bluuebunny/crossref_metadata_2025 huggingface dataset:
Становление и деятельность петербургской целительницы и прорицательницы юродивой Матроны Босоножки
Authors: Мазалова Н.Е.
Published: March 2022

В статье предпринимается попытка создать портрет знаменитой петербургской юродивой Матроны. Уделяется внимание ее социальному статусу, социокультурному облику, особенностям мировоззрения, морально-этическим принципам, различным деяниям. Исследование проблем вопроса женского юродства, странничества, а также биографические исследования выдающихся женщин, направленные на изучение субъективного опыта, повседневного и ритуального поведения индивидуума в конкретную историческую эпоху, относятся к числу актуальных в исторической науке. Образ Матроны Босоножки представляется значимым объектом исследования в пространстве гендерных отношений в исторической ретроспективе и в настоящее время, поскольку до наших дней не утрачен интерес к ее личности. Автором проведено исследование изменения социального статуса Матроны. На примере петербургской блаженной исследованы проблемы милосердия и жертвенности. Отмечены особенности петербургского юродства. Особое внимание уделено вопросам выбора подвига юродства, который у Матроны был обусловлен несколькими обстоятельствами, среди которых несчастливая личной жизнь, смерть двух мужей, пребывание в статусе солдатки, и в большей мере – сестры милосердия, а также пережитые ужасы войны. Проанализирована деятельность Матроны как целительницы и прорицательницы. Актуальность работе придает рассмотрение сохранения представлений о целительских и провидческих способностях блаженной Матроны Босоножке в наши дни во время эпидемии коронавируса.
in English:
The article attempts to portray the famous holy fool from St. Petersburg to describe her social status, socio-cultural appearance, worldview, moral and ethical principles, and deeds. The studies of the female holy foolishness, wandering, and biographical studies of outstanding women aimed at studying their subjective experience, everyday and ritual behavior in a specific historical era, are relevant in historical science. The character of Matrona the Barefoot is important in the light of gender relations in historical retrospect and now, since interest in her personality has not been lost to this day. The author conducted a study of the change in Matrona’s social status. The St. Petersburg holy fool serves as an example for investigating the issues of charity and sacrifice. Special attention is paid to choosing the feat of foolishness, which Matrona did due to several circumstances: an unhappy personal life, the death of two husbands, her status as a female soldier and a nurse, the horrors of war she experienced. The article analyzes Matrona’s activity as a healer and prophetess. The author discusses the popularity of ideas about the powers of the blessed Matrona the Barefoot in our days during the coronavirus epidemic.
Социально-экономическая и миграционная ситуация в провинциальных городах Центральной России (по материалам г. Солигалич и г. Чухлома Костромской области)
Authors: Рыбин А.А.
Published: March 2022

В современном мире вопросам миграции уделяется большое внимание. Многие люди в поисках лучшей жизни покидают свою малую родину, поэтому для понимания общей картины современного мира различные процессы, связанные с миграцией и мигрантами, требуют детального изучения. В ходе реализации научно-исследовательского проекта РФФИ «Миграционные процессы и их влияние на социально-экономическое развитие Центральной России: сравнительный анализ провинциального региона и мегаполиса (на примере Костромской области и г. Москвы)», в 2021 г. были проведены полевые исследования в г. Солигаличе и г. Чухломе Костромской области. Полученные данные дают представление о современной миграционной ситуации в отдаленных районах Костромской области, таких как Солигаличский и Чухломский. До сегодняшнего дня подобные полевые исследования в этих регионах не проводились, в силу чего их результаты представляют собой особую ценность. По итогам работы можно понять, как коренное население Нечерноземья относится к трудовым мигрантам и в целом к пониманию миграционных процессов в стране и регионе.
in English:
In the modern world, much attention is paid to migration issues. Many people leave their homeland searching for a better life. Various processes associated with migration and migrants require a more detailed study to obtain the general picture of the modern world. Field studies in Soligalich and Chukhloma, Kostroma region, were carried out as a part of the "Migration processes and their impact on the socio-economic development of Central Russia: a comparative analysis of the province and megalopolis (the example of the Kostroma region and Moscow)" project (Russian Foundation for the Basic Research). The study sheds light on the migration situation in remote areas of the Kostroma region, namely in Soligalichsky and Chukhlomskoy districts. Such field studies are conducted in these areas for the first time, and therefore their results are of particular value. The work reveals the attitude of the region's population to labor migrants and, in general, to the migration processes in the country.
YALIcloneNHEJ: An Efficient Modular Cloning Toolkit for NHEJ Integration of Multigene Pathway and Terpenoid Production in Yarrowia lipolytica
Authors: Li Ya-Wen , Yang Cai-Ling , Shen Qi , Peng Qian-Qian , Guo Qi , Nie Zhi-Kui , Sun Xiao-Man , Shi Tian-Qiong , Ji Xiao-Jun , Huang He
Published: March 2022

Non-homologous end-joining (NHEJ)-mediated random integration in Yarrowia lipolytica has been demonstrated to be an effective strategy for screening hyperproducer strains. However, there was no multigene assembly method applied for NHEJ integration, which made it challenging to construct and integrate metabolic pathways. In this study, a Golden Gate modular cloning system (YALIcloneNHEJ) was established to develop a robust DNA assembly platform in Y. lipolytica. By optimizing key factors, including the amounts of ligase and the reaction cycles, the assembly efficiency of 4, 7, and 10 fragments reached up to 90, 75, and 50%, respectively. This YALIcloneNHEJ system was subsequently applied for the overproduction of the sesquiterpene (-)-α-bisabolol by constructing a biosynthesis route and enhancing the flux in the mevalonate pathway. The resulting strain produced 4.4 g/L (-)-α-bisabolol, the highest titer reported in yeast to date. Our study expands the toolbox of metabolic engineering and is expected to enable a highly efficient production of various terpenoids.
Study on the Prediction Method of Long-term Benign and Malignant Pulmonary Lesions Based on LSTM
Authors: Liu Xindong , Wang Mengnan , Aftab Rukhma
Published: March 2022

In order to more accurately and comprehensively characterize the changes and development rules of lesion characteristics in pulmonary medical images in different periods, the study was conducted to predict the evolution of pulmonary nodules in the longitudinal dimension of time, and a benign and malignant prediction model of pulmonary lesions in different periods was constructed under multiscale three-dimensional (3D) feature fusion. According to the sequence of computed tomography (CT) images of patients at different stages, 3D interpolation was conducted to generate 3D lung CT images. The 3D features of different size lesions in the lungs were extracted using 3D convolutional neural networks for fusion features. A time-modulated long short-term memory was constructed to predict the benign and malignant lesions by using the improved time-length memory method to learn the feature vectors of lung lesions with temporal and spatial characteristics in different periods. The experiment shows that the area under the curve of the proposed method is 92.71%, which is higher than that of the traditional method.
An Insight in Developing Carrier-Free Immobilized Enzymes
Authors: Chauhan Vivek , Kaushal Diksha , Dhiman Vivek Kumar , Kanwar Shamsher Singh , Singh Devendra , Dhiman Vinay Kumar , Pandey Himanshu
Published: March 2022

Enzymes play vital roles in all organisms. The enzymatic process is progressively at its peak, mainly for producing biochemical products with a higher value. The immobilization of enzymes can sometimes tremendously improve the outcome of biocatalytic processes, making the product(s) relatively pure and economical. Carrier-free immobilized enzymes can increase the yield of the product and the stability of the enzyme in biocatalysis. Immobilized enzymes are easier to purify. Due to these varied advantages, researchers are tempted to explore carrier-free methods used for the immobilization of enzymes. In this review article, we have discussed various aspects of enzyme immobilization, approaches followed to design a process used for immobilization of an enzyme and the advantages and disadvantages of various common processes used for enzyme immobilization.
Reactor Design and Optimization of α-Amino Ester Hydrolase- Catalyzed Synthesis of Cephalexin
Authors: Lagerman Colton E. , Grover Martha A. , Rousseau Ronald. W. , Bommarius Andreas S.
Published: March 2022

Pharmaceutical production quality has recently been a focus for improvement through incorporation of end-to-end continuous processing. Enzymatic ß-lactam antibiotic synthesis has been one focus for continuous manufacturing, and α-amino ester hydrolases (AEHs) are currently being explored for use in the synthesis of cephalexin due to their high reactivity and selectivity. In this study, several reactors were simulated to determine how reactor type and configuration impacts reactant conversion, fractional yield toward cephalexin, and volumetric productivity for AEH-catalyzed cephalexin synthesis. The primary reactor configurations studied are single reactors including a continuous stirred-tank reactor (CSTR) and plug flow reactor (PFR) as well as two CSTRS and a CSTR + PFR in series. Substrate concentrations fed to the reactors as well as enzyme concentration in the reactor were varied. The presence of substrate inhibition was found to have a negative impact on all reactor configurations studied. No reactor configuration simultaneously allowed high substrate conversion, high fractional yield, and high productivity; however, a single PFR was found to enable the highest substrate conversion with higher fractional yields than all other reactor configurations, by minimizing substrate inhibition. Finally, to further demonstrate the impact of substrate inhibition, an AEH engineered to improve substrate inhibition was simulated and Pareto optimal fronts for a CSTR catalyzed with the current AEH were compared to Pareto fronts for the improved AEH. Overall, reduced substrate inhibition would allow for high substrate conversion, fractional yield, and productivity with only a single CSTR.
Tumor-Derived Exosomes Modulate Primary Site Tumor Metastasis
Authors: Bai Suwen , Wang Zunyun , Wang Minghua , Li Junai , Wei Yuan , Xu Ruihuan , Du Juan
Published: March 2022

Tumor-derived exosomes (TDEs) are actively produced and released by tumor cells and carry messages from tumor cells to healthy cells or abnormal cells, and they participate in tumor metastasis. In this review, we explore the underlying mechanism of action of TDEs in tumor metastasis. TDEs transport tumor-derived proteins and non-coding RNA to tumor cells and promote migration. Transport to normal cells, such as vascular endothelial cells and immune cells, promotes angiogenesis, inhibits immune cell activation, and improves chances of tumor implantation. Thus, TDEs contribute to tumor metastasis. We summarize the function of TDEs and their components in tumor metastasis and illuminate shortcomings for advancing research on TDEs in tumor metastasis.
The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer
Authors: Xie Rongrong , Yuan Mengping , Jiang Yiyan
Published: March 2022

Background:EFNA1–5 have important physiological functions in regulating tumorigenesis and metastasis. However, correlating EFNA genes in the tumor immune microenvironment (TIME), and the prognosis of patients with gastric cancer remains to be determined.

Methods: Using public databases, the expression of EFNA1-5 in pan-cancer and gastric cancer was comprehensively analyzed using UCSC Xena, the Oncomine dataset and UALCAN. We further completed survival analysis by Kaplan-Meier plotter to evaluate the prognosis of the high and low expression groups of the EFNAs gene in patients with gastric cancer. The TIMER tool was used to reveal the correlation between immune cell infiltration and genes of interest. Spearman correlation was used to find an association between the EFNA genes and tumor stem cells, TIME, microsatellite instability (MSI) or tumor mutational burden (TMB). We also used cBioportal, GeneMANIA and STRINGS to explore the types of changes in these genes and the protein interactions. Finally, we described the TIME based on QUANTISEQ algorithm, predicted the relationship between the EFNA genes and half-maximal inhibitory concentration (IC50), and analyzed the relationship between the EFNA family genes and immune checkpoints.

Results: The expression of EFNA1, EFNA3, EFNA4, and EFNA5 was elevated in pan-cancer. Compared with normal adjacent tissues, EFNA1, EFNA3, and EFNA4 were up-regulated in gastric cancer. In terms of the influence on the survival of patients, the expression of EFNA3 and EFNA4 were related to overall survival (OS) and disease-free survival (DFS) for patients with gastric cancer. High expression of EFNA5 often predicted poor OS and DFS. In gastric cancer, the expression of EFNA3 and EFNA4 showed a significant negative correlation with B cells. The higher the expression of EFNA5, the higher the abundance of B cells, CD4+T cells and macrophages. CD8+T cells, dendritic cells infiltration and EFNA1-4 expression were negatively correlated. The infiltration of CD4+T cells, macrophages and neutrophils was negatively correlated with the expression of EFNA1, EFNA3, and EFNA4. TMB and MSI were positively correlated with EFNA3/EFNA4 expression. In the tumor microenvironment and drug sensitivity, EFNA3/4/5 also showed a significant correlation. In addition, we explored the relationship between the EFNA family genes and the immune microenvironment (B cells, M2 macrophages, monocytes, CD8+ T cells, regulatory T cells, myeloid dendritic cells, natural killer cells, non-regulatory CD4+ T cells), immune checkpoint (PDCD1, PDCD1LG2, CD274, CTLA4), and IC50 of common chemotherapeutic drugs for gastric cancer (5-fluorouracil, cisplatin, docetaxel and gemcitabine).

Conclusions: Our study provides new ideas for tumor treatment and prognosis from the perspective of TIME, and nominates EFNA1–5 to become potential therapeutic targets for gastric cancer.
Development and Validation of Ferroptosis-Related LncRNA Biomarker in Bladder Carcinoma
Authors: Wang Yiru , Zhang Shijie , Bai Yang , Li Gen , Wang Siyu , Chen Jiayi , Liu Xin , Yin Hang
Published: March 2022

Bladder cancer (BC) is a highly prevalent cancer form of the genitourinary system; however, the effective biomarkers are still ambiguous and deserve deeper investigation. Long non-coding RNA (lncRNA) occupies a prominent position in tumor biology and immunology, and ferroptosis-related genes participate in regulatory processes of cancer. In this study, 538 differentially expressed ferroptosis-related lncRNAs were identified from the The Cancer Genome Atlas database through co-expression method and differential expression analysis. Then, the samples involved were equally and randomly divided into two cohorts for the construction of gene model and accuracy verification. Subsequently, a prediction model containing five ferroptosis-related lncRNAs was constructed by LASSO and Cox regression analysis. Furthermore, in terms of predictive performance, consistent results were achieved in the training set, testing set, and entire set. Kaplan–Meier curve, receiver operating characteristic area under the curve, and principal component analysis results verified the good predictive ability of model, and the gene model was confirmed as an independent prognostic indicator. To further investigate the mechanism, we explored the upstream of five lncRNAs and found that they may be modified by m6A to increase or decrease their expression in BC. Importantly, the low-risk group displayed higher mutation burden of tumors and lower Tumor Immune Dysfunction and Exclusion score, which may be predicted to have a higher response rate to immunotherapy. Interestingly, the patients in the high-risk group appeared to have a higher sensitivity to traditional chemotherapeutic agents through pRRophetic analysis. In general, our research established a five-ferroptosis-related lncRNA signature, which can be served as a promising prognostic biomarker for BC.
Case Report: Intravascular Ultrasound-guided Intervention for Anastomosis Stenosis of the Left Main Coronary Artery Post-Cabrol Technique
Authors: Oh Seok , Kim Ju Han , Hyun Dae Young , Cho Kyung Hoon , Kim Min Chul , Sim Doo Sun , Hong Young Joon , Ahn Youngkeun , Jeong Myung Ho , Jung Yochun
Published: March 2022

Introduction

Some cases of percutaneous coronary intervention (PCI) for the anastomotic site between the Cabrol-type conduit and the left main coronary artery (LMCA) have been reported. Nevertheless, the combination of PCI with a detailed description of lesion appearance using virtual histology-intravascular ultrasound (VH-IVUS) has never been reported. In this study, we present a case of acute myocardial infarction that was successfully treated with intravascular ultrasound (IVUS)-guided PCI for focal stenosis at the anastomotic site, and the plaque composition was studied in detail.

Case Presentation

A 35-year-old Korean male with Behçet's disease was diagnosed with acute myocardial infarction. He had previously undergone three cardiothoracic surgeries including two aortic replacements, followed by modified Bentall operation with a Cabrol-type aortocoronary anastomosis. Coronary angiogram (CAG) showed focal critical stenosis at the anastomosis site between the conduit and the LMCA, and VH-IVUS showed fibrotic plaque with mainly fibrous tissue but without a confluent necrotic core. PCI was performed using a drug-eluting stent (4.5 × 12 mm, SynergyTM, Boston Scientific, Marlborough, MA, USA). Since a repeat CAG and IVUS post-surgery showed an under-expanded stent strut, post-dilation ballooning was additionally performed. Subsequently, the repeat IVUS revealed wellapposed and optimized deployment of the drug-eluting stent with full lesion coverage. Final CAG showed optimal angiographic results. After successful PCI, the patient's anginal symptoms improved dramatically, and he was successfully discharged from our hospital.

Conclusion

This study presents an IVUS-guided PCI case for an anastomotic site between the conduit and the LMCA. It is the first to investigate the characteristics of this lesion through VH-IVUS, which demonstrated the presence of fibrous plaques at the anastomotic site. IVUS radiofrequency data allow for a detailed assessment of plaque composition and provide new insights into the histopathological nature of stenotic lesions at the anastomotic site, especially in patients with chronic inflammatory diseases like Behçet's disease.
Periodontal Wound Healing and Regeneration: Insights for Engineering New Therapeutic Approaches
Authors: Fraser David , Caton Jack , Benoit Danielle S. W.
Published: March 2022

Periodontitis is a widespread inflammatory disease that leads to loss of the tooth supporting periodontal tissues. The few therapies available to regenerate periodontal tissues have high costs and inherent limitations, inspiring the development of new approaches. Studies have shown that periodontal tissues have an inherent capacity for regeneration, driven by multipotent cells residing in the periodontal ligament (PDL). The purpose of this review is to describe the current understanding of the mechanisms driving periodontal wound healing and regeneration that can inform the development of new treatment approaches. The biologic basis underlying established therapies such as guided tissue regeneration (GTR) and growth factor delivery are reviewed, along with examples of biomaterials that have been engineered to improve the effectiveness of these approaches. Emerging therapies such as those targeting Wnt signaling, periodontal cell delivery or recruitment, and tissue engineered scaffolds are described in the context of periodontal wound healing, using keyin vivostudies to illustrate the impact these approaches can have on the formation of new cementum, alveolar bone, and PDL. Finally, design principles for engineering new therapies are suggested which build on current knowledge of periodontal wound healing and regeneration.
Water and Rock Chemistry Inform Our Understanding of the Deep Biosphere: Case Study in an Archaean Banded Iron Formation
Authors: Schuler Cristopher J. , Briscoe Lindsey J. , Alexander Scott C. , Alexander E. Calvin , Gralnick Jeffrey A. , Santelli Cara M. , Toner Brandy M.
Published: March 2022

Research into the deep biosphere requires an understanding of both the microbial community at a given site and the geochemical and hydrological factors that support that microbial community. To highlight the interplay between geochemistry and microbiology in these deep environments, we characterized the hydrogeologic and geochemical systems of a 2.7 Ga banded iron formation within the Canadian Shield in the Soudan Underground Mine State Park in Minnesota, United States, a site known to host a lithotrophic microbial community. Calcium-sodium-chloride brines, characteristic of deep groundwaters throughout the Canadian Shield, were found in the site with total dissolved constituents (<0.2 micron) as high as 116,000 mg/L (ppm) in one borehole. Comparison of the Soudan waters to those found at other sites in the Canadian Shield or other sites of deep biosphere research indicate that they are notable for their high magnesium concentrations relative to total salinity. Additionally, the most saline Soudan waters have distinct 2H and 18O water isotope values suggesting long periods of isolation from the surface, which would allow for the evolution of a distinctive subsurface community. The presence of the banded iron formation along with the long-term isolation of the shield waters make Soudan a site of great potential for future research into deep crustal life. Furthermore, our work at Soudan highlights how geochemical data can inform future research into the deep biosphere and highlights a path for future research at the mine.
Estimates of Methane Release From Gas Seeps at the Southern Hikurangi Margin, New Zealand
Authors: Turco Francesco , Ladroit Yoann , Watson Sally J. , Seabrook Sarah , Law Cliff S. , Crutchley Gareth J. , Mountjoy Joshu , Pecher Ingo A. , Hillman Jess I. T. , Woelz Susi , Gorman Andrew R.
Published: March 2022

The highest concentration of cold seep sites worldwide has been observed along convergent margins, where fluid migration through sedimentary sequences is enhanced by tectonic deformation and dewatering of marine sediments. In these regions, gas seeps support thriving chemosynthetic ecosystems increasing productivity and biodiversity along the margin. In this paper, we combine seismic reflection, multibeam and split-beam hydroacoustic data to identify, map and characterize five known sites of active gas seepage. The study area, on the southern Hikurangi Margin off the North Island of Aotearoa/New Zealand, is a well-established gas hydrate province and has widespread evidence for methane seepage. The combination of seismic and hydroacoustic data enable us to investigate the geological structures underlying the seep sites, the origin of the gas in the subsurface and the associated distribution of gas flares emanating from the seabed. Using multi-frequency split-beam echosounder (EK60) data we constrain the volume of gas released at the targeted seep sites that lie between 1,110 and 2,060 m deep. We estimate the total deep-water seeps in the study area emission between 8.66 and 27.21 × 106 kg of methane gas per year. Moreover, we extrpolate methane fluxes for the whole Hikurangi Margin based on an existing gas seep database, that range between 2.77 × 108 and 9.32 × 108 kg of methane released each year. These estimates can result in a potential decrease of regional pH of 0.015–0.166 relative to the background value of 7.962. This study provides the most quantitative assessment to date of total methane release on the Hikurangi Margin. The results have implications for understanding what drives variation in seafloor biological communities and ocean biogeochemistry in subduction margin cold seep sites.
Numerical Simulations of Combined Brine Flooding With Electrical Heating–Assisted Depressurization for Exploitation of Natural Gas Hydrate in the Shenhu Area of the South China Sea
Authors: Zhang Qi , Wang Yanfei
Published: March 2022

The Shenhu area of the South China Sea (SCS) is one of the most promising fields for natural gas hydrate (NGH) exploitation. However, previous studies conclude that using only depressurization is inefficient for this challenging hydrate deposits surrounded by permeable water zones, which requires assistance by thermal stimulation to promote hydrate decomposition and methane recovery. However, traditional thermal stimulation methods with hot water or steam injection induce massive heat loss along the wellbore. In addition, in situ electrical heating only results in a limited high temperature region due to low thermal conductivity of hydrate deposits. Therefore, we numerically investigate the performance of combined brine flooding with electrical heating–assisted depressurization in horizontal wells for exploitation of natural gas hydrate in the SCS, which simultaneously possesses the merits of low heat loss and enhanced heat transfer by convection. Our simulation results show that thermal stimulation by combined brine flooding with electrical heating can significantly enhance hydrate dissociation and methane recovery. After 20 years of production, the cumulative methane production of combined brine flooding with electrical heating–assisted depressurization is 1.41 times of that conducted by the only depressurization method. Moreover, the energy efficiency can be improved by reducing electrical heating time, and terminating electrical heating with 70% hydrate dissociation achieves the highest net energy gain. In addition, methane recovery and net energy gain increases with electrical heating power and brine injection pressure but with a decreasing rate. Therefore, the selection of electrical heating power and brine injection pressure should be performed carefully and comprehensively considering both the efficiency of gas production and risks of geological hazard. It is hoped that our research results will provide reference and guidance for the development of a similar NGH reservoir in order to promote the industrial development process of NGH.
Development of the Competence Measure of Individual Teacher-Student Relationships (COMMIT): Insight Into the Attitudes, Knowledge, and Self-Efficacy of Pre-service Teachers
Authors: Borremans Liedewij F. N. , Spilt Jantine L.
Published: March 2022

The importance of dyadic teacher-student relationships for both teachers and students is widely acknowledged. However, only limited research has explored how competent teachers feel in building these relationships. The current study aimed, first, to deepen the knowledge on relational competence by targeting teachers’ competence in building dyadic teacher-student relationships specifically. To this end, the Competence Measure of Individual Teacher-student relationships (COMMIT) was developed. This questionnaire is explicitly based on theories used in research on affective teacher-student relationships and addresses multiple aspects of competence (attitudes, knowledge, and self-efficacy). Second, as teacher education programs have been repeatedly criticized for not sufficiently targeting relational competencies, the current study focused on pre-service teachers’ perceived competence and aimed to explore differences in this competence across pre-service teachers in subsequent years of their teacher training. Criterion validity of the newly developed COMMIT was examined in a sample of pre-service teachers in pre-primary and primary teacher education programs (N = 535). Six subscales were created, addressing pre-service teachers’ attitude toward teacher-student relationships (1 scale), their knowledge of teacher-student relationships and coping (2 scales), and their self-efficacy beliefs with regard to building closeness, coping with conflict, and reflective functioning (3 scales). Results showed that pre-service teachers had a rather positive attitude toward teacher-student relationships, and felt quite knowledgeable and self-efficacious, yet not in all aspects of dyadic relationship-building. Results further revealed that pre-service teachers in the final year of teacher training felt more competent, yet, again, not for all aspects of dyadic relationship-building. Notably, differences between pre-service teachers in subsequent years of teacher education were less pronounced in primary compared to pre- primary teacher education programs. Suggestions for future research and implications for initial teacher training are discussed.
Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility
Authors: Jiang Yin , Li Shiping , Xu Wenming , Ying Junjie , Qu Yi , Jiang Xiaohui , Zhang Ayuan , Yue Yan , Zhou Ruixi , Ruan Tiechao , Li Jinhui , Mu Dezhi
Published: March 2022

Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.
KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma
Authors: Lee Bo-Ching , Kang Victor Jing-Wei , Pan Chien-Ting , Huang Jia-Zheng , Lin Yu-Li , Chang Yi-Yao , Tsai Cheng-Hsuan , Chou Chia-Hung , Chen Zheng-Wei , Liao Che-Wei , Chiu Yu-Wei , Wu Vin-Cent , Hung Chi-Sheng , Chang Chin-Chen , Lin Yen-Hung
Published: March 2022

Objective

Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status.

Methods

We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed.

Results

After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04).

Conclusion

KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.
Clinical–Pathological Features and Treatment Outcome of Patients With Hobnail Variant Papillary Thyroid Carcinoma
Authors: Poma Anello Marcello , Macerola Elisabetta , Proietti Agnese , Vignali Paola , Sparavelli Rebecca , Torregrossa Liborio , Matrone Antonio , Basolo Alessio , Elisei Rossella , Santini Ferruccio , Ugolini Clara
Published: March 2022

Papillary thyroid carcinoma (PTC) with hobnail areas above 30% is classified as hobnail variant (HVPTC). Although it is widely accepted that HVPTC has a worse outcome than classical PTC, it is unclear whether PTC with hobnail features below 30% is as aggressive as HVPTC. We gathered the largest mono-institutional series of PTC with hobnail areas and HVPTC to evaluate differences in terms of pathological features of aggressiveness, molecular profile, and treatment outcome. A total of 99 PTC with hobnail features above 5% were retrospectively selected; 34 of them met the criteria for HVPTC (0.4% of all PTC diagnosed at our institution). All tumors showed high rates of extra-thyroidal extension (40.4%), lymph node metastasis (68.1% of patients with lymphadenectomy), and vascular emboli (49.5%), with no differences according to the 30% cutoff. On the other hand, distant metastases were present in HVPTC only (9.4%). Also, advanced age, advanced disease stage, and TERT promoter mutation were associated with HVPTC. More than half of the patients with follow-up had structural or biochemical persistence after 1 year from surgery. Structural persistence was significantly more common in patients with HVPTC (37.5% vs. 8.7%), while no differences were observed considering structural and biochemical persistence together. The presence of hobnail features identifies locally aggressive tumors, and, consequently, it should be always acknowledged in the pathological report. However, tumors with more than 30% hobnail areas frequently present TERT promoter mutations, advanced disease stage, and structural persistence after radioiodine ablation.
Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children
Authors: Tolba Aisha , Mandour Iman , Musa Noha , Elmougy Fatma , Hafez Mona , Abdelatty Sahar , Ibrahim Amany , Soliman Hend , Labib Bahaaeldin , Elshiwy Yasmine , Ramzy Tarek , Elsharkawy Marwa
Published: March 2022

Background: Congenital adrenal hyperplasia (CAH) is a monogenic disorder caused by genetic diversity in the CYP21A2 gene, with 21-hydroxylase deficiency (21-OHD) as the most common type. Early sex assignment and early diagnosis of different genetic variations with a proper technique are important to reduce mortality and morbidity. Proper early sex identification reduces emotional, social, and psychological stress.

Aim: Detection of a spectrum of aberrations in the CYP21A2 gene, including copy number variations, gene conversion, chimeric genes, and point variations.

Methods: The CYP21A2 gene was screened using MLPA assay in 112 unrelated Egyptian children with 21-OHD CAH (33 males and 79 females).

Results: In the studied group, 79.5% were diagnosed within the first month of life. 46.8% of the genetic females were misdiagnosed as males. Among the copy number variation results, large deletions in 15.4% and three types of chimeric genes in 9% (CH-1, CH-7, and CAH-X CH-1) were detected. Regarding gene dosage, one copy of CYP21A2 was found in 5 cases (4.5%), three copies were detected in 7 cases (6.3%), and one case (0.9%) showed four copies. Eight common genetic variants were identified, I2G, large deletions, large gene conversion (LGC), I172N, F306 + T, -113 SNP, 8bp Del, and exon 6 cluster (V237E and M239K) with an allelic frequency of 32.62%, 15.45%, 7.30%, 3.00%, 2.58%, 2.15%, 0.86%, and 0.86%, respectively.

Conclusion: High prevalence of copy number variations highlights the added value of using MLPA in routine laboratory diagnosis of CAH patients.
Monitoring of Circulating CAR T Cells: Validation of a Flow Cytometric Assay, Cellular Kinetics, and Phenotype Analysis Following Tisagenlecleucel
Authors: Peinelt Andreas , Bremm Melanie , Kreyenberg Hermann , Cappel Claudia , Banisharif-Dehkordi Julia , Erben Stephanie , Rettinger Eva , Jarisch Andrea , Meisel Roland , Schlegel Paul-Gerhardt , Beck Olaf , Bug Gesine , Klusmann Jan-Henning , Klingebiel Thomas , Huenecke Sabine , Bader Peter
Published: March 2022

Chimeric antigen receptor (CAR) T cell therapy is a potent new treatment option for relapsed or refractory hematologic malignancies. As the monitoring of CAR T cell kinetics can provide insights into the activity of the therapy, appropriate CAR T cell detection methods are essential. Here, we report on the comprehensive validation of a flow cytometric assay for peripheral blood CD19 CAR T cell detection. Further, a retrospective analysis (n = 30) of CAR T cell and B cell levels over time has been performed, and CAR T cell phenotypes have been characterized. Serial dilution experiments demonstrated precise and linear quantification down to 0.05% of T cells or 22 CAR T cell events. The calculated detection limit at 13 events was confirmed with CAR T cell negative control samples. Inter-method comparison with real-time PCR showed appreciable correlation. Stability testing revealed diminished CAR T cell values already one day after sample collection. While we found long-term CAR T cell detectability and B cell aplasia in most patients (12/17), some patients (5/17) experienced B cell recovery. In three of these patients the coexistence of CAR T cells and regenerating B cells was observed. Repeat CAR T cell infusions led to detectable but limited re-expansions. Comparison of CAR T cell subsets with their counterparts among all T cells showed a significantly higher percentage of effector memory T cells and a significantly lower percentage of naïve T cells and T EMRA cells among CAR T cells. In conclusion, flow cytometric CAR T cell detection is a reliable method to monitor CAR T cells if measurements start without delay and sufficient T cell counts are given.
Whole-Process Treatment of Combined Small Cell Lung Cancer Initially Diagnosed as “Lung Squamous Cell Carcinoma”: A Case Report and Review of the Literature
Authors: Dong Yong , Li Qijun , Li Da , Fang Yong , Wang Chongwei
Published: March 2022

The rarity and complexity of histology lead to the low diagnosis rate and high misdiagnosis rate of combined small cell lung cancer (C-SCLC). Nowadays, C-SCLC has no commonly recommended therapeutic regimen, mainly conforming to SCLC treatment. Here, we report a patient initially diagnosed as IIIA “lung squamous cell carcinoma” by a small specimen. Radical resection was achieved after neoadjuvant immunochemotherapy, and the final surgical pathology was C-SCLC containing three different histological components. Moreover, in the literature review, we explored the therapeutic effect of neoadjuvant immunotherapy in C-SCLC, expounded the therapeutic conflicts among heterogeneous components, and analyzed the pathology complexity at the tissue, cell, and molecule levels in-depth, including possible genetic characteristics, origin, and evolution by next-generation sequencing (NGS).
Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development
Authors: Tang Jialin , Li Zhongxia , Wu Qiong , Irfan Muhammad , Li Weili , Liu Xiangyu
Published: March 2022

Non-homologous end joining (cNHEJ) is a major pathway to repair double-strand breaks (DSBs) in DNA. Several core cNHEJ are involved in the progress of the repair such as KU70 and 80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV, and XRCC4-like factor (XLF). Recent studies have added a number of new proteins during cNHEJ. One of the newly identified proteins is Paralogue of XRCC4 and XLF (PAXX), which acts as a scaffold that is required to stabilize the KU70/80 heterodimer at DSBs sites and promotes the assembly and/or stability of the cNHEJ machinery. PAXX plays an essential role in lymphocyte development in XLF-deficient background, while XLF/PAXX double-deficient mouse embryo died before birth. Emerging evidence also shows a connection between the expression levels of PAXX and cancer development in human patients, indicating a prognosis role of the protein. This review will summarize and discuss the function of PAXX in DSBs repair and its potential role in cancer development.
Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation
Authors: Joudi Anthony M. , Reyes Flores Carla P. , Singer Benjamin D.
Published: March 2022

FoxP3+ regulatory T (Treg) cells maintain immune homeostasis, promote self-tolerance, and have an emerging role in resolving acute inflammation, providing tissue protection, and repairing tissue damage. Some data suggest that FoxP3+ T cells are plastic, exhibiting susceptibility to losing their function in inflammatory cytokine-rich microenvironments and paradoxically contributing to inflammatory pathology. As a result, plasticity may represent a barrier to Treg cell immunotherapy. Here, we discuss controversies surrounding Treg cell plasticity and explore determinants of Treg cell stability in inflammatory microenvironments, focusing on epigenetic mechanisms that clinical protocols could leverage to enhance efficacy and limit toxicity of Treg cell-based therapeutics.
Cetacean Strandings in the US Pacific Northwest 2000–2019 Reveal Potential Linkages to Oceanographic Variability
Authors: Warlick Amanda J. , Huggins Jessica L. , Lambourn Dyanna M. , Duffield Deborah A. , D’Alessandro Dalin N. , Rice James M. , Calambokidis John , Hanson M. Bradley , Gaydos Joseph K. , Jeffries Steven J. , Olson Jennifer K. , Scordino Jonathan J. , Akmajian Adrianne M. , Klope Matthew , Berta Susan , Dubpernell Sandy , Carlson Betsy , Riemer Susan , Hodder Jan , Souze Victoria , Elsby Alysha , King Cathy , Wilkinson Kristin , Boothe Tiffany , Norman Stephanie A.
Published: March 2022

Studying patterns in marine mammal stranding cases can provide insight into changes in population health, abundance, and distribution. Cetaceans along the United States West coast strand for a wide variety of reasons, including disease, injury, and poor nutritional status, all of which may be caused by both natural and anthropogenic factors. Examining the potential drivers of these stranding cases can reveal how populations respond to changes in their habitat, notably oceanographic variability and anthropogenic activities. In this study, we aim to synthesize recent patterns in 1,819 cetacean strandings across 26 species in the Pacific Northwest from 2000 to 2019 to compare with previous findings. Additionally, we aim to quantify the effects of localized and basin-scale oceanographic conditions on monthly stranding cases for five focal species using generalized additive models in order to explore potential relationships between strandings and changes in biophysical features that could affect foraging conditions or other important physiological cues. Our results suggest that strandings of harbor porpoises, gray whales, humpback whales, Dall’s porpoises, and striped dolphins are correlated with certain environmental variables, including sea surface temperature, chlorophyll concentration, and the Pacific Decadal Oscillation depending on the species. While it remains challenging to identify the causal mechanisms that underlie these relationships for a given species or population based on its utilization of such a complex ecosystem, improving our understanding of periods of increased strandings can enhance our knowledge of how these species interact with their environment and assist conservation and management efforts. This study enhances the utility of stranding records over time beyond simply reporting trends and has broader applicability to other geographic regions amid global climate change.
Sub-Regional Marine Heat Waves in the Mediterranean Sea From Observations: Long-Term Surface Changes, Sub-Surface and Coastal Responses
Authors: Juza Mélanie , Fernández-Mora Àngels , Tintoré Joaquin
Published: March 2022

Society is facing climate-related challenges and impacts, such as marine heat wave (MHW) events that adversely affect ecosystems, threaten economies and strengthen storms by warming ocean waters. MHWs are substantially increasing in intensity, duration and frequency worldwide, particularly in the Mediterranean Sea, which responds rapidly to climate change. This study proposes a comprehensive analysis of MHWs in the different sub-regions of the Mediterranean, where the strong spatial variability requires focused attention, from surface to sub-surface and from open to coastal oceans. At surface, the MHW indices have dramatically increased over the last four decades from 1982 to 2020, with an unprecedented acceleration rate in recent years in all sub-regions. Besides the sub-regional features of surface MHWs, the propagation of such events into the ocean interior is also examined highlighting sub-regional and seasonal variability in the sub-surface ocean response. The resulting upper-ocean density stratification to these extreme events is enhanced in all sub-regions which would increase the degree of decoupling between surface and deep oceans causing changes in water masses and marine life. Finally, extremely warm events in coastal waters are also addressed through a case study in the Balearic Islands showing their higher intensity and occurrence in near-shore environment as well as the different response from surface to sub-surface that strongly depends on local features. In addition to this study, the Balearic Islands Coastal Observing and Forecasting System (SOCIB) has implemented a smart platform to monitor, visualize and share timely information on sub-regional MHWs, from event detection in real-time to long-term variations in response to global warming, to diverse stakeholders. Society-aligned ocean information at sub-regional scale will support the policy decision-making and the implementation of specific actions at local, national and regional scales, and thus contribute to respond to societal and worldwide environmental challenges.
Five-Month Incubation of Viviparous Deep-Water Shark Embryos in Artificial Uterine Fluid
Authors: Tomita Taketeru , Toda Minoru , Murakumo Kiyomi , Kaneko Atsushi , Yano Nagisa , Nakamura Masaru , Sato Keiichi
Published: March 2022

In this study, we developed an extra-uterine life-support system (artificial uterus) for viviparous elasmobranchs. Using this system, we maintained two embryonic specimens of the slendertail lantern shark (Etmopterus molleri) for approximately 5 months, the longest published record of the captive maintenance of the embryos of this species. This system is characterized by the use of a urea-containing artificial incubation fluid, of which the salinity and osmotic pressure are approximately equivalent to those of shark blood plasma. We hypothesized that this fluid reduces the salinity gradient between embryonic blood plasma and the environmental fluid, which thereby contributes to countering the low osmoregulatory capacity of viviparous shark embryos. However, the incubated specimens subsequently died during the process of seawater adaptation following “artificial birth.” Accordingly, information pertaining to uterine chemical dynamics throughout the gestation period is necessary for the design of a more effective incubation system. This technique will be relevant and may find application in conservation breeding at public aquaria in the future.