bluuebunny/crossref_metadata_2025 huggingface dataset:
Can China’s Market-Oriented Reform Improve the Efficiency of Industrial Land Use? A Panel Data Empirical Analysis at Prefecture Level From 2007–2019
Authors: Pu Wenfang , Zhang Anlu
Published: May 2022

China is entering rapid industrialization and urbanization since 1990’s with the urban land use payment reform. Nevertheless, higher rate of industrial land in construction land driving by local government-led industrial double growth competition fuels China the global biggest manufacturing giant and second largest economy on one hand, waste water, liquid and green house gas emission from industrial development has become more and more serious on the other hand, which has aroused a great concern nationally and globally. So low industrial land use efficiency (ILUE) is a big challenge besieging China at present. Whether the market-oriented reform of industrial land supply (MRIL) launched by the Chinese government can optimize the allocation of industrial land resources and improve the ILUE is urgent to be addressed at present. Basing on panel data of 270 prefecture-level cities in China from 2007 to 2019, we first construct marketization rate of industrial land (MIL) and examine the temporal and spatial change in MIL in each prefecture-level city. Then the impact of MIL on industrial land use efficiency (ILUE) is illuminated by super-efficient slacks-based measure (SBM) model including desirable and undesirable outputs. The results show that: 1) The overall level of the ILUE in China’s 270 prefecture-level cities was relatively low, which increase and decrease with the years. 2) China’s MRIL plays a positive role in the ILUE, but the impact is low. 3) The effect of MRIL on ILUE varies regionally, namely higher economic development and higher the effect, and the vice versa. We suggest both the central and local governments should target policy reform regarding the land market development and regional economic development. The research will contribute to ongoing market oriented and economic reform both in China and the transitional economies worldwide.
Evaluating the Cumulative Effects of Livestock Grazing on Wildlife With an Integrated Population Model
Authors: Milligan Megan C. , McNew Lance B.
Published: May 2022

Livestock grazing can shape temperate grassland ecosystems, with both positive and negative effects on wildlife documented depending on a variety of grazing and site factors. Historically, research investigating the impacts of livestock grazing on wildlife has been limited by a narrow focus on simple “grazed” vs. “ungrazed” treatments or examining how grazing affects only a single vital rate in isolation. To overcome these limitations, we used a two-stage class, female-based integrated population model (IPM) to examine whether three grazing management regimes (season-long, rest-rotation, and summer rotation) differentially impacted population growth rates of sharp-tailed grouse (Tympanachus phasianellus) in eastern Montana and western North Dakota. We estimated 14 vital rates related to survival and fecundity and examined whether subtle cumulative effects of livestock grazing were present but not detected in prior analyses focused on single vital rates. While the management regimes did not differentially impact survival or fecundity of female grouse in our study system, we found evidence for significant cumulative impacts of grazing regime on population growth rates that were only apparent when all vital rates were evaluated concurrently. Population growth rates were higher in areas managed with season-long livestock grazing. The IPM framework encourages comprehensive investigations into the influence of covariates on critical components of species life histories and can assist in guiding management decisions in a world of limited resources. This integrated approach allowed us to more efficiently use multiple data types to provide a more complete picture of the effects of management on an important indicator species.
Citizen Science Helps Uncover the Secrets to a Bat-Friendly Swimming Pool in an Urban Environment
Authors: Bennett Victoria J. , Agpalo Elizabeth J.
Published: May 2022

For urban environments to support bat communities, resources need to be readily available. For example, bats typically use urban water sources such as drainage ditches and ponds; however, these sources can be ephemeral. During these periods, bats have utilized residential swimming pools, although they only appear to drink at pools when access to more natural equivalents are limited. This posed the question “can we make residential swimming pools friendlier for a diversity of bat species?” Using citizen science to determine which pool characteristics influenced bat activity, we distributed a questionnaire to residents in a suburban neighborhood in Fort Worth, TX, United States. It focused on observations of bat activity and the features of the pools and immediate surroundings. We distributed the questionnaire through social media, local presentations, and by mail throughout 2019 and 2020. We then used classification trees to determine which characteristics in combination influenced bat activity at the pools. We generated three different trees for bats observed (1) flying around the property and backyard, (2) above the swimming pool, and (3) drinking at the pool. We found that more bats were observed at unlit pools without bush or shrub borders. Furthermore, among pools with borders, activity was lowest at pools with textured interiors and ≥6 trees visible. The presence of features, such as fountains, then contributed to a reduction in bat observations in backyards and the presence of pets appeared to further reduce activity specifically over the pools. Where bats were observed drinking, this activity was reported the least at pools with bush or shrub borders, textured interiors, and trees <5 m and >10 m from the edge of the pools. Our study revealed that certain characteristics of residential swimming pools encouraged bat activity, while others discouraged them. Thus, it may be possible to make swimming pools more bat-friendly. For example, turning lights off in the evening when backyards are not in use and reducing clutter around pools could have an immediate positive impact on local bat populations. The implementation of such recommendations could improve urban habitats for bats overall and alleviate some of the negative implications of continued urbanization.
Functional Responses Shape Node and Network Level Properties of a Simplified Boreal Food Web
Authors: Gobin Jenilee , Hossie Thomas J. , Derbyshire Rachael E. , Sonnega Samuel , Cambridge Tucker W. , Scholl Lee , Kloch Nicolas Diaz , Scully Arthur , Thalen Kiefer , Smith Graeme , Scott Carly , Quinby Francis , Reynolds Jordan , Miller Hannah A. , Faithfull Holly , Lucas Owen , Dennison Christopher , McDonald Jordan , Boutin Stan , O’Donoghue Mark , Krebs Charles J. , Boonstra Rudy , Murray Dennis L.
Published: May 2022

Ecological communities are fundamentally connected through a network of trophic interactions that are often complex and difficult to model. Substantial variation exists in the nature and magnitude of these interactions across various predators and prey and through time. However, the empirical data needed to characterize these relationships are difficult to obtain in natural systems, even for relatively simple food webs. Consequently, prey-dependent relationships and specifically the hyperbolic form (Holling’s Type II), in which prey consumption increases with prey density but ultimately becomes saturated or limited by the time spent handling prey, are most widely used albeit often without knowledge of their appropriateness. Here, we investigate the sensitivity of a simplified food web model for a natural, boreal system in the Kluane region of the Yukon, Canada to the type of functional response used. Intensive study of this community has permitted best-fit functional response relationships to be determined, which comprise linear (type I), hyperbolic (type II), sigmoidal (type III), prey- and ratio-dependent relationships, and inverse relationships where kill rates of alternate prey are driven by densities of the focal prey. We compare node- and network-level properties for a food web where interaction strengths are estimated using best-fit functional responses to one where interaction strengths are estimated exclusively using prey-dependent hyperbolic functional responses. We show that hyperbolic functional responses alone fail to capture important ecological interactions such as prey switching, surplus killing and caching, and predator interference, that in turn affect estimates of cumulative kill rates, vulnerability of prey, generality of predators, and connectance. Exclusive use of hyperbolic functional responses also affected trends observed in these metrics over time and underestimated annual variation in several metrics, which is important given that interaction strengths are typically estimated over relatively short time periods. Our findings highlight the need for more comprehensive research aimed at characterizing functional response relationships when modeling predator-prey interactions and food web structure and function, as we work toward a mechanistic understanding linking food web structure and community dynamics in natural systems.
New Era of Mapping and Understanding Common Fragile Sites: An Updated Review on Origin of Chromosome Fragility
Authors: Ji Fang , Zhu Xinli , Liao Hongwei , Ouyang Liujian , Huang Yingfei , Syeda Madiha Zahra , Ying Songmin
Published: May 2022

Common fragile sites (CFSs) are specific genomic loci prone to forming gaps or breakages upon replication perturbation, which correlate well with chromosomal rearrangement and copy number variation. CFSs have been actively studied due to their important pathophysiological relevance in different diseases such as cancer and neurological disorders. The genetic locations and sequences of CFSs are crucial to understanding the origin of such unstable sites, which require reliable mapping and characterizing approaches. In this review, we will inspect the evolving techniques for CFSs mapping, especially genome-wide mapping and sequencing of CFSs based on current knowledge of CFSs. We will also revisit the well-established hypotheses on the origin of CFSs fragility, incorporating novel findings from the comprehensive analysis of finely mapped CFSs regarding their locations, sequences, and replication/transcription, etc. This review will present the most up-to-date picture of CFSs and, potentially, a new framework for future research of CFSs.
Association Between C-Reactive Protein and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study
Authors: Zhu Yahui , Li Mao , Zhang Jinghong , Huang Xusheng
Published: May 2022

Background: Until now, the relationship between C-reactive protein (CRP) levels and amyotrophic lateral sclerosis (ALS) risk has not been fully established. It is necessary to assess whether there is a causal relationship between C-reactive protein levels and ALS risk.

Objective and Methods: We aimed to determine whether CRP has causal effects on risk of ALS. In this present study, summary-level data for ALS (20,806 cases and 59,804 controls) was obtained from large analyses of genome-wide association studies. For instrumental variables, 37 single nucleotide polymorphisms that had been previously identified to be related to CRP levels were used, including 4 SNPs of conservative CRP genetic variants and 33 SNPs of liberal CRP genetic variants. MR estimates were calculated using the inverse-variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods.

Results: There was no significant causal relationship between genetically predicted CRP levels and ALS risk (OR = 1.123, 95% CI = 0.963–1.309, p = 0.139) and results for the conservative CRP instruments were consistent (OR = 0.964, 95% CI = 0.830–1.119, p = 0.628). Pleiotropic bias was not observed in this study.

Conclusions: This study suggests that genetically predicted CRP levels may not be a causal risk factor for ALS.
PD-L1 Protein Expression Is Associated With Good Clinical Outcomes and Nomogram for Prediction of Disease Free Survival and Overall Survival in Breast Cancer Patients Received Neoadjuvant Chemotherapy
Authors: Chen Li , Huang Shaolong , Liu Qiang , Kong Xiangyi , Su Zhaohui , Zhu Mengliu , Fang Yi , Zhang Lin , Li Xingrui , Wang Jing
Published: May 2022

Objective

This study aims to investigate the potential prognostic significance of programmed death ligand-1 (PD-L1) protein expression in tumor cells of breast cancer patients received neoadjuvant chemotherapy (NACT).

Methods

Using semiquantitative immunohistochemistry, the PD-L1 protein expression in breast cancer tissues was analyzed. The correlations between PD-L1 protein expression and clinicopathologic characteristics were analyzed using Chi-square test or Fisher’s exact test. The survival curve was stemmed from Kaplan-Meier assay, and the log-rank test was used to compare survival distributions against individual index levels. Univariate and multivariate Cox proportional hazards regression models were accessed to analyze the associations between PD-L1 protein expression and survival outcomes. A predictive nomogram model was constructed in accordance with the results of multivariate Cox model. Calibration analyses and decision curve analyses (DCA) were performed for the calibration of the nomogram model, and subsequently adopted to assess the accuracy and benefits of the nomogram model.

Results

A total of 104 breast cancer patients received NACT were enrolled into this study. According to semiquantitative scoring for IHC, patients were divided into: low PD-L1 group (61 cases) and high PD-L1 group (43 cases). Patients with high PD-L1 protein expression were associated with longer disease free survival (DFS) (mean: 48.21 months vs. 31.16 months; P=0.011) and overall survival (OS) (mean: 83.18 months vs. 63.31 months; P=0.019) than those with low PD-L1 protein expression. Univariate and multivariate analyses indicated that PD-L1, duration of neoadjuvant therapy, E-Cadherin, targeted therapy were the independent prognostic factors for patients’ DFS and OS. Nomogram based on these independent prognostic factors was used to evaluate the DFS and OS time. The calibration plots shown PD-L1 based nomogram predictions were basically consistent with actual observations for assessments of 1-, 3-, and 5-year DFS and OS time. The DCA curves indicated the PD-L1 based nomogram had better predictive clinical applications regarding prognostic assessments of 3- and 5-year DFS and OS, respectively.

Conclusion

High PD-L1 protein expression was associated with significantly better prognoses and longer DFS and OS in breast cancer patients. Furthermore, PD-L1 protein expression was found to be a significant prognostic factor for patients who received NACT.
ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways
Authors: Jing Lina , Zhang Xin , Liu Dong , Yang Yonghong , Xiong Huabao , Dong Guanjun
Published: May 2022

Toll-like receptors (TLRs) are the first line of defense in the immune system, whose activation plays a key role in the pathogenesis of inflammation and autoimmunity. TLRs can activate a variety of immune cells such as macrophages and dendritic cells, which produce proinflammatory cytokines, chemokines, and co-stimulatory molecules that lead to the development of inflammation and autoimmune diseases. As a nonreceptor tyrosine kinase, ACK1 is involved in multiple signaling pathways and physiological processes. However, the roles of ACK1 in the activation of TLR pathways and in the pathogenesis of inflammation and autoimmune diseases have not yet been reported. We found that the expression of ACK1 could be upregulated by TLR pathways in vivo and in vitro. Intriguingly, overexpression of ACK1 significantly promoted the activation of TLR4, TLR7, and TLR9 pathways, while knockdown of ACK1 or the use of the ACK1 inhibitor AIM-100 significantly inhibited the activation of TLR4, TLR7, and TLR9 pathways. In vivo studies showed that the inhibition of ACK1 activity by AIM-100 could significantly protect mice from the TLR4 agonist lipopolysaccharide (LPS)-mediated endotoxin shock and alleviate the condition of imiquimod-mediated lupus-prone mice and MRL/lpr mice. In summary, ACK1 participates in TLR-mediated inflammation and autoimmunity and has great potential in controlling inflammation and alleviating autoimmune diseases.
The Immunological Roles of Olfactory Ensheathing Cells in the Treatment of Spinal Cord Injury
Authors: Jiang Yizhen , Guo Jianbin , Tang Xiangwen , Wang Xiaohui , Hao Dingjun , Yang Hao
Published: May 2022

Spinal cord injury (SCI) is a devastating type of neurological disorder of the central nervous system (CNS) with high mortality and disability. The pathological processes of SCI can usually be described as two stages, namely, primary and acute secondary injuries. Secondary injury produces more significant exacerbations of the initial injury. Among all the mechanisms of secondary damage, infection and inflammatory responses, as the principle culprits in initiating the second phase of SCI, can greatly contribute to the severity of SCI and numerous sequelae after SCI. Therefore, effectively antagonizing pro-inflammatory responses may be a promising treatment strategy to facilitate functional recovery after SCI. Olfactory ensheathing cells (OECs), a unique type of glial cells, have increasingly become potential candidates for cell-based therapy in the injured CNS. Strikingly, there is growing evidence that the mechanisms underlying the anti-inflammatory role of OECs are associated with the immune properties and secretory functions of these cells responsible for anti-neuroinflammation and immunoregulatory effects, leading to maintenance of the internal microenvironment. Accordingly, a more profound understanding of the mechanism of OEC immunological functions in the treatment of SCI would be beneficial to improve the therapeutic clinical applications of OECs for SCI. In this review, we mainly summarize recent research on the cellular and molecular immune attributes of OECs. The unique biological functions of these cells in promoting neural regeneration are discussed in relation of the development of novel therapies for CNS injury.
Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways
Authors: Zhou Yu , Li Xin , Shen Ru , Wang Xiangzhu , Zhang Fan , Liu Suxing , Li Di , Liu Jian , Li Puhui , Yan Yinfa , Dong Ping , Zhang Zhigao , Wu Heping , Zhuang Linghang , Chowdhury Rasheduzzaman , Miller Matthew , Issa Mena , Mao Yuchang , Chen Hongli , Feng Jun , Li Jing , Bai Chang , He Feng , Tao Weikang
Published: May 2022

A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly block the TYK2-mediated receptor-stimulated pathways by binding to the TYK2 JH2 domain and allosterically regulating the TYK2 JH1 kinase. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. Moreover, TYK2 JH2-binding ligands exhibit remarkable selectivity of TYK2 over JAK isoforms not only biochemically but also in a panel of receptor-stimulated JAK1/JAK2/JAK3-driven cellular functional assays. In addition, the TYK2 JH2-targeting ligands also demonstrate high selectivity in a multi-kinase screening panel. The data in the current study underscores that the TYK2 JH2 pseudokinase is a promising therapeutic target for achieving a high degree of biological selectivity. Meanwhile, targeting the JH2 domain represents an appealing strategy for the development of clinically well-tolerated TYK2 inhibitors that would have superior efficacy and a favorable safety profile compared to the existing Janus kinase inhibitors against autoimmune diseases.
Spatial Analysis for Mariculture Site Selection: A Case Study of Kukup Aquaculture Zones in the Peninsula of Malaysia
Authors: Chor Wei-Kang , Lai Teng-Yun , Mathews Melissa Mary , Chiffings Tony , Cheng Chi-Wei , Andin Victor Charlie , Lai Kok-Song , Loh Jiun-Yan
Published: May 2022

Marine aquaculture sites at Kukup Strait in the peninsula of Malaysia are experiencing a decline in water quality in the last five years, resulting in high mortality rates (50 - 80%), seasonal massive fish mortalities and poor profitability. Currently, Kukup farmers are involved in intensive aquaculture within the existing aquaculture zone. This study explores the sustainability of a modern mariculture method, where fish farms are relocated to deeper waters with higher flushing rates, and high-density polyethylene (HDPE) are used to improve water quality. Several site selection criteria are utilised in identifying the proposed aquaculture industrial zone: 1) bathymetry depth (operational requirement: 10 m to 30 m), 2) located within the Kukup Port Limit, 3) does not interfere with the Kukup ferry navigation route, and 4) distance from Kukup mainland. Site feasibility analysis, including hydrodynamics, meteorology, water quality, sediment quality and macrobenthos assessment, was conducted to compare the proposed and existing aquaculture sites. It was found that the water quality at the existing site contained higher concentrations of fecal coliform and nutrients and salinity fluctuations. Tropical finfish can survive under these conditions with poorer fish health and higher fish mortality. Apart from that, the flushing capacity is higher in the proposed site, indicating the capacity to handle moderate-intensity aquaculture. Moderate-intensity aquaculture using HDPE cages could be profitable for the local fish farmers. Therefore, it is suggested that other locations within Kukup Straits with deeper waters (> 25 m) with possibly improved water quality and the ability for intensive aquaculture production should be explored for a larger depth and economics of scale.
Factors Associated With Neurosyphilis in Patients With Syphilis Treatment Failure: A Retrospective Study of 165 HIV-Negative Patients
Authors: Cui Wenying , Yan Junling , Weng Wenjia , Gao Yanqing , Zhu Wei
Published: May 2022

Background

In recent years, the incidence of syphilis has increased year by year. Our study is to explore the risk factors for the development of neurosyphilis in patients who failed syphilis treatment.

Methods

A total number of 165 patients with complete medical records and who agreed to undergo lumbar puncture were divided into 47 neurosyphilis cases and 118 non-neurosyphilis cases according to the diagnostic criteria of neurosyphilis, and the differences in clinical characteristics and laboratory features between the two groups were analyzed. Significant variables were entered into multivariable logistic regression models.

Results

(1) There were statistical differences (p < 0.05) between the neurosyphilis (NS) group and the non-neurosyphilis (NNS) group in terms of the higher proportion of male and serum rapid plasma reagin (RPR) > 1:32 and the elevated cerebrospinal fluid white blood cell (CSF WBC) and CSF protein in the neurosyphilis group compared with the non-neurosyphilis group. (2) Male gender, serum RPR titers >1:32 at lumbar puncture, CSF WBC >8 × 106/L were significantly associated with neurosyphilis.

Conclusion

For patients who have failed syphilis treatment, lumbar puncture should be performed to exclude neurosyphilis, to enable early diagnosis and treatment, and to prevent irreversible damage of neurosyphilis, especially if the patient is male and has a serum RPR>1:32 and elevated CSF WBC at lumbar puncture, which are risk factors for neurosyphilis.
Inhaled CO2 vs. Hypercapnia Obtained by Low Tidal Volume or Instrumental Dead Space in Unilateral Pulmonary Artery Ligation: Any Difference for Lung Protection?
Authors: Spinelli Elena , Pesenti Antonio , Lopez Gianluca , Damia Anna , Damarco Francesco , Garbelli Erica , Dal Santo Gaia , Caccioppola Alessio , Giudici Giorgio , Figgiaconi Virginia , Biancolilli Osvaldo , Battistin Michele , Lonati Caterina , Vaira Valentina , Rosso Lorenzo , Ferrero Stefano , Gatti Stefano , Mauri Tommaso
Published: May 2022

Background

Unilateral ligation of the pulmonary artery (UPAL) induces bilateral lung injury in pigs undergoing controlled mechanical ventilation. Possible mechanisms include redistribution of ventilation toward the non-ligated lung and hypoperfusion of the ligated lung. The addition of 5% CO2 to the inspiratory gas (FiCO2) prevents the injury, but it is not clear whether lung protection is a direct effect of CO2 inhalation or it is mediated by plasmatic hypercapnia. This study aims to compare the effects and mechanisms of FiCO2vs. hypercapnia induced by low tidal volume ventilation or instrumental dead space.

Methods

Healthy pigs underwent left UPAL and were allocated for 48 h to the following: Volume-controlled ventilation (VCV) with VT 10 ml/kg (injury, n = 6); VCV plus 5% FiCO2 (FiCO2, n = 7); VCV with VT 6 ml/kg (low VT, n = 6); VCV plus additional circuit dead space (instrumental VD, n = 6). Histological score, regional compliance, wet-to-dry ratio, and inflammatory infiltrate were assessed to evaluate lung injury at the end of the study. To investigate the mechanisms of protection, we quantified the redistribution of ventilation to the non-ligated lung, as the ratio between the percentage of tidal volume to the right and to the left lung (VTRIGHT/LEFT), and the hypoperfusion of the ligated lung as the percentage of blood flow reaching the left lung (PerfusionLEFT).

Results

In the left ligated lung, injury was prevented only in the FiCO2 group, as indicated by lower histological score, higher regional compliance, lower wet-to-dry ratio and lower density of inflammatory cells compared to other groups. For the right lung, the histological score was lower both in the FiCO2 and in the low VT groups, but the other measures of injury showed lower intensity only in the FiCO2 group. VTRIGHT/LEFT was lower and PerfusionLEFT was higher in the FiCO2 group compared to other groups.

Conclusion

In a model of UPAL, inhaled CO2 but not hypercapnia grants bilateral lung protection. Mechanisms of protection include reduced overdistension of the non-ligated and increased perfusion of the ligated lung.
Assessment of Antibacterial and Anti-biofilm Effects of Vitamin C Against Pseudomonas aeruginosa Clinical Isolates
Authors: Abdelraheem Wedad M. , Refaie Marwa M. M. , Yousef Rehab Kamal Mohamed , Abd El Fatah Aliaa S. , Mousa Yosra M. , Rashwan Rabab
Published: May 2022

There is a persistent need to look for alternative therapeutic modalities to help control the pandemic of antimicrobial resistance. Assessment of antibacterial and anti-biofilm effects of vitamin C (ascorbic acid) was the aim of the current study. The micro-dilution method determined the minimal inhibitory concentration (MIC) of ascorbic acid or antibiotics alone and in combinations against Pseudomonas aeruginosa (P. aeruginosa) clinical isolates. The micro-titer plate method monitored the effect of ascorbic acid on the biofilm-producing isolates of P. aeruginosa. The effect of ascorbic acid on the differential expression of different antibiotic-resistant genes and biofilm encoding genes of P. aeruginosa isolates were also tested using real-time polymerase chain reaction (PCR). For in vivo assessment of the antibacterial effects of ascorbic acid alone or combined with an antibiotic, rats were infected with P. aeruginosa clinical isolate followed by different treatment regimens. MICs of ascorbic acid among P. aeruginosa isolates were in the range of 156.2–1,250 μg/ml, while MIC50 and MIC90 were 312.5 and 625 μg/ml, respectively. At sub-inhibitory concentrations (19.5–312.5 μg/ml), ascorbic acid had 100% biofilm inhibitory effect. Furthermore, ascorbic acid-treated bacteria showed downregulation of genes underpinning biofilm formation and antibiotic resistance. In vivo assessment of vitamin C and ceftazidime in rats showed that administration of both at a lower dose for treatment of pseudomonas infection in rats had a synergistic and more powerful effect. Vitamin C shows excellent in vitro results as an antibacterial and anti-biofilm agent. Vitamin C should be routinely prescribed with antibiotics to treat bacterial infections in the clinical setting.
Soil Microbes Drive the Flourishing Growth of Plants From Leucocalocybe mongolica Fairy Ring
Authors: Wang Qiqi , Wang Chong , Wei Yumei , Yao Weiqin , Lei Yonghui , Sun Yanfei
Published: May 2022

Fairy ring is a natural phenomenon in which fungal fruiting bodies occur as a ring on a spot. This ring is produced due to spore ejection by Basidiomycetous fungi and forms a lush growing plant belt. However, the drivers for such formations and the potential plant growth-promoting rhizobacteria in fairy ring soils remain unknown. Fairy rings formed by Leucocalocybe mongolica were selected in this study. Soil characteristics and microbial (bacteria and fungi) community structures between beneath and outside the fairy rings were compared through high-throughput sequencing. Beneficial bacterial resources were excavated using dependent culturable methods. Soil electrical conductivity and available potassium were higher in the soil beneath the ring than outside it. These parameters were positively correlated with the dominant microbial community, but microbial diversity was lower. In the soil beneath the fairy ring, Bacteroidetes and Basidiomycota were more abundant, whereas Verrucomicrobia was less prevalent. Bacillus pumilus (strain BG-5) was isolated from the soil beneath the ring. Strain BG-5 can solubilize phosphorus and produce indole-3-acetic acid, NH4+, and siderophores. Furthermore, strain BG-5 enhanced salt tolerance and promoted the growth of Arabidopsis thaliana, wheat (Triticum aestivum), and cotton (Gossypium hirsutum) seedlings. This study indicated the presence of abundant beneficial microbes driving the flourishing growth of plants in the fairy ring soil and provided bio-resources for agricultural growth-promoting agents.
Pharmacokinetics and Pharmacodynamics of Colistin Combined With Isopropoxy Benzene Guanidine Against mcr-1-Positive Salmonella in an Intestinal Infection Model
Authors: Kong Lingli , Lu Yixing , Yang Liuye , Zhang Wanying , Zuo Beini , Peng Xianfeng , Qin Zonghua , Li Miao , Zeng Zhenling , Zeng Dongping
Published: May 2022

Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect Imax model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0−24h/MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0−24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.
Identification of a Diagnostic Signature and Immune Cell Infiltration Characteristics in Keloids
Authors: Xia Yijun , Wang Youbin , Xiao Yingjie , Shan Mengjie , Hao Yan , Zhang Lingyun
Published: May 2022

Background: Keloid disorder is a recurrent fibroproliferative cutaneous tumor. Due to the lack of early identification of keloid patients before the formation of keloids, it is impossible to carry out pre-traumatic intervention and prevention for these patients. This led us to identify and determine signatures with diagnostic significance for keloids.

Methods: Public series of matrix files were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were calculated from expression profiling data, and the diagnostic signature was identified by constructing a protein-protein interaction (PPI) network. The diagnostic efficacy of the screened signature was assessed by employing receiver operating characteristic (ROC) curves. Furthermore, we calculated the proportion of different immune cells in the gene expression matrix microenvironment by the “ssGSEA” algorithm, and assessed the difference in immune cell abundance between keloids and control groups and the relationship between the signature and immune cell infiltration. Clinical keloid and normal skin tissues were collected, and the expression of the screened diagnostic signature was validated by RT-qPCR and immunohistochemical assay.

Results: By screening the key genes in PPI, TGM2 was recognized and validated as a diagnostic signature and the infiltrating abundance of 10 immune cells was significantly correlated with TGM2 expression. Gene ontology enrichment analysis demonstrated that TGM2 and molecules interacting with it were mainly enriched in processes involving wound healing and collagen fiber organization. TGM2 correlated positively with HIF-1A (R = 0.82, p-value = 1.4e-05), IL6 (R = 0.62, p-value = 0.0053), and FN1 (R = 0.66, p-value = 0.0019). Besides, TGM2 was significantly upregulated in clinical keloid samples compared to normal skin tissues.

Conclusion: TGM2 may serve as an auxiliary diagnostic indicator for keloids. However, the role of TGM2 in keloids has not been adequately reported in the current literature, which may provide a new direction for molecular studies of keloids.
Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery
Authors: Kandel Nabin , Wang Chunyu
Published: May 2022

Hedgehog (Hh) signaling plays pivotal roles in embryonic development. In adults, Hh signaling is mostly turned off but its abnormal activation is involved in many types of cancer. Hh signaling is initiated by the Hh ligand, generated from the Hh precursor by a specialized autocatalytic process called Hh autoprocessing. The Hh precursor consists of an N-terminal signaling domain (HhN) and a C-terminal autoprocessing domain (HhC). During Hh autoprocessing, the precursor is cleaved between N- and C-terminal domain followed by the covalent ligation of cholesterol to the last residue of HhN, which subsequently leads to the generation of Hh ligand for Hh signaling. Hh autoprocessing is at the origin of canonical Hh signaling and precedes all downstream signaling events. Mutations in the catalytic residues in HhC can lead to congenital defects such as holoprosencephaly (HPE). The aim of this review is to provide an in-depth summary of the progresses and challenges towards an atomic level understanding of the structural mechanisms of Hh autoprocessing. We also discuss drug discovery efforts to inhibit Hh autoprocessing as a new direction in cancer therapy.
Receptor-Dependent Endocytosis Mediates α-Synuclein Oligomer Transport Into Red Blood Cells
Authors: Li Wei , Hu Junya , Li Xin , Lu Zhe , Li Xuying , Wang Chaodong , Yu Shun
Published: May 2022

Detection of oligomeric α-synuclein (o-α-Syn) in red blood cells (RBCs) has been shown to be promising in diagnosing Parkinson’s disease and other synucleinopathies. However, if RBC o-α-Syn derive from plasma and can reflect changes of plasma o-α-Syn remains unclear. In this study, synthetic o-α-Syn was intravenously injected into mice and dynamic changes in plasma and RBC o-α-Syn levels were investigated. Injection of o-α-Syn induced a temporary increase in plasma o-α-Syn levels, which then decreased to a relatively stable level. In contrast, levels of RBC o-α-Syn increased steadily and significantly. Besides, α-Syn-immunoreactive particles were observed in RBCs of the injected mice, suggesting that RBCs can actively take up and enrich o-α-Syn from plasma. Moreover, incubation of o-α-Syn with isolated RBCs at concentrations lower than those of endogenous o-α-Syn led to a time- and concentration-dependent o-α-Syn elevation in RBCs, which was impaired by lowering the temperature and treatment with proteinase K. The o-α-Syn accumulation in RBCs was also inhibited by specific inhibitors of receptor-dependent endocytosis, including dynamin- and clathrin-dependent endocytosis. The above results suggest that plasma o-α-Syn can be actively transported into RBCs via receptor-dependent endocytic pathways.
N-Methyl-D-Aspartate Receptors Antagonist Prevents Secondary Ischemic Brain Injury Associated With Lipopolysaccharide-Induced Sepsis-Like State Presumably via Immunomodulatory Actions
Authors: Taheri Golnar , Sardari Maryam , Hermann Dirk M. , Sepehri Houri
Published: May 2022

Infection is a major reason for poor stroke outcomes, and sepsis is a major cause of stroke-elated deaths. We herein examined whether NMDA receptor blockade, which was reported to exert anti-inflammatory actions, protects against the deleterious consequences of lipopolysaccharide (LPS)-induced sepsis-like state in adult male NMRI mice exposed to transient intraluminal middle cerebral artery occlusion (MCAO). At 24 h post-ischemia, vehicle or Escherichia coli LPS (2 or 4 mg/kg) was intraperitoneally administered, whereas 30 min later vehicle or ketamine (10 mg/kg), which is a non-competitive NMDA receptor antagonist, was intraperitoneally applied. Delivery of LPS at a dosage of 4 mg/kg induced a sepsis-like state characterized by a rectal temperature reduction by ∼4.0°C, increased neurological deficits in Clark score, cylinder and open-field tests, increased brain infarct volume and reduced neuronal survival in the previously ischemic tissue. Notably, additional treatment with ketamine (10 mg/kg) significantly attenuated the sepsis-associated rectal temperature reduction by ∼1.5°C, reduced neurological deficits, reduced infarct volume, and promoted neuronal survival. Ketamine alone did not influence infarct volume or neurological deficits. Real-time PCR data analysis showed that GFAP, CD86, CD206, IL-1β, and IL-10 mRNA levels were significantly increased in ischemic brains of LPS-treated compared with vehicle-treated mice. Additional treatment with ketamine significantly decreased IL-1β and IL-10, but not GFAP, CD86, and CD206 mRNA levels. Our data show that ketamine at a dose that on its own does not confer neuroprotection reverses the adverse effects of LPS-induced sepsis-like state post-ischemia, presumably via immunomodulatory actions.
Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury
Authors: Du Hao , Li Chang-Hong , Gao Ruo-Bing , Cen Xiao-Qing , Li Ping
Published: May 2022

Pyroptosis plays a significant role in neuroinflammation after traumatic brain injury (TBI). However, the role of pyroptosis executor Gasdermin D (GSDMD) in neurological deficits and neuropathological alterations after TBI have not been elucidated. Our results demonstrated that GSDMD-KO exerted striking neuroprotective effects on motor dysfunction and neuropathological alterations (loss of synaptic proteins, microglia activation, astrogliosis, dendrite injury, and neuron death) at 3 days after TBI. GSDMD-KO inhibited the expression and release of pro-inflammatory cytokine releases (IL-1β and TNF-α) while promoting those of anti-inflammatory cytokines (IL-10 and TGF-β1). The temporal pattern of diverse inflammasome signals showed long-lasting elevations of NLRP3, caspase 1, and caspase 1 p20 after TBI, rather than NLRP1, NLRC4 or AIM2, similar to the change in GSDMD postinjury; and NLRP3-KO not only inhibited the expression and cleavage of GSDMD but also attenuated the loss of synaptic proteins and neurological deficits. Notably, RNA sequencing showed both GSDMD-KO and NLRP3-KO reversed the global expression of neuroinflammation- and neuropathology-related genes after TBI. Our findings proved that the inhibition of GSDMD exerts neuroprotective effects after TBI and is mainly driven by the NLRP3 inflammasome. GSDMD serves as a potent therapeutic target for the treatment of TBI.
Prostaglandin E2 Exerts Biphasic Dose Response on the PreBötzinger Complex Respiratory-Related Rhythm
Authors: Reising Jan Philipp , Phillips Wiktor S. , Ramadan Naify , Herlenius Eric
Published: May 2022

Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.
Tap Test Can Predict Cognitive Improvement in Patients With iNPH—Results From the Multicenter Prospective Studies SINPHONI-1 and –2
Authors: Nakajima Madoka , Yamada Shigeki , Miyajima Masakazu , Kawamura Kaito , Akiba Chihiro , Kazui Hiroaki , Mori Etsuro , Ishikawa Masatsune ,   The SINPHONI-2 Investigators
Published: May 2022

Background: We analyzed the predictive value of the tap test (TT) on the outcome of cerebrospinal fluid (CSF) shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) and cognitive impairment up to 12 months postoperatively.

Methods: We analyzed the data of two prospective multicenter studies on ventriculoperitoneal shunt (VPS) and lumboperitoneal shunt (LPS) use in iNPH patients. We selected patients with Mini-Mental State Examination (MMSE) scores ≤ 26 points as study subjects. We used a multivariate logistic regression model to obtain the optimal threshold of MMSE scores after TT to predict the score improvement at 12 months following shunting and that helped to control for confounding factors such as age and MMSE scores before TT. We used logistic regression models to identify variables with age-adjusted odds ratio (A-OR) and multivariate-adjusted OR (M-OR).

Results: For an improvement of ≥3 points in the MMSE score cutoff 7 days following TT in VPS and LPS cohort studies, the MMSE scores improved by 6 points after 12 months. The VPS cohort had sensitivity, specificity, and area under the curve (AUC) of 69.2, 73.7, and 0.771%, respectively; however, for the LPS cohort, they were 86.2, 90.9, and 0.906%, respectively. For MMSE scores that improved by ≥3 points in patients after the TT, the possibility of an improvement by 6 points at 12 months following CSF shunt had A-OR 7.77 and M-OR 6.3 times for the VPS, and A-OR 62.3 and M-OR 59.6 times for the LPS cohort.

Conclusion: CSF shunting contributes to improved cognitive function in iNPH patients. Furthermore, MMSE score evaluation at the TT can sensitively predict improvement in postoperative MMSE scores following LPS intervention.

Clinical Trial Registration: SINPHONI-1 (ClinicalTrials.gov, no. NCT00221091), first posted: September 22, 2005.

SINPHONI-2 [University Hospital Medical Information Network (UMIN) Clinical Trials no. UMIN000002730], the posted: February 1, 2010.
Minimally Invasive Neurosurgery for Spontaneous Intracerebral Hemorrhage—10 Years of Working Progress at National Taiwan University Hospital
Authors: Hsu Chiu-Hao , Chou Sheng-Chieh , Kuo Lu-Ting , Huang Sheng-Jean , Yang Shih-Hung , Lai Dar-Ming , Huang Abel Po-Hao
Published: May 2022

Intracerebral hemorrhage (ICH) is a life-threatening disease with a global health burden. Traditional craniotomy has neither improved functional outcomes nor reduced mortality. Minimally invasive neurosurgery (MIN) holds promise for reducing mortality and improving functional outcomes. To evaluate the feasibility of MIN for ICH, a retrospective analysis of patients with ICH undergoing endoscopic-assisted evacuation was performed. From 2012 to 2018, a total of 391 patients who underwent ICH evacuation and 76 patients who received early (<8 h) MIN were included. The rebleeding, mortality, and morbidity rates were 3.9, 7.9, and 3.9%, respectively, 1 month after surgery. At 6 months, the median [interquartile range (IQR)] Glasgow Coma Scale score was 12 (4.75) [preoperative: 10 (4)], the median (IQR) Extended Glasgow Outcome Scale score was 3 (1), and the median (IQR) Modified Rankin Scale score was 4 (1). The results suggested that early (<8 h) endoscope-assisted ICH evacuation is safe and effective for selected patients with ICH. The rebleeding, morbidity, and mortality rates of MIN in this study are lower than those of traditional craniotomy reported in previous studies. However, the management of intraoperative bleeding and hard clots is critical for performing endoscopic evacuation. With this retrospective analysis of MIN cases, we hope to promote the specialization of ICH surgery in the field of MIN.