bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal Detection of Fusion Pore Dynamics Using Polarized Total Internal Reflection Fluorescence Microscopy
Authors: Nikolaus Joerg , Hancock Kasey , Tsemperouli Maria , Baddeley David , Karatekin Erdem 
Published: November 2021

The fusion pore is the initial narrow connection that forms between fusing membranes. During vesicular release of hormones or neurotransmitters, the nanometer-sized fusion pore may open-close repeatedly (flicker) before resealing or dilating irreversibly, leading to kiss-and-run or full-fusion events, respectively. Pore dynamics govern vesicle cargo release and the mode of vesicle recycling, but the mechanisms are poorly understood. This is partly due to a lack of reconstituted assays that combine single-pore sensitivity and high time resolution. Total internal reflection fluorescence (TIRF) microscopy offers unique advantages for characterizing single membrane fusion events, but signals depend on effects that are difficult to disentangle, including the polarization of the excitation electric field, vesicle size, photobleaching, orientation of the excitation dipoles of the fluorophores with respect to the membrane, and the evanescent field depth. Commercial TIRF microscopes do not allow control of excitation polarization, further complicating analysis. To overcome these challenges, we built a polarization-controlled total internal reflection fluorescence (pTIRF) microscope and monitored fusion of proteoliposomes with planar lipid bilayers with single molecule sensitivity and ∼15 ms temporal resolution. Using pTIRF microscopy, we detected docking and fusion of fluorescently labeled small unilamellar vesicles, reconstituted with exocytotic/neuronal v-SNARE proteins (vSUVs), with a supported bilayer containing the cognate t-SNAREs (tSBL). By varying the excitation polarization angle, we were able to identify a dye-dependent optimal polarization at which the fluorescence increase upon fusion was maximal, facilitating event detection and analysis of lipid transfer kinetics. An improved algorithm allowed us to estimate the size of the fusing vSUV and the fusion pore openness (the fraction of time the pore is open) for every event. For most events, lipid transfer was much slower than expected for diffusion through an open pore, suggesting that fusion pore flickering limits lipid release. We find a weak correlation between fusion pore openness and vesicle area. The approach can be used to study mechanisms governing fusion pore dynamics in a wide range of membrane fusion processes.
An Integrative Pan-Cancer Analysis of PBK in Human Tumors
Authors: Wen Huantao , Chen Zitao , Li Min , Huang Qiongzhen , Deng Yuhao , Zheng Jiawei , Xiong Moliang , Wang Pengfei , Zhang Wangming 
Published: November 2021

Background: PDZ binding kinase (PBK) is a serine/threonine kinase, which belongs to the mitogen-activated protein kinase kinase (MAPKK) family. It has been shown to be a critical gene in the regulation of mitosis and tumorigenesis, but the role of PBK in various cancers remains unclear. In this study, we systematically explored the prognostic and predictive value of PBK expression in 33 cancer types.Methods: Public databases including the cBioPortal database, GDSC database, GTEx database, CCLE database, and TCGA database were used to detect the PBK expression and its association with the prognosis, clinicopathologic stage, TMB, MSI, immune microenvironment, immune checkpoints, immune cell infiltration, enrichment pathways, and IC50 across pan-cancer. The statistical analyses and visualization were conducted using R software.Results: PBK expression is relatively high in most cancers compared to their normal counterparts, and this gene is barely expressed in normal tissues. High expression of PBK is significantly associated with poor prognosis and clinicopathologic stages I, II, and III in different cancers. Furthermore, PBK expression is strongly associated with TMB in 23 cancer types and associated with MSI in nine cancer types. Moreover, the correlation analysis of the microenvironment and immune cells indicated that PBK is negatively correlated with the immune infiltration levels but positively correlated with the infiltration levels of M0 and M1 macrophages, T cells CD4 memory activated, and T cells follicular helper. GSEA analysis revealed that the biological function or pathways relevant to the cell cycle and mitosis were frequently enriched at the level of high expression of PBK.Conclusion: These results revealed the oncogenic role of PBK, which is significantly upregulated in various cancers and indicated poor prognosis and immune infiltration in multiple cancers. It also suggested that PBK may serve as a biomarker in multiple tumor progress and patient survival.
Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio in Patients With Newly Diagnosed Moyamoya Disease: A Cross-Sectional Study
Authors: Ma Wenyuan , Cui Changmeng , Feng Song , Li Genhua , Han Guangkui , Liu Jilan , Qin Xianyun , Hu Yawei , Wang Mengjie , Zhang Lu , Jin Feng 
Published: November 2021

Inflammation has been proven to be one of the key factors in the pathogenesis of moyamoya disease (MMD). Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are cheap and reliable biomarkers of inflammation. Nevertheless, evidence regarding the relationship among PLR and NLR in patients with MMD is limited. The focus of this subject was to explore the relationship between PLR and NLR in patients with newly diagnosed MMD.Patients and methods: A cross-sectional study was performed including 261 patients with diagnosed MMD for the first time who were enrolled from our hospital, from 24 March 2013 to 24 December 2018. The clinical characteristics were collected for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were showed.Results: The mean levels or median values (interquartile range) of PLR and NLR were 146.979 ± 51.203 and 2.241 (1.589–2.984), respectively. A significant positive correlation between PLR and NLR levels (P &lt; 0.001) was showed by the univariate analysis. Furthermore, a non-linear relationship was detected between PLR and NLR by smooth curve fitting after adjusting for potential confounders. A multivariate piecewise linear regression model revealed a significant positive correlation between PLR and NLR when the PLR level was lower than 219.82 (β 0.012, 95% CI 0.005, 0.019; P = 0.001). PLR was also significantly positively associated with NLR when PLR concentrations were &gt;219.82 (β 0.098, 95% CI 0.069, 0.128; P &lt; 0.001).Conclusion: There seemed to be a positive association between PLR and NLR in patients with MMD. This may help to further explain the role of inflammation in the occurrence and progress of MMD.
Transplanted Human Oligodendrocyte Progenitor Cells Restore Neurobehavioral Deficits in a Rat Model of Preterm White Matter Injury
Authors: Wang Xiaohua , Zang Jing , Yang Yinxiang , Lu Siliang , Guan Qian , Ye Dou , Wang Zhaoyan , Zhou Haipeng , Li Ke , Wang Qian , Wu Youjia , Luan Zuo 
Published: November 2021

Background: Preterm white matter injury (PWMI) is a common brain injury and a leading cause of life-long neurological deficits in premature infants; however, no effective treatment is available yet. This study aimed to investigate the fate and effectiveness of transplanted human oligodendrocyte progenitor cells (hOPCs) in a rat model of PWMI.Methods: Hypoxia-ischemia was induced in rats at postnatal day 3, and hOPCs (6 × 105 cells/5 μL) were intracerebroventricularly transplanted at postnatal day 7. Neurobehavior was assessed 12 weeks post-transplant using the CatWalk test and Morris water maze test. Histological analyses, as well as immunohistochemical and transmission electron microscopy, were performed after transcardial perfusion.Results: Transplanted hOPCs survived for 13 weeks in PWMI brains. They were widely distributed in the injured white matter, and migrated along the corpus callosum to the contralateral hemisphere. Notably, 82.77 ± 3.27% of transplanted cells differentiated into mature oligodendrocytes, which produced myelin around the axons. Transplantation of hOPCs increased the fluorescence intensity of myelin basic protein and the thickness of myelin sheaths as observed in immunostaining and transmission electron microscopy, while it reduced white matter atrophy at the level of gross morphology. With regard to neurobehavior, the CatWalk test revealed improved locomotor function and inter-paw coordination after transplantation, and the cognitive functions of hOPC-transplanted rats were restored as revealed by the Morris water maze test.Conclusions: Myelin restoration through the transplantation of hOPCs led to neurobehavioral improvements in PWMI rats, suggesting that transplanting hOPCs may provide an effective and promising therapeutic strategy in children with PWMI.
First Line and Second Line Chemotherapy in Advanced Cholangiocarcinoma and Impact of Dose Reduction of Chemotherapy: A Retrospective Analysis
Authors: Möhring Christian , Feder Jan , Mohr Raphael U. , Sadeghlar Farsaneh , Bartels Alexandra , Mahn Robert , Zhou Taotao , Marinova Milka , Feldmann Georg , Brossart Peter , von Websky Martin , Matthaei Hanno , Manekeller Steffen , Glowka Tim , Kalff Jörg C. , Weismüller Tobias J. , Strassburg Christian P. , Gonzalez-Carmona Maria A. 
Published: November 2021

ObjectivePrognosis of patients with irresectable cholangiocarcinoma is still poor. The ABC-02 trial established the current first line (1L) standard systemic chemotherapy (CT) with gemcitabine/platinum derivate for advanced cholangiocarcinoma. However, the majority of patients needed therapy adaptions. Thus, the aim of this study was to evaluate 1L and second line (2L) therapy regimens and the impact of therapy adaptions in an unselected real-life cohort of patients with advanced cholangiocarcinoma.Materials and MethodsThis is a single institution retrospective analysis of patients with irresectable cholangiocarcinoma who were treated with gemcitabine/platinum derivate from 2010 to 2018. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially with regard to CT de-escalation.ResultsFifty-eight patients receiving gemcitabine/platinum derivate were included in the analysis. Median OS and PFS were 12.2 and 6.9 months. Interestingly, 41 patients (71%) needed therapy de-escalation. However, despite reduced CT exposition, there was no-significant difference in OS (10.8 months vs. 15.6 months, p = 0.127), and patients suffered from less adverse events during CT. 21 (36%) patients reached 2L CT, most often with FOLFIRI (57%). Survival beyond the end of 1L CT was 7.1 months with 2L CT vs. 2.9 months with BSC.ConclusionIn our study, the combination of gemcitabine/platinum derivate showed similar OS and PFS as randomized prospective phase II/III trials. Therapy regimen adaptions were needed in the majority of patients. However, individualized modifications of the therapy regimen allowed better tolerance as well as continuation of therapy and did not significantly influence median OS. Furthermore, our study revealed a potential survival benefit with 2L CT for selected patients.
Premalignant Changes in the Bronchial Epithelium Are Prognostic Factors of Distant Metastasis in Non-Small Cell Lung Cancer Patients
Authors: Pankova Olga V. , Tashireva Liubov A. , Rodionov Evgeny O. , Miller Sergey V. , Tuzikov Sergey A. , Pismenny Dmitry S. , Gerashchenko Tatiana S. , Zavyalova Marina V. , Vtorushin Sergey V. , Denisov Evgeny V. , Perelmuter Vladimir M. 
Published: November 2021

BackgroundThe study assessed the possibility of dividing patients into groups based on the assessment of morphological changes in the epithelium of small-caliber bronchi located near the primary tumor in order to predict high and low risks of distant metastasis of non-small cell lung cancer.MethodsIn 171 patients with non-small cell lung cancer (T1-4N0-3M0) in small-caliber bronchi taken at a distance of 3–5 cm from the tumor, various variants of morphological changes in the bronchial epithelium (basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia (D)) were assessed. Long-term results of treatment, namely, distant metastasis, were assessed after 2 and 5 years.ResultsDuring the follow-up period, distant metastases were found in 35.1% (60/171) of patients. Most often, they were observed in patients of the high-risk group: BCH+SM−D− (51.6%, 40/95) and BCH−SM+D+ (54.4%, 6/11). Less often, distant metastases were observed in low-risk group patients: BCH+SM+D− (6.7%, 3/45) and BCH−SM−D− (10.0%, 2/20). Tumor size, grade, and stage were significant predictors of metastasis only in the high-risk group. The 5-year metastasis-free survival was better in the low-risk group of distant metastases.ConclusionsIsolated BCH or dysplasia in small bronchi distant from foci of tumor is associated with a high-risk distant metastasis and less 5-year metastasis-free survival.
TERT Promoter Mutations and rs2853669 Polymorphism: Useful Markers for Clinical Outcome Stratification of Patients With Oral Cavity Squamous Cell Carcinoma
Authors: Giunco Silvia , Boscolo-Rizzo Paolo , Rampazzo Enrica , Tirelli Giancarlo , Alessandrini Lara , Di Carlo Roberto , Rossi Marco , Nicolai Piero , Menegaldo Anna , Carraro Valentina , Tofanelli Margherita , Bandolin Luigia , Spinato Giacomo , Emanuelli Enzo , Mantovani Monica , Stellin Marco , Bussani Rossana , Dei Tos Angelo Paolo , Guido Maria , Morello Marzia , Fussey Jonathan , Esposito Giovanni , Polesel Jerry , De Rossi Anita 
Published: November 2021

ObjectiveTo date, no useful prognostic biomarker exists for patients with oral squamous cell carcinoma (OCSCC), a tumour with uncertain biological behaviour and subsequent unpredictable clinical course. We aim to investigate the prognostic significance of two recurrent somatic mutations (-124 C&gt;T and -146 C&gt;T) within the promoter of telomerase reverse transcriptase (TERT) gene and the impact of TERT single nucleotide polymorphism (SNP) rs2853669 in patients surgically treated for OCSCC.MethodsThe genetic frequencies of rs2853669, -124 C&gt;T and -146 C&gt;T as well as the telomere length were investigated in 144 tumours and 57 normal adjacent mucosal (AM) specimens from OCSCC patients.ResultsForty-five tumours harboured TERT promoter mutations (31.3%), with -124 C&gt;T and -146 C&gt;T accounting for 64.4% and 35.6% of the alterations respectively. Patients with -124 C&gt;T TERT promoter mutated tumours had the shortest telomeres in the AM (p=0.016) and showed higher risk of local recurrence (hazard ratio [HR]:2.75, p=0.0143), death (HR:2.71, p=0.0079) and disease progression (HR:2.71, p=0.0024) with the effect being potentiated by the co-occurrence of T/T genotype of rs2853669.Conclusion-124 C&gt;T TERT promoter mutation as well as the T/T genotype of the rs2853669 SNP are attractive independent prognostic biomarkers in patients surgically treated for OCSCC, with the coexistence of these genetic variants showing a synergistic impact on the aggressiveness of the disease.
Age and Gender-Specific Reference Intervals for Uric Acid Level in Children Aged 5–14 Years in Southeast Zhejiang Province of China: Hyperuricemia in Children May Need Redefinition
Authors: Dai Chengjun , Wang Chaoban , Xia Fangqin , Liu Zishuo , Mo Yiqi , Shan Xiaoou , Zhou Yonghai 
Published: November 2021

Context: Hyperuricemia is defined when the plasma uric acid concentration is above 416 μmol/L (7 mg/dl) in male adults, or 357 μmol/L (6 mg/dl) in female adults. However, there are no explicit criteria yet for children.Objective: It is necessary to set up reference intervals for the uric acid level in different age groups among children.Materials and Methods: A total of 5,439 individuals (3,258 males, 2,181 females) were included in the final statistical analysis. Reference values of all age groups were determined by statistical descriptions. Multiple linear regression analysis was applied to determine the relationship between uric acid level, BMI, and age.Results: The level of uric acid increased with age. Gender differences in uric acid level occurred after the onset of puberty. Additionally, linear regression revealed a positive correlation between the uric acid level and BMI.Discussion and Conclusion: The reference range of the uric acid level in children is inconsistent with the previous viewpoint. Body mass index plays an important role in uric acid metabolism.
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs
Authors: Al-Hussaini Abdulrahman , AlSaleem Badr , AlHomaidani Hamad , Asery Ali , Alruwaithi Muhanad , Alameer Mohammed , Afashah Waleed , Salman Bashir Muhammed , Almontashiri Naif 
Published: November 2021

Background: There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe.Objectives: In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS.Methods: We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in ABCC2 gene.Results: Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3–6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5–14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes (p &lt; 0.001). The median urinary coproporphyrin I% was 88% (IQ1–IQ3 = 84.2–92.7%). We identified four homozygous variants in the ABCC2 gene (from 22 unrelated families), one splicing variant (c.3258+1G&gt;A; p.?), and three were missense variants; two of which were novel missense variants [c.1594G&gt;A (p.Glu532Lys) and c.2439G&gt;C (p.Lys813Asn)]. The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families).Conclusions: Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with “founder effects.” Identification of the predominant ABCC2 variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.
Distinguishing Between Multisystem Inflammatory Syndrome, Associated With COVID-19 in Children and the Kawasaki Disease: Development of Preliminary Criteria Based on the Data of the Retrospective Multicenter Cohort Study
Authors: Kostik Mikhail M. , Bregel Liudmila V. , Avrusin Ilia S. , Dondurei Elena A. , Matyunova Alla E. , Efremova Olesya S. , Isupova Eugenia A. , Kornishina Tatiana L. , Masalova Vera V. , Snegireva Ludmila S. , Shprakh Vladimir V. , Kozlov Yuri A. , Kalashnikova Olga V. , Chasnyk Vyacheslav G. 
Published: November 2021

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP &gt;11 mg/dl (18 points), D-dimer &gt;607 ng/ml (27 points), age &gt;5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa &gt;55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.
Training LEADers to Accelerate Global Mental Health Disparities Research (LEAD) Program: A Research Training Program Protocol
Authors: Sensoy Bahar Ozge , Cavazos-Rehg Patricia , Ssewamala Fred M. , Abente Betsy , Peer Laura , Nabunya Proscovia , Soto de Laurido Lourdes E. , Betancourt Theresa S. , Bhana Arvin , Edmond Tonya 
Published: November 2021

Background:There is a critical need to address mental health needs across the globe, especially in low and middle-income countries where mental health disparities are pervasive, including among children. The global mental health disparities suggest an imperative for culturally and contextually-congruent mental health services models that expand upon the existing services and interventions for these groups. Rigorous research is a key tool in providing the scientific evidence to inform public policy and practice efforts to effectively address these needs. Yet, there is a limited number of researchers, especially those from diverse backgrounds, who study these issues. In this paper, we describe the “TrainingLEADers to Accelerate Global Mental Health Disparities Research”(LEAD) program, a research training program funded by the National Institute on Minority Health and Health Disparities and focused on global mental health disparities research for early career researchers from under-represented minority groups.Methods:The LEAD program is designed as a two-phase training program for advanced pre-doctoral students, postdoctoral fellows, and junior faculty from diverse backgrounds in the U.S., including groups underrepresented in biomedical, behavioral, clinical and social sciences research, interested in global mental health disparities research. Trainees are matched with mentors and participate in an intensive 12-week program.Discussion:The LEAD program seeks to provide a robust platform for the development, implementation and expansion of evidence-based culturally and contextually-congruent interventions and services models addressing global mental health disparities across the life cycle, especially in low-resource communities in the global context. By producing a sustainable network of well-trained investigators from underrepresented backgrounds, LEAD will potentially contribute to the shared lessons and efforts relevant to addressing global mental health disparities and improving care for vulnerable populations in low-resource settings.