bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Level of Awareness and Utilization of Preconception Care among Saudi Women in Al Ahsa, Saudi Arabia
Authors: Mousa Ola , Alfadhel Rabab Ali , Almubarak Hawra Ali , Alhaleimi Zainab Hussain , Alobaidan Ferdoos Ibraheem , Al Hassan Bayan Jawad , David Marysheela
Published: February 2022

About 810 women died every day in 2017 from preventable causes related to pregnancy and childbirth. To reduce the risks of maternal and fetal complications during pregnancy, knowledge about preconception care must be increased. Preconception care is closely linked to maternal and infant health. This study aimed to examine the level of knowledge, attitudes, and utilization of preconception care among women in Al Ahsa, Saudi Arabia. A cross- sectional study was conducted between June 27 and September 30, 2021, in three governmental hospitals and three private hospitals from the outpatient department of Al Ahsa, Saudi Arabia. In this study, the participants were recruited using a simple randomization technique. The estimated sample size is 386. Data were collected by using a modified structured questionnaire adapted from similar studies. The questionnaire contains three sections. The validity and reliability of the tool were accomplished. This study was approved by the Institutional Review Board (IRB) of the KFHH, and a letter of informed participation, along with the purposes of the study, was provided with the administered questionnaire. Near to half of the study participants, 166 (43%) had good knowledge, and 186 (48.2%) had fair knowledge on preconception care whereas 34 (8.8%) had poor knowledge on preconception care. Regarding the utilization, most participants 170 (44%) did not receive complete preconception care. The majority of participants (73.6%) said that women don't undertake complete preconception care due to a lack of knowledge. The level of education of participants is strongly correlated with preconception care awareness. The findings concluded that fewer than half of Saudi women in Al Ahsa were aware about preconception care. In general, responders do not use preconception care services due to a lack of knowledge about how these services may affect maternal and neonatal health.
Struktur Populasi Hirangan (Trachypithecus cristatus) di Desa Beringin Kencana Kabupaten Barito Kuala
Authors: Syaumi Annisa Aliffira , Mahrudin Mahrudin , Irianti Riya
Published: February 2022

Beringin Kencana is a village located in Barito Kuala Regency, South Kalimantan Province. The Beringin Kencana area contains mangrove areas, swamp forests, rice fields, settlements and oil palm plantations. The Beringin Kencana area, which is located on the border of the Barito Kuala and Central Kalimantan regions, is an area that has not been widely publicized, especially the diversity of flora and fauna that exist, so it needs to be introduced to the public widely. The results showed that the population of Hirangan in Beringin Kencana Village was obtained from adults 2.61 individuals/Ha, young 1.07 individuals/Ha and tillers 1.90 individuals/Ha. Pyramid on the population structure of hirangan in Banyan Kendi village is in the form of an urn/kendi. Pyramid shaped caddy shows that the number of young people is less than the number of adults.
PEMBERDAYAAN WANITA MELALUI USAHA KRUPUK LELE ORGANIK DI DESA SUMBERNGEPOH, LAWANG KABUPATEN MALANG
Authors: Suhartatik Suhartatik , Purwati Titik , Bangun Wilyati Agustina
Published: February 2022

Women's empowerment is the focus of this community service activity in partnership with mothers from the Krupuk Business Group, Ibu Mujiati and Ibu Tuni. The purpose of this activity is to solve the problems faced by the organic catfish cracker business group partners in Sumberngepoh Village, Lawang, Malang Regency, in terms of production and management aspects. The targets to be achieved from this activity are training and additional production equipment for partners as an effort to empower the community.

Method of program implementation This activity goes through three stages, namely the planning stage, the implementation stage and the evaluation stage. The results achieved from this activity are: 1) a solution to production problems by adding/procuring new production equipment and raw materials for making organic catfish crackers; 2) the existence of solutions to management problems by holding management training which includes production, marketing, sanitation and hygiene. The final result shows that there are indicators of success with increased knowledge of partners and productivity of organic catfish crackers that increase with management training.
PELATIHAN PENGGUNAAN PERANGKAT PEMBELAJARAN ONLINE BAGI GURU-GURU MAN DI KABUPATEN JOMBANG
Authors: Hoesny Mariana Ulfah , Ratnawati Yani , Agustina Lia , Imron Aly
Published: February 2022

The use of online learning tools has been urgent due to covid-19 pandemic. The tools have become primary needs in teaching and learning especially in English teaching. This program aimed at conducting training and workshop to use online learning tools for English teachers of Madrasah Aliyah in Jombang regency, East Java. The workshop was done via zoom meeting because offline meeting was not allowed during the pandemic. The first topic presented in the established workshop was about how technology transform education. The next topics were more specific ones; they were about utilizing online learning tools and project based learning to teach the four skills in English. There were 148 participants attending the workshop. According to te participants, the most interesting topics during the workshop were about the use of story jumper to teach writing and how to make podcast to teach speaking.
TRAUMA HEALING PASCABENCANA PADA ANAK-ANAK KORBAN GEMPA BUMI MELALUI PELATIHAN DA SUMINAGASHI (MELUKIS DI ATAS AIR) DI DESA REMBUN, KECAMATAN DAMPIT KABUPATEN MALANG
Authors: Sumarsih Siti , Rachman Anita Kurnia , Susandi Susandi
Published: February 2022

Community service carried out by Lecturer of Indonesian Language and Literature Education Study Program, IKIP Budi Utomo aims to help children affected by the earthquake to reduce trauma healing through playing activities and painting on water. The implementation method used in this activity is the method of playing and painting together on water (da suminagashi). Trauma Healing is a situation where children feel fear, anxiety, and fear due to events, accidents, natural disasters that have been experienced. This activity was carried out for three days and in collaboration with the Omdobara Command Post in Rembun Village, Dampit District, Malang Regency. This service activity is also assisted by four coordinators at the Omdobara Command Post who are used to interacting with children every day. The results of this activity, which can help parents and children in reducing the trauma caused by the earthquake that occurred a few months ago. Another result is that children can play and learn to paint on water together so that children can be happy again.
SOSIALISASI MENINGKATKAN IMUNITAS KESEHATAN IBU DI MASA PANDEMI DI LINGKUNGAN RW 07 KARANGBESUKI KOTA MALANG
Authors: Bangun Wilyati Agustina , Suhartatik Suhartatik , Purwati Titik
Published: February 2022

In 2020, the outbreak of a new virus that shocked the world, namely  Coronavirus Disease (Covid 19). There are some ways to survive from the pandemic such as obeying government instructions and increase the immunity of body. The purpose of the community service is to provide counseling or social outreach, as well as provide education related to improving maternal health and immunity during the pandemic. The activities of Community Service cover several stages. First, coordinating about the  Community Service  Agenda with the Head of  Neighborhood and Citizens Associations. Second, the executor team prepare some materials of  socialization. Third, the executor team conduct the  educational outreach. In conclusion, improving maternal health and immunity can be reached  by consuming  healty food, providing healthy life, and avoiding stress.
Orta Çağ'ın Bilim Tarihine Mirası
Authors: BAŞARAN Vural
Published: February 2022

Bu çalışmada Orta Çağ'da hem Avrupa'da hem de İslam Uygarlığı'nda bilim tarihi için önemli sayılabilecek gelişmeler verilmiştir. Orta Çağ'da doğa felsefesine dair yürütülen kuramsal ve pratik çabalar Bilimsel Devrim'de önemli bir rol oynamıştır. Bu dönemde hem Doğu hem de Batı uygarlıkları bilimin gelişmesine farklı zeminlerde katkı sunmuşlardır. İslam Uygarlığı'nın ortaya çıkışı ve fetihler yoluyla hem Avrupa'da hem de Asya'da hakimiyet kurması onların buradaki entelektüel faaliyeti de sahiplenmesine neden olmuştur. Daha sonra bilimsel-entelektüel hayat İslam Dünyası'ndan Hıristiyan dünyasına çeviriler yoluyla iletilmiştir. Bu bakımdan Orta Çağ bize, bilim tarihinin gelişimini anlayabilmemiz için üç temel ipucu vermektedir. Bunlardan birincisi bilimsel ve entelektüel ilerlemenin zaman zaman yavaşlasa da devam ettiği ve bütünüyle kesintiye uğratılamadığıdır. Diğeri çeviri faaliyetin bilimlerin gelişmesinde oynadığı rol ve son olarak da epistemik grupların kendi aralarında çatışmasının bilimin ilerlemesinde yaptığı etkidir. Orta Çağ diye anılan dönem bu bakımlardan günümüz bilim tarihçilerine verimli bir empirik araştırma sahası olmaya devam etmektedir.
Spor ve Toplumsal Sınıf
Authors: DEVER Ayhan
Published: February 2022

Bu çalışmanın amacı spora katılım ile içerisinde bulunulan toplumsal sınıf arasındaki ilişkiyi ortaya koymaktır. Bu amaç doğrultusunda öncelikli olarak Karl Marks, Max Weber ve Pierre Bourdieu'nun sınıfla ilgili düşüncelerine değinilmiş ve sınıf teorileri açıklanmaya çalışılmıştır. Sonrasında Antik Yunan ve Roma'da düzenlenen atlı yarışların ve gladyatör dövüşlerinin doğrudan bir şekilde toplumsal sınıf ayrımını beraberinde getirdiği ve antik dönemlerde üst sınıfın spora katılım oranının, toplumun diğer sınıflarına göre daha yüksek olduğu görülmüştür. Günümüze doğru gelinen süreç içerisinde ise alt – orta ve üst sınıfların, spora katılımları açıklanmaya çalışılmıştır. Alt sınıfa mensup bireylerin, doğrudan bir şekilde fiziksel temasın yoğun bir şekilde yaşandığı, şiddet ve bedensel gücü ön plana çıkartan bireysel ve takım sporlarına katılım göstermeleri yüksek bir olasılıktır. Alt sınıfa mensup bireyler, sporu bir toplumsal hareketlilik aracı olarak, daha üst sınıflara erişmek amacıyla kullanmakta ve bu nedenle de profesyonel sporlara ilgi göstermektedirler. Orta sınıfa mensup bireyler ise genellikle takım sporlarına ve üst sınıfın katılım gösterdiği sporlara yoğun ilgi göstermişlerdir. Üst sınıfa mensup bireyler ise daha ziyade hem özel kulüpler aracılığıyla girilen hem de katılmak amacıyla belli bir harcama yapmanın zorunlu olduğu çeşitli sporlara yönelmişlerdir. Bunun dışında üst sınıfın ilgi gösterdiği sporlar, bireysel sporlar olmuştur. Üst sınıfa mensup bireylerin spora katılma olasılıkları, alt sınıfa mensup bireylere göre daha yüksek olmakla beraber, üst sınıfın katıldığı sporlar, üst sınıfın zevkleri ve yaşam tercihleri ile doğru orantılı olmuştur. Ayrıca diğer sınıfların ilgilendiği sporları üst sınıf belirlemektedir. Bu durum, spor ve sosyal sınıf kapsamında üst sınıfın daha baskın olduğunun bir göstergesi olarak yorumlanabilir.
Ljósmyndir Þorláks Sverrissonar í Vík: Kötlugosið 1918 í nýju ljósi
Authors: Larsen Guðrún , Högnadóttir Þórdís
Published: February 2022

Þorlákur Sverrisson kaupmaður í Vík í Mýrdal tók ljósmyndir af Kötlugosinu 1918 „frá byrjun til enda“ svo vitnað sé í hans eigin orð. Raunvísindastofnun fékk 18 glerplötur að gjöf frá erfingjum hans og eftirmyndir af 17 þeirra birtast hér ásamt skýringum og tilraun til tímasetninga. Ef tímaröðin, sem hér er kynnt, er nærri lagi eru myndirnar teknar frá 12. október til 2. nóvember 1918. Samkvæmt henni var fyrsta myndin tekin í Víkurþorpi 12. október, á fyrsta gosdegi og sýnir gosmökk vofa yfir húsunum. Önnur mynd frá sama degi var tekin norðan Víkur og sýnir háan gráleitan mökk yfir Höttu. Þessar tvær gætu verið fyrstu myndir í heiminum sem teknar voru af sprengigosi í jökli. Eftir fyrstu þrjá dagana sljákkaði í gosinu. Fjórar myndir sem sýna lægri gosmökk, meðal annars tvo aðgreinda gosmekki upp úr jöklinum, voru teknar á tímabilinu 15. til 20. október. Mekkirnir eru hvítir að sjá á myndunum og virðast að mestu vatnsgufa. Mynd frá 22. október sýnir
dökkgráan öskumökk yfir fjöllunum norðan Víkur, rétt áður en hann fór að hrynja yfir fjallabrúnirnar og aska fór að falla í þorpinu. Mynd frá 24. október sýnir dökkan mökk yfir Höttu kolsvartri af ösku og einnig virðast upptök makkarins nú austar en áður. Öskufall hófst í Vík síðdegis þann dag og stóð í 13 klst. Fjórar myndir voru teknar 2. nóvember, síðasta daginn sem verulegur gosmökkur sást. Auk mynda af gosmekki tók Þorlákur myndir af hlaupfarvegum og ísgljúfri sem varð til þegar jökulhlaup braust fram undan/úr jaðri Kötlujökuls og braut a.m.k. 1300 m langt og allt að 300 m breitt skarð í hann. Myndir Þorláks eru þær einu sem þekktar eru af þessu gljúfri. Vísindalegt gildi myndanna er töluvert og í þeim eru meiri upplýsingar en dæmin sem tekin eru hér. Þær sýna breytileikann í sprengivirkninni og staðfesta færslu gosstöðvanna meðan á gosinu stóð. Hægt er að reikna hæð gosmakkar og miða út upptök hans. Þær sýna hlaupfarvegi á Mýrdalssandi og hægt er að meta flóðmörk meginhlaupsins á ofanverðum sandinum. Sumar myndanna hafa látið á sjá en með nútímatækni er hægt að laga þær og skerpa og nýta til fulls.
Estimating Gaits of an Ancient Crocodile-Line Archosaur Through Trajectory Optimization, With Comparison to Fossil Trackways
Authors: Polet Delyle T. , Hutchinson John R.
Published: February 2022

Fossil trackways provide a glimpse into the behavior of extinct animals. However, while providing information of the trackmaker size, stride, and even speed, the actual gait of the organism can be ambiguous. This is especially true of quadrupedal animals, where disparate gaits can have similar trackway patterns. Here, predictive simulation using trajectory optimization can help distinguish gaits used by trackmakers. First, we demonstrated that a planar, five-link quadrupedal biomechanical model can generate the qualitative trackway patterns made by domestic dogs, although a systematic error emerges in the track phase (relative distance between ipsilateral pes and manus prints). Next, we used trackway dimensions as inputs to a model of Batrachotomus kupferzellensis, a long-limbed, crocodile-line archosaur (clade Pseudosuchia) from the Middle Triassic of Germany. We found energetically optimal gaits and compared their predicted track phases to those of fossil trackways of Isochirotherium and Brachychirotherium. The optimal results agree with trackways at slow speeds but differ at faster speeds. However, all simulations point to a gait transition around a non-dimensional speed of 0.4 and another at 1.0. The trackways likewise exhibit stark differences in the track phase at these speeds. In all cases, including when simulations are constrained to the fossil track phase, the optimal simulations after the first gait transition do not correspond to a trot, as often used by living crocodiles. Instead, they are a diagonal sequence gait similar to the slow tölt of Icelandic horses. This is the first evidence that extinct pseudosuchians may have exhibited different gaits than their modern relatives and of a gait transition in an extinct pseudosuchian. The results of this analysis highlight areas where the models can be improved to generate more reliable predictions for fossil data while also showcasing how simple models can generate insights about the behavior of extinct animals.
Dysregulated Peripheral Invariant Natural Killer T Cells in Plaque Psoriasis Patients
Authors: Hu Yifan , Chen Youdong , Chen Zeyu , Zhang Xilin , Guo ChunYuan , Yu ZengYang , Xu Peng , Sun Lei , Zhou Xue , Gong Yu , Yu Qian , Shi Yuling
Published: February 2022

Background: Psoriasis is a common immune-mediated skin disease that involves T-cell-mediated immunity. Invariant natural killer T (iNKT) cells are a unique lymphocyte subpopulation that share properties and express surface markers of both NK cells and T cells. Previous reports indicate that iNKT cells regulate the development of various inflammatory diseases. IL-17 is a key cytokine in the pathogenesis of psoriasis and a key therapeutic target. Secukinumab is a fully human IgG1κ antibody that targets IL-17A, thereby antagonizing the biological effects of IL-17.

Objective: To explore the expression of iNKT cells in psoriasis patients and the effect of secukinumab on them.

Methods: We examined the frequencies of iNKT cells, Tregs, naïve and memory CD4+and CD8+T cells in the PBMCs as well as their cytokine production in a cohort of 40 patients with moderate-to-severe plaque psoriasis and 40 gender- and age-matched healthy controls. We further collected peripheral blood of another 15 moderate-to-severe plaque psoriasis patients who were treated with secukinumab and evaluated the proportion of iNKT cells in the PBMCs at baseline and week 12.

Results: The frequencies of conventional CD4+ T cells, CD8+ T cells, and Tregs in the PBMCs were comparable between psoriasis patients and healthy controls, but the frequencies of Th17 cells, Tc1 cells and Tc17 cells were increased in psoriasis patients. The frequency of peripheral iNKT cells and CD69+iNKT cells was significantly decreased in psoriasis patients. Both iNKT2 cells and iNKT17 cells were increased in psoriasis patients, but the ratio of iNKT2 cells vs iNKT17 cells was significantly reduced in psoriasis patients. After receiving secukinumab, the proportion of iNKT cells in the PBMCs of patients was increased, while the proportion of iNKT17 cells was decreased.

Conclusion: Dysregulated iNKT cells may be involved in the pathogenesis of psoriasis and secukinumab may play a regulatory role on iNKT cells.
Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
Authors: Astro Veronica , Alowaysi Maryam , Fiacco Elisabetta , Saera-Vila Alfonso , Cardona-Londoño Kelly J. , Aiese Cigliano Riccardo , Adamo Antonio
Published: February 2022

Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by a 47,XXY karyotype. Less frequently, higher grade sex chromosome aneuploidies (HGAs) can also occur. Here, using a paradigmatic cohort of KS and HGA induced pluripotent stem cells (iPSCs) carrying 49,XXXXY, 48,XXXY, and 47,XXY karyotypes, we identified the genes within the pseudoautosomal region 1 (PAR1) as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, the biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS and HGA iPSCs at the single-cell resolution we showed that PAR1 and non-PAR escape genes are not only resilient to the X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation is disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the nuclear respiratory factor 1 (NRF1) as a key regulator of the zinc finger protein X-linked (ZFX). Our study provides the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.
Profiling Selective Packaging of Host RNA and Viral RNA Modification in SARS-CoV-2 Viral Preparations
Authors: Peña Noah , Zhang Wen , Watkins Christopher , Halucha Mateusz , Alshammary Hala , Hernandez Matthew M. , Liu Wen-Chun , Albrecht Randy A. , Garcia-Sastre Adolfo , Simon Viviana , Katanski Christopher , Pan Tao
Published: February 2022

Viruses package host RNAs in their virions which are associated with a range of functions in the viral life cycle. Previous transcriptomic profiling of host RNA packaging mostly focused on retroviruses. Which host RNAs are packaged in other viruses at the transcriptome level has not been thoroughly examined. Here we perform proof-of-concept studies using both small RNA and large RNA sequencing of six different SARS-CoV-2 viral isolates grown on VeroE6 cells to profile host RNAs present in cell free viral preparations and to explore SARS-CoV-2 genomic RNA modifications. We find selective enrichment of specific host transfer RNAs (tRNAs), tRNA fragments and signal recognition particle (SRP) RNA in SARS-CoV-2 viral preparations. Different viral preparations contain the same set of host RNAs, suggesting a common mechanism of packaging. We estimate that a single SARS-CoV-2 particle likely contains up to one SRP RNA and four tRNA molecules. We identify tRNA modification differences between the tRNAs present in viral preparations and those in the uninfected VeroE6 host cells. Furthermore, we find uncharacterized candidate modifications in the SARS-CoV-2 genomic RNA. Our results reveal an under-studied aspect of viral-host interactions that may be explored for viral therapeutics.
Advances in cGAS-STING Signaling Pathway and Diseases
Authors: Yang Yuting , Huang Yiming , Zeng Zhenguo
Published: February 2022

Pathogens can produce conserved pathogen-associated molecular patterns (PAMPs) after invading the body, which can be specifically recognized by host pattern recognition receptors (PRRs). In recent years, it has been found that cytoplasmic DNA receptors recognize exogenous DNA inducing activation of interferon 1 (IFN1), which is a rapid advance in various research areas. The cyclic GMP–AMP synthase (cGAS) stimulator of interferon gene (STING) signaling pathway is a critical natural immune pathway in cells. Early studies revealed that it plays a crucial regulatory role in pathogen infection and tumor, and it is associated with various human autoimmune diseases. Recently studies have found that activation of cGAS-STING signaling pathway is related to different organ injuries. The present review elaborates on the regulation of the cGAS-STING signaling pathway and its role in various diseases, aiming to provide a theoretical basis for immunotherapy targeting this pathway.
Role of Pyroptosis and Ferroptosis in the Progression of Atherosclerotic Plaques
Authors: Yang Zhen , Shi Junhe , Chen Li , Fu Changgeng , Shi Dazhuo , Qu Hua
Published: February 2022

Pyroptosis is a special way of programmed cell death which is dependent on the activation of cysteinyl aspartate specific proteinase 1 (Caspase-1) and Caspase-4/5/11. Ferroptosis is an iron-dependent cell death that characterized by the intra-cellular lipid peroxidation-mediated membrane damage. Pyroptosis or ferroptosis in macrophages, smooth muscle cells, and vascular endothelial cells are believed to be closely related to the progression of atherosclerotic plaques. Therefore, we discuss the role of pyroptosis and ferroptosis in the development of atherosclerotic plaques and may provide new strategies for the treatment of atherosclerosis.
Interplay Between m6A RNA Methylation and Regulation of Metabolism in Cancer
Authors: Mobet Youchaou , Liu Xiaoyi , Liu Tao , Yu Jianhua , Yi Ping
Published: February 2022

Methylation of adenosine in RNA to N6-methyladenosine (m6A) is widespread in eukaryotic cells with his integral RNA regulation. This dynamic process is regulated by methylases (editors/writers), demethylases (remover/erasers), and proteins that recognize methylation (effectors/readers). It is now evident that m6A is involved in the proliferation and metastasis of cancer cells, for instance, altering cancer cell metabolism. Thus, determining how m6A dysregulates metabolic pathways could provide potential targets for cancer therapy or early diagnosis. This review focuses on the link between the m6A modification and the reprogramming of metabolism in cancer. We hypothesize that m6A modification could dysregulate the expression of glucose, lipid, amino acid metabolism, and other metabolites or building blocks of cells by adaptation to the hypoxic tumor microenvironment, an increase in glycolysis, mitochondrial dysfunction, and abnormal expression of metabolic enzymes, metabolic receptors, transcription factors as well as oncogenic signaling pathways in both hematological malignancies and solid tumors. These metabolism abnormalities caused by m6A’s modification may affect the metabolic reprogramming of cancer cells and then increase cell proliferation, tumor initiation, and metastasis. We conclude that focusing on m6A could provide new directions in searching for novel therapeutic and diagnostic targets for the early detection and treatment of many cancers.
Plasmodium Circumsporozoite Protein Enhances the Efficacy of Gefitinib in Lung Adenocarcinoma Cells by Inhibiting Autophagy via Proteasomal Degradation of LC3B
Authors: Lu Xiao , Zhang Jiao , Li Yan-Qi , Liu Quan-Xing , Zhou Dong , Deng Xu-Feng , Qiu Yuan , Chen Qian , Li Man-Yuan , Liu Xiao-Qing , Dai Ji-Gang , Zheng Hong
Published: February 2022

Background: Almost all lung adenocarcinoma (LUAD) patients with EGFR mutant will develop resistance to EGFR-TKIs, which limit the long-term clinical application of these agents. Accumulating evidence shows one of the main reasons for resistance to EGFR-TKIs is induction of autophagy in tumor cells. Our previous study found that circumsporozoite protein (CSP) in Plasmodium can suppress autophagy in host hepatocytes. However, it is unknown whether CSP-mediated inhibition of autophagy could improve the anti-tumor effect of EGFR-TKIs.

Methods: We constructed A549 and H1975 cell lines with stable overexpression of CSP (OE-CSP cells). CCK-8, Lactate Dehydrogenase (LDH), flow cytometry, and colony analysis were performed to observe the effect of CSP overexpression on cell viability, apoptosis rate, and colony formation ratio. The sensitizing effect of CSP on gefitinib was evaluated in vivo using a subcutaneous tumor model in nude mice and immunohistochemical assay. The role of CSP in regulation of autophagy was investigated by laser confocal microscopy assay and western blotting. A transcriptome sequencing assay and real-time polymerase chain reaction were used to determine the levels of mRNA for autophagy-related proteins. Cycloheximide (CHX), MG132, TAK-243, and immunoprecipitation assays were used to detect and confirm proteasomal degradation of LC3B.

Results: OE-CSP A549 and H1975 cells were more sensitive to gefitinib, demonstrating significant amounts of apoptosis and decreased viability. In the OE-CSP group, autophagy was significantly inhibited, and there was a decrease in LC3B protein after exposure to gefitinib. Cell viability and colony formed ability were recovered when OE-CSP cells were exposed to rapamycin. In nude mice with xenografts of LUAD cells, inhibition of autophagy by CSP resulted in suppression of cell growth, and more marked apoptosis during exposure to gefitinib. CSP promoted ubiquitin-proteasome degradation of LC3B, leading to inhibition of autophagy in LUAD cells after treatment with gefitinib. When LUAD cells were treated with ubiquitin activating enzyme inhibitor TAK-243, cell viability, apoptosis, and growth were comparable between the OE-CSP group and a control group both in vivo and in vitro.

Conclusion: CSP can inhibit gefitinib-induced autophagy via proteasomal degradation of LC3B, which suggests that CSP could be used as an autophagy inhibitor to sensitize EGFR-TKIs.
The Rational Design of a Financially Viable Microbial Electrolysis Cell for Domestic Wastewater Treatment
Authors: Aiken Daniel C. , Curtis Thomas P. , Heidrich Elizabeth S.
Published: February 2022

Microbial electrolysis cells (MECs) are yet to achieve commercial viability. Organic removal rates (ORR) and capital costs dictate an MEC’s financial competitiveness against activated sludge treatments. We used numerical methods to investigate the impact of acetate concentration and the distance between opposing anodes’ surfaces (anode interstices width) on MEC cost-performance. Numerical predictions were calibrated against laboratory observations using an evolutionary algorithm. Anode interstices width had a non-linear impact on ORR and therefore allowable cost. MECs could be financially competitive if anode interstices widths are carefully controlled (2.5 mm), material costs kept low (£5–10/m2-anode), and wastewater pre-treated, using hydrolysis to consistently achieve influent acetate concentrations >100 mg-COD/l.
Transcriptome Analysis of Peripheral Blood Mononuclear Cells in SARS-CoV-2 Naïve and Recovered Individuals Vaccinated With Inactivated Vaccine
Authors: Zhang Yuwei , Guo Xingyu , Li Cunbao , Kou Zengqiang , Lin Lanfang , Yao Mingxiao , Pang Bo , Zhang Xiaomei , Duan Qing , Tian Xueying , Xing Yufang , Jiang Xiaolin
Published: February 2022

The urgent approval of the use of the inactivated COVID-19 vaccine is essential to reduce the threat and burden of the epidemic on global public health, however, our current understanding of the host immune response to inactivated vaccine remains limited. Herein, we performed serum IgG antibody detection and transcriptomics analysis on 20 SARS-CoV-2 naïve individuals who received multiple doses of inactivated vaccine and 5 SARS-CoV-2 recovered individuals who received single dose of inactivated vaccine. Our research revealed the important role of many innate immune pathways after vaccination, identified a significant correlation with the third dose of booster vaccine and proteasome-related genes, and found that SARS-CoV-2 recovered individuals can produces a strong immune response to a single dose of inactivated vaccine. These results help us understand the reaction mechanism of the host’s molecular immune system to the inactivated vaccine, and provide a basis for the choice of vaccination strategy.
Dissecting in Vitro the Activation of Human Immune Response Induced by Shigella sonnei GMMA
Authors: Tondi Serena , Clemente Bruna , Esposito Carmen , Sammicheli Chiara , Tavarini Simona , Martin Laura B. , Rossi Omar , Micoli Francesca , Bartolini Erika , Brazzoli Michela , Ulivieri Cristina , Blohmke Christoph J. , Schiavetti Francesca
Published: February 2022

Generalized Modules for Membrane Antigens (GMMA) are outer membrane exosomes purified from Gram-negative bacteria genetically mutated to increase blebbing and reduce risk of reactogenicity. This is commonly achieved through modification of the lipid A portion of lipopolysaccharide. GMMA faithfully resemble the bacterial outer membrane surface, and therefore represent a powerful and flexible platform for vaccine development. Although GMMA-based vaccines have been demonstrated to induce a strong and functional antibody response in animals and humans maintaining an acceptable reactogenicity profile, the overall impact on immune cells and their mode of action are still poorly understood. To characterize the GMMA-induced immune response, we stimulated human peripheral blood mononuclear cells (hPBMCs) with GMMA from Shigella sonnei. We studied GMMA both with wild-type hexa-acylated lipid A and with the corresponding less reactogenic penta-acylated form. Using multicolor flow cytometry, we assessed the activation of immune cell subsets and we profiled intracellular cytokine production after GMMA stimulation. Moreover, we measured the secretion of thirty cytokines/chemokines in the cell culture supernatants. Our data indicated activation of monocytes, dendritic, NK, B, and γδ T cells. Comparison of the cytokine responses showed that, although the two GMMA have qualitatively similar profiles, GMMA with modified penta-acylated lipid A induced a lower production of pro-inflammatory cytokines/chemokines compared to GMMA with wild-type lipid A. Intracellular cytokine staining indicated monocytes and dendritic cells as the main source of the cytokines produced. Overall, these data provide new insights into the activation of key immune cells potentially targeted by GMMA-based vaccines.
Potential Advances of Adjunctive Hyperbaric Oxygen Therapy in Infective Endocarditis
Authors: Lerche Christian Johann , Schwartz Franziska , Pries-Heje Mia Marie , Fosbøl Emil Loldrup , Iversen Kasper , Jensen Peter Østrup , Høiby Niels , Hyldegaard Ole , Bundgaard Henning , Moser Claus
Published: February 2022

Patients with infective endocarditis (IE) form a heterogeneous group by age, co-morbidities and severity ranging from stable patients to patients with life-threatening complications with need for intensive care. A large proportion need surgical intervention. In-hospital mortality is 15-20%. The concept of using hyperbaric oxygen therapy (HBOT) in other severe bacterial infections has been used for many decades supported by various preclinical and clinical studies. However, the availability and capacity of HBOT may be limited for clinical practice and we still lack well-designed studies documenting clinical efficacy. In the present review we highlight the potential beneficial aspects of adjunctive HBOT in patients with IE. Based on the pathogenesis and pathophysiological conditions of IE, we here summarize some of the important mechanisms and effects by HBOT in relation to infection and inflammation in general. In details, we elaborate on the aspects and impact of HBOT in relation to the host response, tissue hypoxia, biofilm, antibiotics and pathogens. Two preclinical (animal) studies have shown beneficial effect of HBOT in IE, but so far, no clinical study has evaluated the feasibility of HBOT in IE. New therapeutic options in IE are much needed and adjunctive HBOT might be a therapeutic option in certain IE patients to decrease morbidity and mortality and improve the long-term outcome of this severe disease.
More Than Just a Periodontal Pathogen –the Research Progress on Fusobacterium nucleatum
Authors: Chen Yuanxin , Huang Zhijie , Tang Zhengming , Huang Yisheng , Huang Mingshu , Liu Hongyu , Ziebolz Dirk , Schmalz Gerhard , Jia Bo , Zhao Jianjiang
Published: February 2022

Fusobacterium nucleatum is a common oral opportunistic bacterium that can cause different infections. In recent years, studies have shown that F. nucleatum is enriched in lesions in periodontal diseases, halitosis, dental pulp infection, oral cancer, and systemic diseases. Hence, it can promote the development and/or progression of these conditions. The current study aimed to assess research progress in the epidemiological evidence, possible pathogenic mechanisms, and treatment methods of F. nucleatum in oral and systemic diseases. Novel viewpoints obtained in recent studies can provide knowledge about the role of F. nucleatum in hosts and a basis for identifying new methods for the diagnosis and treatment of F. nucleatum-related diseases.
Insulin Resistance Promotes the Formation of Aortic Dissection by Inducing the Phenotypic Switch of Vascular Smooth Muscle Cells
Authors: Zheng Hui , Qiu Zhihuang , Chai Tianci , He Jian , Zhang Yuling , Wang Chaoyun , Ye Jianqiang , Wu Xiaohui , Li Yumei , Zhang Li , Chen Liangwan
Published: February 2022

Background

Insulin resistance (IR) plays a key role in the development of type 2 diabetes mellitus (T2DM) and is one of its most important characteristics. Previous studies have shown that IR and T2DM were independent risk factors for a variety of cardiovascular and cerebrovascular diseases. However, there are few studies on the relationship between IR and aortic dissection (AD). The goal of this research was to find evidence that IR promotes the occurrence of AD.

Methods

Through the statistical analysis, we determined the proportion of glycosylated hemoglobin (HbA1c) abnormalities (HbA1c > 5.7) in people with acute thoracic aortic dissection (ATAD) and compared the difference of messenger RNA (mRNA) and protein expression of GluT1 in the thoracic aorta of normal people and those with ATAD to find evidence that IR is a causative factor in AD. The mouse model of IR and AD and the IR model of human aortic vascular smooth muscle cells (HA-VSMC) were established. Real time-PCR (RT-PCR) and Western blotting were used to study the mRNA and protein expression. Hematoxylin and eosin (H&E), Masson, and elastic fiber staining, and immunofluorescence were used to study the morphological structure.

Results

The proportion of HbA1c abnormalities in patients with ATAD was 59.37%, and the mRNA and protein expression of GluT1 were significantly lower than that in normal people. Fasting glucose concentration (FGC), serum insulin concentration (SIC), and the homeostasis model assessment of insulin resistance (HOMA-IR) of mice was obviously increased in the high-fat diet group and the protein expressions of Glut1 and GluT4 were reduced, indicating that the mouse IR model was successfully established. The incidence of AD was different between the two groups (IR: 13/14, Ctrl: 6/14), and the protein expression of MMP2, MMP9, and OPN were upregulated and SM22 and α-SMA were downregulated in mice. The expressions of mRNA and protein of GluT1 and SM22 in HA-VSMCs with IR were reduced and OPN was increased.

Conclusion

Combined results of clinical findings, mouse models, and cell experiments show that IR induced the phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to synthetic, which contributes to the occurrence of AD. It provides a basis for further research on the specific mechanism of how IR results in AD and a new approach for the prevention and treatment of AD.
Age-Related Electrocardiographic Characteristics of Male Junior Soccer Athletes
Authors: Cavarretta Elena , Sciarra Luigi , Biondi-Zoccai Giuseppe , Maffessanti Francesco , Nigro Antonia , Sperandii Fabio , Guerra Emanuele , Quaranta Federico , Fossati Chiara , Peruzzi Mariangela , Pingitore Annachiara , Stasinopoulos Dimitrios M. , Rigby Robert A. , Adorisio Rachele , Saglietto Andrea , Calò Leonardo , Frati Giacomo , Pigozzi Fabio
Published: February 2022

Introduction

Very limited data exist on normal age-related ECG variations in adolescents and no data have been published regarding the ECG anomalies induced by intensive training, which are relevant in pre-participation screening for sudden cardiac death prevention in the adolescent athletic population. The purpose of this study was to establish normal age-related electrocardiographic measurements (P wave duration, PR interval, QRS duration, QT, and QTc interval) grouped according to 2-year age intervals.

Methods

A total of 2,151 consecutive healthy adolescent Soccer athletes (trained for a mean of 7.2 ± 1.1 h per week, 100% male Caucasians, mean age 12.4 ± 1.4 years, range 7–18) underwent pre-participation screening, which included ECG and transthoracic echocardiography in a single referral center.

Results

Their heart rate progressively slowed as age increased (p < 0.001, ranging from 80.8 ± 13.2 to 59.5 ± 10.2 bpm), as expected. The P wave, PR interval, and QRS duration significantly increased in older age classes (p = 0.019, p = 0.001, and p < 0.001, respectively), and after Bonferroni's correction, the difference remained significant in all age classes for QRS duration. The QTc interval diminished progressively with increasing age (p = 0.003) while the QT interval increased progressively (p < 0.001).

Conclusions

Significant variations in the normal ECG characteristics of young athletes exist between different age groups related to increasing age and training burden, thus, age-specific reference values could be adopted, as already done for echocardiographic measurements, and may help to further discriminate potentially pathologic conditions.
Understanding Clinician Macrocognition to Inform the Design of a Congenital Heart Disease Clinical Decision Support System
Authors: Assadi Azadeh , Laussen Peter C. , Freire Gabrielle , Trbovich Patricia
Published: February 2022

Background and Objectives

Children with congenital heart disease (CHD) are at risk of deterioration in the face of common childhood illnesses, and their resuscitation and acute treatment requires guidance of CHD experts. Many children with CHD, however, present to their local emergency departments (ED) with gastrointestinal and respiratory symptoms that closely mimic symptoms of CHD related heart failure. This can lead to incorrect or delayed diagnosis and treatment where CHD expertise is limited. An understanding of the differences in cognitive decision-making processes between CHD experts and ED physicians can inform how best to support ED physicians when treating CHD patients.

Methods

Cardiac intensivists (CHD experts) and pediatric emergency department physicians (ED physicians) in a major academic cardiac center were interviewed using the critical decision method. Interview transcripts were coded deductively based on Schubert and Klein's macrocognitive frameworks and inductively to allow for new or modified characterization of dimensions.

Results

In total, 6 CHD experts and 7 ED physicians were interviewed for this study. Although both CHD experts and ED physicians spent a lot of time sensemaking, their approaches to sensemaking differed. CHD experts reported readily recognizing the physiology of complex congenital heart disease and focused primarily on ruling out cardiac causes for the presenting illness. ED physicians reported a delay in attributing the signs and symptoms of the presenting illness to congenital heart disease, because these clinical findings were often non-specific, and thus explored different diagnoses. CHD experts moved quickly to treatment and more time anticipating potential problems and making specific contingency plans, while ED physicians spent more time gathering a range of data prior to arriving at a diagnosis. These findings were then applied to develop a prototype web-based decision support application for patients with CHD.

Conclusion

There are differences in the cognitive processes used by CHD experts and ED physicians when managing CHD patients. An understanding of differences in the cognitive processes used by CHD experts and ED physicians can inform the development of potential interventions, such as clinical decision support systems and training pathways, to support decision making pertaining to the acute treatment of pediatric CHD patients.
Heterogeneity of Treatment Effects for Intensive Blood Pressure Therapy by Individual Components of FRS: An Unsupervised Data-Driven Subgroup Analysis in SPRINT and ACCORD
Authors: Wu Yaqian , Bai Jianling , Zhang Mingzhi , Shao Fang , Yi Honggang , You Dongfang , Zhao Yang
Published: February 2022

Background

Few studies have answered the guiding significance of individual components of the Framingham risk score (FRS) to the risk of cardiovascular disease (CVD) after antihypertensive treatment. This study on the systolic blood pressure intervention trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) aimed to reveal previously undetected association patterns between individual components of the FRS and heterogeneity of treatment effects (HTEs) of intensive blood pressure control.

Methods

A self-organizing map (SOM) methodology was applied to identify CVD-risk-specific subgroups in the SPRINT (n = 8,773), and the trained SOM was utilized directly in 4,495 patients from the ACCORD. The primary endpoints were myocardial infarction (MI), non-myocardial infarction acute coronary syndrome (non-MI ACS), stroke, heart failure (HF), death from CVD causes, and a primary composite cardiovascular outcome. Cox proportional hazards models were then used to explore the potential heterogeneous response to intensive SBP control.

Results

We identified four SOM-based subgroups with distinct individual components of FRS profiles and the CVD risk. For individuals with type 2 diabetes mellitus (T2DM) in the ACCORD or without diabetes in the SPRINT, subgroup I characterized by male with the lowest concentrations for total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol measures, experienced the highest risk for major CVD. Conversely, subgroup III characterized by a female with the highest values for these measures represented as the lowest CVD risk. Furthermore, subgroup II, with the highest systolic blood pressure (SBP) and no antihypertensive agent use at baseline, had a significantly greater frequency of non-MI ACS under intensive BP control, the number needed to harm (NNH) was 84.24 to cause 1 non-MI ACS [absolute risk reduction (ARR) = −1.19%; 95% CI: −2.08, −0.29%] in the SPRINT [hazard ratio (HR) = 3.62; 95% CI: 1.33, 9.81; P = 0.012], and the NNH of was 43.19 to cause 1 non-MI ACS (ARR = −2.32%; 95% CI: −4.63, 0.00%) in the ACCORD (HR = 1.81; 95% CI: 1.01–3.25; P = 0.046). Finally, subgroup IV characterized by mostly younger patients with antihypertensive medication use and smoking history represented the lowest risk for stroke, HF, and relatively low risk for death from CVD causes and primary composite CVD outcome in SPRINT, however, except stroke, a low risk for others were not observed in ACCORD.

Conclusion

Similar findings in patients with hypertensive with T2DM or without diabetes by multivariate subgrouping suggested that the individual components of the FRS could enrich or improve CVD risk assessment. Further research was required to clarify the potential mechanism.
Knowledge of Hyperemic Myocardial Blood Flow in Healthy Subjects Helps Identify Myocardial Ischemia in Patients With Coronary Artery Disease
Authors: Lyu Lijuan , Pan Jichen , Li Dumin , Li Xinhao , Yang Wei , Dong Mei , Guo Chenghu , Lin Peixin , Han Yeming , Liang Yongfeng , Sun Junyan , Yu Dexin , Zhang Pengfei , Zhang Mei
Published: February 2022

Backgrounds

Dynamic CT myocardial perfusion imaging (CT-MPI) allows absolute quantification of myocardial blood flow (MBF). Although appealing, CT-MPI has not yet been widely applied in clinical practice, partly due to our relatively limited knowledge of CT-MPI. Knowledge of distribution and variability of MBF in healthy subjects helps in recognition of physiological and pathological states of coronary artery disease (CAD).

Objectives

To describe the distribution and normal range of hyperemic MBF in healthy subjects obtained by dynamic CT-MPI and validate whether it can accurately identify functional myocardial ischemia when the cut-off value of hyperemia MBF is set to the lower limit of the normal range.

Materials and Methods

Fifty-one healthy volunteers (age, 38 ± 12 years; 15 men) were prospectively recruited. Eighty patients (age, 58 ± 10 years; 55 men) with suspected or known CAD who underwent interventional coronary angiography (ICA) examinations were retrospectively recruited. Comprehensive CCTA + dynamic CT-MPI protocol was performed by the third – generation dual-source CT scanner. Invasive fractional flow reserve (FFR) measurements were performed in vessels with 30–90% diameter reduction. ICA/FFR was used as the reference standard for diagnosing functional ischemia. The normal range for the hyperemic MBF were defined as the mean ± 1.96 SD. The cut-off value of hyperemic MBF was set to the lower limit of the normal range.

Results

The global hyperemic MBF were 164 ± 24 ml/100 ml/min and 123 ± 26 ml/100 ml/min for healthy participants and patients. The normal range of the hyperemic MBF was 116–211 ml/100 ml/min. Of vessels with an ICA/FFR result (n = 198), 67 (34%) were functionally significant. In the per-vessel analysis, an MBF cutoff value of <116 ml/100 ml/min can identify myocardial ischemia with a diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 85.9% (170/198), 91.0% (61/67), 83.2 % (109/131), 73.5% (61/83), and 94.8% (109/115). CT-MPI showed good consistency with ICA/FFR in diagnosing functional ischemia, with a Cohen's kappa statistic of 0.7016 (95%CI, 0.6009 – 0.8023).

Conclusion

Recognizing hyperemic MBF in healthy subjects helps better understand myocardial ischemia in CAD patients.