bluuebunny/crossref_metadata_2025 huggingface dataset:
Getting a Grip on the Adhesion Mechanism of Epiphytic Orchids – Evidence From Histology and Cryo-Scanning Electron Microscopy
Authors: Tay Jessica Y. L. , Zotz Gerhard , Gorb Stanislav N. , Einzmann Helena J. R.
Published: November 2021

Plants and animals evolve different attachment structures and strategies for reversible or permanent adhesion to different substrate types. For vascular epiphytes, having the ability to permanently attach to their host plants is essential for establishment and survival. Unlike mistletoe roots, roots of vascular epiphytes do not penetrate the host tissues but instead achieve attachment by growing in close contact to the surface of the substrate. However, the fundamental understanding of the attachment functions of epiphytic roots remains scarce, where majority of studies focused on the general root morphology, their functional properties and the descriptions of associated microbial endophytes. To date, research on attachment strategies in plants is almost entirely limited to climbers. Therefore, this study aims to fill the knowledge gap and elucidate the attachment functions of roots of epiphytic orchids. With the use of histology and high-resolution cryo-scanning electron microscopy (cryo-SEM) technique with freeze fracturing, the intimate root-bark substrate interface of epiphytic orchid Epidendrum nocturnum Jacq was investigated. Results showed a flattened underside of the root upon contact with the substrate surface, and the velamen layer appeared to behave like a soft foam, closely following the contours of the substrate. Root hairs emerged from the outermost velamen layer and entered into the crevices in the substrate, whenever possible. A layer of amorphous substance (glue-like substance) was observed on the surface of the root hairs. Combining the observations from this study and knowledge from previous studies, we hypothesised that epiphytic orchid roots produced a layer of glue-like substance to adhere the root to the substrate. Then root hairs are produced and enter into the voids and crevices of the substrate. This further generates a mechanical interlocking mechanism between root and substrate, thus reinforcing the attachment of the root (and hence the whole plant) to its substrate.
Pathogenesis and Mechanism of Gastrointestinal Infection With COVID-19
Authors: Zhang Hao , Shao Bo , Dang Qin , Chen Zhuang , Zhou Quanbo , Luo Hong , Yuan Weitang , Sun Zhenqiang
Published: November 2021

As a new infectious disease, COVID-19 is spread through the respiratory tract in most cases. Its source and pathological mechanism are not clear. The most common clinical feature is pulmonary infection. Also, a lot patients have gastrointestinal symptoms. Angiotensin-converting enzyme 2 (ACE2) is a functional cellular receptor for SARS-CoV-2, which is like SARS-CoV, a coronavirus associated with severe acute respiratory syndrome (SARS) outbreak in 2003. The tissues and cells expressing ACE2 are potential targets for SARS-CoV-2 infection, and the high expression of ACE2 in intestinal epithelial cells marks that SARS-CoV-2 may directly infect intestinal epithelial cells. Recent studies also suggest that SARS-CoV-2 existed and replicated in intestinal environment for a long time. The interaction between SARS-CoV-2 and RAS system leads to the decrease of local anti-inflammatory ability. The virus cycle leads to excessive imbalance of immune response and cytokine release. The downregulation of ACE2 after viral infection leads to gastrointestinal dysfunction. The above are the causes of gastrointestinal symptoms. Here, we reviewed the possible causes and mechanisms of gastrointestinal symptoms caused by COVID-19. Additionally, we discussed the influence of gastrointestinal symptoms on the prognosis of patients.
Immune Checkpoint Inhibitors With or Without Bone-Targeted Therapy in NSCLC Patients With Bone Metastases and Prognostic Significance of Neutrophil-to-Lymphocyte Ratio
Authors: Bongiovanni Alberto , Foca Flavia , Menis Jessica , Stucci Stefania Luigia , Artioli Fabrizio , Guadalupi Valentina , Forcignanò Maria Rosachiara , Fantini Manuela , Recine Federica , Mercatali Laura , Spadazzi Chiara , Burgio Marco Angelo , Fausti Valentina , Miserocchi Anna , Ibrahim Toni
Published: November 2021

Introduction

Bone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab.

Methods

From 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan–Meier method, with statistical significance of survival differences assessed using the log-rank test.

Results

Median age was 66 (range, 42–84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0–1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8–10.0) and 11.9 (95%CI, 8.2–14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2–not evaluable (NE)] vs. 21.8 months (95%CI, 14.5–not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1–10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS.

Conclusion

BTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.
Age-Related Expression of IFN-λ1 Versus IFN-I and Beta-Defensins in the Nasopharynx of SARS-CoV-2-Infected Individuals
Authors: Gilbert Charly , Lefeuvre Caroline , Preisser Laurence , Pivert Adeline , Soleti Raffaella , Blanchard Simon , Delneste Yves , Ducancelle Alexandra , Couez Dominique , Jeannin Pascale
Published: November 2021

SARS-CoV-2 coronavirus infection induces heterogeneous symptoms, ranging from asymptomatic to lethal forms. Severe forms usually occur in the elderly and/or individuals with comorbidities. Children generally remain asymptomatic to primary infection, suggesting that they may have an effective local innate immune response. IFN-I and -III have non-redundant protective roles against SARS-CoV-2, although sometimes damaging the host. The expression and role of anti-viral peptides during SARS-CoV-2 infection have thus far been little studied. We aimed to identify the innate immune molecules present at the SARS-CoV-2 entry point. We analyzed the mRNA levels of type I (IFN-α and -β) and type III (IFN-λ1-3) interferons and selected antiviral peptides (i.e., β-defensins 1-3, α-defensins [HNP1-3, HD5] pentraxin-3, surfactant protein D, the cathelicidin LL-37 and interleukin-26) in nasopharyngeal swabs from 226 individuals of various ages, either infected with SARS-CoV-2 (symptomatic or asymptomatic) or negative for the virus. We observed that infection induced selective upregulation of IFN-λ1 expression in pediatric subjects (≤15 years), whereas IFN-α, IFN-β, IFN-λ2/λ3, and β-defensin 1-3 expression was unaffected. Conversely, infection triggered upregulation of IFN-α, IFN-β, IFN-λ2/λ3, and β-defensin 1-3 mRNA expression in adults (15-65 years) and the elderly (≥ 65 years), but without modulation of IFN-λ1. The expression of these innate molecules was not associated with gender or symptoms. Expression of the interferon-stimulated genes IFITM1 and IFITM3 was upregulated in SARS-CoV-2-positive subjects and reached similar levels in the three age groups. Finally, age-related differences in nasopharyngeal innate immunity were also observed in SARS-CoV-2-negative subjects. This study shows that the expression patterns of IFN-I/-III and certain anti-viral molecules in the nasopharyngeal mucosa of SARS-CoV-2-infected subjects differ with age and suggests that susceptibility to SARS-CoV-2 may be related to intrinsic differences in the nature of mucosal anti-viral innate immunity.
SARS-CoV-2 Nsp5 Activates NF-κB Pathway by Upregulating SUMOylation of MAVS
Authors: Li Weiling , Qiao Jialu , You Qiang , Zong Shan , Peng Qian , Liu Yuchen , Hu Song , Liu Wei , Li Shufen , Shu Xiji , Sun Binlian
Published: November 2021

The COVID-19 is an infectious disease caused by SARS-CoV-2 infection. A large number of clinical studies found high-level expression of pro-inflammatory cytokines in patients infected with SARS-CoV-2, which fuels the rapid development of the disease. However, the specific molecular mechanism is still unclear. In this study, we found that SARS-CoV-2 Nsp5 can induce the expression of cytokines IL-1β, IL-6, TNF-α, and IL-2 in Calu-3 and THP1 cells. Further research found that Nsp5 enhances cytokine expression through activating the NF-κB signaling pathway. Subsequently, we investigated the upstream effectors of the NF-κB signal pathway on Nsp5 overexpression and discovered that Nsp5 increases the protein level of MAVS. Moreover, Nsp5 can promote the SUMOylation of MAVS to increase its stability and lead to increasing levels of MAVS protein, finally triggering activation of NF-κB signaling. The knockdown of MAVS and the inhibitor of SUMOylation treatment can attenuate Nsp5-mediated NF-κB activation and cytokine induction. We identified a novel role of SARS-CoV-2 Nsp5 to enhance cytokine production by activating the NF-κB signaling pathway.
Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review
Authors: Filippone Edward J. , Newman Eric D. , Li Li , Gulati Rakesh , Farber John L.
Published: November 2021

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.
The Two Sides of the Mediterranean: Population Genomics of the Black Sea Urchin Arbacia lixula (Linnaeus, 1758) in a Warming Sea
Authors: Carreras Carlos , Ordóñez Víctor , García-Cisneros Àlex , Wangensteen Owen S. , Palacín Creu , Pascual Marta , Turon Xavier
Published: November 2021

Global environmental changes may have a profound impact on ecosystems. In this context, it is crucial to gather biological and ecological information of the main species in marine communities to predict and mitigate potential effects of shifts in their distribution, abundance, and interactions. Using genotyping by sequencing (GBS), we assessed the genetic structure of a keystone species in the Mediterranean shallow littoral ecosystems, the black sea urchin Arbacia lixula. This bioengineer species can shape their communities due to its grazing activity and it is experiencing an ongoing expansion with increasing temperatures. The population genomic analyses on 5,241 loci sequenced in 240 individuals from 11 Mediterranean sampled populations revealed that all populations were diverse and showed significant departure from equilibrium. Albeit genetic differentiation was in general shallow, a significant break separated the western and eastern Mediterranean populations, a break not detected in previous studies with less resolutive markers. Notably, no clear effect of the Almería-Oran front, an important break in the Atlanto-Mediterranean transition, could be detected among the western basin populations, where only a slight differentiation of the two northernmost populations was found. Despite the generally low levels of genetic differentiation found, we identified candidate regions for local adaptation by combining different genomic analysis with environmental data. Salinity, rather than temperature, seemed to be an important driver of genetic structure in A. lixula. Overall, from a population genomics standpoint, there is ample scope for A. lixula to continue thriving and adapting in the warming Mediterranean.
Genomic Perspectives on Aeromonas salmonicida subsp. salmonicida Strain 890054 as a Model System for Pathogenicity Studies and Mitigation of Fish Infections
Authors: Gauthier Jeff , Marquis Hélène , Paquet Valérie E. , Charette Steve J. , Levesque Roger C. , Derome Nicolas
Published: November 2021

Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that causes furunculosis, a fish disease claiming substantial economic losses in the aquaculture industry. Major challenges exist in monitoring and controlling fish infections in aquaculture farms. Development of management practices to improve the sustainability of fish farming with disease prevention necessitates studies using well-defined systems and well-characterized bacterial isolates. Even though several A. salmonicida subsp. salmonicida genomes have been completely assembled and thoroughly annotated, in vivo pathogenicity data are lacking. Here we present A. salmonicida subsp. salmonicida 890054 as a prototype strain for standardized furunculosis challenges with survival data. Computational analysis of sequencing results provided a complete circular genome with annotations of plasmids carrying virulence factors, antimicrobial resistance, and secondary metabolite coding genes. The analysis also revealed the presence of an IncU plasmid distinct from other IncU plasmids previously associated with Aeromonas.
The Impact of Reclamation on Tidal Flat Morphological Equilibrium
Authors: Zhong Zehua , Hu Zhan
Published: November 2021

Reclamation is one of the most prominent anthropogenic activities affecting tidal flat morphology and the related ecosystem service. Two representative types of reclamation are upper-flat enclosure and lower-flat enrockment. From a historical perspective, different type of reclamation was adapted in different areas in ancient China. As previous studies on reclamation are often site-specific, the reason that leads to such a difference is unclear. The intertidal dynamic equilibrium theory (DET) provides a comprehensive framework for this quest. Here, we extend the DET with additional effects of reclamation. A model based on DET (DET-ESTMORF) was applied to investigate the impact of reclamation on tidal flats. The model was validated by comparing our results against previous records and observations. Results show that both types of reclamation induce morphological adjustment by enhancing local accretion, which upset the previous equilibrium. Specifically, upper-flat enclosure drives tidal flats into evolution toward wave dominance, whereas lower-flat enrockment causes adjustment toward tidal dominance. Next, the impact of reclamation on tidal flats in different states (prograding or retreating) was investigated. We show that both enclosure and enrockment can induce accretion despite the varying wave climate and sediment supply, with the mean accretion rate raised by 1.8 cm/year and 1.2 cm/year, respectively. However, the resulting profiles are different in shape, especially on retreating flats. Finally, we point out that tidal range and sediment supply are the potential reasons affecting the choice of reclamation types in practices.
Fabrication and Characterization of Ta–GelMA–BG Scaffolds by Chemical Crosslinking Processing for Promotion Osteointegration
Authors: Zhao Fujian , Ji Xiongfa , Yan Yang , Yang Zhen , Chen Xiaofeng , Ma Limin
Published: November 2021

The repair of bone defects in load-bearing positions still faces great challenges. Tantalum (Ta) has attempted to repair bone defects based on the excellent mechanical properties. However, the osseointegration of Ta needs to be improved due to the lack of osteoinduction. Herein, tantalum–gelatin–methacryloyl–bioactive glass (Ta–GelMA–BG) scaffolds were successfully fabricated by loading BG in 3D-printed Ta scaffolds through a chemical crosslinking method. The results showed that the composite scaffolds have the ability to promote cell adhesion and proliferation. The incorporation of BG resulted in a significant increase in apatite-forming and osteogenesis differentiation abilities. In vivo results indicated that the Ta–GelMA–BG scaffolds significantly enhanced the osteointegration at the early stage after implantation. Overall, the Ta–GelMA–BG scaffolds are a promising platform for the load bearing bone regeneration field.
Ellipsoid Zone and External Limiting Membrane-Related Parameters on Spectral Domain-Optical Coherence Tomography and Their Relationships With Visual Prognosis After Successful Macular Hole Surgery
Authors: Yang Jiarui , Xia Huaqin , Liu Yushi , Wang Xinglin , Yuan Hao , Hou Qingyi , Ge Yimeng , Ding Yi , Wang Yuexin , Wang Changguan , Li Xuemin
Published: November 2021

Purpose: To compare structural diameters of the ellipsoid zone (EZ) and external limiting membrane (ELM) bands on spectral domain-optical coherence tomography (SD-OCT) images between vision-improved (group A) and vision-unimproved (group B) patients, and investigate the connection between these parameters and visual prognosis.

Materials and Methods: Forty-five eyes of 43 patients with idiopathic full-thickness macular hole closed after vitrectomy were retrospectively reviewed. Best-corrected visual acuity (BCVA) and SD-OCT were conducted preoperatively and at 1 week, 1 month and 6 months postoperatively. Structural and functional parameters were then measured using ImageJ software.

Results: Among structural and functional parameters, the relative reflectivity of EZ and the ratio of continuous ELM and EZ in group A were significantly higher than in group B from the 1-month postoperative visit. At the 6-month follow-up, the diameter of EZ disruption in group A was significantly smaller than in group B, and the relative reflectivity of ELM/EZ was significantly higher than group B. At 6-months, BCVA was statistically significantly correlated with baseline BCVA, basal diameter (BD), macular hole index (MHI), and diameter of ELM/EZ disruption. Change in BCVA from baseline was found to be significantly correlated with axial length and diameter hole index (DHI).

Conclusions: Postoperative BCVA outcome was significantly correlated with integrity, thickness and reflectivity of the EZ band. Patients with smaller diameter of EZ disruption and higher reflectivity of EZ band tended to have better visual outcomes. Given that the EZ band reflects the recovery of mitochondria in photoreceptors, it is a promising parameter for their functional evaluation.
Circulating Antibodies to Skin Bacteria Detected by Serological Lateral Flow Immunoassays Differentially Correlated With Bacterial Abundance
Authors: Huang Ryan Yuki , Lee Chuen Neng , Moochhala Shabbir
Published: November 2021

The serological lateral flow immunoassay (LFIA) was used to detect circulating antibodies to skin bacteria. Next-generation sequencing analysis of the skin microbiome revealed a high relative abundance of Cutibacterium acnes but low abundance of Staphylococcus aureus and Corynebacterium aurimucosum on human facial samples. Yet, results from both LFIA and antibody titer quantification in 96-well microplates illustrated antibody titers that were not correspondent, and instead negatively correlated, to their respective abundance with human blood containing higher concentrations of antibodies to both S. aureus and C. aurimucosum than C. acnes. Acne vulgaris develops several unique microbial and cellular features, but its correlation with circulating antibodies to bacteria in the pilosebaceous unit remains unknown. Results here revealed that antibodies to C. acnes and S. aureus were approximately 3-fold higher and 1.5-fold lower, respectively, in acne patients than in healthy subjects. Although the results can be further validated by larger sample sizes, the proof-of-concept study demonstrates a newfound discrepancy between the abundance of skin bacteria and amounts of their corresponding antibodies. And in light of acne-correlated amplified titers of specific anticommensal antibodies, we highlight that profiling these antibodies in the pilosebaceous unit by LFIAs may provide a unique signature for monitoring acne vulgaris.
The Regulatory RNA ern0160 Confers a Potential Selective Advantage to Enterococcus faecium for Intestinal Colonization
Authors: Reissier Sophie , Le Neindre Killian , Bordeau Valérie , Dejoies Loren , Le Bot Audrey , Felden Brice , Cattoir Vincent , Revest Matthieu
Published: November 2021

The aim of this study was to evaluate the role of the regulatory small RNA (sRNA) Ern0160 in gastrointestinal tract (GIT) colonization by Enterococcus faecium. For this purpose, four strains of E. faecium were used, Aus0004 (WT), an ern0160-deleted Aus0004 mutant (Δ0160), a trans-complemented Δ0160 strain overexpressing ern0160 (Δ0160_0160), and a strain Δ0160 with an empty pAT29 vector (Δ0160_pAT29). Strains were studied both in vitro and in vivo, alone and in competitive assays. In in vitro experiments, no difference was observed between WT and Δ0160 strains cultured single while Δ0160_0160 strain grew more slowly than Δ0160_pAT29. In competitive assays, the WT strain was predominant compared to the deleted strain Δ0160 at the end of the experiment. Then, in vivo experiments were performed using a GIT colonization mouse model. Several existing models of GIT colonization were compared while a novel one, combining ceftriaxone and amoxicillin, was developed. A GIT colonization was performed with each strain alone, and no significant difference was noticed. By contrast, significant results were obtained with co-colonization experiments. With WT + Δ0160 suspension, a significant advantage for the WT strain was observed from day 5 to the end of the protocol, suggesting the involvement of ern0160 in GIT colonization. With Δ0160_0160 + Δ0160_pAT29 suspension, the strain with the empty vector took the advantage from day 3 to the end of the protocol, suggesting a deleterious effect of ern0160 overexpression. Altogether, these findings demonstrate the potential implication of Ern0160 in GIT colonization of E. faecium. Further investigations are needed for the identification of sRNA target(s) in order to decipher underlying molecular mechanisms.
Ecological Insights Into Community Interactions, Assembly Processes and Function in the Denitrifying Phosphorus Removal Activated Sludge Driven by Phosphorus Sources
Authors: Zheng Lei , Wang Xue , Ding Aizhong , Yuan Dongdan , Tan Qiuyang , Xing Yuzi , Xie En
Published: November 2021

The microbial characteristics in the wastewater treatment plants (WWTPs) strongly affect their optimal performance and functional stability. However, a cognitive gap remains regarding the characteristics of the microbial community driven by phosphorus sources, especially co-occurrence patterns and community assembly based on phylogenetic group. In this study, 59 denitrifying phosphorus removal (DPR) activated sludge samples were cultivated with phosphorus sources. The results suggested that homogeneous selection accounted for the largest proportion that ranged from 35.82 to 64.48%. Deterministic processes dominated in 12 microbial groups (bins):Candidatus_Accumulibacter andPseudomonasin these bins belonged to phosphate-accumulating organisms (PAOs). Network analysis revealed that species interactions were intensive in cyclic nucleoside phosphate-influenced microbiota. Function prediction indicated that cyclic nucleoside phosphates increased the activity of enzymes related to denitrification and phosphorus metabolism and increased the α-diversity of microorganism but decreased the diversity of metabolic function. Based on these results, it was assumed that cyclic nucleoside phosphates, rather than inorganic phosphates, are the most available phosphorus source for majority microorganisms in DPR activated sludge. The study revealed the important role of phosphorus source in the construction and assembly of microbial communities and provided new insights about pollutant removal from WWTPs.
Mobile Electroencephalography for Studying Neural Control of Human Locomotion
Authors: Song Seongmi , Nordin Andrew D.
Published: November 2021

Walking or running in real-world environments requires dynamic multisensory processing within the brain. Studying supraspinal neural pathways during human locomotion provides opportunities to better understand complex neural circuity that may become compromised due to aging, neurological disorder, or disease. Knowledge gained from studies examining human electrical brain dynamics during gait can also lay foundations for developing locomotor neurotechnologies for rehabilitation or human performance. Technical barriers have largely prohibited neuroimaging during gait, but the portability and precise temporal resolution of non-invasive electroencephalography (EEG) have expanded human neuromotor research into increasingly dynamic tasks. In this narrative mini-review, we provide a (1) brief introduction and overview of modern neuroimaging technologies and then identify considerations for (2) mobile EEG hardware, (3) and data processing, (4) including technical challenges and possible solutions. Finally, we summarize (5) knowledge gained from human locomotor control studies that have used mobile EEG, and (6) discuss future directions for real-world neuroimaging research.
Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment
Authors: Ganguli Sourav , Chavali Pavithra L.
Published: November 2021

Intrauterine viral infections during pregnancy by pathogens such as Zika virus, Cytomegalovirus, Rubella and Herpes Simplex virus can lead to prenatal as well as postnatal neurodevelopmental disorders. Although maternal viral infections are common during pregnancy, viruses rarely penetrate the trophoblast. When they do cross, viruses can cause adverse congenital health conditions for the fetus. In this context, maternal inflammatory responses to these neurotropic pathogens play a significant role in negatively affecting neurodevelopment. For instance, intrauterine inflammation poses an increased risk of neurodevelopmental disorders such as microcephaly, schizophrenia, autism spectrum disorder, cerebral palsy and epilepsy. Severe inflammatory responses have been linked to stillbirths, preterm births, abortions and microcephaly. In this review, we discuss the mechanistic basis of how immune system shapes the landscape of the brain and how different neurotropic viral pathogens evoke inflammatory responses. Finally, we list the consequences of neuroinflammation on fetal brain development and discuss directions for future research and intervention strategies.
Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer
Authors: Zheng Xin , Liu Zijian , Mi Mi , Wen Qiuyue , Wu Gang , Zhang Liling
Published: November 2021

Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, disulfiram (DSF) kills tumor cells via regulating multiple signaling pathways and transcription factors. However, its effect on tumor immune microenvironment (TIME) remains unclear. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through bioinformatics analysis, we found that DNMT1 was highly expressed in TNBC tissue and PD-L1 was negatively correlated with IRF7 expression. DSF reduced DNMT1 expression and activity, and hypomethylated IRF7 promoter region resulting in upregulation of IRF7. Furthermore, we found DSF enhanced PD-L1 expression via DNMT1-mediated IRF7 hypomethylation. In in vivo experiments, DSF significantly improved the response to anti-PD-1 antibody (Ab) in 4T1 breast cancer mouse model. Immunohistochemistry staining showed that granzyme B+ and CD8+ T cells in the tumor tissues were significantly increased in the combination group. By analyzing the results of the tumor tissue RNA sequencing, four immune-associated pathways were significantly enriched in the DSF joint anti-PD-1 Ab group. In conclusion, we found that DSF could upregulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate TIME to show much better antitumor efficacy than monotherapy.
Standardized Diagnostic Workup and Patient-Centered Decision Making for Surgery and Neck Dissection Followed by Risk-Factor Adapted Adjuvant Therapy Improve Loco-Regional Control in Local Advanced Oral Squamous Cell Carcinoma
Authors: Wichmann Gunnar , Pavlychenko Mykola , Willner Maria , Halama Dirk , Kuhnt Thomas , Kluge Regine , Gradistanac Tanja , Fest Sandra , Wald Theresa , Lethaus Bernd , Dietz Andreas , Wiegand Susanne , Zebralla Veit
Published: November 2021

Background

Standardized staging procedures and presentation of oral squamous cell carcinoma (OSCC) patients in multidisciplinary tumor boards (MDTB) before treatment and utilization of elective neck dissection (ND) are expected to improve the outcome, especially in local advanced LAOSCC (UICC stages III–IVB). As standardized diagnostics but also increased heterogeneity in treatment applied so far have not been demonstrated to improve outcome in LAOSCC, a retrospective study was initiated.

Methods

As MDTB was introduced into clinical routine in 2007, 316 LAOSCC patients treated during 1991-2017 in our hospital were stratified into cohort 1 treated before (n=104) and cohort 2 since 2007 (n=212). Clinical characteristics, diagnostic procedures and treatment modality of patients were compared using Chi-square tests and outcome analyzed applying Kaplan-Meier plots and log-rank tests as well as Cox proportional hazard regression. Propensity scores (PS) were used to elucidate predictors for impaired distant metastasis-free survival (DMFS) in PS-matched patients.

Results

Most patient characteristics and treatment modalities applied showed insignificant alteration. Surgical treatment included significantly more often resection of the primary tumor plus neck dissection, tracheostomy and percutaneous endoscopic gastrostomy tube use. Cisplatin-based chemo-radiotherapy was the most frequent. Only insignificant improved disease- (DFS), progression- (PFS) and event-free (EFS) as well as tumor-specific (TSS) and overall survival (OS) were found after 2006 as local (LC) and loco-regional control (LRC) were significantly improved but DMFS significantly impaired. Cox regression applied to PS-matched patients elucidated N3, belonging to cohort 2 and cisplatin-based chemo-radiotherapy as independent predictors for shortened DMFS. The along chemo-radiotherapy increased dexamethasone use in cohort 2 correlates with increased DM.

Conclusions

Despite standardized diagnostic procedures, decision-making considering clear indications and improved therapy algorithms leading to improved LC and LRC, shortened DMFS hypothetically linked to increased dexamethasone use had a detrimental effect on TSS and OS.
The Identification of a Tumor Infiltration CD8+ T-Cell Gene Signature That Can Potentially Improve the Prognosis and Prediction of Immunization Responses in Papillary Renal Cell Carcinoma
Authors: Wang Jie , Huang Meiying , Huang Peng , Zhao Jingjie , Tan Junhua , Huang Feifan , Ma Ruiying , Xiao Yu , Deng Gao , Wei Liuzhi , Wei Qiuju , Wang Zechen , He Siyuan , Shen Jiajia , Sooranna Suren , Meng Lingzhang , Song Jian
Published: November 2021

Background

CD8+ T cells, vital effectors pertaining to adaptive immunity, display close relationships to the immunization responses to kill tumor cells. Understanding the effect exerted by tumor infiltration CD8+ T cells in papillary renal cell carcinoma (papRCC) is critical for assessing the prognosis process and responses to immunization therapy in cases with this disease.

Materials and Approaches

The single-cell transcriptome data of papRCC were used for screening CD8+ T-cell-correlated differentially expressed genes to achieve the following investigations. On that basis, a prognosis gene signature associated with tumor infiltration CD8+ T cell was built and verified with The Cancer Genome Atlas data set. Risk scores were determined for papRCC cases and categorized as high- or low-risk groups. The prognosis significance for risk scores was assessed with multiple-variate Cox investigation and Kaplan–Meier survival curves. In addition, the possible capability exhibited by the genetic profiles of cases to assess the response to immunization therapy was further explored.

Results

Six hundred twenty-one cell death-inhibiting RNA genes were screened using single-cell RNA sequencing. A gene signature consisting of seven genes (LYAR, YBX1, PNRC1, TCF25, MYL12B, MINOS1, and LINC01420) was then identified, and this collective was considered to be an independent prognosis indicator that could strongly assess overall survival in papRCC. In addition, the data allowed papRCC cases to fall to cohorts at high and low risks, exhibiting a wide range of clinically related features as well as different CD8+ T-cell immunization infiltration and immunization therapy responses.

Conclusions

Our work provides a possible explanation for the limited response of current immunization checkpoint-inhibiting elements for combating papRCC. Furthermore, the researchers built a novel genetic signature that was able to assess the prognosis and immunotherapeutic response of cases. This may also be considered as a promising therapeutic target for the disease.
EMS1/DLL4-Notch Signaling Axis Augments Cell Cycle-Mediated Tumorigenesis and Progress in Human Adrenocortical Carcinoma
Authors: Huang Yu-Gang , Wang Ya , Zhu Rui-Juan , Tang Kai , Tang Xian-Bin , Su Xiao-Min
Published: November 2021

Adrenocortical carcinoma (ACC) is a rare malignant neoplasm that is prone to local invasion and metastasis. Meanwhile, overexpressed endothelial cell-specific molecule 1 (ESM1) is closely related to tumorigenesis of multitudinous tumors. However, the prognosis value and biological function of ESM1 in ACC remains undefined. In the current essay, the assessment in human ACC samples and multiple public cancer databases suggested that ESM1 was significantly overexpressed in ACC patients. The abnormal expression of ESM1 was evidently correlated with dismal overall survival (OS) in ACC patients. Then, the gene-set enrichment analysis (GSEA) was applied to unravel that ESM1 was mostly involved in cell cycle and Notch4 signaling pathway. Furthermore, in vitro experiment, RNA interference of ESM1 was carried out to state that ESM1 augments CDK1 and p21-mediated G2/M-phase transition of mitosis, cell proliferation via DLL4-Notch signaling pathway in human ACC cell line, SW13 cells. Additionally, two possible or available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. Immune infiltration analysis highlighted that no significant difference was found in ACC patients between EMS1high and EMS1low group for immune checkpoint-related genes. In addition, the overexpression of ESM1 might trigger the accumulation of tumor mutation burden (TMB) during the cell cycle of DNA replication in ACC. The gene-drug interaction network then indicated that ESM1 inhibitors, such as cisplatin, might serve as potential drugs for the therapy of ACC. Collectively, the results asserted that ESM1 and related regulators might act as underlying prognostic biomarkers or novel therapeutic targets for ACC.
Risk Factors for Severe Hand-Foot-Mouth Disease in China: A Systematic Review and Meta-Analysis
Authors: Li Peiqing , Huang Yuge , Zhu Danping , Yang Sida , Hu Dandan
Published: November 2021

Background: This study aimed to identify potential risk factors for severe hand-foot-mouth disease (HFMD).

Methods: The PubMed, Embase, the Cochrane Library, Sinomed, WanFang, CNKI, and VIP databases were searched (up to August 2021).

Results: Twenty-nine studies (9,241 and 927,355 patients with severe HFMD and controls, respectively; all from China) were included. EV71 was associated with higher odds of severe HFMD compared with other agents (OR = 4.44, 95%CI: 3.12–6.33, p < 0.001). Being home-raised (OR = 1.99, 95%CI: 1.59–2.50, p < 0.001), higher number of children in the family (OR = 2.09, 95%CI: 1.93–2.27, p < 0.001), poor hand hygiene (OR = 2.74, 95%CI: 1.78–4.23, p < 0.001), and no breastfeeding (OR = 2.01, 95%CI: 1.45–2.79, p < 0.001) were risk factors for severe HFMD. First consulting to a district-level or above hospital (OR = 0.34, 95%CI: 0.25–0.45, p < 0.001) and diagnosis of HFMD at baseline (OR = 0.17, 95%CI: 0.13–0.24, p < 0.001) were protective factors against severe HFMD. Fever, long fever duration, vomiting, lethargy, leukocytosis, tic, and convulsions were each associated with severe HFMD (all p < 0.05), while rash was not.

Conclusions: EV71, lifestyle habits, frequent hospital visits, and symptoms are risk factors for severe HFMD in children in China, while early diagnosis and admission to higher-level hospitals are protective factors.
Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression
Authors: Eren-Koçak Emine , Dalkara Turgay
Published: November 2021

Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed.
Phospholipases and Reactive Oxygen Species Derived Lipid Biomarkers in Healthy and Diseased Humans and Animals – A Focus on Lysophosphatidylcholine
Authors: Engel Kathrin M. , Schiller Jürgen , Galuska Christina E. , Fuchs Beate
Published: November 2021

Phospholipids (PL) are converted into lipid biomarkers by the action of phospholipases and reactive oxygen species (ROS), which are activated or released under certain physiological and pathophysiological conditions. Therefore, the in vivo concentration of such lipid biomarkers [e.g., lysophospholipids (LPLs)] is altered in humans and animals under different conditions such as inflammation, stress, medication, and nutrition. LPLs are particularly interesting because they are known to possess pro- and anti-inflammatory properties and may be generated by two different pathways: either by the influence of phospholipase A2 or by different reactive oxygen species that are generated in significant amounts under inflammatory conditions. Both lead to the cleavage of unsaturated acyl residues. This review provides a short summary of the mechanisms by which lipid biomarkers are generated under in vitro and in vivo conditions. The focus will be on lysophosphatidylcholine (LPC) because usually, this is the LPL species which occurs in the highest concentration and is, thus, easily detectable by chromatographic and spectroscopic methods. Finally, the effects of lipid biomarkers as signaling molecules and their roles in different human and animal pathologies such as infertility, cancer, atherosclerosis, and aging will be shortly discussed.
Physiological and Transcriptomic Analyses Revealed the Implications of Abscisic Acid in Mediating the Rate-Limiting Step for Photosynthetic Carbon Dioxide Utilisation in Response to Vapour Pressure Deficit in Solanum Lycopersicum (Tomato)
Authors: Zhang Dalong , Du Qingjie , Sun Po , Lou Jie , Li Xiaotian , Li Qingming , Wei Min
Published: November 2021

The atmospheric vapour pressure deficit (VPD) has been demonstrated to be a significant environmental factor inducing plant water stress and affecting plant photosynthetic productivity. Despite this, the rate-limiting step for photosynthesis under varying VPD is still unclear. In the present study, tomato plants were cultivated under two contrasting VPD levels: high VPD (3–5 kPa) and low VPD (0.5–1.5 kPa). The effect of long-term acclimation on the short-term rapid VPD response was examined across VPD ranging from 0.5 to 4.5 kPa. Quantitative photosynthetic limitation analysis across the VPD range was performed by combining gas exchange and chlorophyll fluorescence. The potential role of abscisic acid (ABA) in mediating photosynthetic carbon dioxide (CO2) uptake across a series of VPD was evaluated by physiological and transcriptomic analyses. The rate-limiting step for photosynthetic CO2 utilisation varied with VPD elevation in tomato plants. Under low VPD conditions, stomatal and mesophyll conductance was sufficiently high for CO2 transport. With VPD elevation, plant water stress was gradually pronounced and triggered rapid ABA biosynthesis. The contribution of stomatal and mesophyll limitation to photosynthesis gradually increased with an increase in the VPD. Consequently, the low CO2 availability inside chloroplasts substantially constrained photosynthesis under high VPD conditions. The foliar ABA content was negatively correlated with stomatal and mesophyll conductance for CO2 diffusion. Transcriptomic and physiological analyses revealed that ABA was potentially involved in mediating water transport and photosynthetic CO2 uptake in response to VPD variation. The present study provided new insights into the underlying mechanism of photosynthetic depression under high VPD stress.
Understanding Continuance Usage of Mobile Learning Applications: The Moderating Role of Habit
Authors: Wang Yi-Ting , Lin Kuan-Yu
Published: November 2021

This study explored the factors that affect the intention of users to continue using mobile learning (m-learning) applications (apps). The influence of habit on user behavior toward information systems has been extensively discussed in the literature, but its role in the continuance of users when it comes to their usage of apps, especially m-learning apps, has rarely been reported. To obtain a comprehensive understanding of behaviors regarding the use of m-learning apps, this study constructed a theoretical research framework based on expectation confirmation theory and flow theory by considering habit as a moderating variable. Online questionnaires were administered to users of m-learning apps in Taiwan and data were analyzed through a structural equation modeling approach. The results indicated that the intention of users to continue using m-learning apps was influenced by satisfaction, perceived usefulness, and flow experience. Expectation confirmation affected user satisfaction and perceived usefulness. Differences existed in the intention to continue usage between users with strong and weak habits. In addition, perceived usefulness, expectation confirmation, and flow experience had direct and positive effects on satisfaction. The implications of these findings were discussed.
Exploring the Relationship Between Corporate Social Responsibility, Trust, Corporate Reputation, and Brand Equity
Authors: Zhao Yan , Abbas Manzir , Samma Madeeha , Ozkut Tarik , Munir Mubbasher , Rasool Samma Faiz
Published: November 2021

The purpose of this study is to investigate the relationship between corporate social responsibility (CSR), corporate reputation (CR), and brand equity (BE). Building on the resource-based theory of the firm, this study proposes a theoretical framework. In this framework, CSR is theorized to strengthen CR and brand equity, directly and indirectly, through consumer trust. We used a questionnaire survey approach. In the questionnaire, 17 items were used with a 5-point Likert-Scale (1 stands for “strongly disagree,” and 5 stands for “strongly agree”). Data were collected from the consumers of the banking sector in the vicinity of Lahore, Pakistan. To estimate the proposed relationships in the conceptual model, we use structural equation modeling (SEM) through Smart PLS 3.2. The outcomes of this study confirm that CSR significantly impacts CR and brand equity. It is also demonstrated that trust mediates positively and significantly in the relationship between CSR, CR, and BE. Results of the present study have several implications for the senior management, marketing expert, administrators, and policymakers. This study expresses how CSR boosts BE and CR. Moreover, this study also indicates that trust is an important factor that enhances BE and CR.
Altered Temporal Structure of Neural Phase Synchrony in Patients With Autism Spectrum Disorder
Authors: Jia Huibin , Gao Fei , Yu Dongchuan
Published: November 2021

Functional connectivity, quantified by phase synchrony, between brain regions is known to be aberrant in patients with autism spectrum disorder (ASD). Here, we evaluated the long-range temporal correlations of time-varying phase synchrony (TV-PS) of electrocortical oscillations in patients with ASD as well as typically developing people using detrended fluctuation analysis (DFA) after validating the scale-invariance of the TV-PS time series. By comparing the DFA exponents between the two groups, we found that those of the TV-PS time series of high-gamma oscillations were significantly attenuated in patients with ASD. Furthermore, the regions involved in aberrant TV-PS time series were mainly within the social ability and cognition-related cortical networks. These results support the notion that abnormal social functions observed in patients with ASD may be caused by the highly volatile phase synchrony states of electrocortical oscillations.