colonization of all body surfaces commences, including skin, lung, and gastrointestinal tract, leading to the establishment of the commensal microbiota and the maturation of the newborn immune system, and hence lifelong health. Pregnancy, birth, and the consumption of breast milk shape the immune development in coordination with maternal and newborn microbiota. Discrepancies in these fine-tuned microbiota interactions during each developmental stage can have long-term effects on disease susceptibility, such as metabolic syndrome, childhood asthma, or autoimmune type 1 diabetes. In this review, we will give an overview of the recent studies by discussing the multifaceted emergence of the newborn innate immune development in line with the importance of maternal and early life microbiota exposure and breast milk intake.
Comparative Sensitivities of Zooplankton to Ocean Acidification Conditions in Experimental and Natural Settings
Authors: Keil Katherine E. , Klinger Terrie , Keister Julie E. , McLaskey Anna K.
Published: May 2021

Zooplankton can serve as indicators of ecosystem health, water quality, food web structure, and environmental change, including those associated with climate change and ocean acidification (OA). Laboratory studies demonstrate that low pH and high pCO2 associated with OA can significantly affect the physiology and survival of zooplankton, with differential responses among taxa. While laboratory studies can be indicative of zooplankton response to OA, in situ responses will ultimately determine the fate of populations and ecosystems. In this perspective, we compare expectations from experimental studies with observations made in Puget Sound (Washington, United States), a highly dynamic estuary with known vulnerabilities to low pH and high pCO2. We found little association between empirical measures of in situ pH and the abundance of sensitive taxa as revealed by meta-analysis, calling into question the coherence between experimental studies and field observations. The apparent mismatch between laboratory and field studies has important ramifications for the design of long-term monitoring programs and interpretation and use of the data produced. Important work remains to be done to connect traits that are sensitive to OA with those that are ecologically relevant and reliably observable in the field.
Optimized Application of 68Ga-Prostate-Specific Membrane Antigen-617 Whole-Body PET/CT and Pelvic PET/MR in Prostate Cancer Initial Diagnosis and Staging
Authors: Qin Chunxia , Gai Yongkang , Liu Qingyao , Ruan Weiwei , Liu Fang , Hu Fan , Zhang Xiaoping , Lan Xiaoli
Published: May 2021

Purpose: To analyze 68Ga-PSMA-617 PET/CT or PET/MR and delayed PET/MR images in patients diagnosed with or suspicion of prostate cancer, and to explore the optimal use of PET/CT and PET/MR for initial diagnosis and staging in prostate cancer.

Methods: Images from conventional scan by 68Ga-PSMA whole-body PET/CT or PET/MR followed by delayed pelvic PET/MR were retrospectively analyzed. Prostatic 68Ga-PSMA uptake was measured as SUVmax1 (conventional scan 1 h post injection) and SUVmax2 (delayed scan 3 h post injection). Age, PSA levels, and SUVmax were compared between benign and malignant cases. The correlation of SUVmax1 and SUVmax2 was analyzed. Diagnostic performance was evaluated by ROC analysis.

Results: Fifty-six patients with 41 prostate cancers and 15 benign prostate lesions were enrolled. Fifty-three patients had paired conventional and delayed scans. Age, tPSA, fPSA levels, and SUVmax were significantly different between benign and malignant cases. A good correlation was found between SUVmax1 and SUVmax2. There was significant difference between SUVmax1 and SUVmax2 in the malignant group (p = 0.001). SUVmax1 had superior diagnostic performance than SUVmax2, SUVmax difference and PSA levels, with a sensitivity of 85.4%, a specificity of 100% and an AUC of 0.956. A combination of SUVmax1 with nodal and/or distant metastases and MR PI-RADS V2 score had a sensitivity and specificity of 100%. Delayed pelvic PET/MR imaging in 33 patients were found to be redundant because these patients had nodal and/or distant metastases which can be easily detected by PET/CT. PET/MR provided incremental value in 8 patients at early-stage prostate cancer based on precise anatomical localization and changes in lesion signal provided by MR.

Conclusion: Combined 68Ga-PSMA whole-body PET/CT and pelvic PET/MR can accurately differentiate benign prostate diseases from prostate cancer and accurately stage prostate cancer. Whole-body PET/CT is sufficient for advanced prostate cancer. Pelvic PET/MR contributes to diagnosis and accurate staging in early prostate cancer. Imaging at about 1 h after injection is sufficient in most patients.

ClinicalTrials.gov: NCT03756077. Registered 27 November 2018—Retrospectively registered, https://clinicaltrials.gov/show/NCT03756077.
Biological Control of Chili Damping-Off Disease, Caused by Pythium myriotylum
Authors: Hyder Sajjad , Gondal Amjad Shahzad , Rizvi Zarrin Fatima , Atiq Rashida , Haider Muhammad Irtaza Sajjad , Fatima Nida , Inam-ul-Haq Muhammad
Published: May 2021

Pythium myriotylum is a notorious soil-borne oomycete that causes post-emergence damping-off in chili pepper. Of various disease management strategies, utilization of plant growth promoting rhizobacteria (PGPR) in disease suppression and plant growth promotion is an interesting strategy. The present study was performed to isolate and characterize PGPR indigenous to the chili rhizosphere in Pakistan, and to test the potential to suppress the damping-off and plant growth promotion in chili. Out of a total of 28 antagonists, eight bacterial isolates (4a2, JHL-8, JHL-12, 1C2, RH-24, 1D, 5C, and RH-87) significantly suppressed the colony growth of P. myriotylum in a dual culture experiment. All the tested bacterial isolates were characterized for biochemical attributes, and 16S rRNA sequence based phylogenetic analysis identified these isolates as Flavobacterium spp., Bacillus megaterium, Pseudomonas putida, Bacillus cereus, and Pseudomonas libanensis. All the tested bacterial isolates showed positive test results for ammonia production, starch hydrolase (except 4a2), and hydrogen cyanide production (except 4a2 and 1D). All the tested antagonists produced indole-3-acetic acid (13.4–39.0 μg mL–1), solubilized inorganic phosphate (75–103 μg mL–1), and produced siderophores (17.1–23.7%) in vitro. All the tested bacterial isolates showed varying levels of susceptibility and resistance response against different antibiotics and all these bacterial isolates were found to be non-pathogenic to chili seeds and notably enhanced percentage seed germination, plumule, redical length, and vigor index over un-inoculated control. Additionally, under pathogen pressure, bacterization increased the defense related enzymes such as Peroxidase (PO), polyphenol oxidase (PPO), and phenylalanine ammonia-lyase (PAL) activates. Moreover, the treatment of chili seeds with these bacterial isolates significantly suppressed the damping-off caused by P. myriotylum and improved PGP traits compared to the control. In addition, a positive correlation was noticed between shoot, root length, and dry shoot and root weight, and there was a negative correlation between dry shoot, root weight, and seedling percentage mortality. These results showed that native PGPR possesses multiple traits beneficial to the chili plants and can be used to develop eco-friendly and effective seed treatment formulation as an alternative to synthetic chemical fungicides.
A Win–Loss Interaction on Fe0 Between Methanogens and Acetogens From a Climate Lake
Authors: Palacios Paola Andrea , Francis Warren Russell , Rotaru Amelia-Elena
Published: May 2021

Diverse physiological groups congregate into environmental corrosive biofilms, yet the interspecies interactions between these corrosive physiological groups are seldom examined. We, therefore, explored Fe0-dependent cross-group interactions between acetogens and methanogens from lake sediments. On Fe0, acetogens were more corrosive and metabolically active when decoupled from methanogens, whereas methanogens were more metabolically active when coupled with acetogens. This suggests an opportunistic (win–loss) interaction on Fe0 between acetogens (loss) and methanogens (win). Clostridia and Methanobacterium were the major candidates doing acetogenesis and methanogenesis after four transfers (metagenome sequencing) and the only groups detected after 11 transfers (amplicon sequencing) on Fe0. Since abiotic H2 failed to explain the high metabolic rates on Fe0, we examined whether cell exudates (spent media filtrate) promoted the H2-evolving reaction on Fe0 above abiotic controls. Undeniably, spent media filtrate generated three- to four-fold more H2 than abiotic controls, which could be partly explained by thermolabile enzymes and partly by non-thermolabile constituents released by cells. Next, we examined the metagenome for candidate enzymes/shuttles that could catalyze H2 evolution from Fe0 and found candidate H2-evolving hydrogenases and an almost complete pathway for flavin biosynthesis in Clostridium. Clostridial ferredoxin-dependent [FeFe]-hydrogenases may be catalyzing the H2-evolving reaction on Fe0, explaining the significant H2 evolved by spent media exposed to Fe0. It is typical of Clostridia to secrete enzymes and other small molecules for lytic purposes. Here, they may secrete such molecules to enhance their own electron uptake from extracellular electron donors but indirectly make their H2-consuming neighbors—Methanobacterium—fare five times better in their presence. The particular enzymes and constituents promoting H2 evolution from Fe0 remain to be determined. However, we postulate that in a static environment like corrosive crust biofilms in lake sediments, less corrosive methanogens like Methanobacterium could extend corrosion long after acetogenesis ceased, by exploiting the constituents secreted by acetogens.
Reprogramming of the Caseinolytic Protease by ADEP Antibiotics: Molecular Mechanism, Cellular Consequences, Therapeutic Potential
Authors: Brötz-Oesterhelt Heike , Vorbach Andreas
Published: May 2021

Rising antibiotic resistance urgently calls for the discovery and evaluation of novel antibiotic classes and unique antibiotic targets. The caseinolytic protease Clp emerged as an unprecedented target for antibiotic therapy 15 years ago when it was observed that natural product-derived acyldepsipeptide antibiotics (ADEP) dysregulated its proteolytic core ClpP towards destructive proteolysis in bacterial cells. A substantial database has accumulated since on the interaction of ADEP with ClpP, which is comprehensively compiled in this review. On the molecular level, we describe the conformational control that ADEP exerts over ClpP, the nature of the protein substrates degraded, and the emerging structure-activity-relationship of the ADEP compound class. On the physiological level, we review the multi-faceted antibacterial mechanism, species-dependent killing modes, the activity against carcinogenic cells, and the therapeutic potential of the compound class.
Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome
Authors: Haseloff Reiner F. , Trudel Stephanie , Birke Ramona , Schümann Michael , Krause Eberhard , Gomila Cathy , Heard Jean-Michel , Blasig Ingolf E. , Ausseil Jérôme
Published: May 2021

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydroxylase alpha-l-iduronidase (IDUA). The resulting accumulation of dermatan and heparan sulfate induces intellectual disabilities and pre-mature death, and only a few treatment options are available. In a previous study, we demonstrated the feasibility, safety, and efficacy of gene therapy by injecting recombinant adeno-associated viral vector serotype (AAV)2/5-IDUA into the brain of a canine model of MPS I. We report on a quantitative proteomic analysis of control dogs and untreated dogs with MPS I cerebrospinal fluid (CSF) that had been collected throughout the study in the MPS I dogs. Mass spectrometry (MS) analysis identified numerous proteins present at altered levels in MPS I CSF samples. Quantitative immunoblotting, performed on CSF from healthy controls, untreated MPS I dogs, and MPS I dogs early treated and late treated by gene therapy, confirmed the MS data for a subset of proteins with higher abundance (neuronal pentraxin 1, chitinase 3-like 1, monocyte differentiation antigen CD14, and insulin-like growth factor-binding protein 2). Scoring of the results shows that the expression levels of these proteins are close to those of the control group for dogs that underwent gene therapy early in life but not for older treated animals. Our results disclose four novel predictive biomarker candidates that might be valuable in monitoring the course of the neurological disease in MPS patients at diagnosis, during clinical follow-up, and after treatment.
Development and Validation of a Nomogram to Predict the Individual Future Stroke Risk for Adult Patients With Moyamoya Disease: A Multicenter Retrospective Cohort Study in China
Authors: Ye Fei , Wang Tianzhu , Yin Haoyuan , Li Jiaoxing , Li Haiyan , Guo Tongli , Zhang Xiong , Yang Tingting , Jie Liang , Wu Xiaoxin , Li Qi , Sheng Wenli
Published: May 2021

Background: Studies exploring the predictive performance of major risk factors associated with future stroke events are insufficient, and a useful tool to predict individual risk is not available. Therefore, personalized advice for preventing future stroke in patients with moyamoya disease (MMD) cannot provide evidence-based recommendations. The aim of this study was to develop a novel nomogram with reliable validity to predict the individual risk of future stroke for adult MMD patients.

Methods: This study included 450 patients from seven medical centers between January 2013 and December 2018. Follow-ups were performed via clinical visits and/or telephone interviews from initial discharge to December 2019. The cohort was randomly assigned to a training set (2/3, n = 300) for nomogram development and a test set (1/3, n = 150) for external validation. The Kaplan-Meier analyses and receiver operating characteristic (ROC) curves were applied to assess the clinical benefits of this nomogram.

Results: Diabetes mellitus, a family history of MMD, a past history of stroke or transient ischemic attack, clinical manifestation, and treatment were identified as major risk factors via the least absolute shrinkage and selection operator (LASSO) method. A nomogram including these predictors was established via a multivariate Cox regression model, which displayed excellent discrimination [Harrell's concordance index (C-index), 0.85; 95% confidence interval (CI): 0.75–0.96] and calibration. In the external validation, the nomogram was found to have good discrimination (C-index, 0.81; 95% CI: 0.68–0.94) and calibration. In the subgroup analysis, this predictive nomogram also showed great performance in both ischemic-type (C-index, 0.90; 95% CI: 0.77–1.00) and hemorrhagic-type MMD (C-index, 0.72; 95% CI: 0.61–0.83). Furthermore, the nomogram was shown to have potential in clinical practice through Kaplan-Meier analyses and ROC curves.

Conclusions: We developed a novel nomogram incorporating several clinical characteristics with relatively good accuracy, which may have considerable potential for evaluating individual future stroke risk and providing useful management recommendations for adult patients with MMD in clinical practice.
Machine Learning for Predicting Individual Severity of Blepharospasm Using Diffusion Tensor Imaging
Authors: Liu Gang , Gao Yanan , Liu Ying , Guo Yaomin , Yan Zhicong , Ou Zilin , Zhong Linchang , Xie Chuanmiao , Zeng Jinsheng , Zhang Weixi , Peng Kangqiang , Lv Qingwen
Published: May 2021

Accumulating diffusion tensor imaging (DTI) evidence suggests that white matter abnormalities evaluated by local diffusion homogeneity (LDH) or fractional anisotropy (FA) occur in patients with blepharospasm (BSP), both of which are significantly correlated with disease severity. However, whether the individual severity of BSP can be identified using these DTI metrics remains unknown. We aimed to investigate whether a combination of machine learning techniques and LDH or FA can accurately identify the individual severity of BSP. Forty-one patients with BSP were assessed using the Jankovic Rating Scale and DTI. The patients were assigned to non-functionally and functionally limited groups according to their Jankovic Rating Scale scores. A machine learning scheme consisting of beam search and support vector machines was designed to identify non-functionally versus functionally limited outcomes, with the input features being LDH or FA in 68 white matter regions. The proposed machine learning scheme with LDH or FA yielded an overall accuracy of 88.67 versus 85.19% in identifying non-functionally limited versus functionally limited outcomes. The scheme also identified a sensitivity of 91.40 versus 85.87% in correctly identifying functionally limited outcomes, a specificity of 83.33 versus 83.67% in accurately identifying non-functionally limited outcomes, and an area under the curve of 93.7 versus 91.3%. These findings suggest that a combination of LDH or FA measurements and a sophisticated machine learning scheme can accurately and reliably identify the individual disease severity in patients with BSP.
A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis
Authors: Pan Hong , Diao Huanrong , Zhong Wen , Wang Taifang , Wen Ping , Wu Chunli
Published: May 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence worldwide. Late detection and particularly aggressive characteristics are the major challenges that lead to therapeutic failure of this disease. A well described gene program and core regulators are yet to be discovered to drive the metastasis of the PDAC cells. As the development of single cell omics technologies including single cell RNA-sequencing (scRNA-seq), detailed characterization of the cellular composition of solid tumors and their microenvironments are well elaborated. In the current study, we accessed a recently published scRNA-seq dataset on primary and metastatic PDAC tissues and subset the tumor cells. By comparative analysis, we profiled the differentially expressed gene programs of primary and metastatic PDAC and found several long intergenic non-coding RNAs (LincRNAs) in top genes. The PDAC cancer cells showed some heterogeneity and were divided into four major subclusters based on gene profiles, one of which was mostly contributed by metastatic PDAC. Interestingly, this subcluster was remarkably marked by one of the above LincRNAs, MEG3, and exhibited significantly increased Epithelial–Mesenchymal-Transition (EMT) signatures. Ingenuity Pathway Analysis (IPA) on the signature genes of this subcluster gave multiple cancer metastasis associated and EMT signaling pathways, suggesting a critical role of this cluster in leading tumor cell metastasis. Taken together, this study displayed a PDAC cancer subcluster and its marker gene, biologically targeting of which might significantly attenuate the metastasis of tumor and might be a potential strategy for the therapeutic treatment of cancer.
Viral Gene Therapy for Glioblastoma Multiforme: A Promising Hope for the Current Dilemma
Authors: Li Junsheng , Wang Wen , Wang Jia , Cao Yong , Wang Shuo , Zhao Jizong
Published: May 2021

Glioblastoma multiforme (GBM), as one of the most common malignant brain tumors, was limited in its treatment effectiveness with current options. Its invasive and infiltrative features led to tumor recurrence and poor prognosis. Effective treatment and survival improvement have always been a challenge. With the exploration of genetic mutations and molecular pathways in neuro-oncology, gene therapy is becoming a promising therapeutic approach. Therapeutic genes are delivered into target cells with viral vectors to act specific antitumor effects, which can be used in gene delivery, play an oncolysis effect, and induce host immune response. The application of engineering technology makes the virus vector used in genetics a more prospective future. Recent advances in viral gene therapy offer hope for treating brain tumors. In this review, we discuss the types and designs of viruses as well as their study progress and potential applications in the treatment of GBM. Although still under research, viral gene therapy is promising to be a new therapeutic approach for GBM treatment in the future.
Case Report: 18F-PSMA PET/CT May Improve the Clinical Management of Penile Metastases From Prostate Cancer
Authors: Fan Junjie , Liang Hua , Zhang Xing , Chen Xingfa , Duan Xiaoyi , Li Lei , He Dalin , Wu Kaijie
Published: May 2021

Metastases from prostate cancer (PCa) to the penis are extremely rare, and few case reports exist in the literature. Because most patients usually present with multiple distant metastases at diagnosis, the prognosis is very poor. With the wide application of prostate-specific membrane antigen (PSMA) PET/CT, penile metastases may be detected at an early stage. Thus, questions regarding whether early diagnosis and precise treatment will equate to a survival advantage have recently been raised. In the present study, we reported 3 cases of penile metastasis from castration-resistant PCa. Moreover, a patient with asymptomatic penile metastases was diagnosed by 18F-PSMA PET/CT followed by lesion biopsy, and the prognosis was very well, despite with an aggressive pathological feature and low treatment intensity. In addition, we performed a literature review and found 62.5% of asymptomatic penile metastases were diagnosed by PSMA PET/CT in past seven years. Thus, we believe that PSMA PET/CT may detect more asymptomatic penile metastases in future, which led to early diagnosis, treatment and survival advantage.
Critical Breaths in Transit: A Review of Non-invasive Ventilation (NIV) for Neonatal and Pediatric Patients During Transportation
Authors: Ide Nellie , Allen Grace , Ashworth Henry Charles , Dada Sara
Published: May 2021

Respiratory illnesses are a leading cause of death for children worldwide, with the majority of these cases occurring from preterm birth complications or acute respiratory infections. Appropriate respiratory intervention must be provided quickly to lower the chances of death or permanent harm. As a result, respiratory support given in prehospital and interfacility transport can substantially improve health outcomes for these patients, particularly in areas where transportation time to appropriate facilities is lengthy. Existing literature supports the use of non-invasive ventilation (NIV), such as nasal or bilevel continuous positive airway pressure, as a safe form of respiratory support for children under 18 years old in certain transportation settings. This mini review summarizes the literature on pediatric NIV in transport and highlights significant gaps that future researchers should address. In particular, we identify the need to: solidify clinical guidelines for the selection of eligible pediatric patients for transport on NIV; explore the range of factors influencing successful NIV implementation during transportation; and apply appropriate best practices in low and middle income countries.
Root Extract of Lindera aggregata (Sims) Kosterm. Modulates the Th17/Treg Balance to Attenuate DSS-Induced Colitis in Mice by IL-6/STAT3 Signaling Pathway
Authors: Lai Huimin , Yang Zhengbiao , Lou Zhaohuan , Li Feng , Xie Feng , Pan Wei , Xu Cong , Zhang Lili , Zhang Sheng , Zhang Lijiang , Huang Mincong
Published: May 2021

Ulcerative colitis (UC) is a chronic, idiopathic and relapsing inflammatory disease of the gastrointestinal tract that has a prolonged disease duration. Lindera aggregata (Sims) Kosterm. is a traditional Chinese herb which has been used to treat gastrointestinal diseases for thousand years. However, there are few reports about the application of L. aggregata in the treatment of UC at present. Herein, we investigated the therapeutic effect of the root extract of L. aggregata (LREE) against UC and explored its underlying mechanisms based on IL-6 signaling pathway and the balance of T helper (Th) 17 and regulatory T (Treg) cells. Results showed that LREE could not only decrease the production and secretion of IL-6, but also could inhibit the signal transduction of IL-6/STAT3 signaling pathway. Moreover, LREE could significantly inhibit the differentiation of CD4+ T cells to Th17 cells in vitro and decrease the proportion of Th17 cells in mesenteric lymph nodes (MLNs) of model mice in vivo. Besides, LREE could also alleviate the disease symptoms, reduce intestinal permeability and improve histopathological changes of colitis model mice. Together, LREE can significantly inhibit the production and secretion of IL-6, regulate IL-6/STAT3 signal transduction, and modulate the balance of Th17 and Treg cells and effectively attenuate UC.
p53 Rather Than β-Catenin Mediated the Combined Hypoglycemic Effect of Cinnamomum cassia (L.) and Zingiber officinale Roscoe in the Streptozotocin-Induced Diabetic Model
Authors: Ayuob Nasra , Al-Shathly Mona Ramadan , Bakhshwin Abdulaziz , Al-Abbas Nouf Saeed , Shaer Nehad A , Al Jaouni Soad , Hamed Walaa H. E.
Published: May 2021

Background: The antioxidant, hypoglycemic, and insulin-enhancing effects of ginger and cinnamon were previously confirmed in experimental and human studies, while the combined effect of ginger and cinnamon was not thoroughly investigated until now.

Objectives: This study was designed to assess the antidiabetic effect of combined administration of ginger (Zingiber officinale Roscoe) and cinnamon (Cinnamomum cassia L.) in streptozotocin (STZ)-induced diabetic rats compared to metformin and to explain the mechanism behind this effect.

Materials and methods: STZ was utilized to induce diabetes mellitus in male Sprague–Dawley rats. Assessments of fasting blood glucose level (BGL), the total antioxidant capacity (TAC), serum insulin, HOMA-IR, and HOMA–β cells were performed. Pancreatic gene expression of β-catenin and p53 was assessed using RT-PCR. Assessment of histopathological alterations of pancreatic islet cells was performed using routine and immunohistochemical techniques.

Results: BGL significantly decreased (p = 0.01), while serum insulin and TAC significantly increased (p < 0.001) in both metformin- and ginger plus cinnamon–treated groups compared to the untreated diabetic group. HOMA–β cell index significantly increased (p = 0.001) in ginger plus cinnamon, indicating their enhancing effect on insulin secretion in diabetic conditions. p53 gene expression was significantly upregulated (p < 0.001), while β-catenin was insignificantly downregulated (p = 0.32) in ginger plus cinnamon–treated groups. Insulin immunoexpression in β cells significantly increased (p = 0.001, p = 0.004) in metformin- and ginger plus cinnamon–treated groups, respectively.

Conclusions: The combined administration of ginger and cinnamon has a significant hypoglycemic and antioxidant effect in STZ-induced diabetes mostly through enhancing repair of islet cells mediated via upregulation of pancreatic p53 expression. Therefore, testing this effect in diabetic patients is recommended.