bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Accuracy of Circular RNAs in Different Types of Samples for Detecting Hepatocellular Carcinoma: A Meta-Analysis
Authors: Nie Guilin , Peng Dingzhong , Li Bei , Lu Jiong , Xiong Xianze
Published: December 2021

The lack of accurate biomarkers impeded the screening, diagnosis and early treatment of hepatocellular carcinoma (HCC). As a result of the development of high-throughput transcriptome analysis techniques, circular RNAs, a newly discovered class of noncoding RNAs, were recognized as potential novel biomarkers. This meta-analysis was performed to update the diagnostic roles of circular RNAs for HCC. We acquired 23 articles from PubMed, Web of Science, EMBASE, and Cochrane Library databases up to September 2021. The overall sensitivity was 0.80 (95% CI: 0.77–0.84), and the specificity was 0.83 (95% CI: 0.79–0.85), with an AUC of 0.88 (0.85–0.91). Considering of the significant heterogeneity, studies were divided into four groups based on the control types. The circular RNAs in exosomes had a sensitivity of 0.69 (95% CI: 0.61–0.75), and a highest specificity of 0.91 (95% CI: 0.83–0.96). The pooled sensitivity of circular RNAs in serum/plasma was 0.84 (95% CI: 0.81–0.87), and the pooled specificity was 0.83 (95% CI: 0.79–0.86). The pooled sensitivity of circular RNAs distinguishing tumor tissue from chronic hepatitis/cirrhosis tissues was 0.56 (95% CI: 0.48–0.64), and specificity was 0.76 (95% CI: 0.67–0.82). When the controls were adjacent tissues, the sensitivity was 0.78 (95% CI: 0.70–0.84), and the specificity was 0.78 (95% CI: 0.71–0.85). Hsa_circ_0001445 with a pooled sensitivity of 0.81, a specificity of 0.76 and an AUC of 0.85 in two studies, might be a suitable diagnostic blood biomarker for HCC. Relying on function in HCC, the AUC of subgroups were 0.88 (95%CI: 0.84–0.90) (function group) and 0.87 (95%CI: 0.84–0.90) (unknown function group). As for only reported in HCC or not, these circular RNAs had an AUC of 0.89 (95%CI: 0.86–0.91) (only in HCC) and 0.85 (95%CI: 0.82–0.88) (not only in HCC). In conclusion, the results suggested that circular RNAs were acceptable biomarkers for detecting HCC, especially those circular RNAs existing in exosomes or serum/plasma.
Glycoprotein Targeted CAR-NK Cells for the Treatment of SARS-CoV-2 Infection
Authors: Christodoulou Ilias , Rahnama Ruyan , Ravich Jonas W. , Seo Jaesung , Zolov Sergey N. , Marple Andrew N. , Markovitz David M. , Bonifant Challice L.
Published: December 2021

H84T-Banana Lectin (BanLec) CAR-NK cells bind high mannose glycosites that decorate the SARS-CoV-2 envelope, thereby decreasing cellular infection in a model of SARS-CoV-2. H84T-BanLec CAR-NK cells are innate effector cells, activated by virus. This novel cellular agent is a promising therapeutic, capable of clearing circulating SARS-CoV-2 virus and infected cells. Banana Lectin (BanLec) binds high mannose glycans on viral envelopes, exerting an anti-viral effect. A point mutation (H84T) divorces BanLec mitogenicity from antiviral activity. SARS-CoV-2 contains high mannose glycosites in proximity to the receptor binding domain of the envelope Spike (S) protein. We designed a chimeric antigen receptor (CAR) that incorporates H84T-BanLec as the extracellular moiety. Our H84T-BanLec CAR was devised to specifically direct NK cell binding of SARS-CoV-2 envelope glycosites to promote viral clearance. The H84T-BanLec CAR was stably expressed at high density on primary human NK cells during two weeks of ex vivo expansion. H84T-BanLec CAR-NK cells reduced S-protein pseudotyped lentiviral infection of 293T cells expressing ACE2, the receptor for SARS-CoV-2. NK cells were activated to secrete inflammatory cytokines when in culture with virally infected cells. H84T-BanLec CAR-NK cells are a promising cell therapy for further testing against wild-type SARS-CoV-2 virus in models of SARS-CoV-2 infection. They may represent a viable off-the-shelf immunotherapy for patients suffering from COVID-19.
Single Nucleotide Polymorphisms in the Bovine TLR2 Extracellular Domain Contribute to Breed and Species-Specific Innate Immune Functionality
Authors: Bartens Marie-Christine , Gibson Amanda J. , Etherington Graham J. , Di Palma Federica , Holder Angela , Werling Dirk , Willcocks Sam
Published: December 2021

Recent evidence suggests that several cattle breeds may be more resistant to infection with the zoonotic pathogen Mycobacterium bovis. Our data presented here suggests that the response to mycobacterial antigens varies in macrophages generated from Brown Swiss (BS) and Holstein Friesian (HF) cattle, two breeds belonging to the Bos taurus family. Whole genome sequencing of the Brown Swiss genome identified several potential candidate genes, in particular Toll-like Receptor-2 (TLR2), a pattern recognition receptor (PRR) that has previously been described to be involved in mycobacterial recognition. Further investigation revealed single nucleotide polymorphisms (SNP) in TLR2 that were identified between DNA isolated from cells of BS and HF cows. Interestingly, one specific SNP, H326Q, showed a different genotype frequency in two cattle subspecies, Bos (B.) taurus and Bos indicus. Cloning of the TLR2 gene and subsequent gene-reporter and chemokine assays revealed that this SNP, present in BS and Bos indicus breeds, resulted in a significantly higher response to mycobacterial antigens as well as tri-acylated lipopeptide ligands in general. Comparing wild-type and H326Q containing TLR2 responses, wild-type bovine TLR2 response showed clear, diminished mycobacterial antigen responses compared to human TLR2, however bovine TLR2 responses containing H326Q were found to be partially recovered compared to human TLR2. The creation of human:bovine TLR2 chimeras increased the response to mycobacterial antigens compared to the full-length bovine TLR2, but significantly reduced the response compared to the full-length human TLR2. Thus, our data, not only present evidence that TLR2 is a major PRR in the mammalian species-specific response to mycobacterial antigens, but furthermore, that there are clear differences between the response seen in different cattle breeds, which may contribute to their enhanced or reduced susceptibility to mycobacterial infection.
Syk-MyD88 Axis Is a Critical Determinant of Inflammatory-Response in Activated Macrophages
Authors: Yi Young-Su , Kim Han Gyung , Kim Ji Hye , Yang Woo Seok , Kim Eunji , Jeong Deok , Park Jae Gwang , Aziz Nur , Kim Suk , Parameswaran Narayanan , Cho Jae Youl
Published: December 2021

Background

Inflammation, a vital immune response to infection and injury, is mediated by macrophage activation. While spleen tyrosine kinase (Syk) and myeloid differentiation primary response 88 (MyD88) are reportedly involved in inflammatory responses in macrophages, their roles and underlying mechanisms are largely unknown.

Methods

Here, the role of the MyD88-Syk axis and the mechanism by which Syk and MyD88 cooperate during macrophage-mediated inflammatory responses are explored using knockout conditions of these proteins and mutation strategy as well as flowcytometric and immunoblotting analyses.

Results

Syk rapidly activates the nuclear factor-kappa B (NF-κB) signaling pathway in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the activation of the NF-κB signaling pathway is abolished in Syk−/− RAW264.7 cells. MyD88 activates Syk and Syk-induced activation of NF-κB signaling pathway in LPS-stimulated RAW264.7 cells but Syk-induced inflammatory responses are significantly inhibited in MyD88−/− RAW264.7 cells. MyD88 interacts with Syk through the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88, leading to Syk activation and Syk-induced activation of the NF-κB signaling pathway. Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain. In addition, Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and Rac1-induced formation of filamentous actin (F actin) activate Src in LPS-stimulated RAW264.7 cells.

Conclusions

These results suggest that the MyD88-Syk axis is a critical player in macrophage-mediated inflammatory responses, and its function is promoted by an upstream Src kinase activated by Rac1-generated filamentous actin (F-actin).
Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation
Authors: Zhu Damin , Zou Huijuan , Liu Jinxian , Wang Jing , Ma Cong , Yin Jiaqian , Peng Xiaoqing , Li Danyang , Yang Yulu , Ren Yu , Zhang Zhiguo , Zhou Ping , Wang Xiangyan , Cao Yunxia , Xu Xiaofeng
Published: December 2021

Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.
Changes in Coral Skeleton Growth Recorded by Density Band Stratigraphy, Crystalline Structure, and Hiatuses
Authors: Fouke Kyle W. , Trop Jeffrey M. , Sivaguru Mayandi
Published: December 2021

Next-generation high resolution brightfield microscopy, x-radiography, and microcomputed tomography (microCT) analyses indicate that coral skeleton high density band (HDB) and low density band (LDB) stratigraphic sequences record dynamic changes in coral growth history. HDB-LDB sequences were studied within three small heads of Orbicella annularis, an ecological keystone species in the Caribbean Sea, collected from the leeward fringing reefs on Curaçao. Results indicate that HDB layers are formed by the thickening of exothecal and endothecal dissepiments, costae, and theca located at the margin and external to individual skeletal cups (corallites). Conversely, septa and columellas located inside individual corallites do not change in thickness. HDB-LDB stratigraphic sequences were laterally traced from the center to the margins of individual coral heads, demonstrating that shifts took place in the trajectory of coral skeleton growth. Normal HDB layers in the center of individual coral heads are formed at the same time (age-equivalent) as surfaces of erosion and no skeleton growth (hiatuses) on the margins of the heads. These hiatus surfaces within HDB-LDB stratal geometries indicate that multiple marine ecological and environmental processes affect the orientation, size, shape, and geometry of coral skeletons during coral growth history. The presence of these hiatus surfaces in other large coral heads would strongly impact sclerochronology and the interpretation of multiple environmental factors including sea surface temperature (SST).
Male Humpback Whale Chorusing in Hawai‘i and Its Relationship With Whale Abundance and Density
Authors: Kügler Anke , Lammers Marc O. , Zang Eden J. , Pack Adam A.
Published: December 2021

Passive acoustic monitoring (PAM) with autonomous bottom-moored recorders is widely used to study cetacean occurrence, distribution and behaviors, as it is less affected by factors that limit other observation methods (e.g., vessel, land and aerial-based surveys) such as inclement weather, sighting conditions, or remoteness of study sites. During the winter months in Hawai‘i, humpback whale male song chorusing becomes the predominant contributor to the local soundscape and previous studies showed a strong seasonal pattern, suggesting a correlation with relative whale abundance. However, the relationship between chorusing levels and abundance, including non-singing whales, is still poorly understood. To investigate how accurately acoustic monitoring of singing humpback whales tracks their abundance, and therefore is a viable tool for studying whale ecology and population trends, we collected long-term PAM data from three bottom-moored Ecological Acoustic Recorders off west Maui, Hawaii during the winter and spring months of 2016–2021. We calculated daily medians of root-mean-square sound pressure levels (RMS SPL) of the low frequency acoustic energy (0–1.5 kHz) as a measure of cumulative chorusing intensity. In addition, between December and April we conducted a total of 26 vessel-based line-transect surveys during the 2018/19 through 2020/21 seasons and weekly visual surveys (n= 74) from a land-based station between 2016 and 2020, in which the location of sighted whale pods was determined with a theodolite. Combining the visual and acoustic data, we found a strong positive second-order polynomial correlation between SPLs and abundance (land: 0.72 ≤ R2≤ 0.75, vessel: 0.81 ≤ R2≤ 0.85 for three different PAM locations; Generalized Linear Model:pland≪ 0.001,pvessel≪ 0.001) that was independent from recording location (pland= 0.23,pvessel= 0.9880). Our findings demonstrate that PAM is a relatively low-cost, robust complement and alternative for studying and monitoring humpback whales in their breeding grounds that is able to capture small-scale fluctuations during the season and can inform managers about population trends in a timely manner. It also has the potential to be adapted for use in other regions that have previously presented challenges due to their remoteness or other limitations for conducting traditional surveys.
Evaluating the Spring-Neap Tidal Effects on Chlorophyll-a Variations Based on the Geostationary Satellite
Authors: Xing Qinwang , Yu Huaming , Yu Haiqing , Wang Hui , Ito Shin-ichi , Yuan Chunxin
Published: December 2021

Tides are the dominant hydrodynamic processes in most continental shelf seas and have been proven to have a significant impact on both marine ecosystem dynamics and biogeochemical cycles. In situ and satellite observations have suggested that the spring-neap tide results in fluctuations of chlorophyll-a concentrations (Chl-a) with a fortnightly period in some shelf waters. However, a large number of missing values and low observation frequency in satellite-observed Chl-a have been recognized as the major obstacle to investigating the regional pattern showing where and to what extent of the effects of spring-neap tide on Chl-a and the seasonal variations in the effects within a relatively large region. Taking Himawari-8 as an example, a simple algorithm appropriate for geostationary satellites was proposed in this study with the purpose of obtaining a tide-related daily climatological Chl-a dataset (TDCD) and to quantitatively estimate the effects of the spring-neap tide on Chl-a variations. Based on the Chl-a time series from TDCD, significant fortnightly signals of Chl-a fluctuations and high contribution together with high explanations of the fortnightly fluctuations for Chl-a variations were found in some specific inshore waters, especially in the East China Sea, Bay of Bengal, South China Sea, and northern Australian waters. The spring-neap tide was found able to induce the spatio-temporal fortnightly fluctuations of Chl-a with an annual amplitude of 12–33% of the mean in these inshore areas. Significant seasonal variations in the fortnightly fluctuation of Chl-a were observed in the temperate continental shelf regions, while levels remained relatively stable in the tropical waters. Further analysis implied that the spatio-temporal fortnightly fluctuations of Chl-a were closely associated with the tidal current differences between the spring and neap tides. Seasonal variations in the tidal current differences were found to be a key driving factor for seasonal fluctuations of the spring-neap tidal effects on Chl-a in the temperate continental shelf regions. This study provides a better understanding of tide-related marine ecosystem dynamics and biogeochemical cycles and is helpful in improving physical–biogeochemical models.
Optical Detection of Harmful Algal Blooms in the Belgian Coastal Zone: A Cautionary Tale of Chlorophyll c3
Authors: Castagna Alexandre , Dierssen Heidi , Organelli Emanuele , Bogorad Margarita , Mortelmans Jonas , Vyverman Wim , Sabbe Koen
Published: December 2021

Phaeocystis globosa is a nuisance haptophyte species that forms annual blooms in the southern North Sea and other coastal waters. At high biomass concentration, these are considered harmful algal blooms due to their deleterious impact on the local ecosystems and economy, and are considered an indicator for eutrophication. In the last two decades, methods have been developed for the optical detection and quantification of these blooms, with potential applications for autonomous in situ or remote observations. However, recent experimental evidence suggests that the interpretation of the optical signal and its exclusive association with P. globosa may not be accurate. In the North Sea, blooms of P. globosa are synchronous with those of the diatom Pseudo-nitzschia delicatissima, another harmful bloom-forming species with similar pigmentation and optical signature. Here we combine new and published measurements of pigmentation composition and inherent optical properties from pure cultures of several algal and cyanobacterial groups, together with environmental spectroscopy data, to identify the pigments generating the optical signals captured by two established algorithms. We further evaluate the association of those pigments and optical signals with P. globosa. We found that the interpretation of the pigment(s) generating the optical signals were incorrect and that previous methods are not specific to P. globosa, even in the context of the phytoplankton assemblage of the southern North Sea. Additionally, we found that the optical and pigment signatures of Phaeocystis species are part of a broad pigmentation trend across unrelated taxonomic groups related to chlorophyll c3 presence, with important consequences for the interpretation of pigment and optical data. We then develop and evaluate an algorithm to detect this pigmentation pattern with minimal influence of co-occurring species and elaborate general recommendations for the future development of algorithms.
Mussel Byssal Attachment Weakened by Anthropogenic Noise
Authors: Zhao Xinguo , Sun Shuge , Shi Wei , Sun Xuemei , Zhang Yan , Zhu Lin , Sui Qi , Xia Bin , Qu Keming , Chen Bijuan , Liu Guangxu
Published: December 2021

The increasing underwater noise generated by anthropogenic activities has been widely recognized as a significant and pervasive pollution in the marine environment. Marine mussels are a family of sessile bivalves that attach to solid surfaces via the byssal threads. They are widely distributed along worldwide coastal areas and are of great ecological and socio-economic importance. Studies found that anthropogenic noise negatively affected many biological processes and/or functions of marine organisms. However, to date, the potential impacts of anthropogenic noise on mussel byssal attachment remain unknown. Here, the thick shell mussels Mytilus coruscus were exposed to an ambient underwater condition (∼50 dB re 1 μPa) or the playbacks of pile-driving noise (∼70 or ∼100 dB re 1 μPa) for 10 days. Results showed that the noise significantly reduced the secretion of byssal threads (e.g., diameter and volume) and weakened their mechanical performances (e.g., strength, extensibility, breaking stress, toughness and failure location), leading to a 16.95–44.50% decrease in mussel byssal attachment strength. The noise also significantly down-regulated the genes expressions of seven structural proteins (e.g., mfp-1, mfp-2, mfp-3, mfp-6, preCOL-P, preCOL-NG, and preCOL-D) of byssal threads, probably mediating the weakened byssal attachment. Given the essential functions of strong byssal attachment, the findings demonstrate that the increasing underwater anthropogenic noise are posing a great threat to mussel population, mussel-bed community and mussel aquaculture industry. We thus suggest that future work is required to deepen our understanding of the impacts of anthropogenic noise on marine invertebrates, especially these with limited locomotion ability, like bivalves.
Exploring New Strategies for Ultrahigh Strength Steel via Tailoring the Precipitates
Authors: Tian Jialong , Jiang Zhouhua
Published: December 2021

Ultrahigh-strength (UHS) steels have shown great potential in the field of high-end equipment manufacturing in demand of lightweight engineering and performance upgrade. A significant research effort has been directed toward the development of advanced UHS steels with excellent combination of strength and toughness. In the course of development, tailoring precipitates by means of composition design and process optimization is absolutely a critical module. In this mini review, typical UHS steels strengthened by carbides and intermetallics are systematically summarized and discussed. With the increase of strength, the toughness losses of UHS steels strengthened by carbides and intermetallics have been compared in detail. In particular, the in-depth mechanisms leading to various strength/toughness variation trends have been discussed, extracting the bottleneck in developing new-generation UHS steels containing merely one type of precipitate. Meanwhile, prospects on designing advanced UHS steels strengthened by coexisting dispersive precipitates have been proposed to achieve better performance.
Microstructures and Mechanical Properties of As Cast (Al7.5Co21.9Cr10.9Ti5.0Fe21.9Ni32.8)100-xCux High-Entropy Alloys
Authors: Li Jiajun , Dong Yu , Wang Zemin , Liu Min , Ding Yi , Fu Bin , Wang Zhanyong
Published: December 2021

This study focused on the role of Cu in the microstructure characteristics and tensile properties of novel L12-strengthened multicomponent high-entropy alloys (HEAs). A series of as-cast (Al7.5Co21.9Cr10.9Ti5.0Fe21.9Ni32.8)100-xCux (x = 0.5, 2.5, 5.0) high-entropy alloys (HEAs) were prepared. The microstructures and mechanical properties of HEAs were investigated using X-ray diffraction, a scanning electron microscope, a transmission electron microscope, and atom probe tomography. The XRD patterns of HEAs confirmed that all HEAs consisted of the FCC phase and the L12 phase. As Cu content increased, the dendritic was gradually coarsened. The spherical L12 size decreased, and number density increased in the interdendritic regions (ID). The L12 mainly contained Ni, Ti, Al, and Cu. The acicular L12 size increased and was continuously distributed in the dendritic regions (DR) as the Cu content increased gradually. The ultimate strength and elongation decreased from 1,002 MPa, 20.0% to 906 MPa, 13.1%, respectively. The segregation rates of Ti, Cu, and Al increased in the DR and ID. The L12 nano-precipitates in the DR become denser and finer, while the L12 islets in the ID region increase and elongate. Large lattice distortion caused by Cu addition weakens the strength of the L12-FCC phase boundary, leading to the premature fracture of the three HEAs, which were the main reasons for the decreases in strength and ductility as Cu content increased.
COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl4-Induced Liver Fibrosis and Portal Hypertension
Authors: Zhao Zhifeng , Zhang Chihao , Lin Jiayun , Zheng Lei , Li Hongjie , Qi Xiaoliang , Huo Haizhong , Lou Xiaolou , Hammock Bruce D. , Hwang Sung Hee , Bao Yongyang , Luo Meng
Published: December 2021

Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT).

Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis.

Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-β (TGF-β).

Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-β.
Binocular Summation Is Intact in Intermittent Exotropia After Surgery
Authors: Xu Meiping , Chen Yiya , Peng Yiyi , He Zhifen , Jiang Jun , Yu Xinping , Hou Fang , Zhou Jiawei , Qu Jia
Published: December 2021

Purpose: To determine binocular summation of surgically treated intermittent exotropia (IXT) patients by measuring the contrast threshold.

Methods: We recruited 38 surgically treated IXT patients aged 8–24 years and 20 age-matched healthy controls. All participants had normal or corrected-to-normal visual acuity (Snellen ≥ 20/20) in both eyes. The IXT patients had undergone the surgery at least a year prior to the study. Twenty-one of them obtained good alignment and 17 experienced a recurrence of exotropia. We measured the observers' monocular and binocular contrast sensitivities (CS) at six spatial frequencies (1.5, 3, 6, 12, 18, 24 cycles/degree) as an index of visual information processing at the threshold level. Binocular summation was evaluated against a baseline model of simple probability summation based on the CS at each spatial frequency and the area under the log contrast sensitivity function (AULCSF).

Results: The exo-deviation of IXTs with good alignment was −6.38 ± 3.61 prism diopters (pd) at 33 cm and −5.14 ± 4.07 pd at 5 m. For the patients with recurrence, it was −23.47 ± 5.53 pd and −21.12 ± 4.28 pd, respectively. There was no significant difference in the binocular summation ratio (BSR) between the surgically treated IXT patients, including those with good alignment and recurrence, and normal controls at each spatial frequency [F(2,55) = 0.416, P = 0.662] and AULCSF [F(2,55) = 0.469, P = 0.628]. In addition, the BSR was not associated with stereopsis (r = −0.151, P = 0.365).

Conclusion: Our findings of normal contrast sensitivity binocular summation ratio in IXT after surgical treatment suggest that the ability of the visual cortex in processing binocular information is intact at the contrast threshold level.
Pancreatic Cancer Patient-Derived Organoid Platforms: A Clinical Tool to Study Cell- and Non-Cell-Autonomous Mechanisms of Treatment Response
Authors: Piro Geny , Agostini Antonio , Larghi Alberto , Quero Giuseppe , Carbone Carmine , Esposito Annachiara , Rizzatti Gianenrico , Attili Fabia , Alfieri Sergio , Costamagna Guido , Tortora Giampaolo
Published: December 2021

For many years, cell lines and animal models have been essential to improve our understanding of the basis of cell metabolism, signaling, and genetics. They also provided an essential boost to cancer drug discovery. Nevertheless, these model systems failed to reproduce the tumor heterogeneity and the complex biological interactions between cancer cells and human hosts, making a high priority search for alternative methods that are able to export results from model systems to humans, which has become a major bottleneck in the drug development. The emergent human in vitro 3D cell culture technologies have attracted widespread attention because they seem to have the potential to overcome these limitations. Organoids are unique 3D culture models with the ability to self-organize in contained structures. Their versatility has offered an exceptional window of opportunity to approach human cancers. Pancreatic cancers (PCs) patient-derived-organoids (PDOs) preserve histological, genomic, and molecular features of neoplasms they originate from and therefore retain their heterogeneity. Patient-derived organoids can be established with a high success rate from minimal tissue core specimens acquired with endoscopic-ultrasound-guided techniques and assembled into platforms, representing tens to hundreds of cancers each conserving specific features, expanding the types of patient samples that can be propagated and analyzed in the laboratory. Because of their nature, PDO platforms are multipurpose systems that can be easily adapted in co-culture settings to perform a wide spectrum of studies, ranging from drug discovery to immune response evaluation to tumor-stroma interaction. This possibility to increase the complexity of organoids creating a hybrid culture with non-epithelial cells increases the interest in organoid-based platforms giving a pragmatic way to deeply study biological interactions in vitro. In this view, implementing organoid models in co-clinical trials to compare drug responses may represent the next step toward even more personalized medicine. In the present review, we discuss how PDO platforms are shaping modern-day oncology aiding to unravel the most complex aspects of PC.
Alterations in the Gut Microbiota and Hepatitis-B-Virus Infection in Southern Chinese Patients With Coexisting Non-Alcoholic Fatty Liver Disease and Type-2 Diabetes Mellitus
Authors: Han Weijia , Huang Chunyang , Ji Yali , Zhou Ling , Chen Jinjun , Hou Jinlin
Published: December 2021

Background: Hepatitis B virus (HBV) infection has been reported to affect the bacterial characteristics in the host. We aimed to elucidate the compositional and functional characteristics of the microbiota in southern Chinese patients with coexistent HBV infection, non-alcoholic fatty liver disease (NAFLD), and type-2 diabetes mellitus (T2DM).

Methods: Healthy controls (HCs) and patients with coexistent NAFLD and T2DM were enrolled. Patients were divided into two groups: N1 (without HBV infection) and N2 (with HBV infection). Stool samples were collected for 16s RNA gene sequencing and untargeted metabolomics analysis.

Results: Bacterial diversity was decreased in the N2 group. There was a significantly lower abundance of bacteria of Faecalibacterium, Gemmiger, and Clostridium_XIVA genera, but a higher abundance of Megamonas and Phascolarctobacterium genera in the N2 group. Compared with the N1 group, the abundance of Gemmiger species was even lower, and alterations in the abundance of Phascolarctobacterium and Clostridium_XIVA genera only occurred in the N2 group. There were significantly different fecal metabolic features, which were enriched in glucose and lipid metabolic pathways (e.g., fatty acid and glycerophospholipid metabolism) between the N2 and HC groups. Metabolites in glycerophospholipid metabolism, such as Sn-3-o-(geranylgeranyl)glycerol1-phosphate, were even higher in the N2 group than in the N1 group. The decreased Faecalibacterium and Gemmiger contributed to the increased level of Sn-3-o-(geranylgeranyl) glycerol1-phosphate, palmitoylcarnitine, and serum triglycerides. Clostridium_XIVA species were positively correlated to 15(s)-hpete. Megamonas species were positively correlated with the serum level of glucose indirectly.

Conclusions: The distinct gut-microbiome profile associated with HBV infection has a role in lipid metabolism and glucose metabolism in patients with coexistent NAFLD and T2DM.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03525769.
Disruption of the Snf1 Gene Enhances Cell Growth and Reduces the Metabolic Burden in Cellulase-Expressing and Lipid-Accumulating Yarrowia lipolytica
Authors: Wei Hui , Wang Wei , Knoshaug Eric P. , Chen Xiaowen , Van Wychen Stefanie , Bomble Yannick J. , Himmel Michael E. , Zhang Min
Published: December 2021

Yarrowia lipolytica is known to be capable of metabolizing glucose and accumulating lipids intracellularly; however, it lacks the cellulolytic enzymes needed to break down cellulosic biomass directly. To develop Y. lipolytica as a consolidated bioprocessing (CBP) microorganism, we previously expressed the heterologous CBH I, CBH II, and EG II cellulase enzymes both individually and collectively in this microorganism. We concluded that the coexpression of these cellulases resulted in a metabolic drain on the host cells leading to reduced cell growth and lipid accumulation. The current study aims to build a new cellulase coexpressing platform to overcome these hinderances by (1) knocking out the sucrose non-fermenting 1 (Snf1) gene that represses the energetically expensive lipid and protein biosynthesis processes, and (2) knocking in the cellulase cassette fused with the recyclable selection marker URA3 gene in the background of a lipid-accumulating Y. lipolytica strain overexpressing ATP citrate lyase (ACL) and diacylglycerol acyltransferase 1 (DGA1) genes. We have achieved a homologous recombination insertion rate of 58% for integrating the cellulases-URA3 construct at the disrupted Snf1 site in the genome of host cells. Importantly, we observed that the disruption of the Snf1 gene promoted cell growth and lipid accumulation and lowered the cellular saturated fatty acid level and the saturated to unsaturated fatty acid ratio significantly in the transformant YL163t that coexpresses cellulases. The result suggests a lower endoplasmic reticulum stress in YL163t, in comparison with its parent strain Po1g ACL-DGA1. Furthermore, transformant YL163t increased in vitro cellulolytic activity by 30%, whereas the “total in vivo newly formed FAME (fatty acid methyl esters)” increased by 16% in comparison with a random integrative cellulase-expressing Y. lipolytica mutant in the same YNB-Avicel medium. The Snf1 disruption platform demonstrated in this study provides a potent tool for the further development of Y. lipolytica as a robust host for the expression of cellulases and other commercially important proteins.
WSV056 Inhibits Shrimp Nitric Oxide Synthase Activity by Downregulating Litopenaeus vannamei Sepiapterin Reductase to Promote White Spot Syndrome Virus Replication
Authors: Wang Wei , Zheng Qin , Yu Chen , Pan Changkun , Luo Peng , Chen Jianming
Published: December 2021

Sepiapterin reductase (Spr) plays an essential role in the biosynthesis of tetrahydrobiopterin (BH4), a key cofactor of multiple enzymes involved in various physiological and immune processes. Suppression of Spr could result in BH4 deficiency-caused diseases in human and murine models. However, information on the biological function of Spr in invertebrates is limited. In this study, two Sprs (CG12116 and Sptr) from Drosophila melanogaster were found to be downregulated in transgenic flies overexpressing white spot syndrome virus (WSSV) immediate-early protein WSV056. CG12116 and Sptr exerted an inhibitory effect on the replication of the Drosophila C virus. A Litopenaeus vannamei Spr (LvSpr) exhibiting similarity of 64.1–67.5% and 57.3–62.2% to that of invertebrate and vertebrate Sprs, respectively, were cloned. L. vannamei challenged with WSSV revealed a significant decrease in LvSpr transcription and Spr activity in hemocytes. In addition, the BH4 co-factored nitric oxide synthase (Nos) activity in shrimp hemocytes was reduced in WSSV-infected and LvSpr knockdown shrimp, suggesting WSSV probably inhibits the LvNos activity through LvSpr downregulation to limit the production of nitric oxide (NO). Knockdown of LvSpr and LvNos caused the reduction in NO level in hemocytes and the increase of viral copy numbers in WSSV-infected shrimp. Supplementation of NO donor DETA/NO or double gene knockdown of WSV056 + LvSpr and WSV056 + LvNos recovered the NO production, whereas the WSSV copy numbers were decreased. Altogether, the findings demonstrated that LvSpr and LvNos could potentially inhibit WSSV. In turn, the virus has evolved to attenuate NO production via LvSpr suppression by WSV056, allowing evasion of host antiviral response to ensure efficient replication.
Multiple Cross Displacement Amplification Combined With Real-Time Polymerase Chain Reaction Platform: A Rapid, Sensitive Method to Detect Mycobacterium tuberculosis
Authors: Jiao Wei-wei , Wang Gui-rong , Sun Lin , Xiao Jing , Li Jie-qiong , Wang Ya-cui , Quan Shu-ting , Huang Hai-rong , Shen A-dong
Published: December 2021

In this study, we evaluated the diagnostic accuracy of multiple cross displacement amplification (MCDA) combined with real-time PCR platform in pulmonary tuberculosis (PTB) patients. Total 228 PTB patients and 141 non-TB cases were enrolled. Based on the analysis of the first available sample of all participants, MCDA assay showed a higher overall sensitivity (64.0%), with a difference of more than 10% compared with Xpert MTB/RIF (Xpert) assay (51.8%, P < 0.05) and combined liquid and solid culture (47.8%, P < 0.001) for PTB diagnosis. In particular, MCDA assay detected 31 probable TB patients, which notably increased the percentage of confirmed TB from 57.9% (132/228) to 71.5% (163/228). The specificities of microscopy, culture, Xpert and MCDA assay were 100% (141/141), 100% (141/141), 100% (141/141), and 98.6% (139/141), respectively. Among the patients with multiple samples, per patient sensitivity of MCDA assay was 60.5% (52/86) when only the first available sputum sample was taken into account, and the sensitivity increased to 75.6% (65/86) when all samples tested by MCDA assay were included into the analysis. Therefore, MCDA assay established in this study is rapid, accurate and affordable, which has the potential in assisting the accurate and rapid diagnosis of PTB and speed up initiation of TB treatment in settings equipped with real-time PCR platform.
Treadmill Exercise During Cerebral Hypoperfusion Has Only Limited Effects on Cognitive Function in Middle-Aged Subcortical Ischemic Vascular Dementia Mice
Authors: Ohtomo Ryo , Ishikawa Hidehiro , Kinoshita Keita , Chung Kelly K. , Hamanaka Gen , Ohtomo Gaku , Takase Hajime , Wrann Christiane D. , Katsuki Hiroshi , Iwata Atsushi , Lok Josephine , Lo Eng H. , Arai Ken
Published: December 2021

Clinical and basic research suggests that exercise is a safe behavioral intervention and is effective for improving cognitive function in cerebrovascular diseases, including subcortical ischemic vascular dementia (SIVD). However, most of the basic research uses young animals to assess the effects of exercise, although SIVD is an age-related disease. In this study, therefore, we used middle-aged mice to examine how treadmill exercise changes the cognitive function of SIVD mice. As a mouse model of SIVD, prolonged cerebral hypoperfusion was induced in 8-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into two groups: a group that received 6-week treadmill exercise and a sedentary group for observation. After subjecting the mice to multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to only be effective in ameliorating cognitive decline in the Y-maze test. We previously demonstrated that the same regimen of treadmill exercise was effective in young hypoperfused-SIVD mice for all three cognitive tests. Therefore, our study may indicate that treadmill exercise during cerebral hypoperfusion has only limited effects on cognitive function in aging populations.
Effects of Robot-Assisted Therapy on Gait Parameters in Pediatric Patients With Spastic Cerebral Palsy
Authors: Manikowska Faustyna , Brazevic Sabina , Krzyżańska Anna , Jóźwiak Marek
Published: December 2021

Background: Gait dysfunction is a crucial factor that restricts independence and quality of life in children with cerebral palsy (CP). Gait training based on robotic-assisted therapy (RAT) is widely used, but information about effectiveness and ideal patient profile is not sufficient. Aim of this study was to assess the effect of RAT on gait parameters in spastic children with CP, and to determine whether changes in gait parameters are different among patients on different ambulatory levels.

Method: A total of 26 children with bilateral spastic CP were divided into two groups based on their functional ability: non-assisted ambulator (NAS) or assisted ambulator (AS); and underwent a RAT program (30 training sessions of RAT during 10 weeks). Gait analysis was performed: before the therapy (t1), right after (t2), and 6 weeks later (t3).

Results: No significant changes in spatiotemporal parameters or gait deviation index at t2 or t3. Double support symmetry significantly improved (t1 vs. t3, p = 0.03) for the whole group (NAS + AS). Walking speed symmetry significantly improved (t2 vs. t3, p = 0.02) for group AS.

Conclusion: RAT based on our protocol did not change spatiotemporal parameters and kinematics of walking except limited improvement in some aspects of gait symmetry. We did not find differences in changes in selected objective gait parameters among children with CP in different ambulatory levels.
A Historical Perspective on Surgical Manipulation of the Membranous Labyrinth for Treatment of Meniere's Disease
Authors: Kersbergen Calvin J. , Ward Bryan K.
Published: December 2021

Meniere's disease is an inner ear disorder without a known cause. Endolymphatic hydrops is a swelling of the endolymph spaces that has been observed consistently on post-mortem histology in patients with a history of Meniere's disease but can occur in asymptomatic individuals and in association with other diseases. Since its discovery, Meniere's disease has been a disorder managed primarily by otolaryngologists. Surgical treatments, therefore, have accompanied attempts at medical management. Inspired by patients' sensations of ear fullness and later by the histologic findings of hydrops, surgeons began manipulating the membranous labyrinth to relieve episodes of vertigo while attempting to preserve hearing. This review highlights this history of manipulation of the membranous labyrinth. These procedures indicate a rich history of innovation that parallels developments in otologic surgery. The studies involving patients are uniformly retrospective, with some procedures performed first in animal models of endolymphatic hydrops. Many approaches were endorsed by eminent otologic surgeons. Surgeries on the endolymphatic sac are performed by some surgeons today; however, procedures on the membranous labyrinth resulted in similar symptomatic relief through a minimally invasive technique, in many cases performed using only local anesthetic. Episodic vertigo in patients with Meniere's disease is a distressing symptom, yet spontaneous remissions are common. The reports of procedures on the membranous labyrinth reviewed here consistently indicated fewer vertigo episodes. Variable degrees of hearing loss were common following these procedures, and many were abandoned. Additional innovative surgeries are inevitable, but we must understand better the relationships among endolymphatic hydrops, Meniere's disease pathophysiology, and patient symptoms.
Retinal Neurodegeneration in Different Risk Phenotypes of Diabetic Retinal Disease
Authors: Madeira Maria H. , Marques Inês P. , Ferreira Sónia , Tavares Diana , Santos Torcato , Santos Ana Rita , Figueira João , Lobo Conceição , Cunha-Vaz José
Published: December 2021

Diabetic retinopathy (DR) has been considered a microvascular disease, but it has become evident that neurodegeneration also plays a key role in this complex pathology. Indeed, this complexity is reflected in its progression which occurs at different rates in different type 2 diabetic (T2D) individuals. Based on this concept, our group has identified three DR progression phenotypes that might reflect the interindividual differences: phenotype A, characterized by low microaneurysm turnover (MAT <6), phenotype B, low MAT (<6) and increased central retinal thickness (CRT); and phenotype C, with high MAT (≥6). In this study, we evaluated the progression of DR neurodegeneration, considering ganglion cell+inner plexiform layers (GCL+IPL) thinning, in 170 T2D individuals followed for a period of 5 years, to explore associations with disease progression or risk phenotypes. Ophthalmological examinations were performed at baseline, first 6 months, and annually. GCL+IPL average thickness was evaluated by optical coherence tomography (OCT). Microaneurysm turnover (MAT) was evaluated using the RetMarkerDR. ETDRS level and severity progression were assessed in seven-field color fundus photography. In the overall population there was a significant loss in GCL+IPL (−0.147 μm/year), independently of glycated hemoglobin, age, sex, and duration of diabetes. Interestingly, this progressive thinning in GCL + IPL reached higher values in phenotypes B and C (−0.249 and −0.238 μm/year, respectively), whereas phenotype A remained relatively stable. The presence of neurodegeneration in all phenotypes suggests that it is the retinal vascular response to the early neurodegenerative changes that determines the course of the retinopathy in each individual. Therefore, classification of different DR phenotypes appears to offer relevant clarification of DR disease progression and an opportunity for improved management of each T2D individual with DR, thus playing a valuable role for the implementation of personalized medicine in DR.
Molecular and Clinical Significance of Fibroblast Growth Factor 2 in Development and Regeneration of the Auditory System
Authors: Jeong Minjin , Bojkovic Katarina , Sagi Varun , Stankovic Konstantina M.
Published: December 2021

The fibroblast growth factor 2 (FGF2) is a member of the FGF family which is involved in key biological processes including development, cellular proliferation, wound healing, and angiogenesis. Although the utility of the FGF family as therapeutic agents has attracted attention, and FGF2 has been studied in several clinical contexts, there remains an incomplete understanding of the molecular and clinical function of FGF2 in the auditory system. In this review, we highlight the role of FGF2 in inner ear development and hearing protection and present relevant clinical studies for tympanic membrane (TM) repair. We conclude by discussing the future implications of FGF2 as a potential therapeutic agent.