bluuebunny/crossref_metadata_2025 huggingface dataset:
Connexin26 Modulates the Radiosensitivity of Cutaneous Squamous Cell Carcinoma by Regulating the Activation of the MAPK/NF-κB Signaling Pathway
Authors: Sun Minqiong , Li Yuan , Qian Jing , Ding Siwei , Sun Mingyu , Tan Bowen , Zhao Ye
Published: July 2021

Previous studies have confirmed that the gap junction protein Connexin26 (Cx26) is specifically expressed in human skin tissue. Cx26 can transmit radiation-induced damage signals. However, no study has yet reported whether Cx26 expression affects the radiosensitivity of human skin squamous cancer cells or the mechanism by which this occurs. In this study, we found that human skin squamous cell carcinoma cells (A431 cells) expressed significantly more Cx26 and were more sensitive to radiation compared to normal human keratinocytes (HaCaT cells). Knockdown of Cx26 in A431 cells (A431Cx26–/–) decreased radiosensitivity relative to control cells and altered the expression of key proteins in the MAPK and NF-κB signaling pathways. These results demonstrate that Cx26 expression might play an important role in mediating radiation damage in A431 cells and could serve as a potential target for clinical radiotherapy for cutaneous squamous cell carcinoma.
p63 and p53: Collaborative Partners or Dueling Rivals?
Authors: Woodstock Dana L. , Sammons Morgan A. , Fischer Martin
Published: July 2021

The tumor suppressor p53 and its oncogenic sibling p63 (ΔNp63) direct opposing fates in tumor development. These paralog proteins are transcription factors that elicit their tumor suppressive and oncogenic capacity through the regulation of both shared and unique target genes. Both proteins predominantly function as activators of transcription, leading to a paradigm shift away from ΔNp63 as a dominant negative to p53 activity. The discovery of p53 and p63 as pioneer transcription factors regulating chromatin structure revealed new insights into how these paralogs can both positively and negatively influence each other to direct cell fate. The previous view of a strict rivalry between the siblings needs to be revisited, as p53 and p63 can also work together toward a common goal.
GLP-2 Is Locally Produced From Human Islets and Balances Inflammation Through an Inter-Islet-Immune Cell Crosstalk
Authors: He Wei , Rebello Osmond D. , Henne Antonia , Nikolka Fabian , Klein Thomas , Maedler Kathrin
Published: July 2021

Glucagon-like peptide-1 (GLP-1) shows robust protective effects on β-cell survival and function and GLP-1 based therapies are successfully applied for type-2 diabetes (T2D) and obesity. Another cleavage product of pro-glucagon, Glucagon-like peptide-2 (GLP-2; both GLP-1 and GLP-2 are inactivated by DPP-4) has received little attention in its action inside pancreatic islets. In this study, we investigated GLP-2 production, GLP-2 receptor (GLP-2R) expression and the effect of GLP-2R activation in human islets. Isolated human islets from non-diabetic donors were exposed to diabetogenic conditions: high glucose, palmitate, cytokine mix (IL-1β/IFN-γ) or Lipopolysaccharide (LPS) in the presence or absence of the DPP4-inhibitor linagliptin, the TLR4 inhibitor TAK-242, the GLP-2R agonist teduglutide and/or its antagonist GLP-2(3-33). Human islets under control conditions secreted active GLP-2 (full-length, non-cleaved by DPP4) into the culture media, which was increased by combined high glucose/palmitate, the cytokine mix and LPS and highly potentiated by linagliptin. Low but reproducible GLP-2R mRNA expression was found in all analyzed human islet isolations from 10 donors, which was reduced by pro-inflammatory stimuli: the cytokine mix and LPS. GLP-2R activation by teduglutide neither affected acute or glucose stimulated insulin secretion nor insulin content. Also, teduglutide had no effect on high glucose/palmitate- or LPS-induced dysfunction in cultured human islets but dampened LPS-induced macrophage-dependent IL1B and IL10 expression, while its antagonist GLP-2(3-33) abolished such reduction. In contrast, the expression of islet macrophage-independent cytokines IL6, IL8 and TNF was not affected by teduglutide. Medium conditioned by teduglutide-exposed human islets attenuated M1-like polarization of human monocyte-derived macrophages, evidenced by a lower mRNA expression of pro-inflammatory cytokines, compared to vehicle treated islets, and a reduced production of itaconate and succinate, marker metabolites of pro-inflammatory macrophages. Our results reveal intra-islet production of GLP-2 and GLP-2R expression in human islets. Despite no impact on β-cell function, local GLP-2R activation reduced islet inflammation which might be mediated by a crosstalk between endocrine cells and macrophages.
Phosphorylated EGFR (pEGFR T693) as a Novel Predictor of Recurrence in Non-Functioning Pituitary Adenomas
Authors: Rai Ashutosh , Das Liza , Mukherjee Kanchan K. , Dhandapani Sivashanmugam , Tripathi Manjul , Ahuja Chirag Kamal , Radotra Bishan Dass , Dutta Pinaki
Published: July 2021

Purpose

Non-functioning pituitary adenomas (NFPAs) exhibit high recurrence rates after surgery. However, the determinants of recurrence are inconsistent in the available literature. The present study sought to investigate the association between nuclear phosphorylated EGFR (pEGFR) levels and recurrence of NFPAs.

Methods

Tissue microarrays from patients undergoing adenomectomy for NFPAs at our tertiary care center from 2003 to 2015 and having a minimum of 60 months of follow-up (n=102) were accessed. Immunohistochemical analysis (IHC) was performed to determine the expression of nuclear pEGFR T693. h-score was calculated as the product of staining intensity and the number of positively staining cells. Radiological surveillance (MRI) was performed to categorize NFPAs as recurrent or non-recurrent on follow-up.

Results

The mean age of the cohort was 50 ± 11 years with a male preponderance (61.1%). Recurrence was observed in 46.1% of the patients at a median of 123 months (IQR 72-159) of follow-up. pEGFR T693 positivity was higher in a significantly greater number of recurrent NFPAs as compared to non-recurrent NFPAs (95.7%vs81%, p=0.02). h-scores were also significantly higher in recurrent NFPAs (122.1 ± 6vs81.54 ± 3.3, p<0.0001). pEGFR T693 positivity significantly predicted recurrence in NFPAs (HR=4.9, CI 2.8-8.8, p<0.0001). ROC analysis revealed an h-score cutoff of 89.8 as being associated significantly with recurrence (sensitivity 80%, specificity 78%, AUC 0.84, p<0.0001).

Conclusion

pEGFR T693 was expressed in significantly higher number of recurrent NFPAs. The h-scores were also higher in recurrent NFPAs. Nuclear pEGFR T693 may serve as a predictor of recurrence in NFPAs.
Non-human Primate Models to Investigate Mechanisms of Infection-Associated Fetal and Pediatric Injury, Teratogenesis and Stillbirth
Authors: Li Miranda , Brokaw Alyssa , Furuta Anna M. , Coler Brahm , Obregon-Perko Veronica , Chahroudi Ann , Wang Hsuan-Yuan , Permar Sallie R. , Hotchkiss Charlotte E. , Golos Thaddeus G. , Rajagopal Lakshmi , Adams Waldorf Kristina M.
Published: July 2021

A wide array of pathogens has the potential to injure the fetus and induce teratogenesis, the process by which mutations in fetal somatic cells lead to congenital malformations. Rubella virus was the first infectious disease to be linked to congenital malformations due to an infection in pregnancy, which can include congenital cataracts, microcephaly, hearing impairment and congenital heart disease. Currently, human cytomegalovirus (HCMV) is the leading infectious cause of congenital malformations globally, affecting 1 in every 200 infants. However, our knowledge of teratogenic viruses and pathogens is far from complete. New emerging infectious diseases may induce teratogenesis, similar to Zika virus (ZIKV) that caused a global pandemic in 2016–2017; thousands of neonates were born with congenital microcephaly due to ZIKV exposurein utero, which also included a spectrum of injuries to the brain, eyes and spinal cord. In addition to congenital anomalies, permanent injury to fetal and neonatal organs, preterm birth, stillbirth and spontaneous abortion are known consequences of a broader group of infectious diseases including group B streptococcus (GBS),Listeria monocytogenes, Influenza A virus (IAV), and Human Immunodeficiency Virus (HIV). Animal models are crucial for determining the mechanism of how these various infectious diseases induce teratogenesis or organ injury, as well as testing novel therapeutics for fetal or neonatal protection. Other mammalian models differ in many respects from human pregnancy including placentation, labor physiology, reproductive tract anatomy, timeline of fetal development and reproductive toxicology. In contrast, non-human primates (NHP) most closely resemble human pregnancy and exhibit key similarities that make them ideal for research to discover the mechanisms of injury and for testing vaccines and therapeutics to prevent teratogenesis, fetal and neonatal injury and adverse pregnancy outcomes (e.g., stillbirth or spontaneous abortion). In this review, we emphasize key contributions of the NHP model pre-clinical research for ZIKV, HCMV, HIV, IAV,L. monocytogenes, Ureaplasma species, and GBS. This work represents the foundation for development and testing of preventative and therapeutic strategies to inhibit infectious injury of human fetuses and neonates.
Adjacent Cell Marker Lateral Spillover Compensation and Reinforcement for Multiplexed Images
Authors: Bai Yunhao , Zhu Bokai , Rovira-Clave Xavier , Chen Han , Markovic Maxim , Chan Chi Ngai , Su Tung-Hung , McIlwain David R. , Estes Jacob D. , Keren Leeat , Nolan Garry P. , Jiang Sizun
Published: July 2021

Multiplex imaging technologies are now routinely capable of measuring more than 40 antibody-labeled parameters in single cells. However, lateral spillage of signals in densely packed tissues presents an obstacle to the assignment of high-dimensional spatial features to individual cells for accurate cell-type annotation. We devised a method to correct for lateral spillage of cell surface markers between adjacent cells termed REinforcement Dynamic Spillover EliminAtion (REDSEA). The use of REDSEA decreased contaminating signals from neighboring cells. It improved the recovery of marker signals across both isotopic (i.e., Multiplexed Ion Beam Imaging) and immunofluorescent (i.e., Cyclic Immunofluorescence) multiplexed images resulting in a marked improvement in cell-type classification.
Antibody Subclass and Glycosylation Shift Following Effective TB Treatment
Authors: Grace Patricia S. , Dolatshahi Sepideh , Lu Lenette L. , Cain Adam , Palmieri Fabrizio , Petrone Linda , Fortune Sarah M. , Ottenhoff Tom H. M. , Lauffenburger Douglas A. , Goletti Delia , Joosten Simone A. , Alter Galit
Published: July 2021

With an estimated 25% of the global population infected withMycobacterium tuberculosis(Mtb), tuberculosis (TB) remains a leading cause of death by infectious diseases. Humoral immunity following TB treatment is largely uncharacterized, and antibody profiling could provide insights into disease resolution. Here we focused on the distinctive TB-specific serum antibody features in active TB disease (ATB) and compared them with latent TB infection (LTBI) or treated ATB (txATB). As expected, di-galactosylated glycan structures (lacking sialic acid) found on IgG-Fc differentiated LTBI from ATB, but also discriminated txATB from ATB. Moreover, TB-specific IgG4 emerged as a novel antibody feature that correlated with active disease, elevated in ATB, but significantly diminished after therapy. These findings highlight 2 novel TB-specific antibody changes that track with the resolution of TB and may provide key insights to guide TB therapy.
ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease
Authors: Krick Stefanie , Helton E. Scott , Easter Molly , Bollenbecker Seth , Denson Rebecca , Zaharias Rennan , Cochran Phillip , Vang Shia , Harris Elex , Wells James M. , Barnes Jarrod W.
Published: July 2021

Chronic obstructive pulmonary disease (COPD) is a systemic disease strongly associated with cigarette smoking, airway inflammation, and acute disease exacerbations. Changes in terminal sialylation and fucosylation of asparagine (N)-linked glycans have been documented in COPD, but the role that glycosyltransferases may play in the regulation of N-linked glycans in COPD has not been fully elucidated. Recent studies suggest that modulation of ST6GAL1 (ST6 beta-galactoside alpha-2,6-sialyltransferase-1), which catalyzes terminal α2-6 sialylation of cellular proteins, may regulate inflammation and contribute to COPD phenotype(s). Interestingly, it has been previously demonstrated that ST6GAL1, a Golgi resident protein, can be proteolytically processed by BACE1 (beta-site amyloid precursor protein cleaving enzyme-1) to a circulating form that retains activity. In this study, we showed that loss of ST6GAL1 expression increased interleukin (IL)-6 expression and secretion in human bronchial epithelial cells (HBECs). Furthermore, exposure to cigarette smoke medium/extract (CSE) or BACE1 inhibition resulted in decreased ST6GAL1 secretion, reduced α2-6 sialylation, and increased IL-6 production in HBECs. Analysis of plasma ST6GAL1 levels in a small COPD patient cohort demonstrated an inverse association with prospective acute exacerbations of COPD (AECOPD), while IL-6 was positively associated. Altogether, these results suggest that reduced ST6GAL1 and α2-6 sialylation augments IL-6 expression/secretion in HBECs and is associated with poor clinical outcomes in COPD.
The 13-Valent Pneumococcal Conjugate Vaccine Elicits Serological Response and Lasting Protection in Selected Patients With Primary Humoral Immunodeficiency
Authors: Robbins Ailsa , Bahuaud Mathilde , Hentzien Maxime , Maestraggi Quentin , Barbe Coralie , Giusti Delphine , Le Naour Richard , Batteux Frederic , Servettaz Amélie
Published: July 2021

Background

Patients with primary humoral immunodeficiency are more prone to invasive as well as recurrent pneumococcal infections. Therefore, anti-pneumococcal vaccination including the 13-valent conjugate vaccine is recommended. Nevertheless, to date, no data is available on immunogenicity of this vaccine in this population.

Objective

To assess the immunogenicity and the persistence of protection up to one year after a 13-valent pneumococcal conjugate vaccine in patients with primary humoral immunodeficiency.

Methods

Twenty-nine patients with common variable immunodeficiency or IgG subclass deficiency were vaccinated. Immune response and immune protection at baseline as well as at one, six and twelve months after vaccination were evaluated by measuring specific IgG serum concentrations (ELISA), and opsonophagocytic activities directed against selected pneumococcal (MOPA).

Results

By ELISA, half of the patients had protective IgG concentrations before vaccination, 35.7% showed an immune response one month after vaccination, 71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively. Conversely, by MOPA, 3.4% of the patients were protected at baseline, 10.7% showed an immune response and 28.6%, 48.2% and 33.3% were protected at one, six and twelve months respectively. IgG subclass deficiency, Ig replacement therapy and higher IgG2 concentrations at diagnosis were associated with long-term protection.

Conclusion

Pneumococcal conjugate vaccine improves immune protection and antibodies’ functionality in a subset of patients with primary immunodeficiency. Prime-boost vaccine strategy needs to be better and individually adapted.
Efficient PCR Amplification Protocol of Nuclear Microsatellites for Exuviae-Derived DNA of Cicada, Yezoterpnosia nigricosta
Authors: Yumoto Keisuke , Kanbe Takashi , Saito Yoko , Kaneko Shingo , Tsuda Yoshiaki
Published: July 2021

Although insect exuviae-based genetics is challenging, it can be a valuable method for obtaining reliable DNA resources by non-invasive sampling. This approach is especially effective when the target species is endangered/endemic or when sampling the adult is difficult. One example is cicadas, which during molt leave their exoskeletons on tree trunks, making them easily collectable. While cicada exuviae-derived DNA has previously been employed for mitochondrial DNA sequencing, this study aimed to develop a reliable method for the PCR amplification of nuclear microsatellite loci from cicada exuviae derived DNA for application in molecular ecology, conservation and population genetics. Five different PCR amplification protocols were performed, and the fragment patterns compared with those obtained using DNA extracted from adult individuals. Moreover, the relationship between the freshness of the exuviae and genotyping success was evaluated. TaKaRa LA Taq provided the best performance in the PCR amplification of DNA isolated from cicada exuviae and the electropherogram showed a clear fragment pattern that was equivalent to that obtained from the DNA extracted from the adult individual. This result suggests that cicada exuviae-derived DNA can be amplified by PCR and that multiple independent loci of nuclear DNA microsatellite markers can be easily genotyped. This study demonstrates that fresh cicada exuviae provide high quality DNA, which can be used for microsatellite genotyping. The methods developed in this study are applicable not only for cicada but other insect species for which exuviae are available. Thus, this study can make a significant contribution to insect sciences.
Effects of Nutrient Availability on the Release of Dissolved and Particulate Organic Carbon by Pyropia haitanensis and Its Implications
Authors: Xu Ningning , Wang Wenlei , Xu Yan , Ji Dehua , Chen Changsheng , Xie Chaotian , Xu Kai
Published: July 2021

As an important component of the coastal-offshore ecosystem, Pyropia haitanensis aquaculture is continually being challenged due to rapid environmental changes because of global climate change and anthropogenic pressures. To explore the effect of nutrient availability on carbon metabolism by P. haitanensis, two strains of thalli were incubated for 15 days under four different concentrations of nitrogen and phosphorus. Significant increases in carbon, nitrogen, and phosphorus contents were observed in the algal tissue after the nitrates and phosphates enrichment, leading to elemental stoichiometry gradually approaching the Redfield ratio. Our results also showed a positive correlation between carbon or phosphorous accumulation and growth rate. Furthermore, under the natural seawater conditions, the release rates of dissolved organic carbon (DOC) and particulate organic carbon (POC) were highest, and more DOC was released than POC. The release rates tended to decrease with nutrient enrichment. The average proportions of DOC compared to total carbon were 6.3%–25.7%, while the average proportions of POC compared to total carbon were 2.1%–5.4%. Our results support the proposed importance of P. haitanensis in contributing the DOC and POC that play a significant role in the biological carbon pump and in sustaining marine aquaculture ecosystems in eutrophic environments.
16S and 18S rRNA Gene Metabarcoding Provide Congruent Information on the Responses of Sediment Communities to Eutrophication
Authors: Harrison Jesse P. , Chronopoulou Panagiota-Myrsini , Salonen Iines S. , Jilbert Tom , Koho Karoliina A.
Published: July 2021

Metabarcoding analyses of bacterial and eukaryotic communities have been proposed as efficient tools for environmental impact assessment. It has been unclear, however, to which extent these analyses can provide similar or differing information on the ecological status of the environment. Here, we used 16S and 18S rRNA gene metabarcoding to compare eutrophication-induced shifts in sediment bacterial and eukaryotic community structure in relation to a range of porewater, sediment and bottom-water geochemical variables, using data obtained from six stations near a former rainbow trout farm in the Archipelago Sea (Baltic Sea). Shifts in the structure of both community types were correlated with a shared set of variables, including porewater ammonium concentrations and the sediment depth-integrated oxygen consumption rate. Distance-based redundancy analyses showed that variables typically employed in impact assessments, such as bottom water nutrient concentrations, explained less of the variance in community structure than alternative variables (e.g., porewater NH4+ inventories and sediment depth-integrated O2 consumption rates) selected due to their low collinearity (up to 40 vs. 58% of the variance explained, respectively). In monitoring surveys where analyses of both bacterial and eukaryotic communities may be impossible, either 16S or 18S rRNA gene metabarcoding can serve as reliable indicators of wider ecological impacts of eutrophication.
The Verification of Thermoelectric Performance Obtained by High-Throughput Calculations: The Case of GeS2 Monolayer From First-Principles Calculations
Authors: Wang Xiaolian , Feng Wei , Shen Chen , Sun Zhehao , Qi Hangbo , Yang Mao , Liu Yonghui , Wu Yuchen , Wu Xiaoqiang
Published: July 2021

Electronic fitness function (EFF, achieved by the electrical transport properties) as a new quantity to estimate thermoelectric (TE) performance of semiconductor crystals is usually used for screening novel TE materials. In recent years, because of the high EFF values, an increasing number of two-dimensional materials have been predicted to have the potential for TE applications via high-throughput calculations. Among them, the GeS2 monolayer has many interesting physical properties and is being used for industrial applications. Hence, in this work, we systematically investigated the TE performance, including both electronic and thermal transport properties, of the GeS2 monolayer with first-principles calculations. The results show that the structure of the GeS2 monolayer at 700 K is thermally unstable, so we study its TE performance only at 300 and 500 K. As compared with other typical TE monolayers, the GeS2 monolayer exhibits excellent electronic transport properties but a relatively high lattice thermal conductivity of 5.71 W m−1 K−1 at 500 K, and thus an unsatisfactory ZT value of 0.23. Such a low ZT value indicates that it is necessary to consider not only the electron transport properties but also the thermal transport properties to screen the thermoelectric materials with excellent performance through high-throughput calculations.
The Emergence and Molecular Characteristics of New Delhi Metallo β-Lactamase-Producing Escherichia coli From Ducks in Guangdong, China
Authors: Wang Min-Ge , Yu Yang , Wang Dong , Yang Run-Shi , Jia Ling , Cai Da-Tong , Zheng Si-Lin , Fang Liang-Xing , Sun Jian , Liu Ya-Hong , Liao Xiao-Ping
Published: July 2021

This study aimed to determine the prevalence and transmission characteristics of New Delhi metallo β-lactamase (NDM)-producing Escherichia coli from ducks in Guangdong, China. In this study, a total of 28 NDM-producing E. coli isolates were recovered from 88 unduplicated diseased duck samples (31.8%) from veterinary clinics in Guangzhou, Foshan, Qingyuan, and Huizhou. Two variants, blaNDM−1 and blaNDM−5, were detected and the latter was present in 89.6% of the isolates (25/28). Multilocus sequence typing (MLST) analysis indicated that these E. coli isolates possessed six distinct STs, and ST156 was the most prevalent followed by ST648, ST746, ST354, ST10, and ST162. In addition, phylogenomic analysis found that two of the isolates that were recovered from a single sample possessed different genomes, and the blaNDM-carrying IncX3 plasmids may be horizontal transfer between E. coli isolates in the intestinal tracts of ducks. Whole-genome sequencing (WGS) analysis further revealed that blaNDM co-existed with other 25 types of antimicrobial resistance genes (ARGs), of which 16 ARGs were highly prevalent with detection rates >50%, and a high incidence of coproducing blaNDM and mcr-1 E. coli isolates (22/88, 25.0%) was detected in ducks. This study underscores the importance of surveillance for blaNDM-harboring microbes in ducks.
The Efficacy of Phage Therapy in a Murine Model of Pseudomonas aeruginosa Pneumonia and Sepsis
Authors: Yang Xu , Haque Anwarul , Matsuzaki Shigenobu , Matsumoto Tetsuya , Nakamura Shigeki
Published: July 2021

The emergence of multi-drug resistant Pseudomonas aeruginosa necessitates the search for treatment options other than antibiotic use. The use of bacteriophages is currently being considered as an alternative to antibiotics for the treatment of bacterial infections. A number of bacteriophages were introduced to treat pneumonia in past reports. However, there are still lack of knowledge regarding the dosages, application time, mechanism and safety of phage therapy against P. aeruginosa pneumonia. We used the bacteriophage KPP10 against P. aeruginosa strain D4-induced pneumonia mouse models and observed their outcomes in comparison to control models. We found that the nasal inhalation of highly concentrated KPP10 (MOI = 80) significantly improved survival rate in pneumonia models (P < 0.01). The number of viable bacteria in both lungs and in serum were significantly decreased (P < 0.01) in phage-treated mice in comparison to the control mice. Pathological examination showed that phage-treated group had significantly reduced bleeding, inflammatory cell infiltration, and mucus secretion in lung interstitium. We also measured inflammatory cytokine levels in the serum and lung homogenates of mice. In phage-treated models, serum TNFα, IL-1β, and IFN-γ levels were significantly lower (P < 0.05, P < 0.01, and P < 0.05, respectively) than those in the control models. In the lung homogenate, the mean IL-1β level in phage-treated models was significantly lower (P < 0.05) than that of the control group. We confirmed the presence of phage in blood and lungs, and evaluated the safety of bacteriophage use in living models since bacteriophage mediated bacterial lysis arise concern of endotoxic shock. The study results suggest that phage therapy can potentially be used in treating lung infections caused by Pseudomonas aeruginosa.
An Improved Transformation System for Phytophthora cinnamomi Using Green Fluorescent Protein
Authors: Dai Tingting , Xu Yue , Yang Xiao , Jiao Binbin , Qiu Min , Xue Junxin , Arredondo Felipe , Tyler Brett M.
Published: July 2021

Phytophthora cinnamomi is a destructive pathogen causing root rot and dieback diseases on hundreds of economically and ecologically important plant species. Effective transformation systems enable modifications of candidate genes to understand the pathogenesis of P. cinnamomi. A previous study reported a polyethylene glycol and calcium dichloride (PEG/CaCl2)-mediated protoplast transformation method of P. cinnamomi. However, the virulence of the transformants was compromised. In this study, we selected ATCC 15400 as a suitable wild-type isolate for PEG/CaCl2 transformation using the green fluorescent protein after screening 11 P. cinnamomi isolates. Three transformants, namely, PcGFP-1, PcGFP-3, and PcGFP-5, consistently displayed a green fluorescence in their hyphae, chlamydospores, and sporangia. The randomly selected transformant PcGFP-1 was as virulent as the wild-type isolate in causing hypocotyl lesions on lupines. Fluorescent hyphae and haustoria were observed intracellularly and intercellularly in lupine tissues inoculated with PcGFP-1 zoospores. The potential application of this improved transformation system for functional genomics studies of P. cinnamomi is discussed.
Probiotic and Antifungal Attributes of Levilactobacillus brevis MYSN105, Isolated From an Indian Traditional Fermented Food Pozha
Authors: Somashekaraiah Rakesh , Mottawea Walid , Gunduraj Adithi , Joshi Udit , Hammami Riadh , Sreenivasa M. Y.
Published: July 2021

The use of probiotics and antifungal capabilities of the lactic acid bacteria (LAB) isolated from different niches is a strategy to prepare functional cultures and biopreservatives for food/feed industries. In the present study, LAB strains isolated from an Indian traditional fermented food, Pozha, were evaluated for their probiotic properties and biocontrol potential. A total of 20 LAB isolates were selected from Pozha samples collected aseptically and screened for their antagonistic activity against Fusarium verticillioides. Among the bioactive isolates, Lacticaseibacillus brevis MYSN105 showed the highest antifungal activity in vitro, causing some morphological alterations such as damaged mycelia and deformed conidia. Cell-free supernatant (CFS) from L. brevis MYSN105 at 16% concentration effectively reduced the mycelial biomass to 0.369 g compared to 1.938 g in control. Likewise, the conidial germination was inhibited to 20.12%, and the seed treatment using CFS induced a reduction of spore count to 4.1 × 106 spores/ml compared to 1.1 × 109 spores/ml for untreated seeds. The internal transcribed spacer (ITS) copy number of F. verticillioides decreased to 5.73 × 107 and 9.026 × 107 by L. brevis MYSN105 and CFS treatment, respectively, compared to 8.94 × 1010 in control. The L. brevis MYSN105 showed high tolerance to in vitro gastrointestinal conditions and exhibited high adhesive abilities to intestinal epithelial cell lines. The comparative genome analysis demonstrated specific secondary metabolite region coding for bacteriocin and T3PKS (type III polyketide synthase) possibly related to survival and antimicrobial activity in the gut environment. Our results suggest that L. brevis MYSN105 has promising probiotic features and could be potentially used for developing biological control formulations to minimize F. verticillioides contamination and improve food safety measures.
QPX7728, An Ultra-Broad-Spectrum B-Lactamase Inhibitor for Intravenous and Oral Therapy: Overview of Biochemical and Microbiological Characteristics
Authors: Lomovskaya Olga , Tsivkovski Ruslan , Sun Dongxu , Reddy Raja , Totrov Maxim , Hecker Scott , Griffith David , Loutit Jeffery , Dudley Michael
Published: July 2021

QPX7728 is a novel β-lactamase inhibitor (BLI) that belongs to a class of cyclic boronates. The first member of this class, vaborbactam, is a BLI in the recently approved Vabomere (meropenem-vaborbactam). In this paper we provide the overview of the biochemical, structural and microbiological studies that were recently conducted with QPX7728. We show that QPX7728 is an ultra-broad-spectrum β-lactamase inhibitor with the broadest spectrum of inhibition reported to date in a single BLI molecule; in addition to potent inhibition of clinically important serine β-lactamases, including Class A and D carbapenemases from Enterobacterales and notably, diverse Class D carbapenemases from Acinetobacter, it also inhibits many metallo β-lactamases. Importantly, it is minimally affected by general intrinsic resistance mechanisms such as efflux and porin mutations that impede entry of drugs into gram-negative bacteria. QPX7728 combinations with several intravenous (IV) β-lactam antibiotics shows broad coverage of Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa, including strains that are resistant to other IV β-lactam-BLI combinations, e.g., ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and imipenem-relebactam that were recently approved for clinical use. Based on studies with P. aeruginosa, different partner β-lactams in combination with QPX7728 may be optimal for the coverage of susceptible organisms. This provides microbiological justification for a stand-alone BLI product for co-administration with different β-lactams. QPX7728 can also be delivered orally; thus, its ultra-broad β-lactamase inhibition spectrum and other features could be also applied to oral QPX7728-based combination products. Clinical development of QPX7728 has been initiated.
Negative Impact of Citral on Susceptibility of Pseudomonas aeruginosa to Antibiotics
Authors: Tetard Alexandre , Foley Sarah , Mislin Gaëtan L. A. , Brunel Jean-Michel , Oliva Estefania , Torrealba Anzola Freddy , Zedet Andy , Cardey Bruno , Pellequer Yann , Ramseyer Christophe , Plésiat Patrick , Llanes Catherine
Published: July 2021

Essential oils (EOs) or their components are widely used by inhalation or nebulization to fight mild respiratory bacterial infections. However, their interaction with antibiotics is poorly known. In this study we evaluated the effects of citral, the main component of lemongrass oil, on in vitro susceptibility of Pseudomonas aeruginosa to antibiotics. Exposure of strain PA14 to subinhibitory concentrations of citral increased expression of operons encoding the multidrug efflux systems MexEF-OprN and MexXY/OprM, and bacterial resistance to anti-pseudomonal antibiotics including imipenem (twofold), gentamicin (eightfold), tobramycin (eightfold), ciprofloxacin (twofold), and colistin (≥128-fold). Use of pump deletion mutants showed that in addition to efflux other mechanisms were involved in this citral-induced phenotype. Determination of Zeta potential suggested that citral impairs the cell surface binding of aminoglycosides and colistin used at low concentrations (≤10 μg/mL). Moreover, experiments based on Raman spectroscopy and high-resolution mass spectrometry demonstrated formation of a Schiff base between the aldehyde group of citral and amino-groups of tobramycin and colistin. Chemical synthesis of tobracitryl, the imine compound resulting from condensation of citral and tobramycin, confirmed the loss of antibiotic activity due to adduct formation. Altogether these data point to the potential risk concern of self-medication with EOs containing citral in patients suffering from P. aeruginosa chronic lung infections and being treated with aerosols of aminoglycoside or colistin.
A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma
Authors: Song Jiahang , Liu Yanhu , Guan Xiang , Zhang Xun , Yu Wenda , Li Qingguo
Published: July 2021

Esophageal squamous cell carcinoma (ESCC) accounts for the main esophageal cancer (ESCA) type, which is also associated with the greatest malignant grade and low survival rates worldwide. Ferroptosis is recently discovered as a kind of programmed cell death, which is indicated in various reports to be involved in the regulation of tumor biological behaviors. This work focused on the comprehensive evaluation of the association between ferroptosis-related gene (FRG) expression profiles and prognosis in ESCC patients based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). ALOX12, ALOX12B, ANGPTL7, DRD4, MAPK9, SLC38A1, and ZNF419 were selected to develop a novel ferroptosis-related gene signature for GEO and TCGA cohorts. The prognostic risk model exactly classified patients who had diverse survival outcomes. In addition, this study identified the ferroptosis-related signature as a factor to independently predict the risk of ESCC. Thereafter, we also constructed the prognosis nomogram by incorporating clinical factors and risk score, and the calibration plots illustrated good prognostic performance. Moreover, the association of the risk score with immune checkpoints was observed. Collectively, the proposed ferroptosis-related gene signature in our study is effective and has a potential clinical application to predict the prognosis of ESCC.
An Immune-Gene-Based Classifier Predicts Prognosis in Patients With Cervical Squamous Cell Carcinoma
Authors: Yang Huixia , Han Xiaoyan , Hao Zengping
Published: July 2021

Objective: Immunity plays a vital role in the human papilloma virus (HPV) persistent infection, and closely associates with occurrence and development of cervical squamous cell carcinoma (CSCC). Herein, we performed an integrated bioinformatics analysis to establish an immune-gene signature and immune-associated nomogram for predicting prognosis of CSCC patients.

Methods: The list of immunity-associated genes was retrieved from ImmPort database. The gene and clinical information of CSCC patients were obtained from The Cancer Genome Atlas (TCGA) website. The immune gene signature for predicting overall survival (OS) of CSCC patients was constructed using the univariate Cox-regression analysis, random survival forests, and multivariate Cox-regression analysis. This signature was externally validated in GSE44001 cohort from Gene Expression Omnibus (GEO). Then, based on the established signature and the TCGA cohort with the corresponding clinical information, a nomogram was constructed and evaluated via Cox regression analysis, concordance index (C-index), receiver operating characteristic (ROC) curves, calibration plots and decision curve analyses (DCAs).

Results: A 5-immune-gene prognostic signature for CSCC was established. Low expression of ICOS, ISG20 and high expression of ANGPTL4, SBDS, LTBR were risk factors for CSCC prognosis indicating poor OS. Based on this signature, the OS was significantly worse in high-risk group than in low-risk group (p-value < 0.001), the area under curves (AUCs) for 1-, 3-, 5-years OS were, respectively, 0.784, 0.727, and 0.715. A nomogram incorporating the risk score of signature and the clinical stage was constructed. The C-index of this nomogram was 0.76. AUC values were 0.811, 0.717, and 0.712 for 1-, 3-, 5-years OS. The nomogram showed good calibration and gained more net benefits than the 5-immune-gene signature and the clinical stage.

Conclusion: The 5-immune-gene signature may serve as a novel, independent predictor for prognosis in patients with CSCC. The nomogram incorporating the signature risk score and clinical stage improved the predictive performance than the signature and clinical stage alone for predicting 1-year OS.
Toward Software-Equivalent Accuracy on Transformer-Based Deep Neural Networks With Analog Memory Devices
Authors: Spoon Katie , Tsai Hsinyu , Chen An , Rasch Malte J. , Ambrogio Stefano , Mackin Charles , Fasoli Andrea , Friz Alexander M. , Narayanan Pritish , Stanisavljevic Milos , Burr Geoffrey W.
Published: July 2021

Recent advances in deep learning have been driven by ever-increasing model sizes, with networks growing to millions or even billions of parameters. Such enormous models call for fast and energy-efficient hardware accelerators. We study the potential of Analog AI accelerators based on Non-Volatile Memory, in particular Phase Change Memory (PCM), for software-equivalent accurate inference of natural language processing applications. We demonstrate a path to software-equivalent accuracy for the GLUE benchmark on BERT (Bidirectional Encoder Representations from Transformers), by combining noise-aware training to combat inherent PCM drift and noise sources, together with reduced-precision digital attention-block computation down to INT6.
Combination of Rescue Stenting and Antiplatelet Infusion Improved Outcomes for Acute Intracranial Atherosclerosis-Related Large-Vessel Occlusion
Authors: Baek Jang-Hyun , Jung Cheolkyu , Kim Byung Moon , Heo Ji Hoe , Kim Dong Joon , Nam Hyo Suk , Kim Young Dae , Lim Eun Hyun , Kim Jun-Hwee , Kim Jun Yup , Kim Jae Hyoung
Published: July 2021

Background and Purpose: Intracranial atherosclerosis-related large-vessel occlusion caused by in situ thrombo-occlusion (ICAS-LVO) has been regarded an important reason for refractoriness to mechanical thrombectomy (MT). To achieve better outcomes for ICAS-LVO, different endovascular strategies should be explored. We aimed to investigate an optimal endovascular strategy for ICAS-LVO.

Methods: We retrospectively reviewed three prospective registries of acute stroke underwent endovascular treatment. Among them, patients with ICAS-LVO were assigned to four groups based on their endovascular strategy: (1) MT alone, (2) rescue intracranial stenting after MT failure (MT-RS), (3) glycoprotein IIb/IIIa inhibitor infusion after MT failure (MT-GPI), and (4) a combination of MT-RS and MT-GPI (MT-RS+GPI). Baseline characteristics and outcomes were compared among the groups. To evaluate whether the endovascular strategy resulted in favorable outcome, multivariable analysis was also performed.

Results: A total of 184 patients with ICAS-LVO were included. Twenty-four patients (13.0%) were treated with MT alone, 25 (13.6%) with MT-RS, 84 (45.7%) with MT-GPI, and 51 (27.7%) with MT-RS+GPI. The MT-RS+GPI group showed the highest recanalization efficiency (98.0%). Frequency of patent arteries on follow-up (98.0%, p < 0.001) and favorable outcome (84.3%, p < 0.001) were higher in the MT-RS+GPI group than other groups. The MT-RS+GPI strategy remained an independent factor for favorable outcome (odds ratio, 20.4; 95% confidence interval, 1.97–211.4; p = 0.012).

Conclusion: Endovascular strategy was significantly associated with procedural and clinical outcomes in acute stroke by ICAS-LVO. A combination of RS and GPI infusion might be an optimal rescue modality when frontline MT fails.
As Time Goes by: Understanding Child and Family Factors Shaping Behavioral Outcomes After Traumatic Brain Injury
Authors: Ewing-Cobbs Linda , Montroy Janelle J. , Clark Amy E. , Holubkov Richard , Cox Charles S. , Keenan Heather T.
Published: July 2021

Objective: To model pre-injury child and family factors associated with the trajectory of internalizing and externalizing behavior problems across the first 3 years in children with pediatric traumatic brain injury (TBI) relative to children with orthopedic injuries (OI). Parent-reported emotional symptoms and conduct problems were expected to have unique and shared predictors. We hypothesized that TBI, female sex, greater pre-injury executive dysfunction, adjustment problems, lower income, and family dysfunction would be associated with less favorable outcomes.

Methods: In a prospective longitudinal cohort study, we examined the level of behavior problems at 12 months after injury and rate of change from pre-injury to 12 months and from 12 to 36 months in children ages 4–15 years with mild to severe TBI relative to children with OI. A structural equation model framework incorporated injury characteristics, child demographic variables, as well as pre-injury child reserve and family attributes. Internalizing and externalizing behavior problems were indexed using the parent-rated Emotional Symptoms and Conduct Problems scales from the Strengths and Difficulties questionnaire.

Results: The analysis cohort of 534 children [64% boys, M (SD) 8.8 (4.3) years of age] included 395 with mild to severe TBI and 139 with OI. Behavior ratings were higher after TBI than OI but did not differ by TBI severity. TBI, higher pre-injury executive dysfunction, and lower income predicted the level and trajectory of both Emotional Symptoms and Conduct Problems at 12 months. Female sex and poorer family functioning were vulnerability factors associated with greater increase and change in Emotional Symptoms by 12 months after injury; unique predictors of Conduct Problems included younger age and prior emotional/behavioral problems. Across the long-term follow-up from 12 to 36 months, Emotional Symptoms increased significantly and Conduct Problems stabilized. TBI was not a significant predictor of change during the chronic stage of recovery.

Conclusions: After TBI, Emotional Symptoms and Conduct Problem scores were elevated, had different trajectories of change, increased or stayed elevated from 12 to 36 months after TBI, and did not return to pre-injury levels across the 3 year follow-up. These findings highlight the importance of addressing behavioral problems after TBI across an extended time frame.
The Influence of Radio-Frequency Transmit Field Inhomogeneities on the Accuracy of G-ratio Weighted Imaging
Authors: Emmenegger Tim M. , David Gergely , Ashtarayeh Mohammad , Fritz Francisco J. , Ellerbrock Isabel , Helms Gunther , Balteau Evelyne , Freund Patrick , Mohammadi Siawoosh
Published: July 2021

G-ratio weighted imaging is a non-invasive, in-vivo MRI-based technique that aims at estimating an aggregated measure of relative myelination of axons across the entire brain white matter. The MR g-ratio and its constituents (axonal and myelin volume fraction) are more specific to the tissue microstructure than conventional MRI metrics targeting either the myelin or axonal compartment. To calculate the MR g-ratio, an MRI-based myelin-mapping technique is combined with an axon-sensitive MR technique (such as diffusion MRI). Correction for radio-frequency transmit (B1+) field inhomogeneities is crucial for myelin mapping techniques such as magnetization transfer saturation. Here we assessed the effect of B1+ correction on g-ratio weighted imaging. To this end, the B1+ field was measured and the B1+ corrected MR g-ratio was used as the reference in a Bland-Altman analysis. We found a substantial bias (≈-89%) and error (≈37%) relative to the dynamic range of g-ratio values in the white matter if the B1+ correction was not applied. Moreover, we tested the efficiency of a data-driven B1+ correction approach that was applied retrospectively without additional reference measurements. We found that it reduced the bias and error in the MR g-ratio by a factor of three. The data-driven correction is readily available in the open-source hMRI toolbox (www.hmri.info) which is embedded in the statistical parameter mapping (SPM) framework.
Thalamus Radiomics-Based Disease Identification and Prediction of Early Treatment Response for Schizophrenia
Authors: Cui Long-Biao , Zhang Ya-Juan , Lu Hong-Liang , Liu Lin , Zhang Hai-Jun , Fu Yu-Fei , Wu Xu-Sha , Xu Yong-Qiang , Li Xiao-Sa , Qiao Yu-Ting , Qin Wei , Yin Hong , Cao Feng
Published: July 2021

Background

Emerging evidence suggests structural and functional disruptions of the thalamus in schizophrenia, but whether thalamus abnormalities are able to be used for disease identification and prediction of early treatment response in schizophrenia remains to be determined. This study aims at developing and validating a method of disease identification and prediction of treatment response by multi-dimensional thalamic features derived from magnetic resonance imaging in schizophrenia patients using radiomics approaches.

Methods

A total of 390 subjects, including patients with schizophrenia and healthy controls, participated in this study, among which 109 out of 191 patients had clinical characteristics of early outcome (61 responders and 48 non-responders). Thalamus-based radiomics features were extracted and selected. The diagnostic and predictive capacity of multi-dimensional thalamic features was evaluated using radiomics approach.

Results

Using radiomics features, the classifier accurately discriminated patients from healthy controls, with an accuracy of 68%. The features were further confirmed in prediction and random forest of treatment response, with an accuracy of 75%.

Conclusion

Our study demonstrates a radiomics approach by multiple thalamic features to identify schizophrenia and predict early treatment response. Thalamus-based classification could be promising to apply in schizophrenia definition and treatment selection.
Effects of Chronic Pain Treatment on Altered Functional and Metabolic Activities in the Brain: A Systematic Review and Meta-Analysis of Functional Neuroimaging Studies
Authors: Kim Dongwon , Chae Younbyoung , Park Hi-Joon , Lee In-Seon
Published: July 2021

Previous studies have identified altered brain changes in chronic pain patients, however, it remains unclear whether these changes are reversible. We summarized the neural and molecular changes in patients with chronic pain and employed a meta-analysis approach to quantify the changes. We included 75 studies and 11 of these 75 studies were included in the activation likelihood estimation (ALE) analysis. In the 62 functional magnetic resonance imaging (fMRI) studies, the primary somatosensory and motor cortex (SI and MI), thalamus, insula, and anterior cingulate cortex (ACC) showed significantly decreased activity after the treatments compared to baseline. In the 13 positron emission tomography (PET) studies, the SI, MI, thalamus, and insula showed significantly increased glucose uptake, blood flow, and opioid-receptor binding potentials after the treatments compared to baseline. A meta-analysis of fMRI studies in patients with chronic pain, during pain-related tasks, showed a significant deactivation likelihood cluster in the left medial posterior thalamus. Further studies are warranted to understand brain reorganization in patients with chronic pain compared to the normal state, in terms of its relationship with symptom reduction and baseline conditions.