bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-protein spatial signatures in ductal carcinoma in situ (DCIS) of breast
Authors: Badve Sunil S. , Cho Sanghee , Gökmen-Polar Yesim , Sui Yunxia , Chadwick Chrystal , McDonough Elizabeth , Sood Anup , Taylor Marian , Zavodszky Maria , Tan Puay Hoon , Gerdes Michael , Harris Adrian L. , Ginty Fiona
Published: January 2021

Background

There is limited knowledge about DCIS cellular composition and relationship with breast cancer events (BCE).

Methods

Immunofluorescence multiplexing (MxIF) was used to image and quantify 32 cellular biomarkers in FFPE DCIS tissue microarrays. Over 75,000 DCIS cells from 51 patients (median 9 years follow-up for non-BCE cases) were analysed for profiles predictive of BCE. K-means clustering was used to evaluate cellular co-expression of epithelial markers with ER and HER2.

Results

Only ER, PR and HER2 significantly correlated with BCE. Cluster analysis identified 6 distinct cell groups with different levels of ER, Her2, cMET and SLC7A5. Clusters 1 and 3 were not significant. Clusters 2 and 4 (high ER/low HER2 and SLC7A5/mixed cMET) significantly correlated with low BCE risk (P = 0.001 and P = 0.034), while cluster 6 (high HER2/low ER, cMET and SLC7A5) correlated with increased risk (P = 0.018). Cluster 5 (similar to cluster 6, except high SLC7A5) trended towards significance (P = 0.072). A continuous expression score (Escore) based on these 4 clusters predicted likelihood of BCE (AUC = 0.79, log-rank test P = 5E–05; LOOCV AUC = 0.74, log-rank test P = 0.006).

Conclusion

Multiplexed spatial analysis of limited tissue is a novel method for biomarker analysis and predicting BCEs. Further validation of Escore is needed in a larger cohort.
TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways
Authors: Zhou Yan , Tao Tao , Liu Guangjie , Gao Xuan , Gao Yongyue , Zhuang Zong , Lu Yue , Wang Han , Li Wei , Wu Lingyun , Zhang Dingding , Hang Chunhua
Published: January 2021

Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.
CXCR4 uses STAT3-mediated slug expression to maintain radioresistance of non-small cell lung cancer cells: emerges as a potential prognostic biomarker for lung cancer
Authors: Kim Jeong-Yub , Kim Hee-Jin , Jung Chan-Woong , Lee Tae Sup , Kim Eun Ho , Park Myung-Jin
Published: January 2021

Lung cancer is one of the most common reasons for cancer-induced mortality across the globe, despite major advancements in the treatment strategies including radiotherapy and chemotherapy. Existing reports suggest that CXCR4 is frequently expressed by malignant tumor and is imperative for vascularization, tumor growth, cell migration, and metastasis pertaining to poor prognosis. In this study, we infer that CXCR4 confers resistance to ionizing radiation (IR) in nonsmall cell lung cancer (NSCLC) cells. Further, on the basis of colony forming ability, one finds that drug-resistant A549/GR cells with improved CXCR4 expression exhibited more resistance to IR than A549 cells evidenced along with a reduction in the formation of γ-H2AX foci after IR. Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR. Conversely, the overexpression of CXCR4 in A549 and H460 cell lines was found to improve clonogenic survival, and reduce the formation of γ-H2AX foci after IR. CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.
ACOX2 is a prognostic marker and impedes the progression of hepatocellular carcinoma via PPARα pathway
Authors: Zhang Qifan , Zhang Yunbin , Sun Shibo , Wang Kai , Qian Jianping , Cui Zhonglin , Tao Tao , Zhou Jie
Published: January 2021

Hepatocellular carcinoma (HCC) has been extensively studied as one of the most aggressive tumors worldwide. However, its mortality rate remains high due to ideal diagnosis and treatment strategies. Uncovering novel genes with prognostic significance would shed light on improving the HCC patient’s outcome. In our study, we applied data-independent acquisition (DIA) quantitative proteomics to investigate the expression landscape of 24 paired HCC patients. A total of 1029 differentially expressed proteins (DEPs) were screened. Then, we compared DEPs in our cohort with the differentially expressed genes (DEGs) in The Cancer Genome Atlas, and investigated their prognostic significance, and found 183 prognosis-related genes (PRGs). By conducting protein–protein interaction topological analysis, we identified four subnetworks with prognostic significance. Acyl-CoA oxidase 2 (ACOX2) is a novel gene in subnetwork1, encodes a peroxisomal enzyme, and its function in HCC was investigated in vivo and in vitro. The lower expression of ACOX2 was validated by real-time quantitative PCR, immunohistochemistry, and Western blot. Cell Counting Kit-8 assay, wound healing, and transwell migration assay were applied to evaluate the impact of ACOX2 overexpression on the proliferation and migration abilities in two liver cancer cell lines. ACOX2 overexpression, using a subcutaneous xenograft tumor model, indicated a tumor suppressor role in HCC. To uncover the underlying mechanism, gene set enrichment analysis was conducted, and peroxisome proliferator-activated receptor-α (PPARα) was proposed to be a potential target. In conclusion, we demonstrated a PRG ACOX2, and its overexpression reduced the proliferation and metastasis of liver cancer in vitro and in vivo through PPARα pathway.
TRIB2 modulates proteasome function to reduce ubiquitin stability and protect liver cancer cells against oxidative stress
Authors: Guo Susu , Chen Yuxin , Yang Yueyue , Zhang Xiao , Ma Lifang , Xue Xiangfei , Qiao Yongxia , Wang Jiayi
Published: January 2021

The regulation of homeostasis in the Ubiquitin (Ub) proteasome system (UPS) is likely to be important for the development of liver cancer. Tribbles homolog 2 (TRIB2) is known to affect Ub E3 ligases (E3s) in liver cancer. However, whether TRIB2 regulates the UPS in other ways and the relevant mechanisms are still unknown. Here, we reveal that TRIB2 decreased Ub levels largely by stimulating proteasome degradation of Ub. In the proteasome, proteasome 20S subunit beta 5 (PSMB5) was critical for the function of TRIB2, although it did not directly interact with TRIB2. However, poly (rC) binding protein 2 (PCBP2), which was identified by mass spectrometry, directly interacted with both TRIB2 and PSMB5. PCBP2 was a prerequisite for the TRIB2 induction of PSMB5 activity and decreased Ub levels. A significant correlation between TRIB2 and PCBP2 was revealed in liver cancer specimens. Interestingly, TRIB2 suppressed the K48-ubiquitination of PCBP2 to increase its level. Therefore, a model showing that TRIB2 cooperates and stimulates PCBP2 to reduce Ub levels was established. Additionally, the reduction in Ub levels induced by TRIB2 and PCBP2 was dependent on K48-ubiquitination. PCBP2 was one of the possible downstream factors of TRIB2 and their interaction relied on the DQLVPD element of TRIB2 and the KH3 domain of PCBP2. This interaction was necessary to maintain the viability of the liver cancer cells and promote tumor growth. Mechanistically, glutathione peroxidase 4 functioned as one of the terminal effectors of TRIB2 and PCBP2 to protect liver cancer cells from oxidative damage. Taken together, the data indicate that, in addition to affecting E3s, TRIB2 plays a critical role in regulating UPS by modulating PSMB5 activity in proteasome to reduce Ub flux, and that targeting TRIB2 might be helpful in liver cancer treatments by enhancing the oxidative damage induced by therapeutic agents.
MEX3A contributes to development and progression of glioma through regulating cell proliferation and cell migration and targeting CCL2
Authors: Yang Chao , Zhan Haoqiang , Zhao Yiqing , Wu Yasong , Li Lisha , Wang Heping
Published: January 2021

Glioma is one of the most commonly diagnosed intracranial malignant tumors with extremely high morbidity and mortality, whose treatment was seriously limited because of the unclear molecular mechanism. In this study, in order to identify a novel therapeutic target for glioma treatment, we explored the functions and mechanism of MEX3A in regulating glioma. The immunohistochemical staining of MEX3A in glioma and normal tissues revealed the upregulation of MEX3A and further indicated the relationship between high MEX3A expression and higher malignancy as well as poorer prognosis of glioma. In vitro loss-of-function and gain-of-function experiments comprehensively demonstrated that MEX3A may promote glioma development through regulating cell proliferation, cell apoptosis, cell cycle, and cell migration. In vivo experiments also suggested the inhibition of glioma growth by MEX3A knockdown. Moreover, our mechanistic study identifies CCL2 as a potential downstream target of MEX3A, which possesses similar regulatory effects on glioma development with MEX3A and could attenuate the promotion of glioma induced by MEX3A overexpression. Overall, MEX3A was identified as a potential tumor promoter in glioma development and therapeutic target in glioma treatment.
LncRNA DANCR represses Doxorubicin-induced apoptosis through stabilizing MALAT1 expression in colorectal cancer cells
Authors: Xiong Minmin , Wu Mengshi , Dan Peng  , Huang Weijun , Chen Zehong , Ke Haoxian , Chen Zewen , Song Wu , Zhao Yonghua , Xiang Andy P. , Zhong Xiaomin
Published: January 2021

Long non-coding RNA (lncRNA) DANCR has been reported to participate in key processes such as stem cell differentiation and tumorigenesis. In a high throughput screening for lncRNAs involved in Doxorubicin-induced apoptosis, we found DANCR was suppressed by Doxorubicin and it acted as an important repressor of apoptosis in colorectal cancer. Further studies demonstrated that DANCR promoted the oncogenic lncRNA MALAT1 expression via enhancing the RNA stability of MALAT1 to suppress apoptosis. MALAT1 could efficiently mediate the suppressive function of DANCR on apoptosis. Mechanistic studies found the RNA-binding protein QK served as an interacting partner of both DANCR and MALAT1, and the protein level of QK was subjected to the regulation by DANCR. Furthermore, QK was able to modulate the RNA stability of MALAT1, and the interaction between QK and MALAT1 was controlled by DANCR. In addition, QK could mediate the function of DANCR in regulating the expression of MALAT1 and suppressing apoptosis. These results revealed DANCR played a critical role in Doxorubicin-induced apoptosis in colorectal cancer cells, which was achieved by the interaction between DANCR and QK to enhance the expression of MALAT1.
HOXA5 counteracts the function of pathological scar-derived fibroblasts by partially activating p53 signaling
Authors: Liang Yimin , Zhou Renpeng , Fu Xiujun , Wang Chen , Wang Danru
Published: January 2021

The inactivation of p53 can lead to the formation of pathological scars, including hypertrophic scars and keloids. HOXA5 has been reported to be a critical transcription factor in the p53 pathway in cancers. However, whether HOXA5 also plays a role in pathological scar progression through activating p53 signaling remains unknown. In this study, we first demonstrated that HOXA5 overexpression in hypertrophic scar-or keloids-derived fibroblasts decreased cell proliferation, migration and collagen synthesis, whereas increased cell apoptosis. Furthermore, the results of luciferase activity assays and ChIP PCR assays indicated that HOXA5 transactivated p53 by binding to the ATTA-rich core motif in the p53 promoter. HOXA5 also increased the levels of p21 and Mdm2, which are downstream targets of p53. Interestingly, silencing p53 in these pathological scar-derived fibroblasts partially attenuated HOXA5-mediated growth inhibition effect and HOXA5-induced apoptosis. In addition, 9-cis-retinoic acid augmented the expression of HOXA5 and promoted the effects of HOXA5 on pathological scar-derived fibroblasts, and these effects could be suppressed by HOXA5 knockdown. Thus, our study reveals a role of HOXA5 in mediating the cellular processes of pathological scar-derived fibroblasts by transcriptionally activating the p53 signaling pathway, and 9-cis-retinoic acid may be a potential therapy for pathological scars.
Interplay between p53 and non-coding RNAs in the regulation of EMT in breast cancer
Authors: Parfenyev Sergey , Singh Aastha , Fedorova Olga , Daks Alexandra , Kulshreshtha Ritu , Barlev Niсkolai A.
Published: January 2021

The epithelial–mesenchymal transition (EMT) plays a pivotal role in the differentiation of vertebrates and is critically important in tumorigenesis. Using this evolutionarily conserved mechanism, cancer cells become drug-resistant and acquire the ability to escape the cytotoxic effect of anti-cancer drugs. In addition, these cells gain invasive features and increased mobility thereby promoting metastases. In this respect, the process of EMT is critical for dissemination of solid tumors including breast cancer. It has been shown that miRNAs are instrumental for the regulation of EMT, where they play both positive and negative roles often as a part of a feed-back loop. Recent studies have highlighted a novel association of p53 and EMT where the mutation status of p53 is critically important for the outcome of this process. Interestingly, p53 has been shown to mediate its effects via the miRNA-dependent mechanism that targets master-regulators of EMT, such as Zeb1/2, Snail, Slug, and Twist1. This regulation often involves interactions of miRNAs with lncRNAs. In this review, we present a detailed overview of miRNA/lncRNA-dependent mechanisms that control interplay between p53 and master-regulators of EMT and their importance for breast cancer.
Autophagy impairment as a key feature for acetaminophen-induced ototoxicity
Authors: Zhao Tong , Zheng Tihua , Yu Huining , Hu Bo Hua , Hu Bing , Ma Peng , Yang Ying , Yang Naidi , Hu Juan , Cao Tongtao , Chen Gang , Yan Bin , Peshoff Melina , Hatzoglou Maria , Geng Ruishuang , Li Bo , Zheng Qing Yin
Published: January 2021

Macroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.
Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms
Authors: Noguchi Takuya , Sekiguchi Yuto , Kudoh Yuki , Naganuma Rio , Kagi Tomohiro , Nishidate Akiko , Maeda Kazuhiro , Ishii Chizuru , Toyama Takashi , Hirata Yusuke , Hwang Gi-Wook , Matsuzawa Atsushi
Published: January 2021

Anticancer drug gefitinib causes inflammation-based side effects, such as interstitial pneumonitis. However, its mechanisms remain unknown. Here, we provide evidence that gefitinib elicits pro-inflammatory responses by promoting mature-interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release. Mitochondrial reactive oxygen species (mtROS) driven by gefitinib stimulated the formation of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, leading to mature-IL-1β release. Notably, gefitinib also stimulated HMGB1 release, which is, however, not mediated by the NLRP3 inflammasome. On the other hand, gefitinib-driven mtROS promoted the accumulation of γH2AX, a hallmark of DNA damage, leading to the activation of poly (ADP-ribose) polymerase-1 (PARP-1) and subsequent active release of HMGB1. Together our results reveal the potential ability of gefitinib to initiate sterile inflammation via two distinct mechanisms, and identified IL-1β and HMGB1 as key determinants of gefitinib-induced inflammation that may provide insights into gefitinib-induced interstitial pneumonitis.
MIEF2 reprograms lipid metabolism to drive progression of ovarian cancer through ROS/AKT/mTOR signaling pathway
Authors: Zhao Shuhua , Cheng Lu , Shi Yuan , Li Jia , Yun Qinghui , Yang Hong
Published: January 2021

MIEF2 (mitochondrial elongation factor 2) is one of the key regulators of mitochondrial fission. Bioinformatics analysis indicated that high expression of MIEF2 predicted a poor prognosis in ovarian cancer patients. However, the relationship between MIEF2 and aberrant lipid metabolism in OC remains elusive. In this study, we demonstrated that MIEF2 significantly promoted lipid synthesis, while has no significant effect on fatty acid uptake and oxidation in OC cells. MIEF2 enhanced de novo fatty acid synthesis through up-regulating the expression of sterol regulatory element binding protein 1 (SREBP1) and its transcriptional target lipogenic genes ACC1, FASN and SCD1. Meanwhile, MIEF2-promoted cholesterol biosynthesis through up-regulating the expression of sterol regulatory element binding protein 2 (SREBP2) and its transcriptional target cholesterol biosynthesis genes HMGCS1 and HMGCR. Mechanistically, increased mitochondrial reactive oxygen species (ROS) production and subsequently activation of AKT/mTOR signaling pathway was found to be involved in the up-regulation of SREBP1 and SREBP2 in OC cells. Moreover, cell growth and metastasis assays indicated that MIEF2-regulated fatty acid synthesis and cholesterol biosynthesis played a critical role in the progression of OC. Taken together, our findings indicate that MIEF2 is a critical regulator of lipid synthesis in OC, which provides a strong line of evidence for this molecule to serve as a drug target in the treatment of this malignancy.
TRIM21-regulated Annexin A2 plasma membrane trafficking facilitates osteosarcoma cell differentiation through the TFEB-mediated autophagy
Authors: Zhang Huan-Tian , Zeng Qingzhong , Wu Baomeng , Lu Junlei , Tong Kui-Leung , Lin Jiebin , Liu Qiu-Yu , Xu Lipei , Yang Jie , Liu Xiaohui , Liu Wanting , Zhang Yun-Fang , Lian Qionghua , Liu Langxia , Gao Xuejuan
Published: January 2021

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, which is characterized by dysfunctional autophagy and poor differentiation. Our recent studies have suggested that the tripartite motif containing-21 (TRIM21) plays a crucial role in regulating OS cell senescence and proliferation via interactions with several proteins. Yet, its implication in autophagy and differentiation in OS is largely unknown. In the present study, we first showed that TRIM21 could promote OS cell autophagy, as determined by the accumulation of LC3-II, and the degradation of cargo receptor p62. Further, we were able to identify that Annexin A2 (ANXA2), as a novel interacting partner of TRIM21, was critical for TIRM21-induced OS cell autophagy. Although TRIM21 had a negligible effect on the mRNA and protein expressions of ANXA2, we did find that TRIM21 facilitated the translocation of ANXA2 toward plasma membrane (PM) in OS cells through a manner relying on TRIM21-mediated cell autophagy. This functional link has been confirmed by observing a nice co-expression of TRIM21 and ANXA2 (at the PM) in the OS tissues. Mechanistically, we demonstrated that TRIM21, via facilitating the ANXA2 trafficking at the PM, enabled to release the transcription factor EB (TFEB, a master regulator of autophagy) from the ANXA2-TFEB complex, which in turn entered into the nucleus for the regulation of OS cell autophagy. In accord with previous findings that autophagy plays a critical role in the control of differentiation, we also demonstrated that autophagy inhibited OS cell differentiation, and that the TRIM21/ANXA2/TFEB axis is implicated in OS cell differentiation through the coordination with autophagy. Taken together, our results suggest that the TRIM21/ANXA2/TFEB axis is involved in OS cell autophagy and subsequent differentiation, indicating that targeting this signaling axis might lead to a new clue for OS treatment.
NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis
Authors: Sever Dror , Hershko-Moshe Anat , Srivastava Rohit , Eldor Roy , Hibsher Daniel , Keren-Shaul Hadas , Amit Ido , Bertuzzi Federico , Krogvold Lars , Dahl-Jørgensen Knut , Ben-Dov Iddo Z. , Landsman Limor , Melloul Danielle
Published: January 2021

NF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet β-cell development. Interestingly, inhibiting the NF-κB pathway in β-cells during embryogenesis, but not after birth, in both ToIβ and NOD/ToIβ mice, increased β-cell turnover, ultimately resulting in a reduced β-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal β-cells, significant activation was not detected in β-cells of either adult NOD/ToIβ mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIβ mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or β-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of β-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating β-cell mass and the development of diabetes in the mouse model of T1D.
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance
Authors: Ting Darren Shu Jeng , Ho Charlotte Shan , Deshmukh Rashmi , Said Dalia G. , Dua Harminder S.
Published: January 2021

Corneal opacity is the 5th leading cause of blindness and visual impairment globally, affecting ~6 million of the world population. In addition, it is responsible for 1.5–2.0 million new cases of monocular blindness per year, highlighting an ongoing uncurbed burden on human health. Among all aetiologies such as infection, trauma, inflammation, degeneration and nutritional deficiency, infectious keratitis (IK) represents the leading cause of corneal blindness in both developed and developing countries, with an estimated incidence ranging from 2.5 to 799 per 100,000 population-year. IK can be caused by a wide range of microorganisms, including bacteria, fungi, virus, parasites and polymicrobial infection. Subject to the geographical and temporal variations, bacteria and fungi have been shown to be the most common causative microorganisms for corneal infection. Although viral andAcanthamoebakeratitis are less common, they represent important causes for corneal blindness in the developed countries. Contact lens wear, trauma, ocular surface diseases, lid diseases, and post-ocular surgery have been shown to be the major risk factors for IK. Broad-spectrum topical antimicrobial treatment is the current mainstay of treatment for IK, though its effectiveness is being challenged by the emergence of antimicrobial resistance, including multidrug resistance, in some parts of the world. In this review, we aim to provide an updated review on IK, encompassing the epidemiology, causative microorganisms, major risk factors and the impact of antimicrobial resistance.
Impact of macular fluid volume fluctuations on visual acuity during anti-VEGF therapy in eyes with nAMD
Authors: Chakravarthy Usha , Havilio Moshe , Syntosi Annie , Pillai Natasha , Wilkes Emily , Benyamini Gidi , Best Catherine , Sagkriotis Alexandros
Published: January 2021

Objectives

To study the effect of repeated retinal thickness fluctuations during the anti-VEGF therapy maintenance phase in neovascular age-related macular degeneration (nAMD).

Methods

Data were extracted from electronic medical records of 381 nAMD patients, aged ≥50 years; baseline VA ≥33 and ≤73 letters; ≥24 months’ follow-up and ≥2 optical coherence tomography (OCT) measurements. OCT scans were analysed using an artificial intelligence algorithm that quantified the volumes of intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachments (PED) and central subfield thickness (CSFT). IRF, SRF and PED were summed to obtain total fluid (TF). The standard deviation (SD) of IRF, SRF, PED, CSFT and TF was computed and categorised into quartiles (SD-Q). Relationships between SD-Qs for each OCT feature and VA change was tested using generalised estimating equations and linear regression.

Results

By Month 24, compared to SD-Q1, eyes in SD-Q2, SD-Q3, and SD-Q4 for IRF, SRF, PED, CSFT and TF showed greater VA losses. Eyes in SD-Q4 of TF were 9.4 letters worse compared to eyes in Q1 (95% Confidence Interval: −12.9 to −6.0). The frequency of clinic visits with IRF and SRF present on OCT scans by quartiles of CSFT was lower in eyes with least fluctuation (Q1) compared to eyes with the most fluid fluctuation (Q4) (median [IQR] IRF: 0.3 [0.0–0.7] versus 0.8 [0.5–1.0]; SRF: 0.0 [0.0–0.5] versus 0.6 [0.3–1.0]).

Conclusions

Greater fluctuations in retinal fluid volumes during the maintenance phase of anti-VEGF treatment in nAMD is associated with worse VA by 2 years.
TgAP2IX-5 is a key transcriptional regulator of the asexual cell cycle division in Toxoplasma gondii
Authors: Khelifa Asma S. , Guillen Sanchez Cecilia , Lesage Kevin M. , Huot Ludovic , Mouveaux Thomas , Pericard Pierre , Barois Nicolas , Touzet Helene , Marot Guillemette , Roger Emmanuel , Gissot Mathieu
Published: January 2021

Apicomplexan parasites have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells (budding) is a decisive element. However, the molecular mechanisms that provide the proper timing of parasite budding remain unknown. Using Toxoplasma gondii as a model Apicomplexan, we identified a master regulator that controls the timing of the budding process. We show that an ApiAP2 transcription factor, TgAP2IX-5, controls cell cycle events downstream of centrosome duplication. TgAP2IX-5 binds to the promoter of hundreds of genes and controls the activation of the budding-specific cell cycle expression program. TgAP2IX-5 regulates the expression of specific transcription factors that are necessary for the completion of the budding cycle. Moreover, TgAP2IX-5 acts as a limiting factor that ensures that asexual proliferation continues by promoting the inhibition of the differentiation pathway. Therefore, TgAP2IX-5 is a master regulator that controls both cell cycle and developmental pathways.
Correction: Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy
Authors: Xue Kaihang , Wei Feng , Lin Jinyan , Tian Haina , Zhu Fukai , Li Yang , Hou Zhenqing
Published: January 2021

Correction for ‘Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy’ by Kaihang Xue et al., Biomater. Sci., 2021, DOI: 10.1039/D0BM01864C.
Poly(dimethylsiloxane) and oligo(dimethylsiloxane) solvent effects on aromatic donor–acceptor interactions
Authors: Amemori Shogo , Kikuchi Kyoka , Mizuno Motohiro
Published: January 2021

Dimethylsiloxane solvents strengthened the donor–acceptor interactions between pyrene and pyromellitic diimide derivatives and were compared with aliphatic solvents.
Multiple selectivity-determining mechanisms of H2O2formation in iron porphyrin-catalysed oxygen reduction
Authors: Brezny Anna C. , Nedzbala Hannah S. , Mayer James M.
Published: January 2021

Multiple H2O2-forming mechanisms are accessible in Fe(porphyrin)-catalysed oxygen reduction, a key reaction in both fuel cell technologies and oxygen-utilizing enzymes.
An antimony based organic–inorganic hybrid coating material with high quantum efficiency and thermal quenching effect
Authors: Lin Fang , Wang Hao , Lin Haoran , Liu Wei , Li Jing
Published: January 2021

An antimony based luminescent organic–inorganic hybrid compound has been prepared by the solvothermal method and exhibits bright green light and an internal quantum yield of 73%.
Capturing single molecules by nanopores: measured times and thermodynamics
Authors: Berezhkovskii Alexander M. , Bezrukov Sergey M.
Published: January 2021

In nanopore sensing, transient interruptions of the nanopore ion current induced by capturing solute molecules are characterized by bimodal time distributions with most of the capture events being too fast to be experimentally resolved.
Reactivity of dicationic N-heterocyclic chalcogen carbene analogues with methane and ethene: a theoretical investigation
Authors: Li Tsung-Lung , Zhang Zheng-Feng , Su Ming-Der
Published: January 2021

The reactions of the chalcogen N-heterocyclic carbenic (NHC) dications with methane and ethene are computationally investigated and analyzed by the energy decomposition analysis (EDA) to understand the reactivity.
Sustainable, self-cleaning, transparent, and moisture/oxygen-barrier coating films for food packaging
Authors: Thuy Vu Thi Tuyet , Hao Lam Tan , Jeon Hyeonyeol , Koo Jun Mo , Park Jaeduk , Lee Eun Seong , Hwang Sung Yeon , Choi Sejin , Park Jeyoung , Oh Dongyeop X.
Published: January 2021

Food packaging requirements of gas barrier and self-cleaning are satisfied with the use of bio-renewable cellulose, chitosan, silica, and sunflower oil.
An efficient method to prepare aryl acetates by the carbonylation of aryl methyl ethers or phenols
Authors: Zhang Dejin , Yang Guoqiang , Xiong Junping , Liu Jia , Hu Xingbang , Zhang Zhibing
Published: January 2021

A low pressure of CO was used to prepare aryl acetates directly.
Reactivity of steroidal 1-azadienes toward enamines: an approach to novel chiral penta- and hexacyclic steroids
Authors: Lopes Susana M. M. , Santos Joana R. C. , Pinho e Melo Teresa M. V. D.
Published: January 2021

Steroidal 1-azadienes react with cyclic ketones to afford hexacyclic steroids via annulation reaction while the reaction with aldehydes gives pentacyclic steroids via hetero-Diels–Alder reactions.
A biobased low dielectric resin derived from vanillin and guaiacol
Authors: Fang Linxuan , Tao Yangqing , Zhou Junfeng , Wang Caiyun , Dai Menglu , Sun Jing , Fang Qiang
Published: January 2021

A new bio-based low dielectric resin derived from vanillin and guaiacol has been synthesized, which exhibits good dielectric properties and high thermostability.
C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles by tuning Pd catalytic modes: Pd(i)–Pd(ii) catalysis vs. Pd(ii) catalysis
Authors: Cheng Yaohang , Yu Shijie , He Yuhang , An Guanghui , Li Guangming , Yang Zhenyu
Published: January 2021

C4-arylation via Pd(i)–Pd(ii) catalysis and domino C4-arylation/3,2-carbonyl migration of indoles via Pd(ii) catalysis tuning by acids have been developed.
Productivité et efficience des systèmes agroforestiers à base d’oliviers au Maroc : cas de Moulay Driss Zerhoun
Authors: Amassaghrou Asmae , Bouaziz Ahmed , Daoui Khalid , Belhouchette Hatem , Ezzahouani Abdelaziz , Barkaoui Karim
Published: January 2021

Au Maroc, les systèmes agroforestiers à base d’olivier sont très répandus et diversifiés. Ce travail vise à caractériser leur diversité et leurs performances dans la région de Moulay Driss Zerhoun, au Nord du Maroc. Pour ce faire, 72 enquêtes ont été réalisées auprès des agriculteurs. Pour chaque exploitation, les systèmes agroforestiers ont été comparés à des systèmes de culture pure et à des vergers d’oliviers purs. En condition pluviale, l’insertion des légumineuses et des céréales dans les oliveraies constitue la pratique dominante. Il y a des différences très significatives de rendements pour les cultures annuelles et pour les oliviers entre systèmes associés d’agroforesterie, témoins en cultures annuelles pures et témoins en verger d’olivier. Le Land Equivalent Ratio (surface équivalente assolée) des rendements et celui des marges brutes sont toujours supérieurs à 1 avec les céréales et les légumineuses en agroforesterie. Nos résultats suggèrent que les systèmes agroforestiers sont plus productifs, rentables et efficients que les cultures pures. L’agroforesterie constituerait donc une stratégie pour une production durable, mais il faudrait d’autres expérimentations pour mieux appréhender la productivité de ces systèmes et préciser leurs atouts et leurs limites.
Human Capital Management and Industry 4.0
Authors: Kucharčíková Alžbeta , Mičiak Martin , Bartošová Aneta , Budzeľová Monika , Bugajová Simona , Maslíková Alžbeta , Pisoňová Simona
Published: January 2021

Human capital (HC) is considered to be an important factor influencing the success of. The concept of human capital management (HCM) deals with the effectiveness of human capital, as the most precious intangible asset. However, with the advancement in technology and the introduction of Industry 4.0, the position of human capital in companies can alter with regard to the expected changes. On the other hand, new elements being brought in by Industry 4.0 will allow for the HCM process to be performed better, in favour of the improvement in the performance and competitiveness of companies. The aim of this article is to point out the interconnection between the concept of HCM and some elements of Industry 4.0, as well as to explain the findings from a questionnaire survey focused on how IT companies in Slovakia use information systems for the implementation of HCM, whether these systems enable them to analyse data related to HC, and whether these companies are prepared for the introduction of changes in this field in the future.
Innovations in the Management of E-Commerce Entities Operating on the Slovak Market – Analysis of Customer Interactions during the COVID-19 Pandemic
Authors: Pollak Frantisek , Malinak Bozka , Markovic Peter , Vilagi Robert
Published: January 2021

This paper deals with the issue of innovation in e-commerce, specifically with the application of innovative methods of evaluating customer interactions in the environment of the virtual social network Facebook. The first part presents the results of desk research on the issue of the utilization of virtual social media Facebook in e-commerce in order to approach the knowledge base of the analysed issues. The aim of the second part of the study presented in the paper was to describe and evaluate the activities of customer groups of the five largest e-commerce entities operating in the Slovak virtual market. The data needed for the analysis were collected during the state of emergency declared in connection with the COVID-19 pandemic. From the point of view of findings, the initial trends in the customers interactions were declining online activity over the weekend and an increase in online activity at the beginning of the working week. In general, it can be stated that data were analysed in a highly non-standard market situation. With respect to the social media e-communication of selected e-commerce entities, it was possible to outline specific patterns of consumer behaviour. As a result, it was possible to create a qualitative knowledge base for further research into the impact of the COVID-19 pandemic on national and international economies, for both economics and management sciences.
The Effect of Entrepreneurial Marketing on the Performance of Small and Medium-sized Enterprises
Authors: Abdissa Shuremo Gemechu , Bálint Illés Csaba , Törőné Dunay Anna
Published: January 2021

Entrepreneurial marketing is a non-conventional marketing technique that provides business owners a method to successfully operate their business with limited resources. The main objective of this study is to therefore investigate whether entrepreneurial marketing can affect the performance of small and medium-sized enterprises operating in Ethiopia, specifically in the city of Jimma. A purposive sampling technique was employed to gather data from 100 business owners that have been on market for more than 7 years. The data were analysed using Minitab and SPSS statistical software packages. The study showed that some elements of entrepreneurial marketing indeed affect the performance of small and medium-sized enterprises. Innovation orientation and customer intensity have a positive relationship with the performance of small and medium-sized enterprises and are statistically significant, while risk-taking orientation has a negative relationship and is statistically significant. It is therefore recommended that business owners apply the concept of entrepreneurial marketing to leverage their limited resources to cope with competitors and maintain the sustainability of their business.
Overcoming the barriers to dissemination and implementation of quality measures for gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology (UEG) position statement
Authors: Bisschops Raf , Rutter Matthew D. , Areia Miguel , Spada Cristiano , Domagk Dirk , Kaminski Michel F. , Veitch Andrew , Khannoussi Wafaa , Gralnek Ian M. , Hassan Cesare , Messmann Helmut , Ponchon Thierry , Fockens Paul , Dignass Alex , Dinis-Ribeiro Mario
Published: January 2021

The European Society of Gastrointestinal Endoscopy (ESGE) has developed performance measures and established a framework for quality assessment for gastrointestinal endoscopy in Europe. Most national societies actively undertake initiatives to implement and explicitly endorse these quality indicators. Given this, ESGE proposes that, at a national level, strong leadership should exist to disseminate and implement quality parameters. Thus, understanding the potential barriers that may vary locally is of paramount importance. ESGE suggests that each national society should prioritize quality and standards of care in gastrointestinal endoscopy in their activities and should survey/understand which measures are a local priority to their members and make measuring quality intrinsic to daily endoscopy practice.
Nutzungsgrad und Nutzergruppen der Online-Videosprechstunde in der
ambulanten ärztlichen Versorgung – Eine
Routinedatenanalyse
Authors: Gensorowsky Daniel , Surmann Bastian , Schmidt Juliana , Greiner Wolfgang
Published: January 2021

Ziel Trotz wahrgenommener Potenziale, einer Abrechenbarkeit als
Regelleistung gegenüber der gesetzlichen Krankenversicherung und
verschiedener Fördermaßnahmen hat sich die
Online-Videosprechstunde noch nicht als fester Bestandteil des ambulanten
Versorgungsalltags etabliert. An längerfristigen quantitativen
Untersuchungen zum Nutzungsgrad mangelt es bislang. Diese sind jedoch
essenziell für ein besseres Verständnis der
Diffusionsprozesse sowie der Auswirkungen von
Fördermaßnahmen. Die vorliegende Arbeit stellt einen ersten
Schritt in Richtung einer fortlaufenden Begleitforschung dar.

Methodik Die Entwicklung des Nutzungsgrades der Videosprechstunde in
der ambulant ärztlichen Versorgung wird auf Grundlage von
Routineabrechnungsdaten einer großen gesetzlichen Krankenkasse von
Beginn der Erstattungsfähigkeit im April 2017 bis Ende 2018
untersucht. Um einen Überblick über die Nutzergruppen zu
erhalten, werden zudem relevante und in den Abrechnungsdaten abbildbare
Arzt- und Patientencharakteristika (Facharztgruppe, Alter, Region)
untersucht.

Ergebnisse In den 21 Monaten des Beobachtungszeitraumes wurden
insgesamt 320 Videosprechstunden abgerechnet, wobei die Nutzungszahlen in
2018 monatlich bereits doppelt so hoch waren, wie in 2017. Insgesamt nahmen
105 verschiedene Versicherte eine Videosprechstunde in Anspruch. Diese
hatten ein Durchschnittsalter von 74,6 Jahren und kamen mit 59,8%
vorwiegend aus städtischen Regionen. Unter den insgesamt 30
Ärzten, die Videosprechstunden durchgeführt haben, stellten
die Allgemeinmediziner mit 36,7% die größte
Facharztgruppe.

Schlussfolgerung Die Untersuchung unterstreicht den geringen
Stellenwert der Online-Videosprechstunde in der ambulanten
ärztlichen Versorgung in den ersten 21 Monaten nach ihrer
Einführung. Die Ergebnisse decken sich mit den bisherigen
Erkenntnissen aus Kurzfristanalysen und demoskopischen Untersuchungen. Sie
deuten darüber hinaus auf erste Nutzungstrends hin, die es im Rahmen
einer kontinuierlichen Auseinandersetzung weiter zu untersuchen gilt. Eine
entsprechende Begleitforschung sollte den Beobachtungszeitraum fortlaufend
ausweiten und eine breitere, kassenübergreifende Datenbasis
anstreben.
Sequencing Groebke–Blackburn–Bienaymé and Aza-Michael Addition Reactions: A Modular Strategy for Accessing a Diverse Collection of Constrained Benzoxazepine and Imidazopyrazine Systems
Authors: Al-Tel Taleb H. , Srinivasulu Vunnam , Al-Marzooq Farah , Hamad Mohamad , Khanfar Monther A. , Ramanathan Mani , Soares Nelson C.
Published: January 2021

We present a divergent strategy that permits access to diversely functionalized benzoxazepinium scaffolds fused to various heterocycles. The described strategy features a one-pot combination of the Groebke–Blackburn–Bienaymé reaction and an aza-Michael addition. Methyl (E)-4-(2-formylphenoxy)but-2-enoate and its derivatives are utilized as central elements in this cascade. These building blocks are reacted with a variety of functionalized amino-azines and tert-butyl isocyanide under ytterbium triflate [Yb(OTf)3] catalysis. The ensuing cascade represents a rapid, modular and atom-economic process that leads to the construction of a diverse collection of constrained benzoxazepinium systems from a wide substrate scope.
Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor
Authors: Schilling Uta , Dingemanse Jasper , Dobrow Michael , Baumann Martine , Riederer Markus A. , Juif Pierre-Eric , Ufer Mike
Published: January 2021

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t
max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.
Symmetry classification and exact solutions of (3 + 1)-dimensional fractional nonlinear incompressible non-hydrostatic coupled Boussinesq equations
Authors: Singla Komal , Gupta R. K.
Published: January 2021

The symmetry classifications of two fractional higher dimensional nonlinear systems, namely, (3 + 1)-dimensional incompressible non-hydrostatic Boussinesq equations and (3 + 1)-dimensional Boussinesq equations with viscosity, are discussed. Both the fractional Boussinesq equations are considered to have derivatives with respect to all variables of fractional type, and some exact solutions are reported along with graphical illustrations.