bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting Batch Normalization for Training Low-Latency Deep Spiking Neural Networks From Scratch
Authors: Kim Youngeun , Panda Priyadarshini
Published: December 2021

Spiking Neural Networks (SNNs) have recently emerged as an alternative to deep learning owing to sparse, asynchronous and binary event (or spike) driven processing, that can yield huge energy efficiency benefits on neuromorphic hardware. However, SNNs convey temporally-varying spike activation through time that is likely to induce a large variation of forward activation and backward gradients, resulting in unstable training. To address this training issue in SNNs, we revisit Batch Normalization (BN) and propose a temporal Batch Normalization Through Time (BNTT) technique. Different from previous BN techniques with SNNs, we find that varying the BN parameters at every time-step allows the model to learn the time-varying input distribution better. Specifically, our proposed BNTT decouples the parameters in a BNTT layer along the time axis to capture the temporal dynamics of spikes. We demonstrate BNTT on CIFAR-10, CIFAR-100, Tiny-ImageNet, event-driven DVS-CIFAR10 datasets, and Sequential MNIST and show near state-of-the-art performance. We conduct comprehensive analysis on the temporal characteristic of BNTT and showcase interesting benefits toward robustness against random and adversarial noise. Further, by monitoring the learnt parameters of BNTT, we find that we can do temporal early exit. That is, we can reduce the inference latency by ~5 − 20 time-steps from the original training latency. The code has been released at https://github.com/Intelligent-Computing-Lab-Yale/BNTT-Batch-Normalization-Through-Time.
Development of a Vitamin K Database for Commercially Available Food in Australia
Authors: Palmer Claire R. , Koch Henrietta , Shinde Sujata , Blekkenhorst Lauren C. , Lewis Joshua R. , Croft Kevin D. , Hodgson Jonathan M. , Sim Marc
Published: December 2021

Vitamin K content of foods is known to vary substantially by geographical location. In Australia, no Vitamin K database of food exists, thereby creating ambiguity when trying to develop national dietary intake guidelines. This investigation aimed to develop a Vitamin K database for commonly consumed foods that are commercially available in Australian supermarkets. The Vitamin K1 (phylloquinone; PK) and K2 (menaquinone; MK4, MK7) content of 60 foods known to contain Vitamin K were assessed (e.g., vegetables fruits, oils, animal products, dairy and fermented foods). A liquid chromatography with tandem mass spectrometry (LCMS/MS) method was developed and used to measure PK and MKs in different foods with an improved chromatographic separation and detection of Vitamin K's and their analogs. The LOD and LOQ for PK and MK4 was 0.1, 0.5 ng/ml and 0.5, 1.0 ng/ml, respectively. The majority foods contained detectable PK (53/60), about half contained MK4 (31/60), and few contained MK7 (3/60). PK was highest in green leafy vegetables, with moderate amounts in oils. Highest MK4 content was in chicken eggs and meat products such as ham and chicken. This database enables nutritional epidemiologist to estimate dietary Vitamin K intake, especially in Australian cohorts, for a range of health outcomes.
Enzymatic Hydrolysis of Broken Rice Protein: Antioxidant Activities by Chemical and Cellular Antioxidant Methods
Authors: Ren Likun , Fan Jing , Yang Yang , Xu Yue , Chen Fenglian , Bian Xin , Xing Tonglin , Liu Linlin , Yu Dehui , Zhang Na
Published: December 2021

Excessive reactive oxygen species (ROS) is an important cause of aging, and supplementing antioxidants through diet is one of the important ways to delay aging. Some studies have confirmed that rice protease hydrolysate has antioxidant activity, but was rarely been investigated on cells. Thus, commercial enzymes, alkaline enzyme, neutral enzyme, pepsin, chymotrypsin, and trypsin were selected to hydrolyze broken rice protein (BRP) to obtain the corresponding hydrolysates, which were A-broken rice protein hydrolysate (BRPH), N-BRPH, P-BRPH, C-BRPH, and T-BRPH, respectively. Then the antioxidant properties of BRPHs were evaluated by different chemical and cellular antioxidation. Molecular weight, peptide length distribution, and amino acid sequence were detected to insight into the antioxidant properties. Among BRPHs, the A-BRPH displayed the strongest hydroxyl radical scavenging activity (IC50 = 1.159 mg/ml) and metal ion-chelating activities (IC50 = 0.391 mg/ml). Furthermore, cellular antioxidation confirmed that A-BRPH significantly increased cell viability and inhibited the intracellular ROS release in both aging cells and cell-aging processes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) results revealed that peptides with molecular weight <14.5 KDa were produced by enzymatic hydrolysis. Additionally, A-BRPH rich in low molecular weight (<3 kDa) and short-length peptides with some specific amino acids, such as aromatic and hydrophobic amino acids, contributes to the antioxidant properties. This study provided theoretical to the utilization of broken rice and confirmed that A-BRPH could be used in new anti-aging food and health products for human consumption.
Tricarboxylate Citrate Transporter of an Oleaginous Fungus Mucor circinelloides WJ11: From Function to Structure and Role in Lipid Production
Authors: Yang Wu , Shah Aabid Manzoor , Dong Shiqi , Sun Caili , Zhang Huaiyuan , Mohamed Hassan , Gao Xiuzhen , Fan Huirong , Song Yuanda
Published: December 2021

The citrate transporter protein (CTP) plays an important role in citrate efflux from the mitochondrial matrix to cytosol that has great importance in oleaginous fungi. The cytoplasmic citrate produced after citrate efflux serves as the primary carbon source for the triacylglycerol and cholesterol biosynthetic pathways. Because of the CTP's importance, our laboratory has extensively studied its structure/function relationships in Mucor circinelloides to comprehend its molecular mechanism. In the present study, the tricarboxylate citrate transporter (Tct) of M. circinelloides WJ11 has been cloned, overexpressed, purified, kinetically, and structurally characterized. The Tct protein of WJ11 was expressed in Escherichia coli, isolated, and functionally reconstituted in a liposomal system for kinetic studies. Our results showed that Tct has a high affinity for citrate with Km 0.018 mM. Furthermore, the tct overexpression and knockout plasmids were created and transformed into M. circinelloides WJ11. The mitochondria of the tct-overexpressing transformant of M. circinelloides WJ11 showed a 49% increase in citrate efflux, whereas the mitochondria of the tct-knockout transformant showed a 39% decrease in citrate efflux compared to the mitochondria of wild-type WJ11. To elucidate the structure-function relationship of this biologically important transporter a 3D model of the mitochondrial Tct protein was constructed using homology modeling. The overall structure of the protein is V-shaped and its 3D structure is dimeric. The transport stability of the structure was also assessed by molecular dynamics simulation studies. The activity domain was identified to form hydrogen bond and stacking interaction with citrate and malate upon docking. Tricarboxylate citrate transporter has shown high binding energy of −4.87 kcal/mol to citric acid, while −3.80 kcal/mol to malic acid. This is the first report of unraveling the structural characteristics of WJ11 mitochondrial Tct protein and understanding the approach of the transporting toward its substrate. In conclusion, the present findings support our efforts to combine functional and structural data to better understand the Tct of M. circinelloides at the molecular level and its role in lipid accumulation.
Case Report: Graft Versus Tumor Effect After Non-Myeloablative Allogeneic Stem-Cell Transplantation in a Patient With Brentuximab-Vedotin Refractory Sezary Syndrome
Authors: Franke Georg-Nikolaus , Dumann Konstantin , Jentzsch Madlen , Monecke Astrid , Doehring Christine , Nehring-Vucinic Claudia , Schwind Sebastian , Niederwieser Dietger , Platzbecker Uwe , Ziemer Mirjana , Vucinic Vladan
Published: December 2021

Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.
FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma
Authors: Lv Zheng , Cui Bo , Huang Xing , Feng Hua-Yi , Wang Tao , Wang Han-Feng , Xuan Yun-Dong , Li Hong-Zhao , Ma Xin , Huang Yan , Zhang Xu
Published: December 2021

Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.
Nomogram Model for Dynamic and Individual Prediction of Cardiac Response and Survival for Light Chain Amyloidosis in 737 Patients With Cardiac Involvement
Authors: Li Yang , Cao Yanze , Zheng Mingxin , Hu Jiaqi , Yan Wei , Liu Xiaoyu , Liao Aijun , Yang Wei , Li Jian , Wang Huihan
Published: December 2021

Objective

Light chain amyloidosis (AL) with cardiac involvement is associated with poor prognosis. The existing prognostic assessment system does not consider treatment-related factors, and there is currently no effective system for predicting the response. The purpose of this study was to build an individualized, dynamic assessment model for cardiac response and overall survival (OS) for AL patients with cardiac involvement.

Methods

The records of 737 AL patients with cardiac involvement were collected through cooperation with 18 hospitals in the Chinese Registration Network for Light-chain Amyloidosis (CRENLA). We used univariate and multivariate analyses to evaluate the prognostic factors for OS and cardiac response. Then, two nomogram models were developed to predict OS and cardiac response in AL patients with cardiac involvement.

Results

A nomogram including four independent factors from the multivariate Cox proportional hazards analysis—Mayo staging, courses of treatment, hematologic response, and cardiac response—was constructed to calculate the possibility of achieving survival by adding all the points associated with four variables. The higher the score, the more likely death would occur. The other nomogram model included the courses of treatment, hematological response, and different treatment regimens, and was correlated with cardiac response. The higher the score, the more likely a cardiac response would occur.

Conclusion

In conclusion, based on the large Chinese cohort of patients with AL and cardiac involvement, we identified nomogram models to predict cardiac response and OS. These models are more individualized and dynamic, and therefore, they have important clinical application value.
Targeting TRIM54/Axin1/β-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma
Authors: Zhu Jinrong , Wu Yongqi , Lao Shaoxi , Shen Jianfei , Yu Yijian , Fang Chunqiang , Zhang Na , Li Yan , Zhang Rongxin
Published: December 2021

Accumulating evidence demonstrates that dysregulation of ubiquitin-mediated degradation of oncogene or suppressors plays an important role in several diseases. However, the function and molecular mechanisms of ubiquitin ligases underlying hepatocellular carcinoma (HCC) remain elusive. In the current study, we show that overexpression of TRIM54 was associated with HCC progression. TRIM54 overexpression facilitates proliferation and lung metastasis; however, inhibition of TRIM54 significantly suppressed HCC progression both in vitro and in vivo. Mechanically, we demonstrated that TRIM54 directly interacts with Axis inhibition proteins 1 (Axin1) and induces E3 ligase-dependent proteasomal turnover of Axin1 and substantially induces sustained activation of wnt/β-catenin in HCC cell lines. Furthermore, we showed that inhibition of the wnt/β-catenin signaling pathway via small molecule inhibitors significantly suppressed TRIM54-induced proliferation. Our data suggest that TRIM54 might function as an oncogenic gene and targeting the TRIM54/Axin1/β-catenin axis signaling may be a promising prognostic factor and a valuable therapeutic target for HCC.
Prognostic Value of Cell-Surface Vimentin-Positive CTCs in Pediatric Sarcomas
Authors: Dao Long , Ragoonanan Dristhi , Batth Izhar , Satelli Arun , Foglesong Jessica , Wang Jian , Zaky Wafik , Gill Jonathan B. , Liu Diane , Albert Aisha , Gordon Nancy , Huh Winston , Harrison Douglas , Herzog Cynthia , Kleinerman Eugenie , Gorlick Richard , Daw Najat , Li Shulin
Published: December 2021

Background

Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety.

Methods

Here, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease.

Results

We constructed a ROC with an AUC of 0.831 resulting in a sensitivity of 85.3% and a specificity of 75%. Additionally, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative. We additionally found the use of available molecular testing increased the accuracy of our diagnostic and prognostic tests.

Conclusions

Our findings indicate that CSV+ CTCs have prognostic value and can possibly serve as a measure of disease burden.
Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer
Authors: Yang Szu-Chun , Kunst Natalia , Gross Cary P. , Wang Jung-Der , Su Wu-Chou , Wang Shi-Yi
Published: December 2021

Background

First-line treatment with nivolumab plus ipilimumab (N+I) or nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), yet researchers have not concomitantly compared the cost-effectiveness of N+I and N+I+chemotherapy with chemotherapy alone.

Materials and methods

Using outcomes data from the CheckMate 227 and CheckMate 9LA phase 3 randomized trials, we developed a Markov model with lifetime horizon to compare the costs and effectiveness of N+I and N+I+chemotherapy versus chemotherapy from the U.S. health care sector perspective. Subgroup analysis by programmed death-ligand 1 (PD-L1) expression levels (≥1% and <1%) and probabilistic analysis were performed.

Results

The incremental cost-effectiveness ratio (ICER) of N+I versus chemotherapy was $239,072 per QALY, and $838,198 per QALY for N+I+chemotherapy versus N+I. The ICER of N+I versus chemotherapy was $246,584 per QALY for patients with PD-L1 ≥ 1% and $185,620 per QALY for those with PD-L1 < 1%. In probabilistic analysis, N+I had a 2.6% probability of being cost-effective at a willingness-to-pay threshold of $150,000 per QALY. The probability was 0.4% for patients with PD-L1 ≥ 1% and 10.6% for patients with PD-L1 < 1%.

Conclusion

First-line N+I or N+I+chemotherapy for metastatic NSCLC was not cost-effective regardless of PD-L1 expression levels from the U.S. health care sector perspective.
Response Evaluation and Survival Prediction Following PD‐1 Inhibitor in Patients With Advanced Hepatocellular Carcinoma: Comparison of the RECIST 1.1, iRECIST, and mRECIST Criteria
Authors: Zhou Meng , Zhang Chunhui , Nie Jianhua , Sun Yajuan , Xu Ye , Wu Fangfang , Huang Yuhong , Li Shun , Wang Yuan , Zhou Yang , Zheng Tongsen
Published: December 2021

Background

Precise evaluation of the efficacy of immunotherapy is critical in the effective management and treatment of advanced hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to compare the response assessments achieved by different criteria and to evaluate the correlation between survival outcome and response assessment in HCC treated with programmed cell death protein 1 (PD-1) inhibitor.

Methods

Fifty patients with advanced HCC treated with first-line PD-1 inhibitor with baseline and follow‐up CT images were analyzed. The patients were categorized into responders and nonresponders according to the criteria.

Results

When the response assessments between RECIST 1.1 and mRECIST were compared, no statistically significant differences were observed. Overall response rate was 16% by RECIST 1.1 and iRECIST and was 24% by mRECIST. According to RECIST 1.1 and mRECIST, overall survival (OS) and progression-free survival (PFS) were not statistically different between the complete response (CR) and partial response (PR) groups and the stable disease (SD) and progressive disease (PD) groups. The OS and PFS were significantly different between responders and nonresponders according to mRECIST. The Cohen’s Kappa for RECIST 1.1, iRECIST, and mRECIST was 0.534, 0.438, and 0.363, respectively.

Conclusion

The mRECIST criteria have a powerful ability to discriminate between responders and nonresponders and demonstrated significantly longer OS and PFS in responders than in nonresponders. However, mRECIST needs to be further improved in order for it to be widely used in the clinical evaluation of immunotherapy in HCC.
3D Extracellular Matrix Regulates the Activity of T Cells and Cancer Associated Fibroblasts in Breast Cancer
Authors: Gao Huan , Tian Qi , Zhu Lizhe , Feng Jinteng , Zhou Yan , Yang Jin
Published: December 2021

Background

Breast cancer progression has been gradually recognized as a bidirectional interaction between cancer cells and tumor microenvironment including stroma cells, immune cells, and the dynamically altered ECM. However, there still lacks direct experimental evidences about how ECM properties modulate the activities of stroma and immune cells.

Method

The transcriptomic data and corresponding clinical information of breast cancer pawere obtained from TCGA. Patients were divided into ECM-high, ECM-median and ECM-low groups based on ssGSEA scores of C-ECM genes. The prognostic value of ECM was confirmed by univariate/multivariate Cox regression and survival analyses. GO and KEGG analyses were performed between ECM-high and -low groups. Then associations between ECM characteristics and clinical stages were verified by Masson’s trichrome and Sirius red/Fast Green staining of clinical breast cancer tissues. To evaluate the effects of ECM on CAF induction and T cell activation, the MRC-5, NIH/3T-3, primary T cells and Jurkat T cells were encapsulated in 3D collagen with different densities and organizations, and the expression levels of CAF biomarkers and secretion levels of IL-2 were assessed.

Results

ECM scores showed broad variation across paracancerous and cancer samples as well as breast cancer molecular subtypes, and patients with different ECM groups showed distinct prognosis. Immunological activity and ECM associated biology processes were identified by GO and KEGG analyses across ECM-high and -low groups. According to MCP-counter algorithm, the infiltration of T cells was significantly lower in the ECM-high group, while CAF abundance was significantly higher. It is furtherly confirmed by clinical samples that collagen density and organization were associate with breast cancer progression. Finally, in vitro 3D-cultured fibroblasts and T cells validated that the density and organization of collagen showed significant effects on CAF induction and T cell activation.

Conclusion

Our study revealed a new mechanism of T cell immunosuppression and CAF induction, which could be of central importance for the breast cancer invasion and may constitute novel therapeutic targets to improve breast cancer outcomes.
Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway
Authors: Kim Namkyoung , Shin Injae , Kim Younghoon , Jeon Eunhye , Lee Jiwon , Lee Chaeyoung , Nam Yunju , Lee Sumin , Ju Eunhye , Kim Chan , Son Woolim , Ryu SeongShick , Ko Minjoo , Sim Taebo
Published: December 2021

RAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest on cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on cancer cells harboring mtRAS.
Analysis of the Clinical Features of Intrauterine Ureaplasma urealyticum Infection in Preterm Infants: A Case-Control Study
Authors: Sun Tong , Fu Jianhua
Published: December 2021

Objective: To analyze the clinical characteristics of intrauterine Ureaplasma urealyticum (UU) infection in premature infants.

Method: In this single-center retrospective case-control study, 291 preterm infants born in our hospital and hospitalized in our department and gestational age no more than 32 weeks, birth weight no more than 2000 g were included from January 2019 to January 2021. Lower respiratory tract secretion, gastric fluid and urine were collected for UU RNA detection within 48 h after birth. Intrauterine UU infection is defined by at least one positive UU-PCR test of secreta or excreta of preterm infants after birth. The UU infection group included 86 preterm infants and the non-UU infection group included 205 preterm infants. We compared their clinical features, hemogram changes and disease outcomes using statistical analyses.

Results: The clinical characteristics of premature infants such as the duration of oxygen use and ventilator use in hospital were significantly prolonged in the UU infection group (P < 0.05). The levels of leukocytes, platelet and procalcitonin in the UU infection group were significantly higher than in the non-UU infection group (P < 0.05). In terms of preterm complications, only the incidences of bronchopulmonary dysplasia, retinopathy of prematurity and metabolic bone disease in premature infants in the UU infection group were significantly higher than those in the non-UU infection group (P < 0.05). The mode of delivery, maternal premature rupture of membranes, and postnatal leukocyte level were independent risk factors for UU infection, while gestational hypertension was a protective factor for UU infection. The level of leukocytes in postnatal hemogram of premature infants could be used as a diagnostic index of UU infection, but the diagnostic accuracy was poor.

Conclusion: In our study, UU infection can increase the incidence of bronchopulmonary dysplasia, retinopathy of prematurity and metabolic bone disease in preterm infants, but have no effect on the incidence of necrotizing enterocolitis, intracranial hemorrhage, white matter damage and other diseases in preterm infants. For high-risk premature infants, UU should be detected as soon as possible after birth, early intervention and drug treatment necessarily can improve the prognosis as much as possible.
Dual sEH/COX-2 Inhibition Using PTUPB—A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity
Authors: Jankiewicz Wojciech K. , Barnett Scott D. , Stavniichuk Anna , Hwang Sung Hee , Hammock Bruce D. , Belayet Jawad B. , Khan A. H. , Imig John D.
Published: December 2021

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague–Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%–70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improvedin vitrothe viability of human mesangial cells.Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.
9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
Authors: Poloznikov Andrey , Nikulin Sergey , Bolotina Larisa , Kachmazov Andrei , Raigorodskaya Maria , Kudryavtseva Anna , Bakhtogarimov Ildar , Rodin Sergey , Gaisina Irina , Topchiy Maxim , Asachenko Andrey , Novosad Victor , Tonevitsky Alexander , Alekseev Boris
Published: December 2021

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.
Airway Basal Cells Mediate Hypoxia-Induced EMT by Increasing Ribosome Biogenesis
Authors: Hou Yapeng , Ding Yan , Du Danni , Yu Tong , Zhou Wei , Cui Yong , Nie Hongguang
Published: December 2021

Excessive secretion of airway mucus and fluid accumulation are the common features of many respiratory diseases, which, in turn, induce cell hypoxia in the airway epithelium, resulting in epithelial–mesenchymal transition (EMT) and ultimately fibrosis. However, the mechanisms of EMT induced by hypoxia in the airway are currently unclear. To mimic the status of edematous fluid retention in the airway, we cultured primary mouse tracheal epithelial cells (MTECs) in a liquid–liquid interface (LLI) mode after full differentiation in a classic air–liquid interface (ALI) culture system. The cell hypoxia was verified by the physical characteristics and lactate production in cultured medium as well as HIF expression in MTECs cultured by LLI mode. EMT was evidenced and mainly mediated by basal cells, supported by flow cytometry and immunofluorescence assay. The differently expressed genes of basal and other airway epithelial cells were found to be enriched in the ribosome by our analysis of an MTEC single-cell RNA sequencing data set and Myc, the global regulator of ribosome biogenesis was identified to be highly expressed in basal cells. We next separated basal cells from bulk MTECs by flow cytometry, and the real-time PCR results showed that ribosome biogenesis was significantly upregulated in basal cells, whereas the inhibition of ribosome biogenesis alleviated the phosphorylation of the mammalian target of rapamycin/AKT and abrogated hypoxia-induced EMT in MTECs. Collectively, these observations strongly suggest that basal cells in the airway epithelium may mediate the process of hypoxia-induced EMT, partly through enhancing ribosome biogenesis.
The Protective Effects of Cath-MH With Anti-Propionibacterium Acnes and Anti-Inflammation Functions on Acne Vulgaris
Authors: Wu Jiena , Guo Ruiyin , Chai Jinwei , Xiong Weichen , Tian Maolin , Lu Wancheng , Xu Xueqing
Published: December 2021

Acne vulgaris is a common adolescent skin condition which is mainly caused by Propionibacterium acnes overcolonization and subsequent inflammation. Our previous studies have demonstrated that Cath-MH, an antimicrobial peptide from the skin of the frog Microhyla heymonsivogt, possesses potential antimicrobial, LPS-binding, and anti-septicemic properties. However, its protective effects and potential mechanisms against acne vulgaris are still unclear. In the present study, its anti-P. acnes effects were measured by two-fold broth dilution method, agglutination assay, scanning electron microscopy and confocal laser scanning microscopy experiments. Its treatment potential for acne vulgaris was further evaluated in mice ear inoculated by P. acnes. In addition, the binding ability between Cath-MH and LTA was measured by the Circular Dichroism and antibacterial assay. Moreover, the anti-inflammatory efficiency of Cath-MH was evaluated in LTA- and LPS-induced RAW 264.7 macrophage cells. Cath-MH was found to kill P. acnes with a MIC value of about 1.56 μM by membrane disruption mechanism. It also exhibited agglutination activity against P. acnes. Cath-MH was able to bind LTA as well as LPS, inhibit LTA/LPS-stimulated TLR2/4 expression, and subsequently decreased the inflammatory response in RAW 264.7 cells. As expected, Cath-MH alleviated the formation of edema and the infiltration of inflammatory cells in acne mouse model with concurrent suppression of P. acnes growth and inflammatory cytokines expression in vivo. The potent P. acnes inhibition activity combined with powerful anti-inflammatory effect of Cath-MH indicates its potential as a novel therapeutic option for acne vulgaris.
Metabolic and Redox Biomarkers in Skeletal Muscle Underlie Physiological Adaptations of Two Estivating Anuran Species in a South American Semi-arid Environment
Authors: Moreira Daniel C. , Carvajalino-Fernández Juan M. , Navas Carlos A. , de Carvalho José E. , Hermes-Lima Marcelo
Published: December 2021

The upregulation of endogenous antioxidants (i.e., preparation for oxidative stress, POS) is part of the biochemical responses underlying the adaptation of animals to adverse environments. Despite the phylogenetic diversity of animals in which POS has been described, most studies focus on animals under controlled laboratory conditions. To address this limitation, we have recently assessed the redox metabolism in the skeletal muscle of Proceratophrys cristiceps estivating under natural settings in the Caatinga. Here, we analyzed biochemical biomarkers in the muscle of another Caatinga species, Pleurodema diplolister, during the rainy (active) and dry (estivating frogs) seasons. We aimed to determine whether P. diplolister enhances its antioxidants during estivation under field conditions and to identify any effect of species on the biochemical responses of P. diplolister and P. cristiceps associated with estivation. To do so, we measured the activities of representative enzymes of intermediary metabolism and antioxidant systems, as well as glutathione and protein carbonyl levels, in the skeletal muscle of P. diplolister. Our findings revealed the suppression of oxidative metabolism and activation of antioxidant enzymes in estivating P. diplolister compared with active specimens. No changes in oxidative damage to proteins were observed and estivating P. diplolister had lower levels of disulfide glutathione (GSSG) and disulfide-to-total glutathione ratio (GSSG/tGSH) than those observed in active individuals. When data for P. diplolister and P. cristiceps were assembled and analyzed, significant effects of species were detected on the activities of metabolic enzymes (citrate synthase, isocitric dehydrogenase, malic enzyme, and creatine kinase) and antioxidant enzymes (catalase, glutathione peroxidase and glutathione transferase), as well as on GSSG/tGSH ratio. Such effects might underlie the physiological and behavioral differences between these two species that share the same microhabitat and survival strategy (i.e., to estivate) during the dry season. Despite some peculiarities, which reflect the physiological diversity of the mechanisms associated with estivation in the Brazilian Caatinga, both P. diplolister and P. cristiceps seem to balance the suppression of oxidative pathways, the maintenance of the capacity of oxygen-independent pathways, and the activation of endogenous antioxidants to preserve muscle function and be ready to resume activity whenever the unpredictable rainy period arrives.
A Novel Chloroplast Protein RNA Processing 8 Is Required for the Expression of Chloroplast Genes and Chloroplast Development in Arabidopsis thaliana
Authors: Kong Mengmeng , Wu Yaozong , Wang Ziyuan , Qu Wantong , Lan Yixin , Chen Xin , Liu Yanyun , Shahnaz Perveen , Yang Zhongnan , Yu Qingbo , Mi Hualing
Published: December 2021

Chloroplast development involves the coordinated expression of both plastids- and nuclear-encoded genes in higher plants. However, the underlying mechanism still remains largely unknown. In this study, we isolated and characterized an Arabidopsis mutant with an albino lethality phenotype named RNA processing 8 (rp8). Genetic complementation analysis demonstrated that the gene AT4G37920 (RP8) was responsible for the mutated phenotype. The RP8 gene was strongly expressed in photosynthetic tissues at both transcription and translation protein levels. The RP8 protein is localized in the chloroplast and associated with the thylakoid. Disruption of the RP8 gene led to a defect in the accumulation of the rpoA mature transcript, which reduced the level of the RpoA protein, and affected the transcription of PEP-dependent genes. The abundance of the chloroplast rRNA, including 23S, 16S, 4.5S, and 5S rRNA, were reduced in the rp8 mutant, respectively, and the amounts of chloroplast ribosome proteins, such as, PRPS1(uS1c), PRPS5(uS5c), PRPL2 (uL2c), and PRPL4 (uL4c), were substantially decreased in the rp8 mutant, which indicated that knockout of RP8 seriously affected chloroplast translational machinery. Accordingly, the accumulation of photosynthetic proteins was seriously reduced. Taken together, these results indicate that the RP8 protein plays an important regulatory role in the rpoA transcript processing, which is required for the expression of chloroplast genes and chloroplast development in Arabidopsis.
Interaction Effects of Nitrogen Rates and Forms Combined With and Without Zinc Supply on Plant Growth and Nutrient Uptake in Maize Seedlings
Authors: Xue Yanfang , Yan Wei , Gao Yingbo , Zhang Hui , Jiang Liping , Qian Xin , Cui Zhenling , Zhang Chunyan , Liu Shutang , Wang Huimin , Li Zongxin , Liu Kaichang
Published: December 2021

Previous studies have shown that zinc (Zn) accumulation in shoot and grain increased as applied nitrogen (N) rate increased only when Zn supply was not limiting, suggesting a synergistic effect of N on plant Zn accumulation. However, little information is available about the effects of different mineral N sources combined with the presence or absence of Zn on the growth of both shoot and root and nutrient uptake. Maize plants were grown under sand-cultured conditions at three N forms as follows: NO3– nutrition alone, mixture of NO3–/NH4+ with molar ratio of 1:1 (recorded as mixed-N), and NH4+ nutrition alone including zero N supply as the control. These treatments were applied together without or with Zn supply. Results showed that N forms, Zn supply, and their interactions exerted a significant effect on the growth of maize seedlings. Under Zn-sufficient conditions, the dry weight (DW) of shoot, root, and whole plant tended to increase in the order of NH4+ < NO3– < mixed-N nutrition. Compared with NH4+ nutrition alone, mixed-N supply resulted in a 27.4 and 28.1% increase in leaf photosynthetic rate and stomatal conductance, which further resulted in 35.7 and 33.5% of increase in shoot carbon (C) accumulation and shoot DW, respectively. Furthermore, mixed-N supply resulted in a 19.7% of higher shoot C/N ratio vs. NH4+ nutrition alone, which means a higher shoot biomass accumulation, because of a significant positive correlation between shoot C/N ratio and shoot DW (R2 = 0.682***). Additionally, mixed-N supply promoted the greatest root DW, total root length, and total root surface area and synchronously improved the root absorption capacity of N, iron, copper, manganese, magnesium, and calcium. However, the above nutrient uptake and the growth of maize seedlings supplied with NH4+ were superior to either NO3– or mixed-N nutrition under Zn-deficient conditions. These results suggested that combined applications of mixed-N nutrition and Zn fertilizer can maximize plant growth. This information may be useful for enabling integrated N management of Zn-deficient and Zn-sufficient soils and increasing plant and grain production in the future.
Coupled Development of Salt Glands, Stomata, and Pavement Cells in Limonium bicolor
Authors: Gao Yaru , Zhao Boqing , Jiao Xiangmei , Chen Min , Wang Baoshan , Yuan Fang
Published: December 2021

Salt-resistant plants have different mechanisms to limit the deleterious effects of high salt in soil; for example, recretohalophytes secrete salt from unique structures called salt glands. Salt glands are the first differentiated epidermal structure of the recretohalophyte sea lavender (Limonium bicolor), followed by stomata and pavement cells. While salt glands and stomata develop prior to leaf expansion, it is not clear whether these steps are connected. Here, we explored the effects of the five phytohormones salicylic acid, brassinolide, methyl jasmonate, gibberellic acid, and abscisic acid on the development of the first expanded leaf of L. bicolor and its potential connection to salt gland, stomata, and pavement cell differentiation. We calculated the total number of salt glands, stomata, and pavement cells, as well as leaf area and pavement cell area, and assessed the correlations between these parameters. We detected strong and positive correlations between salt gland number and pavement cell area, between stomatal number and pavement cell area, and between salt gland number and stomatal number. We observed evidence of coupling between the development of salt glands, stomata, and pavement cells in L. bicolor, which lays the foundation for further investigation of the mechanism behind salt gland development.
Effects of Root Zone Warming on Maize Seedling Growth and Photosynthetic Characteristics Under Different Phosphorus Levels
Authors: Xia Zhenqing , Zhang Shibo , Wang Qi , Zhang Guixin , Fu Yafang , Lu Haidong
Published: December 2021

Phosphorus content and root zone temperature are two major environmental factors affecting maize growth. Both low phosphorus and root zone high temperature stress significantly affect the growth of maize, but the comprehensive effects of phosphorus deficiency and root zone warming are less studied. This study aimed to explore the effects of phosphorus deficiency and root zone warming on the root absorption capacity, total phosphorus content, and photosynthetic fluorescence parameters of maize seedlings. The results showed that maize shoots and roots had different responses to root zone warming and phosphorus deficiency. Properly increasing the root zone temperature was beneficial to the growth of maize seedlings, but when the root zone temperature was too high, it significantly affected the root and shoot development of maize seedlings. The root zone warming had a more significant impact on the root system, while phosphorus deficiency had a greater impact on the shoots. Phosphorus content and root zone warming had a strong interaction. Under the comprehensive influence of normal phosphorus supply and medium temperature in the root zone, the growth of maize seedlings was the best. Under the combined effects of low phosphorus and high temperature in the root zone, the growth was the worst. Compared with the combination of normal phosphorus and root zone medium temperature treatment, the dry mass of the low-phosphorus root zone high temperature treatment was decreased by 55.80%. Under the condition of low-phosphorus too high root zone temperature reduced root vitality, plant phosphorus content, which in turn affected plant growth and light energy utilization efficiency. In the case of sufficient phosphate fertilizer supply, appropriately increasing the soil temperature in the root zone is beneficial to increase the absorption and utilization of phosphorus by plants and promote the growth and development of maize seedlings.