bluuebunny/crossref_metadata_2025 huggingface dataset:
The 2003 Ms6.1 Minle Earthquake: An Earthquake in the Minle-Yongchang Reverse Fault-Related Fold Belt in the Hexi Corridor, NW China
Authors: Zou Xiaobo , Yuan Daoyang , Shao Yanxiu , Liu Xingwang , Ge Weipeng , Zhang Bo
Published: April 2021

The Minle-Yongchang fault is an active reverse fault-related fold structural belt developed in the Hexi Corridor Basin on the northeastern edge of the Tibetan Plateau. An earthquake of Ms6.1 occurred near the Minle-Yongchang fault zone in 2003. The deformation pattern of the Minle-Yongchang fault and its relationship with this strong earthquake, however, are still not well known. In this study, we used the methods of HYPOINVERSE absolute location and double-difference location with waveform cross-correlation technology to relocate the 2003 Minle earthquake sequence. In total, 383 earthquakes are precisely relocated. Based on the results of precise seismic relocation, using the method of determining fault planes by small earthquakes, the seismogenic fault is found to be a low-angle thrust with a strike of 311°, a dip of NE, and a dip angle of 14°. It does not rupture the surface, extends to 19–20 km depth, and is hidden beneath the Yonggu Anticline. We also employed the cut-and-paste (CAP) method with a broadband waveform to determine the focal mechanism of the mainshock in 2003: the strike is 311°; the dip is 34°; and the rake is 90°. The fault plane parameters obtained in these two ways are roughly consistent. We also used a digital elevation model (DEM) derived from the SPOT 6 stereo image pair and high-precision differential Global Positioning System (GPS) to measure the displacement of terraces. Topographic profiles along the terraces across the Minle-Yongchang fault show that high alluvial terrain exhibits fold deformation. The vertical offsets of the T2 and T3 terraces along the Tongziba River are approximately 2.3 and 22 m, respectively. Optically stimulated luminescence (OSL) dating indicates that the ages of T2 and T3 are 11.3 and 106 ka, respectively. We calculated an average uplift rate of 0.21 ± 0.05 mm/a by dividing the vertical offset by age. According to the spatial distribution of the relocated earthquake sequence and terrace deformation in the study area, the Ms6.1 Minle earthquake in 2003 was caused by the latest activity of a blind reverse fault-related fold in the Hexi Corridor Basin.
Improved Stability of Organic Photovotlaic Devices With FeCl3 Intercalated Graphene Electrodes
Authors: Walsh Kieran K. , Murphy Conor , Russo Saverio , Craciun Monica F.
Published: April 2021

In this paper, we present the first organic photovoltaic (OPV) devices fabricated with FeCl3 intercalated few layer graphene (i-FLG) electrodes. i-FLG electrodes were first fabricated and characterized by electrical and spectroscopic means, showing enhanced conductive properties compared to pristine graphene. These electrodes were then used in the fabrication of OPV devices and tested against devices made with commercially available Indium Tin Oxide (ITO) electrodes. Both types of device achieved similar efficiencies, while the i-FLG based device exhibited superior charge transport properties due to the increase in work function characterizing i-FLG. Both types of device underwent a stability study using both periodic and continuous illumination measurements, which revealed i-FLG based OPVs to be significantly more stable than those based on ITO. These improvements are expected to translate to increased device lifetimes and a greater total energy payback from i-FLG based photovoltaic devices. These results highlight the potential benefits of using intercalated graphene materials as an alternative to ITO in photovoltaic devices.
Analysis of the Screening Results for Congenital Adrenal Hyperplasia Involving 7.85 Million Newborns in China: A Systematic Review and Meta-Analysis
Authors: Li Zhuoguang , Huang Lianjing , Du Caiqi , Zhang Cai , Zhang Mini , Liang Yan , Luo Xiaoping
Published: April 2021

Background

Congenital adrenal hyperplasia (CAH) is a group of congenital genetic diseases caused by defective steroidogenesis. Our study aims to systematically analyze the screening results for CAH in Chinese newborns.

Methods

Studies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to September, 2020. Meta-analysis was performed after quality assessment and data extraction.

Results

After a review of 2 694 articles, we included 41 studies enrolling 7 853 756 newborns. In our study, we found that the incidence of CAH in China was 0.43‱ [95% confidence intervals(CI), (0.39‱, 0.48‱)], or 1/23 024 [95%CI, (1/25 757,1/20 815)]. 27 studies were included for analysis of the screening positive rate, which gave a rate of 0.66% [95%CI, (0.54%, 0.78%)]. As for the recall rate of positive cases, 17 studies were included and showed that the recall rate reached 86.17% [95%CI, (82.70%, 89.64%)]. Among the CAH patients, the ratio of males to females was 1.92:1 (119:62), and the ratio of salt wasting (SW) to simple virilization (SV) type was 3.25:1 (104:32). The average 17-hydroxyprogesterone (17-OHP) value of CAH was 393.40 ± 291.85 nmol/L (Range 33-1 300 nmol/L); there was no significant difference between male and female patients (437.17 ± 297.27 nmol/L v.s. 322.25 ± 293.04 nmol/L, P=0.16), but a significant difference was found between SW and SV patients (483.29 ± 330.07 nmol/L v.s. 73.80 ± 7.83nmol/L, P=0.04).

Conclusion

We systematically analyzed the current situation of neonatal CAH screening in China, which will deepen our understanding for future CAH screening and early diagnosis.
Clinical Manifestations of Polycystic Ovary Syndrome and Associations With the Vaginal Microbiome: A Cross-Sectional Based Exploratory Study
Authors: Hong Xiang , Qin Pengfei , Yin Jiechen , Shi Yong , Xuan Yan , Chen Zhengqi , Zhou Xu , Yu Hong , Peng Danhong , Wang Bei
Published: April 2021

Background

Previous studies suggest that the vaginal microbiome is associated with polycystic ovary syndrome (PCOS). However, the clinical manifestations of PCOS are heterogeneous. Whether the vaginal microbiome is related with different clinical symptoms was unknown.

Materials and Methods

In this cross-sectional study, 89 female patients with PCOS admitted to Zhongda Hospital (Nanjing, China) were included. Basic demographic information, health-related behaviors, clinical manifestations and sex hormone levels were comprehensively recorded for all patients. Vaginal swabs were acquired for microbiota sequencing of the V3–V4 region of the 16S rRNA gene.

Results

The prevalence of bacterial vaginitis and vulvovaginal candidiasis was 15.7% and 13.5%, respectively, within the PCOS patients, which were the most important factors affecting the vaginal microbiome (permutational multivariate analysis of variance test, R2 = 0.108, P = 0.001). The vaginal microbiome was associated with specific clinical manifestations of PCOS, including acanthosis nigricans, intermenstrual bleeding, pregnancy history, testosterone level and anti-müllerian hormone level, with P values < 0.05. The abundance of Lactobacillus crispatus was higher (P = 0.010) while that of Lactobacillus iners was lower (P = 0.036) among PCOS patients with elevated testosterone levels. Other potential bacterial biomarkers were not statistically significant after adjusting for confounding factors. No evidence of associations of other common manifestations of PCOS, such as obesity and acne, with the vaginal microbiome was obtained.

Conclusion

Vaginal bacterial species among PCOS patients with variable clinical manifestations, especially differences in testosterone levels, are distinct. Further studies are essential to investigate the microbiota and molecular mechanisms underpinning this disease.
Assessment of the Potential Risk of Rock-Climbing for Cliff Plant Species and Natural Protected Areas of Spain
Authors: deCastro-Arrazola Indradatta , March-Salas Martí , Lorite Juan
Published: April 2021

In recent years, the popularity of rock-climbing has grown tremendously, setting an increasing pressure on cliff habitats. Climbing may be particularly harmful in the Mediterranean biome due to its appropriate environmental conditions for climbing. A few studies have identified the effect of climbing on plant diversity at a small-scale (namely locally or even just in specific climbing areas). However, no studies exist assessing the potential risk of rock-climbing on a broad-scale (e.g., regional or national). The study aims to identify the priority locations and priority cliff plant species in Spain to focus future study efforts. Spain was selected because it is a plant biodiversity hotspot, with a great diversity of endemic and endangered species, and one of the most popular destinations for climbers. We used a geographic information system-based approach to model the spatial concurrence among Spanish climbing areas (and climbing intensity), natural protected areas (NPAs), and distribution of threatened cliff plants (and their IUCN threat category). We found that 53.5% of climbing areas in Spain are located within a NPA, most of them falling into NPAs of medium protection level. We mapped 151 threatened cliff plants, identifying four medium priority Mediterranean locations and eight priority species in which future research efforts should be focused. High-priority study locations are absent in Spain according to our spatial modeling. For the first time on a national scale, this study identifies areas in which climbing represents a potential threat for cliff habitats and threatened plants. These findings contribute to designing field studies on the effects of rock-climbing on Mediterranean cliffs, laying the groundwork for a sustainable, yet challenging, balance between the protection of these unique habitats and rock-climbing.
20-Years Cumulative Impact From Shrimp Farming on Mangroves of Northeast Brazil
Authors: de Lacerda Luiz Drude , Ward Raymond D. , Godoy Mario Duarte Pinto , de Andrade Meireles Antônio Jeovah , Borges Rebecca , Ferreira Alexander Cesar
Published: April 2021

Brazilian mangroves cover about 11,100 km2and provide a wide range of ecosystem services. Despite their importance, they are one of the most impacted ecosystems because of combined influences of climate change, pollution, and direct conversion and loss. A major driver of environmental impacts is shrimp farming and this is particularly acute in the semi-arid northeast of Brazil, where mangroves are constrained in a narrow band along ephemeral estuaries that are often impacted by multi-year droughts. Recent changes to Brazilian law, in particular the Forest Code, have weakened protection for mangroves and associated “apicum” (salt pan) ecosystems. In NE Brazil, most shrimp ponds are converted from mangrove-adjacent “apicuns” rather than the mangroves themselves with periodic hydrological connectivity through dammed channels, allowing the flushing of effluents. As a result, the main impacts on mangroves are typically indirect, because of pollution inputs from shrimp pond effluents and associated loss of ecosystem services including reductions in primary productivity, carbon storage capacity, resilience to other environmental stressors, their efficiency as estuarine filters, and biodiversity and abundance of subsistence use of marine species. Soil damage and infrastructure remaining after shrimp pond deactivation impairs mangrove recovery. This extends the duration of the damage and allows the occupation of degraded areas by other activities that can permanently impair ecosystem function. In this review, we address several aspects of the shrimp culture boom in NE Brazilian, their features and consequences, and the future of mangroves in the region considering climate change and rising poverty. Our conclusions on the practices and outcomes of shrimp farming in mangroves are likely to apply to areas with similar environmental settings, e.g., semiarid regions worldwide, and particularly in the Latin America and Caribbean region, and our findings can be taken into account to improve conservation and management of these forests at the least to a regional scale.
Combined Analysis of Volatile Terpenoid Metabolism and Transcriptome Reveals Transcription Factors Related to Terpene Synthase in Two Cultivars of Dendrobium officinale Flowers
Authors: Li Ninghong , Dong Yingxue , Lv Min , Qian Li , Sun Xu , Liu Lin , Cai Yongping , Fan Honghong
Published: April 2021

Dendrobium officinale is a kind of traditional Chinese herbal medicine. Its flowers could be used as health care tea for its aroma flavor and medicinal value. Most recent studies demonstrated that terpenoids are the main components of the aromatic compounds in the flowers, but the biosynthesis of terpenoids is poorly understood in D. officinale. In the experiment, the flowers from two cultivars of D. officinale with different smells were collected. The transcriptome analysis and combined volatile terpenoids determination were performed to identify the genes related to the biosynthesis of the terpenoids. The results showed that the different products of volatile terpenoids are α-thujene, linalool, α-terpineol, α-phellandrene, γ-muurolene, α-patchoulene, and δ-elemene in two cultivar flowers. The transcriptome analysis detected 25,484 genes in the flowers. And 18,650 differentially expressed genes were identified between the two cultivars. Of these genes, 253 genes were mapped to the terpenoid metabolism pathway. Among these genes, 13 terpene synthase (TPS) genes may have correlations with AP2/ERF, WRKY, MYB, bHLH, and bZIP transcription factors by weighted gene co-expression network analysis (WGCNA). The transcription factors have regulatory effects on TPS genes. These results may provide ideas for the terpenoid biosynthesis and regulatory network of D. officinale flowers.
HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure
Authors: Khor Seik-Soon , Omae Yosuke , Nishida Nao , Sugiyama Masaya , Kinoshita Noriko , Suzuki Tetsuya , Suzuki Michiyo , Suzuki Satoshi , Izumi Shinyu , Hojo Masayuki , Ohmagari Norio , Mizokami Masashi , Tokunaga Katsushi
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February–August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27–3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24–3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50–7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01–1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31–6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.
Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?
Authors: van Geffen Chiel , Deißler Astrid , Quante Markus , Renz Harald , Hartl Dominik , Kolahian Saeed
Published: April 2021

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.
Protocols for Assessing Transformation Rates of Nitrous Oxide in the Water Column
Authors: Bourbonnais Annie , Frey Claudia , Sun Xin , Bristow Laura A. , Jayakumar Amal , Ostrom Nathaniel E. , Casciotti Karen L. , Ward Bess B.
Published: April 2021

Nitrous oxide (N2O) is a potent greenhouse gas and an ozone destroying substance. Yet, clear step-by-step protocols to measure N2O transformation rates in freshwater and marine environments are still lacking, challenging inter-comparability efforts. Here we present detailed protocols currently used by leading experts in the field to measure water-column N2O production and consumption rates in both marine and other aquatic environments. We present example 15N-tracer incubation experiments in marine environments as well as templates to calculate both N2O production and consumption rates. We discuss important considerations and recommendations regarding (1) precautions to prevent oxygen (O2) contamination during low-oxygen and anoxic incubations, (2) preferred bottles and stoppers, (3) procedures for 15N-tracer addition, and (4) the choice of a fixative. We finally discuss data reporting and archiving. We expect these protocols will make 15N-labeled N2O transformation rate measurements more accessible to the wider community and facilitate future inter-comparison between different laboratories.
Corrosion Behavior of Al0.1CoCrFeNi High Entropy Alloy in Various Chloride-Containing Solutions
Authors: Wang K. , Lan A. D. , Qiao J. W.
Published: April 2021

The present work investigates the corrosion behavior of Al0.1CoCrFeNi high entropy alloy (HEA) in various concentrations of chloride-containing solutions. Electrochemical tests exhibit overall excellent corrosion resistance of this alloy against the attack of Cl−-containing solutions. The main type of corrosion topography presents an intergranular feature. In addition, electrochemical impedance spectroscopy (EIS) investigation of the HEA samples under immersion test suggests chloride anion–containing environment leads to the decline of passivation film quality. Further analysis of XPS results reveals that significant amounts of elements exist with atomic states in the passive films.
Associations Between Sputum Torque Teno Virus Load and Lung Function and Disease Severity in Patients With Chronic Obstructive Pulmonary Disease
Authors: Xie Yu , Xue Qing , Jiao Weike , Wu Jianhui , Yu Yan , Zhao Lili , Xu Yu , Deng Xinyu , Fang Guiju , Zheng Yali , Gao Zhancheng
Published: April 2021

Purpose: Viral load of Torque Teno virus (TTV) is elevated in immunosuppressed patients. The weakened immune response is typical in chronic obstructive pulmonary disease (COPD) patients. However, the relationship between TTV and COPD is still unknown.

Patients and Methods: We enrolled 91 patients admitted to hospitals with acute exacerbation of COPD (AECOPD) between January 2017 and August 2017 (ClinicalTrials.gov ID, NCT03236480). Sputum samples were gathered during hospitalization and the 120-day follow-up. TTV distribution and genogroups were assessed, and the associations between viral loads and clinical parameters were analyzed.

Results: TTV DNA was detected in 95.6% of COPD patients, and the viral load was nearly invariable at the stable and exacerbation states. Most TTV DNA-positive patients carried four distinct genotypes. Sputum load of TTV was positively associated with RV/TLC (r = 0.378, p = 0.030), and negatively correlated with FEV1/pre and FEV1/FVC (r = −0.484, −0.432, p = 0.011, 0.024, respectively). Neutral correlation between the TTV DNA load and COPD assessment test (CAT) scores (r = 0.258, p = 0.018) was observed.

Conclusion: Sputum loads of TTV DNA could be a novel indicator for lung function and disease severity assessment in COPD patients.
Delta Shock Index During Emergency Department Stay Is Associated With in Hospital Mortality in Critically Ill Patients
Authors: Huang Yi-Syun , Chiu I-Min , Tsai Ming-Ta , Lin Chun-Fu , Lin Chien-Fu
Published: April 2021

Background: Delta shock index (SI; i.e., change in SI over time) has been shown to predict mortality and need for surgical intervention among trauma patients at the emergency department (ED). However, the usefulness of delta SI for prognosis assessment in non-traumatic critically ill patients at the ED remains unknown. The aim of this study was to analyze the association between delta SI during ED management and in-hospital outcomes in patients admitted to the intensive care unit (ICU).

Method: This was a retrospective study conducted in two tertiary medical centers in Taiwan from January 1, 2016, to December 31, 2017. All adult non-traumatic patients who visited the ED and who were subsequently admitted to the ICU were included. We calculated delta SI by subtracting SI at ICU admission from SI at ED triage, and we analyzed its association with in-hospital outcomes. SI was defined as the ratio of heart rate to systolic blood pressure (SBP). The primary outcome was in-hospital mortality, and the secondary outcomes were hospital length of stay (HLOS) and early mortality. Early mortality was defined as mortality within 48 h of ICU admission.

Result: During the study period, 11,268 patients met the criteria and were included. Their mean age was 64.5 ± 15.9 years old. Overall, 5,830 (51.6%) patients had positive delta SI. Factors associated with a positive delta SI were multiple comorbidities (51.2% vs. 46.3%, p < 0.001) and high Simplified Acute Physiology Score [39 (29–51) vs. 37 (28–47), p < 0.001). Patients with positive delta SI were more likely to have tachycardia, hypotension, and higher SI at ICU admission. In the regression analysis, high delta SI was associated with in-hospital mortality [aOR (95% CI): 1.21 (1.03–1.42)] and early mortality [aOR (95% CI): 1.26 (1.07–1.48)], but not for HLOS [difference (95% CI): 0.34 (−0.48 to 1.17)]. In the subgroup analysis, high delta SI had higher odds ratios for both mortality and early mortality in elderly [aOR (95% CI): 1.59 (1.11–2.29)] and septic patients [aOR (95% CI): 1.54 (1.13–2.11)]. It also showed a higher odds ratio for early mortality in patients with triage SBP <100 mmHg [aOR (95% CI): 2.14 (1.21–3.77)] and patients with triage SI ≥ 0.9 [aOR (95% CI): 1.62 (1.01–2.60)].

Conclusion: High delta SI during ED stay is correlated with in-hospital mortality and early mortality in patients admitted to the ICU via ED. Prompt resuscitation should be performed, especially for those with old age, sepsis, triage SBP <100 mmHg, or triage SI ≥ 0.9.
Genomics of Environmental Salmonella: Engaging Students in the Microbiology and Bioinformatics of Foodborne Pathogens
Authors: Greenman Noah A. , Jurgensen Sophie K. , Holmes Charles P. , Kapsak Curtis J. , Davis Raechel E. , Maza William M. , Edemba Desiree , Esser Bethany A. , Hise Selena M. , Keen Tara N. , Larson Hunter G. , Lockwood Dominique J. , Wang Brian , Harsh Joseph A. , Herrick James B.
Published: April 2021

We have developed and implemented an undergraduate microbiology course in which students isolate, characterize, and perform whole genome assembly and analysis of Salmonella enterica from stream sediments and poultry litter. In the development of the course and over three semesters, successive teams of undergraduate students collected field samples and performed enrichment and isolation techniques specific for the detection of S. enterica. Eighty-eight strains were confirmed using standard microbiological methods and PCR of the invA gene. The isolates’ genomes were Illumina-sequenced by the Center for Food Safety and Applied Nutrition at the FDA and the Virginia state Division of Consolidated Laboratory Services as part of the GenomeTrakr program. Students used GalaxyTrakr and other web- and non-web-based platforms and tools to perform quality control on raw and assembled sequence data, assemble, and annotate genomes, identify antimicrobial resistance and virulence genes, putative plasmids, and other mobile genetic elements. Strains with putative plasmid-borne antimicrobial resistance genes were further sequenced by students in our research lab using the Oxford Nanopore MinIONTM platform. Strains of Salmonella that were isolated include human infectious serotypes such as Typhimurium and Infantis. Over 31 of the isolates possessed antibiotic resistance genes, some of which were located on large, multidrug resistance plasmids. Plasmid pHJ-38, identified in a Typhimurium isolate, is an apparently self-transmissible 183 kb IncA/C2 plasmid that possesses multiple antimicrobial resistance and heavy-metal resistance genes. Plasmid pFHS-02, identified in an Infantis isolate, is an apparently self-transmissible 303 kb IncF1B plasmid that also possesses numerous heavy-metal and antimicrobial resistance genes. Using direct and indirect measures to assess student outcomes, results indicate that course participation contributed to cognitive gains in relevant content knowledge and research skills such as field sampling, molecular techniques, and computational analysis. Furthermore, participants self-reported a deeper interest in scientific research and careers as well as psychosocial outcomes (e.g., sense of belonging and self-efficacy) commonly associated with student success and persistence in STEM. Overall, this course provided a powerful combination of field, wet lab, and computational biology experiences for students, while also providing data potentially useful in pathogen surveillance, epidemiological tracking, and for the further study of environmental reservoirs of S. enterica.
JD419, a Staphylococcus aureus Phage With a Unique Morphology and Broad Host Range
Authors: Feng Tingting , Leptihn Sebastian , Dong Ke , Loh Belinda , Zhang Yan , Stefan Melanie I. , Li Mingyue , Guo Xiaokui , Cui Zelin
Published: April 2021

Phage therapy represents a possible treatment option to cure infections caused by multidrug-resistant bacteria, including methicillin and vancomycin-resistant Staphylococcus aureus, to which most antibiotics have become ineffective. In the present study, we report the isolation and complete characterization of a novel phage named JD219 exhibiting a broad host range able to infect 61 of 138 clinical strains of S. aureus tested, which included MRSA strains as well. The phage JD419 exhibits a unique morphology with an elongated capsid and a flexible tail. To evaluate the potential of JD419 to be used as a therapeutic phage, we tested the ability of the phage particles to remain infectious after treatment exceeding physiological pH or temperature. The activity was retained at pH values of 6.0–8.0 and below 50°C. As phages can contain virulence genes, JD419’s complete genome was sequenced. The 45509 bp genome is predicted to contain 65 ORFs, none of which show homology to any known virulence or antibiotic resistance genes. Genome analysis indicates that JD419 is a temperate phage, despite observing rapid replication and lysis of host strains. Following the recent advances in synthetic biology, JD419 can be modified by gene engineering to remove prophage-related genes, preventing potential lysogeny, in order to be deployed as a therapeutic phage.
Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling
Authors: Song Xiangqing , Zeng Meizi , Wu Yi , Pan Yong
Published: April 2021

The increasing emergence of bacterial strains with high VAN MICs (BSH–VAN–M), such as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus bovis, results in growing concern that VAN is not effective against these isolates. Due to the limited data on VAN against BSH–VAN–M and the application limits of drugs currently considered to be effective for BSH–VAN–M, exploration of “new usages for old drugs” is reasonable to improve and maximize the efficacy of existing antibiotics. This study aimed to construct a novel dosing strategy to mine the competence of VAN in the management of BSH–VAN–M infections. Herein, we optimized the traditional intermittent i.v. infusion (TIII) method to create an optimal two-step infusion (OTSI). With pharmacokinetic (PK)/pharmacodynamic (PD) modeling at the targeted ratio of the daily area under the concentration-time curve (AUC0–24) to the minimum inhibitory concentration (MIC) (AUC0–24/MIC) of 400, we used Monte Carlo simulations to evaluate the efficacy of 25 VAN regimens (including 15 OTSI regimens and 10 TIII regimens with daily doses of up to 6 g) to treat pneumonia, meningitis, sternal osteomyelitis, mastitis, pleuritis, bacteremia, and bacterial pericarditis resulting from isolates with MICs of ≤64 mg/L and to the current E. faecalis, E. faecium, S. aureus, S. epidermidis, and S. bovis populations with a pooled MIC distribution. Our data indicated that 4 g/day VAN, with an OTSI but not a TIII, for mastitis, pleuritis, bacteremia, and bacterial pericarditis due to isolates with MICs of ≤4 mg/L or to the current E. faecalis, S. aureus, S. epidermidis, and S. bovis populations achieved the desired PK/PD exposure at the AUC0–24/MIC target of 400. This study suggests the superiority and feasibility of OTSI relative to TIII for the competence mining of VAN against BSH–VAN–M from the perspective of PK/PD and provides a new resource for understanding how PK/PD modeling shapes the performance of VAN to meet the growing challenges of BSH–VAN–M infections.
SphK2/S1P Promotes Metastasis of Triple-Negative Breast Cancer Through the PAK1/LIMK1/Cofilin1 Signaling Pathway
Authors: Shi Weiwei , Ma Ding , Cao Yin , Hu Lili , Liu Shuwen , Yan Dongliang , Zhang Shan , Zhang Guang , Wang Zhongxia , Wu Junhua , Jiang Chunping
Published: April 2021

Background

Triple-negative breast cancer (TNBC) features a poor prognosis, which is partially attributed to its high metastatic rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, and HER-2, respectively) in cancer. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalyst sphingosine-1-phosphate (S1P) in TNBC metastasis and the effect of the SphK2-specific inhibitor ABC294640 on TNBC metastasis.

Methods

The function of SphK2 and S1P in TNBC cell metastasis was evaluated using transwell migration and wound-healing assays. The molecular mechanism of SphK2/S1P mediating TNBC metastasis was investigated using Western blot, histological examination, and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in an in vivo TNBC lung metastatic model.

Results

Sphingosine kinase 2 promoted TNBC cell migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo. p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1), and Cofilin1 were the downstream signaling molecules of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P-induced TNBC cell migration.

Conclusion

Sphingosine kinase 2/sphingosine-1-phosphate promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 inhibits TNBC metastasis in vivo and could be developed as a novel agent for the clinical treatment of TNBC.
Graphene Oxide Nanoparticle–Loaded Ginsenoside Rg3 Improves Photodynamic Therapy in Inhibiting Malignant Progression and Stemness of Osteosarcoma
Authors: Lu Shou-Liang , Wang Yan-Hua , Liu Guang-Fei , Wang Lu , Li Yong , Guo Zhi-Yuan , Cheng Cai
Published: April 2021

Osteosarcoma serves as a prevalent bone cancer with a high metastasis and common drug resistance, resulting in poor prognosis and high mortality. Photodynamic therapy (PDT) is a patient-specific and non-invasive tumor therapy. Nanoparticles, like graphene oxide have been widely used in drug delivery and PDT. Ginsenoside Rg3 is a principal ginseng component and has presented significant anti-cancer activities. Here, we constructed the nanoparticles using GO linked with photosensitizer (PS) indocyanine green (ICG), folic acid, and polyethylene glycol (PEG), and loaded with Rg3 (PEG–GO–FA/ICG–Rg3). We aimed to explore the effect of PEG–GO–FA/ICG–Rg3 combined with PDT for the treatment of osteosarcoma. Significantly, we found that Rg3 repressed proliferation, invasion, and migration, and enhanced apoptosis and autophagy of osteosarcoma cells, while the PEG–GO–FA/ICG–Rg3 presented a higher activity, in which NIR laser co-treatment could remarkably increase the effect of PEG–GO–FA/ICG–Rg3. Meanwhile, stemness of osteosarcoma cell–derived cancer stem cells was inhibited by Rg3 and PEG–GO–FA/ICG–Rg3, and the combination of PEG–GO–FA/ICG–Rg3 with NIR laser further significantly attenuated this phenotype in the system. Moreover, NIR laser notably improved the inhibitor effect of PEG–GO–FA/ICG–Rg3 on the tumor growth of osteosarcoma cellsin vivo.Consequently, we concluded that PEG–GO–FA/ICG–Rg3 improved PDT in inhibiting malignant progression and stemness of osteosarcoma cell. Our finding provides a promising and practical therapeutic strategy for the combined treatment of osteosarcoma.
Clinical Features Observed in General Practice Associated With the Subsequent Diagnosis of Progressive Supranuclear Palsy
Authors: Kwasny Mary J. , Oleske Denise M. , Zamudio Jorge , Diegidio Robert , Höglinger Günter U.
Published: April 2021

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that is difficult for primary care physicians to recognize due to its progressive nature and similarities to other neurologic disorders. This case-control study aimed to identify clinical features observed in general practice associated with a subsequent diagnosis of PSP.

Methods: We analyzed a de-identified dataset of 152 PSP cases and 3,122 matched controls from electronic medical records of general practices in Germany. We used a random forests algorithm based on machine learning techniques to identify clinical features (medical conditions and treatments received) associated with pre-diagnostic PSP without using an a priori hypothesis. We then assessed the relative effects of the features with the highest importance scores and generated multivariate models using clustered logistic regression analyses to identify a subset of clinical features associated with subsequent PSP diagnosis.

Results: Using the random forests approach, we identified 21 clinical features associated with pre-diagnostic PSP (odds ratio ≥2.0 in univariate analyses). From these, we constructed a multivariate model comprising 9 clinical features with ~90% likelihood of identifying a subsequent PSP diagnosis. These features included known PSP symptoms, common misdiagnoses, and 2 novel associations, diabetes mellitus and cerebrovascular disease, which are possible modifiable risk factors for PSP.

Conclusion: In this case-control study using data from electronic medical records, we identified 9 clinical features, including 2 previously unknown factors, associated with the pre-diagnostic stage of PSP. These may be used to facilitate recognition of PSP and reduce time to referral by primary care physicians.
The Renin–Angiotensin System Modulates Dopaminergic Neurotransmission: A New Player on the Scene
Authors: Kobiec Tamara , Otero-Losada Matilde , Chevalier Guenson , Udovin Lucas , Bordet Sofía , Menéndez-Maissonave Camila , Capani Francisco , Pérez-Lloret Santiago
Published: April 2021

Parkinson’s disease (PD) is an extrapyramidal disorder characterized by neuronal degeneration in several regions of the peripheral and central nervous systems. It is the second most frequent neurodegenerative disease after Alzheimer’s. It has become a major health problem, affecting 1% of the world population over 60 years old and 3% of people beyond 80 years. The main histological findings are intracellular Lewy bodies composed of misfolded α-synuclein protein aggregates and loss of dopaminergic neurons in the central nervous system. Neuroinflammation, apoptosis, mitochondrial dysfunction, altered calcium homeostasis, abnormal protein degradation, and synaptic pathobiology have been put forward as mechanisms leading to cell death, α-synuclein deposition, or both. A progressive loss of dopaminergic neurons in the substantia nigra late in the neurodegeneration leads to developing motor symptoms like bradykinesia, tremor, and rigidity. The renin–angiotensin system (RAS), which is involved in regulating blood pressure and body fluid balance, also plays other important functions in the brain. The RAS is involved in the autocrine and paracrine regulation of the nigrostriatal dopaminergic synapses. Dopamine depletion, as in PD, increases angiotensin II expression, which stimulates or inhibits dopamine synthesis and is released via AT1 or AT2 receptors. Furthermore, angiotensin II AT1 receptors inhibit D1 receptor activation allosterically. Therefore, the RAS may have an important modulating role in the flow of information from the brain cortex to the basal ganglia. High angiotensin II levels might even aggravate neurodegeneration, activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which leads to increased reactive oxygen species production.
State Transitions During Discrimination Learning in the Gerbil Auditory Cortex Analyzed by Network Causality Metrics
Authors: Kozma Robert , Hu Sanqing , Sokolov Yury , Wanger Tim , Schulz Andreas L. , Woldeit Marie L. , Gonçalves Ana I. , Ruszinkó Miklós , Ohl Frank W.
Published: April 2021

This work studies the evolution of cortical networks during the transition from escape strategy to avoidance strategy in auditory discrimination learning in Mongolian gerbils trained by the well-established two-way active avoidance learning paradigm. The animals were implanted with electrode arrays centered on the surface of the primary auditory cortex and electrocorticogram (ECoG) recordings were made during performance of an auditory Go/NoGo discrimination task. Our experiments confirm previous results on a sudden behavioral change from the initial naïve state to an avoidance strategy as learning progresses. We employed two causality metrics using Granger Causality (GC) and New Causality (NC) to quantify changes in the causality flow between ECoG channels as the animals switched to avoidance strategy. We found that the number of channel pairs with inverse causal interaction significantly increased after the animal acquired successful discrimination, which indicates structural changes in the cortical networks as a result of learning. A suitable graph-theoretical model is developed to interpret the findings in terms of cortical networks evolving during cognitive state transitions. Structural changes lead to changes in the dynamics of neural populations, which are described as phase transitions in the network graph model with small-world connections. Overall, our findings underscore the importance of functional reorganization in sensory cortical areas as a possible neural contributor to behavioral changes.
Role of the Heart in Lactate Shuttling
Authors: Brooks George A.
Published: April 2021

After almost a century of misunderstanding, it is time to appreciate that lactate shuttling is an important feature of energy flux and metabolic regulation that involves a complex series of metabolic, neuroendocrine, cardiovascular, and cardiac events in vivo. Cell–cell and intracellular lactate shuttles in the heart and between the heart and other tissues fulfill essential purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. One powerful example of cell–cell lactate shuttling was the exchange of carbohydrate energy in the form of lactate between working limb skeletal muscle and the heart. The exchange of mass represented a conservation of mass that required the integration of neuroendocrine, autoregulatory, and cardiovascular systems. Now, with greater scrutiny and recognition of the effect of the cardiac cycle on myocardial blood flow, there brings an appreciation that metabolic fluxes must accommodate to pressure-flow realities within an organ in which they occur. Therefore, the presence of an intra-cardiac lactate shuttle is posited to explain how cardiac mechanics and metabolism are synchronized. Specifically, interruption of blood flow during the isotonic phase of systole is supported by glycolysis and subsequent return of blood flow during diastole allows for recovery sustained by oxidative metabolism.
Long Noncoding RNA Small Nucleolar Host Gene: A Potential Therapeutic Target in Urological Cancers
Authors: Yang Zitong , Li Qinchen , Zheng Xiangyi , Xie Liping
Published: April 2021

The incidence of urological cancer has been gradually increasing in the last few decades. However, current diagnostic tools and treatment strategies continue to have limitations. Substantial evidence shows that long noncoding RNAs (lncRNAs) play essential roles in carcinogenesis and the progression, treatment response and prognosis of multiple human cancers, including urological cancers, gastrointestinal tumours, reproductive cancers and respiratory neoplasms. LncRNA small nucleolar RNA host genes (SNHGs), a subgroup of lncRNAs, have been found to be dysregulated in tumour cell biology. In this review, we summarize the impacts of lncRNA SNHGs in urological malignancies and the underlying mechanisms.
Downregulation of GLYAT Facilitates Tumor Growth and Metastasis and Poor Clinical Outcomes Through the PI3K/AKT/Snail Pathway in Human Breast Cancer
Authors: Tian Xin , Wu Lina , Jiang Min , Zhang Zhenyong , Wu Rong , Miao Jianing , Liu Caigang , Gao Song
Published: April 2021

Background

The Glycine N-acyltransferase (GLYAT) gene encodes a protein that catalyzes the transfer of acyl groups from acyl CoA to glycine, resulting in acyl glycine and coenzyme A. Aberrant GLYAT expression is associated with several malignant tumors, but its clinical importance in human breast cancer (BC), has yet to be fully addressed. This study aims to evaluate the clinical function of GLYAT in BC patients.

Methods

GLYAT expression was determined by immune blot and immunohistochemistry in three BC cell lines and primary cancer tissues. The MDA-MB 231 cell line was used for GLYAT gene knockdown experiments while the MCF7 cell line for overexpression experiments. Colony formation experiments, soft agar experiments, and transwell assays were utilized for further inspection of cell proliferation and migration capabilities. Immunofluorescence and western blot were used to detect markers of the epithelial-mesenchymal transition (EMT) and changes in the PI3K/AKT/Snail pathway. The role of GLYAT in tumor growth and metastasis was also assessed in nude mice in vivo. Also, a correlation analysis was performed between clinicopathological features and GLYAT expression in BC patients.

Results

GLYAT was decreased in human BC tissues and cell lines. Functional analysis showed that knockdown of GLYAT augmented BC cell proliferation in vitro and in vivo. However, this phenomenon was reversed when GLYAT was overexpressed in the transfected cells. Moreover, downregulation of GLYAT promoted the migratory properties of BC cells, likely through the activation of PI3K/AKT/Snail signaling, which subsequently induced the EMT. IHC analysis indicated that GLYAT was decreased in human BC tissues and lower GLYAT expression was correlated with histological grade, tumor TNM stage, Ki-67 status, and poorer survival in BC patients. Furthermore, lower GLYAT expression seemed as an independent risk factor related to poor prognosis in BC patients based on Cox regression analyses.

Conclusion

Our findings demonstrate that downregulation of GLYAT expression in human breast cancer is correlated with EMT via the PI3K/AKT/Snail pathway and is also associated with histological grade, tumor TNM stage, Ki-67 status, and poor survival in breast cancer patients.
Effect of Pelvic Bone Marrow Sparing Intensity Modulated Radiation Therapy on Acute Hematologic Toxicity in Rectal Cancer Patients Undergoing Chemo-Radiotherapy
Authors: Huang Wei , Dang Jun , Li Ying , Cui Hai-xia , Lu Wen-li , Jiang Qing-feng
Published: April 2021

Background

While chemo-radiotherapy improves local control in patients with locally advanced rectal cancer, it can also increase acute hematological toxicity (HT), which leads to poor outcomes. Patients receiving bone marrow radiation have been shown to develop acute HT. However, the safety and efficacy of bone marrow sparing is undetermined. The aim of our study was to explore the feasible dosimetric constraints for pelvic bone marrow (PBM) that can be widely used in rectal cancer patients undergoing chemo-radiotherapy.

Methods

112 rectal cancer patients were selected and divided into the PBM sparing IMRT group (60 cases) and the non-PBM sparing IMRT group (52 cases). All patients underwent pelvic radiotherapy with concurrent capecitabine-based chemotherapy. The PBM dosimetric constraints in the PBM sparing IMRT group were set to:V10 ≤ 85%, V20 ≤ 65% and V30 ≤ 45%. An independent sample t test was applied for the dose-volume parameters, and Chi-squared analysis was applied for clinical parameters and adverse events.

Results

The radiation dose to PBM (V5~V45, Dmean, P<0.05), PBM sub-regions (V10~V35, Dmean, P<0.05) and both femoral heads (V5~V40, Dmean, P<0.05) decreased significantly in the PBM sparing IMRT group compared with that of the non-PBM sparing IMRT group (P<0.05). There was no significant difference in any dose-volume parameters of the bladder and small bowel in either groups, and none in the planning target volume (PTV) dose homogeneity and conformity (P>0.05). For acute HT observation, the incidence of grade 3 acute HT (χ2 = 7.094, P=0.008) was significantly reduced in patients treated with PBM sparing IMRT compared with patients treated with non-PBM sparing IMRT. There was no statistical difference in the incidence of vomiting, diarrhea, fatigue, anorexia, nausea, hand-foot syndrome, cystitis, perianal pain and perianal dermatitis in patients of both groups (P >0.05).

Conclusions

Applying PBM dosimetric constraints (V10 ≤ 85%, V20 ≤ 65% and V30 ≤ 45%) can significantly reduce the radiation dose to PBM. The patients treated with PBM sparing IMRT had a lower incidence of acute HT compared with those treated with non-PBM sparing IMRT. Applying the PBM dosimetric constraints proposed by our study can benefits the patients with rectal cancer undergoing capecitabine-based chemo-radiotherapy.