bluuebunny/crossref_metadata_2025 huggingface dataset:
Perbaikan Proses Bisnis Pembuatan Laporan Produksi Harian untuk Memperpendek Lead Time pada Perusahaan Manufaktur Mobil
Authors: Maukar Anastasia Lidya
Published: February 2022

This research was conducted at a four-wheeled vehicle manufacturing company located in Jakarta. The average lead time for making the Plant 2 Daily Production Report is currently around 12 minutes. With the long reporting time, this process is considered less efficient. In this research, business process improvement will be carried out by identifying non value-added activities and using business process improvement methodology. In improving the reporting process, Excel Macros will be used. After the implementation of business process improvements, the average time for making Daily Production Reports is reduced to 4 minutes or there is a time saving of 67%.

 

 
Sprichwörter und Redensarten in der ungarischen Sprache von Jugoslawien
Authors: Penavin Olga
Published: February 2022

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AKADEMİSYEN ANNELERİN GÖZÜYLE AİLEDE ÇOCUĞUN DİN EĞİTİMİ
Authors: İNAN KILIÇ Ayşe
Published: February 2022

Dünyaya neredeyse hiçbir şey bilmez olarak gelen insanın her konuda bilgi, beceri, tutum ve davranış şemalarının oluştuğu ilk yer ailedir. Hayata gözlerini açtığı andan itibaren çevresi ile etkileşime geçen çocuklar, gözlemleyerek ve tecrübe ederek ailenin sahip olduğu kültürü içselleştirirler. Aile içinde konuşulan dil, iletişim biçimi, değerler ve dinî yaşantı gibi hemen her şey çocuklar tarafından taklit yoluyla öğrenilir. Bu bakımdan çocuk eğitimi söz konusu olduğunda aileye bakarak işe başlamak doğru bir başlangıç olacaktır.
Çocuklara yönelik aile içinde din eğitimi vermek hem kültürün devamlılığı hem de insandaki manevi ihtiyaçların karşılanması adına önemlidir. Zira eğitime konu edilen dinin insanın en temel problemlerine ve anlam arayışına cevap verebilme potansiyeli vardır. Doğumdan itibaren çocukların yaşına ve dinî gelişim seyrine paralel şekilde din eğitimi vermek, bilişsel ve ruhsal gelişimin dengeli bir şekilde sürdürülmesine katkı sağlar. Çocukların ruhsal açıdan sağlıklı kişiler olarak yetişmeleri ise hem bireysel hem de toplumsal açıdan son derece mühimdir. Bu bağlamda ailelerin çocuklara yönelik din eğitimi konusundaki tutum ve davranışlarını tespit etmek, ailede din eğitimi konusuna ışık tutacaktır.
Bu araştırmanın amacı, akademisyen annelerin ailede çocuğun din eğitimi konusundaki görüşlerinin neler olduğunu ortaya koymaktır. Araştırmanın örneklemini Sinop Üniversitesinde görev yapan akademisyen annelerden seçilen gönüllüler oluşturmaktadır. Çalışmada veri toplama aracı olarak mülakat, verilerin çözümlenmesinde ise betimsel analiz tekniği kullanılmıştır.
Differentiation of Mouse Embryonic Fibroblasts (MEFs) into Cardiomyocytes Using Human-Derived Cardiac Inducing RNA (CIR)
Authors: Lemanski Larry F. , Kochegarov Andrei , Kaveh Kamran , Neal Michael , Arms Ashley , Rodriguez Yelica L , Hong Lan , Equbal M. Javed , Biswas Pipasha , Biswas Priya , Gonzalez Matthew , Ross-Ferguson Jewel , Rusk Justin , Lyman- Henley Lani , McRae-Kee Tearah , Ivory Curtis , Zhao Zhengshan
Published: February 2022

The present study explores an RNA we have discovered in human heart that induces differentiation of mouse embryonic stem cells and human induced pluripotent stem cells into cardiomyocytes in vitro. We have designated this RNA as Cardiac Inducing RNA or CIR. We now find that CIR also induces mouse embryonic fibroblasts (MEF) to form cardiomyocytes in vitro. For these studies, human-derived CIR is transfected into MEF using lipofectamine. The CIR-transfected mouse fibroblasts exhibit spindle-shaped cells, characteristic of myocardial cells in culture and express cardiac-specific troponin-T and cardiac tropomyosin. As such, the CIR-induced conversion of the fibroblasts into cardiomyocytes in vitro appears to take place without initial dedifferentiation into pluripotent stem cells. Instead, after CIR transfection using a lipofectamine transfection system, over the next 8 days there appears to be a direct transdifferentiation of Ëƒ80% of the cultured fibroblasts into definitive cardiomyocytes. Fewer than Ë‚7% of the untreated controls using non-active RNA or lipofectamine by itself show cardiomyocyte characteristics. Thus, discovery of CIR may hold significant potential for future use in repair/regeneration of damaged myocardial tissue in humans after myocardial infarction or other disease processes such that affected patients may be able to return to pre-heart-disease activity levels.
Genetic improvement of Ilex paraguariensis in western Santa Catarina State: estimate of phenotypic and genetic parameters
Authors: Floss Paulo Alfonso , Stuepp Carlos André , Wendling Ivar , Cipriani Vânia Beatriz , Reis Cristiane Aparecida Fioravante
Published: February 2022

An especially important species in South America, yerba mate (Ilex paraguariensis A.St.-Hil) is traditionally consumed as tea, chimarrão and tererê. Due to the formation of mate plantations with low productivity and high heterogeneity, genetic improvement actions have been conducted as a way to generate more productive cultivars of this species. In this sense, the present study aimed to estimate phenotypic and genetic parameters of yerba mate production traits earlier in provenance and progeny tests, implanted in the municipalities of Chapecó and Guatambu, in the western region of Santa Catarina State (South America). In each environment, 55 open pollinated yerba mate progenies were evaluated in a randomized complete block design, with five replications and three plants per plot. The traits measured at two years old were: height and crown diameter (m) and at three years were: visually estimated commercial biomass, weighed commercial biomass and thick branch mass (kg). The data obtained was analyzed using the genetic-statistical Selegen software. The results obtained support that there is genetic variability in the open pollinated yerba mate progenies evaluated in Santa Catarina, with possible gains by selecting the best parent trees for future production of improved seeds and for cloning.
The Issue in Assessing Listening: What Listening Aspect May Be Problematic Assessed Trough the Utilization of Technology
Authors: Rohaniyah Jaftiyatur , Nasrullah Nasrullah
Published: February 2022

Assessing listening is the process of assessing the spoken text through the auditory insight. It requires the ability to recognize the spoken input with the auditory capacity and the knowledge of spoken language. The task and the activities are served in six listening types (reactive, intensive, selective, responsive, extensive and interactive listening) and the indicative answer is encoded by particular listening type focus on. While technology as vehicle to assess the learners’ listening skill, that by using the technology much more spoken input are established by native-speaker and teachers’ own record is used any. This study uses document analysis from the available previous studies to analyzing, evaluating and answering the problem which is encountered by student’s listening and either or not technology used in assessing listening can help them to improve their listening ability. An overview of some researches provide that student get challenge to comprehend the native spoken input delivery such as, an accent, the length of speech, long spoken passage and linguistic feature. The authentic dialogue provides less density and length of the information than the dialogue created in the textbook, that the information incorporated in the machine/technology less improve the students’ listening comprehension. It lacks to assess in the selective listening type that the task focus on taking the important information from the spoken text.
Teaching and Learning Using Whatsapp: English Teachers' Perception
Authors: Al Arief Yusuf , Amelia Rizky , Elyani Eka Puteri
Published: February 2022

Social media has become part of the lives of Indonesian teenagers today. Referring to a survey conducted by the Indonesian Internet Network Organizing Association (APJII) in 2017, young people dominate the internet users in Indonesia to adults with a percentage of 75.50 % in the age range of 13-18 years, and teachers must deal with this fact. The researchers were interested in using teenagers' addiction to these gadgets to support the learning process. In this study, researchers used descriptive qualitative methods and took English teachers in Banjarmasin as research. The research was conducted by holding social media training, focusing on WhatsApp to learn English. Next, the researchers asked the subjects to use WhatsApp in the teaching and learning process. Next, researchers distributed questionnaires to figure out the perception of teachers. As a result, it was found that: 1) WhatsApp was very useful as a learning medium, 2) Students were motivated to follow the learning process because they used something they like, 3) WhatsApp can also promote more interaction between students.
YATARAK TEDAVİ GÖREN HASTALARDA COVID-19 'UN AKUT DÖNEM PSİKİYATRİK ETKİLERİ: GERİYE DÖNÜK BİR İNCELEME
Authors: CANSEL Neslihan
Published: February 2022

COVID-19’un ruh sağlığında ciddi etkilenme yarattığı bilinmesine rağmen, yatarak tedavi gören hastalardaki akut dönem komplikasyonlar hakkında az sayıda araştırma vardır. Bu çalışmada, konsültasyon liyezon psikiyatrisine danışılan COVID-19 enfekte hastalarda konsültasyon istenme nedeni, psikiyatrik hastalık yaygınlığı ve önerilen psikiyatrik müdahalelerin değerlendirilmesi amaçlanmıştır. Çalışma, Türkiye’de bir üniversite hastanesinde, Mart 2020- Ekim 2021 tarihleri arasında, COVID-19 nedeniyle yatarak tedavi gören 138 hastaya ait psikiyatrik konsültasyon raporlarının geriye doğru incelenmesiyle yürütülmüştür. Hastalara ait veriler elektronik tıbbi kayıtlardan elde edilmiştir. Yapılan analiz sonuçlarına göre, konsültasyon istenme nedenleri sırasıyla uykusuzluk (%26.22), kaygı/ölüm korkusu (%20.76), ajitasyon (%17.48) ve halüsinasyon/bilinçte dalgalanma (%11.47) idi. En sık konulan psikiyatrik tanılar deliryum ve uyku bozuklukları (%22.5) idi, bunları sırasıyla uyum bozukluğu (%11.6), anksiyete (%10.9) ve depresyon (%3.6) izliyordu. Hastaların % 85.5’ine medikal tedavi önerilmişti ve haloperidol en sık önerilen ajandı. Yoğun bakımda tedavi gören hastaların %44.1’i deliryum tanısı almıştı ve bunların yaşları daha yüksekti. İleri yaş, deliryum ve ölüm oranlarında artışa neden olmuştu. Bu bulgular, COVID-19 hastaları arasında psikiyatrik morbiditelerin ve deliryumun yaygın olduğuna, pandemisi sırasında konsültasyon-liyezon hizmetlerine olan ihtiyacın artabileceğine işaret etmektedir.
Effects of Attrition Shoes on Kinematics and Kinetics of Lower Limb Joints During Walking
Authors: Chen Shane Fei , Wang Yan , Peng Yinghu , Zhang Ming
Published: February 2022

Shoe attrition is inevitable as wearing time increases, which may produce diverse influences on kinematics and kinetics of lower limb joints. Excessive attrition may change support alignment and lead to deleterious impacts on the joints. The study identifies the biomechanical influences of aging shoes on lower limb joints. The shoes in the experiment were manually worn in the lateral heel. Nineteen healthy participants, including thirteen males and six females, were recruited to conduct walking experiments wearing attrition shoes (AS) and new shoes (NS) with a random order. A Vicon motion analysis system was used to collect kinematic data and ground reaction force. Kinematic and kinetic parameters of the hip, knee, and ankle joints were calculated using the Anybody Musculoskeletal Model and compared between the two conditions, AS and NS. The results showed that wearing an attrition shoe decreased the plantarflexion angle and plantarflexion moment of the ankle joint, while significantly increasing the magnitude of the first peak of the knee adduction moment and hip abduction moment and hip internal rotation moment (p < .05). The results of the study implied that wearing attrition shoes is not recommended for those people with knee problems due to increase in medial loading.
Spatial Multiomics Analysis Reveals Only Minor Genetic and Epigenetic Changes in Human Liver Cancer Stem-Like Cells Compared With Other Tumor Parenchymal Cells
Authors: Liu Dan , Li Hong , Dong Hui , Qu Mincheng , Yang Liguang , Chen Lina , Li Yixue , Wang Hongyang , He Yufei
Published: February 2022

Cancer stem cells (CSCs) usually account for a very small tumor cell population but play pivotal roles in human cancer development and recurrence. A fundamental question in cancer biology is what genetic and epigenetic changes occur in CSCs. Here we show that the in-situ global levels of DNA cytosine modifications, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC), are similar between liver cancer stem-like (LCSL) cells and paratumor liver cells of liver cancer patients. We then developed a robust method combining immunohistochemistry, laser capture microdissection and genome sequencing with ultra-low-input cells (CIL-seq) to study the detailed genetic and DNA methylation changes in human LCSL cells. We first used clinical samples of mixed hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) with stem cell features to investigate human LCSL cells. The CIL-seq analysis of HCC-CCA and HCC patients showed that LCSL cells had strong spatial genetic and epigenetic heterogeneity. More interestingly, although the LCSL cells had some potential key changes in their genome, they had substantially fewer somatic single nucleotide variants (SNVs), copy number alterations (CNAs) and differentially methylated regions than other tumor parenchymal cells. The cluster analysis of SNVs, CNAs, DNA methylation patterns and spatial transcriptomes all clearly showed that the LCSL cells were clustered with the paratumor liver cells. Thus, spatial multiomics analysis showed that LCSL cells had only minor genetic and epigenetic changes compared with other tumor parenchymal cells. Targeting key changes in CSCs, not just changes in bulk tumor cells, should be more effective for human cancer therapy.
Diagnostic, Therapeutic, and Prognostic Value of the m6A Writer Complex in Hepatocellular Carcinoma
Authors: Gu Zongting , Du Yongxing , Zhao Xueping , Wang Chengfeng
Published: February 2022

Hepatocellular carcinoma (HCC) has poor prognosis and is usually diagnosed only at an advanced stage. Identification of novel biomarkers is critical to early diagnosis and better prognosis for HCC patients. N6-methyladenosine (m6A) RNA methylation regulators play important roles in the development of many tumors. However, the m6A writer complex, a key executor of m6A methylation modification, has not been independently investigated, and its specific bioinformatics analysis has not yet been performed in HCC. In this study, we used multiple public databases to evaluate the diagnostic, therapeutic, and prognostic value of the m6A writers in HCC. The results showed that expression levels of METTL3, VIRMA and CBLL1 were significantly increased, while expression levels of METTL14 and ZC3H13 were significantly decreased in HCC, which was closely related to clinicopathological factors, such as tumor stage and prognosis. Bioinformatics further explored the possible underlying mechanisms by which the m6A writer complex are involved in activation of tumor-promoting pathways and/or inhibition of tumor-suppressing pathways, including apoptosis, cell cycle, DNA damage response and EMT. Furthermore, we showed that the m6A writer complex is correlated with immune cell infiltration and immunoregulator expression in HCC. In conclusion, the m6A writer complex may represent a promising biomarker and target that can guide targeted therapy or immunotherapy for HCC patients.
Radiocarbon Dating of the Nyixoi Chongco Rock Avalanche, Southern Tibet: Search for Signals of Seismic Shaking and Hydroclimatic Events
Authors: Ha Guanghao , Liu Feng , Cai Maotang , Pei Junling , Yao Xin , Li Lingjing
Published: February 2022

Landslides are important agents of the surface processes involved in the growth of mountainous topography. Dating prehistoric landslides is a prerequisite for establishing the relationships between prehistoric slope instability, and past climatic regimes and paleoseismic records. The Nyixoi Chongco rock avalanche (NCRA) is located in the Angang graben within the N–S trending rift zone in southern Tibet. It represents a giant prehistoric mass wasting event that was characterized by exceptional mobility and a large volume. However, the exact emplacement time and origin of the NCRA are still controversial. In this study, we conducted 14C dating of peat layers and snail shells to constrain the emplacement age of the NCRA. The 14C ages of the organic material and plant remnants in the basal peat layer are 1272–1389 and 1299–1404 cal AD, respectively. The 14C ages of aquatic snail shells and the bog overlying the rock avalanche are 425–565 and 1022–159 cal AD, respectively. These results indicate that the NCRA consisted of at least two separate and distinct events, instead of the single event suggested by previous studies. Based on field investigations and temporal correlations, we infer that there may be no paleoseismic records in the Angang graben that would corroborate a coseismic trigger for the NCRA. Therefore, we suggest that the 14C ages of the sediments below and above the landslide rocks should be interpreted carefully. The 14C ages alone do not provide sufficient evidence to infer the true trigger of the NCRA event.
Resource Remobilization Efficiency Varies With Plant Growth Form but Not Between Fens and Bogs
Authors: Cong Yu , Zhang Zhongsheng , Liu Bo , Chen Yingyi , Li Xiao , Jiang Ming , Li Mai-He
Published: February 2022

Resource resorption from senescing leaves is an important strategy for internal nutrient recycling in plants. However, our understanding of whether the responses of resource remobilization to mire types (fens vs. bogs) differ among various plant growth forms remains unclear. We thus assessed resource remobilization among various growth forms in fens and bogs in the Hani peatland in the Changbai Mountains, northeastern China. We analyzed and compared the concentrations of non-structural carbohydrates (NSCs), nitrogen (N), phosphorus (P), and potassium (K) in leaves and roots collected in August (mid-season) and September (end-season), and calculated the resource remobilization efficiency (RRE) of four species belonging to four growth forms grown in both fens and bogs. The deciduous dwarf trees (Betula fruticosa) and perennial grass (Phragmites australis) had relative higher leaf RRE than the moss (Sphagnum magellanicum). Although leaf nutrient RRE did not differ between fens and bogs, the deciduous dwarf trees had a higher leaf NSC RRE in bogs than in fens, and the moss NSC RRE was lower in bogs than in fens. Our results suggest that reallocation of mobile carbohydrates seems to be more sensitive to the growth condition than nutrients (N, P, and K) under nutrient-poor inhabits, which may be one of the reasons leading to nutrient limitation in peatlands.
Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma
Authors: Wang Wei-Ming , Yang Si-Si , Shao Shu-Hui , Nie Huan-Quan , Zhang Jing , Su Tong
Published: February 2022

Purpose

Type 2 diabetes mellitus (T2DM) is among the risk factors for the occurrence and development of cancer. Metformin is a potential anticancer drug. Epidermal growth factor receptor (EGFR) plays an important role in the progression of oral squamous cell carcinoma(OSCC), but the relationship between metformin and EGFR expression in OSCC remains unclear.

Methods

This study involved the immunohistochemical detection of EGFR expression in cancer tissues of patients with T2DM and OSCC. The patients were divided into groups according to whether they were taking metformin for the treatment of T2DM, and the expression of EGFR in different groups was compared. Correlation analysis between the expression of EGFR and the fluctuation value of fasting blood glucose (FBG) was carried out. Immunohistochemistry was used to detect the expression of EGFR in cancer tissues of patients with recurrent OSCC. These patients had normal blood glucose and took metformin for a long time after the first operation.

Results

EGFR expression in T2DM patients with OSCC taking metformin was significantly lower than that in the non-metformin group. FBG fluctuations were positively correlated with the expression of EGFR in the OSCC tissues of the non-metformin group of T2DM patients. In patients with recurrent OSCC with normal blood glucose, metformin remarkably reduced the expression of EGFR in recurrent OSCC tissues.

Conclusion

Metformin may regulate the expression of EGFR in a way that does not rely on lowering blood glucose. These results may provide further evidence for metformin in the treatment of OSCC.
High Remnant Cholesterol Level Potentiates the Development of Hypertension
Authors: Chen Ming-Ming , Huang Xuewei , Xu Chengsheng , Song Xiao-Hui , Liu Ye-Mao , Yao Dongai , Lu Huiming , Wang Gang , Zhang Gui-Lan , Chen Ze , Sun Tao , Yang Chengzhang , Lei Fang , Qin Juan-Juan , Ji Yan-Xiao , Zhang Peng , Zhang Xiao-Jing , Zhu Lihua , Cai Jingjing , Wan Feng , She Zhi-Gang , Li Hongliang
Published: February 2022

Background

Emerging evidence suggests an association between remnant cholesterol (RC) and vascular damage and hypertension. However, this association has not been explored in a large-scale population in China, and a temporal relationship between RC and hypertension also needs to be investigated.

Methods

We conducted a retrospective cross-sectional study in 2,199,366 individuals and a longitudinal study in 24,252 individuals with repeated measurements of lipid profile and blood pressure in at least a 3-year follow-up. The logistic model was used to explore the association between lipid components and hypertension in the cross-sectional analysis. The Cox model was used to analyze the association between high RC (HRC) at baseline and the subsequent incidence of hypertension or the association between hypertension at baseline and incidence of HRC. The cross-lagged panel model was applied to analyze the temporal relationship between RC and hypertension.

Results

RC level as a continuous variable had the highest correlation with hypertension among lipid profiles, including RC, low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, with an odds ratio of 1.59 (95% confidence interval: 1.58–1.59). In the longitudinal cohort, HRC at baseline was associated with incident hypertension. We further explored the temporal relationship between RC and hypertension using the cross-lagged analysis, and the results showed that RC increase preceded the development of hypertension, rather than vice versa.

Conclusions

RC had an unexpected high correlation with the prevalence and incidence of hypertension. Moreover, RC increase might precede the development of hypertension, suggesting the potential role of RC in the development of hypertension.
Ecological Opportunity and Necessity: Biotic and Abiotic Drivers Interact During Diversification of Digital Host-Parasite Communities
Authors: Acosta Monica M. , Zaman Luis
Published: February 2022

Most of Earth’s diversity has been produced in rounds of adaptive radiation, but the ecological drivers of diversification, such as abiotic complexity (i.e.,ecological opportunity) or predation and parasitism (i.e.,ecological necessity), are hard to disentangle. However, most of these radiations occurred hundreds of thousands if not millions of years ago, and the mechanisms promoting contemporary coexistence are not necessarily the same mechanisms that drove diversification in the first place. Experimental evolution has been one fruitful approach used to understand how different ecological mechanisms promote diversification in simple microbial microcosms, but these microbial systems come with their own limitations. To test how ecological necessity and opportunity interact, we use an unusual system of self-replicating computer programs that diversify to fill niches in a virtual environment. These organisms are subject to ecological pressures just like their natural counterparts. They experience biotic interactions from digital parasites, which steal host resources to replicate their own code and spread in the population. With the control afforded by experimenting with computational ecologies, we begin to unweave the complex interplay between ecological drivers of diversification. In particular, we find that the complexity of the abiotic environment and the size of the phenotypic space in which organisms are able to interact play different roles depending on the ecological driver of diversification. We find that in some situations, both ecological opportunity and necessity drive similar levels of diversity. However, the phenotypes that hosts uncover while coevolving with parasites are dramatically more complex than hosts evolving alone.
Fast and Easy Nanopore Sequencing Workflow for Rapid Genetic Testing of Familial Hypercholesterolemia
Authors: Soufi Muhidien , Bedenbender Simon , Ruppert Volker , Kurt Bilgen , Schieffer Bernhard , Schaefer Juergen R.
Published: February 2022

Familial hypercholesterolemia (FH) is an autosomal dominant lipid metabolism disorder characterized by severely elevated plasma low-density lipoprotein cholesterol levels. The disease is caused by mutations in 3 genes (LDLR,APOBandPCSK9) while over 90% of the mutations are located within theLDLRgene. Thus, genetic analysis of theLDLRgene is the first step in the genetic diagnosis of FH. However, conventional methods like Sanger and NextGen sequencing are still costly and time-consuming. In contrast, Oxford Nanopore technology sequencing is an emerging third-generation sequencing technology featured by easy operability, low cost, small size and the capability of parallel sample sequencing. Here, we present an easy Nanopore-sequencing-based workflow for the rapid genetic testing of FH taking only 3 days and costing less than $50 per sample without the requirement for deep bioinformatic knowledge. Using our workflow, we were able to identify the underlying pathogenic variants of 10 FH patients including one novel, not yet recorded pathogenic variants. Our workflow allows the rapid evaluation of the pathogenic variants by utilizing detailed variant information from Ensembl. Additionally, our workflow is not restricted to sequencing theLDLRgene alone but can be easily adapted to the other FH-causing genes and more importantly, to any desired gene contributing to any hereditary disease. Therefore, our workflow is an attractive opportunity for every diagnostic laboratory to offer fast and easy in-house genetic diagnostics.
FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer
Authors: Sarkar Tania , Dhar Subhanki , Chakraborty Dwaipayan , Pati Subhadip , Bose Sayantan , Panda Abir K. , Basak Udit , Chakraborty Sourio , Mukherjee Sumon , Guin Aharna , Jana Kuladip , Sarkar Diptendra K. , Sa Gaurisankar
Published: February 2022

Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.
The EPICC Family of Anti-Inflammatory Peptides: Next Generation Peptides, Additional Mechanisms of Action, and In Vivo and Ex Vivo Efficacy
Authors: Krishna Neel K. , Cunnion Kenji M. , Parker Grace A.
Published: February 2022

The EPICC peptides are a family of peptides that have been developed from the sequence of the capsid protein of human astrovirus type 1 and previously shown to inhibit the classical and lectin pathways of complement. The EPICC peptides have been further optimized to increase aqueous solubility and identify additional mechanisms of action. Our laboratory has developed the lead EPICC molecule, PA-dPEG24 (also known as RLS-0071), which is composed of a 15 amino acid peptide with a C-terminal monodisperse 24-mer PEGylated moiety. RLS-0071 has been demonstrated to possess other mechanisms of action in addition to complement blockade that include the inhibition of neutrophil-driven myeloperoxidase (MPO) activity, inhibition of neutrophil extracellular trap (NET) formation as well as intrinsic antioxidant activity mediated by vicinal cysteine residues contained within the peptide sequence. RLS-0071 has been tested in various ex vivo and in vivo systems and has shown promise for the treatment of both immune-mediated hematological diseases where alterations in the classical complement pathway plays an important pathogenic role as well as in models of tissue-based diseases such as acute lung injury and hypoxic ischemic encephalopathy driven by both complement and neutrophil-mediated pathways (i.e., MPO activity and NET formation). Next generation EPICC peptides containing a sarcosine residue substitution in various positions within the peptide sequence possess aqueous solubility in the absence of PEGylation and demonstrate enhanced complement and neutrophil inhibitory activity compared to RLS-0071. This review details the development of the EPICC peptides, elucidation of their dual-acting complement and neutrophil inhibitory activities and efficacy in ex vivo systems using human clinical specimens and in vivo efficacy in animal disease models.
IFN-β Deficiency Results in Fatal or Demyelinating Disease in C57BL/6 Mice Infected With Theiler’s Murine Encephalomyelitis Viruses
Authors: Bühler Melanie , Runft Sandra , Li Dandan , Götting Jasper , Detje Claudia N. , Nippold Vanessa , Stoff Melanie , Beineke Andreas , Schulz Thomas , Kalinke Ulrich , Baumgärtner Wolfgang , Gerhauser Ingo
Published: February 2022

Type I Interferons (IFN-I) are important inducers of the antiviral immune response and immune modulators. IFN-β is the most highly expressed IFN-I in the central nervous system (CNS). The infection of SJL mice with the BeAn or the DA strain of Theiler’s murine encephalomyelitis virus (TMEV) results in a progressive demyelinating disease. C57BL/6 mice are usually resistant to TMEV-induced demyelination and eliminate these strains from the CNS within several weeks. Using C57BL/6 IFN-β knockout (IFN-β-/-) mice infected with TMEV, we evaluated the role of IFN-β in neuroinfection. Despite the resistance of C57BL/6 wild type (WT) mice to TMEV infection, DA-infected IFN-β-/- mice had to be killed at 7 to 8 days post infection (dpi) due to severe clinical disease. In contrast, BeAn-infected IFN-β-/- mice survived until 98 dpi. Nevertheless at 14 dpi, BeAn-infected IFN-β-/- mice showed a stronger encephalitis and astrogliosis, higher viral load as well as higher mRNA levels of Isg15, Eif2ak2 (PKR), Tnfa, Il1b, Il10, Il12 and Ifng in the cerebrum than BeAn-infected WT mice. Moreover, the majority of IFN-β-/- mice did not clear the virus from the CNS and developed mild demyelination in the spinal cord at 98 dpi, whereas virus and lesions were absent in the spinal cord of WT mice. Persistently infected IFN-β-/- mice also had higher Isg15, Eif2ak1, Tnfa, Il1a, Il1b and Ifng mRNA levels in the spinal cord at 98 dpi than their virus-negative counterparts indicating an activation of IFN-I signaling and ongoing inflammation. Most importantly, BeAn-infected NesCre+/- IFN-βfl/fl mice, which do not express IFN-β in neurons, astrocytes and oligodendrocytes, only developed mild brain lesions similar to WT mice. Consequently, IFN-β produced by neuroectodermal cells does not seem to play a critical role in the resistance of C57BL/6 mice against fatal and demyelinating disease induced by TMEV strains.
Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages
Authors: Frühbeck Gema , Gómez-Ambrosi Javier , Ramírez Beatriz , Mentxaka Amaia , Rodríguez Amaia , Becerril Sara , Reina Gabriel , Valentí Victor , Moncada Rafael , Silva Camilo , Catalán Victoria
Published: February 2022

Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36γ was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P<0.05) circulating levels of IL-36γ in patients with obesity decreased (P<0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P<0.05) and in the peripheral blood mononuclear cells (P<0.01) from patients with obesity. We also demonstrated increased (P<0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P<0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36γ for 24 h strongly induced (P<0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P<0.01) the release of IL-36γ and the expression (P<0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36γ in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities.
Case Report: Rapid Desensitization to Ocrelizumab for Multiple Sclerosis Is Effective and Safe
Authors: Aun Marcelo Vivolo , Freua Fernando , Marussi Victor Hugo Rocha , Giavina-Bianchi Pedro
Published: February 2022

Monoclonal antibodies have become a mainstay of treatment for many inflammatory diseases and malignancies. Multiple sclerosis is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system and a common cause of disability in young adults. Ocrelizumab is a recombinant humanized monoclonal antibody that targets CD20-positive B cells and has been approved in the treatment of multiple sclerosis. Although considered safe, more than 30% of patients treated with Ocrelizumab developed infusion-related reactions, mostly regarded as mild. When severe, they can lead to a definite suspension of that drug. We present a case report of Ocrelizumab desensitization in a female patient who presented an immediate hypersensitivity reaction (urticaria and angioedema) during the first Ocrelizumab infusion. Although mechanisms involved in the response were not elucidated, the procedure occurred uneventfully and permitted first-line multiple sclerosis treatment maintenances. Desensitization should be considered a safe therapeutic option in patients with immediate hypersensitivity reactions to Ocrelizumab.
Tracing the Trophic Fate of Aquafeed Macronutrients With Carbon Isotope Ratios of Amino Acids
Authors: Larsen Thomas , Wang Yiming V. , Wan Alex H. L.
Published: February 2022

To meet future seafood demands, ingredients derived from algae and other novel and sustainable sources are increasingly being tested and used as replacers to traditional aquafeed ingredients. Algal ingredients in particular are being promoted for their sustainability and their additional functional attributes in farmed aquatic animals. Test on algal supplemented aquafeeds typically focus on a suite of immunological and physiological indicators along with fish growth performance or muscle quality. However, to optimize the replacement of fish meal with algal derived ingredients, it is crucial to understand the metabolic fate in the algal macronutrients (carbohydrates, fats, and proteins), and their nutritional interactions with other ingredients after ingestion. Here, we assess the potential of using the emerging technology- stable carbon isotope (δ13C) analysis of single amino acids (AAs) as a nutritional biomarker in aquaculture. Applications of δ13CAA-based approaches in feeding trials show promise in closing the knowledge gap in terms of understanding how fish and other aquaculture taxa assimilate and metabolize algal derived macronutrients. Source diagnostic δ13C fingerprints among the essential AAs can trace the protein origins to broad phylogenetic groups such as red macroalgae, brown macroalgae, bacteria, and terrestrial plants. Among the non-essential AAs, δ13C patterns have the potential to inform about metabolic routing and utilization of dietary lipids and carbohydrates. Despite the potential of δ13CAA as a nutritional biomarker, the few applications to date in fish feeding trials warrant further development and implementation of δ13CAA-based approaches to improve understanding of protein origins and macronutrient metabolic routing.
Metagenomic Analysis Reveals a Changing Microbiome Associated With the Depth of Invasion of Oral Squamous Cell Carcinoma
Authors: Liu Yuan , Li Zhengrui , Qi Yanxu , Wen Xutao , Zhang Ling
Published: February 2022

The relationship between oral squamous cell carcinoma (OSCC) development and the microbiome has attracted increasing attention. The depth of invasion (DOI) is an important indicator of tumor progression, staging and prognosis, and the change in the oral microbiome based on the DOI is unclear. This report describes the use of metagenomic analyses to investigate the relationship between the oral microbiome and the DOI. Forty patients in different DOI categories were recruited; 10 healthy people served as the control group. Swab samples collected from the participants were subjected to metagenomic analyses, and the oral microbial communities and their functions were investigated. The abundances ofFusobacterium nucleatum,Capnocytophaga sputigena,Porphyromonas endodontalis, andGemella haemolysanswere significantly increased in the patients compared with the controls. The abundances of some bacteria exhibited a stage-related trend. The abundances ofP. endodontalis,Gemella morbillorumandG. haemolysansincreased with increasing DOI. In contrast, the abundances ofPrevotella melaninogenica, Haemophilus parainfluenzaeandNeisseria flavescensdecreased with increasing DOI. Based on receiver operating characteristic (ROC) curve analysis, eight species were found to have predictive value:Rothia mucilaginosa,P. melaninogenica,H. parainfluenzae, andN. flavescensin the healthy control group andP. endodontalis,G. morbillorum,G. haemolysansandFusobacterium periodonticumin the high DOI group. In the functional analysis, several metabolic pathways were decreased, whereas flagellar assembly and bacterial chemotaxis showed an increasing trend as the disease progressed. Biofilm formation, flagella, lipopolysaccharide (LPS) and other virulence factors exhibited staging-related changes. These pathogenic pathways and factors had a clear correlation with specific pathogens. In particular, when OSCC progressed to the late stage, microbial diversity and functional potential changed greatly.
ROS-Induced DCTPP1 Upregulation Contributes to Cisplatin Resistance in Ovarian Cancer
Authors: Wang Yu , Chen Peishi , Chen Xueping , Gong Daoyuan , Wu Yingsong , Huang Liping , Chen Yao
Published: February 2022

Cisplatin resistance hinders the improvement of the prognosis of patients with ovarian cancer. Cisplatin induces cancer cell apoptosis by inducing reactive oxygen species (ROS). dCTP pyrophosphatase 1 (DCTPP1) is a newly discovered dNTP pyrophosphatase. This study aimed to identify the role of DCTPP1 in oxidative stress and cisplatin response of ovarian cancer. Our results indicates cisplatin-induced ROS generation was responsible for the upregulation of DCTPP1 in ovarian cancer cells, whereas DCTPP1 knockdown significantly enhanced the sensitivity of ovarian cancer cells to cisplatin, reflect in reactive oxygen species (ROS) generation, double-strand DNA breaks, and cell apoptosis. The expression of redox-related genes and the activation of the PI3/Akt signaling pathway were also inhibited by DCTPP1 knockdown. Our data proposes that the development of therapeutic approaches targeting DCTPP1 may be useful in the treatment of ovarian cancer.
Validation and Normative Data of the Spanish Version of the Rey Auditory Verbal Learning Test and Associated Long-Term Forgetting Measures in Middle-Aged Adults
Authors: Alviarez-Schulze Vanessa , Cattaneo Gabriele , Pachón-García Catherine , Solana-Sánchez Javier , Tormos Josep M. , Pascual-Leone Alvaro , Bartrés-Faz David
Published: February 2022

Rey Auditory Verbal Learning Test (RAVLT) is an episodic memory helpful measure to detect changes associated with abnormal aging. There is a lack of RAVLT validation and normalization studies in Spain. The aim was to determine its psychometric properties and explore long-term forgetting (LTF) performance through 1-week delayed recall under three different modes of administration. The RAVLT was administered to 602 cognitively healthy volunteers, aged between 41 and 65 years, of whom 251 completed the LTF assessment. Findings reveal a factorial structure of four components, with satisfactory goodness of fit, and adequate convergent and divergent validity. We also demonstrated the differential effect of three methodologies used in LTF assessment, supporting that test expectancy positively influences long-term storage. Finally, normative data were generated according to age, sex, and education. The test, including the LTF measure, is a promising tool to estimate memory in middle-aged adults and develop predictive brain aging models.
Exploring Alternative Measurements of Cardiorespiratory Fitness in Patients With Mild Ischemic Stroke at Acute Phase
Authors: Qu Qingming , Zhu Jie , Wang Hewei , Zhang Qi , Zhang Yongli , Yan Zhijie , Fan Qiwei , Wang Yuanyuan , He Ying , Yao Liqing , Xu Lijuan , Zhang Chao , Jia Jie
Published: February 2022

Background

While emerging studies have suggested an association of cardiorespiratory fitness (CRF) with stroke risk and overall health outcomes, little is known regarding the optimum methods of CRF measurement in patients with mild acute ischemic stroke.

Objective

The aim of this study was to explore the association between the 6-min walk distance (6MWD) and other measurements related to CRF in patients with mild ischemic stroke at the acute stage.

Methods

A total of 30 patients with stroke and 71 healthy subjects matched for age and grip strength (GS) were prospectively recruited. All patients were within 14 days after stroke onset and presented mild motor impairment (with a full score of Fugl-Meyer Motor Assessment). Demographic data of both groups and clinical information of the stroke group were documented, and the CRF comparison between the two groups was conducted. Each participant underwent a one-time assessment of 6MWD and a series of measurements related to CRF, including GS, 10-m walk test (10mWT), five-times sit-to-stand time (FTSST), functional reaching test (FRT), Berg Balance Scale (BBS), and waistline. Pearson's product-moment correlation coefficient test and multiple linear regression were performed to explore the indicators of CRF.

Results

Significant moderate correlations (0.3 <r<0.6) were found between 6MWD and GS of left hand (GS-left) (r= 0.573,p= 0.001), GS of right hand (GS-right) (r= 0.524,p= 0.003), FTSST (r= −0.551,p= 0.002), 10mWT (r= 0.554,p= 0.001), and FRT (r= 0.449,p= 0.021) in the patient group. While 6MWD displayed significant moderate correlations with waistline (r= 0.364,p= 0.002), 10mWT (r= 0.512,p< 0.001), FTSST (r= −0.573,p< 0.001), and FRT (r= 0.550,p< 0.001) in the healthy group. All these dependent variables were entered into a stepwise multiple linear regression analysis to evaluate their values in estimating CRF as measured by 6MWD in each group. Analyses suggested that GS-left (p= 0.002) and FTSST (p= 0.003) were the indicators of CRF in the patient group with stroke and explained 51.4% of the variance of 6MWD (R2= 0.514); FTSST (p< 0.001), 10mWT (p< 0.001), and FRT (p= 0.021) were the indicators of CRF in the healthy group and explained 58.9% of variance of 6MWD (R2= 0.589).

Conclusions

Our data confirmed that CRF is impaired in patients with mild ischemic stroke at the acute phase. Moreover, GS-left may be an optional indicator of CRF in patients with mild acute ischemic stroke, but not in healthy people.

Clinical Trial Registration

www.chictr.org.cn, identifier: ChiCTR2000031379.
Research Progress of Anti-PD-1/PD-L1 Immunotherapy Related Mechanisms and Predictive Biomarkers in NSCLC
Authors: Bie Fenglong , Tian He , Sun Nan , Zang Ruochuan , Zhang Moyan , Song Peng , Liu Lei , Peng Yue , Bai Guangyu , Zhou Bolun , Gao Shugeng
Published: February 2022

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) is an important pair of immune checkpoints (IC), which play an essential role in the immune escaping process of tumors. Anti-PD-1/PD-L1 immunotherapy can block the suppression effect of the immune system produced by tumor cells through the PD-1/PD-L1 axis and restore the pernicious effect of the immune system on tumor cells. The specific mechanism of anti-PD-1/PD-L1 immunotherapy is closely related to PI3K (phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase 1), JNK (c-Jun N-terminal kinase), NF-kB (nuclear factor-kappa B subunit 1), and other complex signaling pathways. Patients receiving anti-PD-1/PD-L1 immunotherapy are prone to drug resistance. The mechanisms of drug resistance mainly include weakening recognition of tumor antigens by immune cells, inhibiting activation of immune cells, and promoting the production of suppressive immune cells and molecules. Anti-PD-1/PD-L1 immunotherapy plays a vital role in non-small cell lung cancer (NSCLC). It is essential to find better efficacy prediction-related biomarkers and screen patients suitable for immunotherapy. At present, common biomarkers related to predicting immune efficacy mainly include PD-L1 expression level in tumors, tumor mutation burden (TMB), microsatellite instability (MSI)/mismatch repair (MMR), mutations of driver gene, etc. However, the screening efficacy of each indicator is not ideal, and the combined application of multiple indicators is currently used. This article comprehensively reviews anti-PD-1/PD-L1 immunotherapy-related mechanisms, drug resistance-related mechanisms, and therapeutic efficacy-related predictive biomarkers.