bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients: final results of the GIMEMA LAL1509 protocol
Authors: Chiaretti Sabina , Ansuinelli Michela , Vitale Antonella , Elia Loredana , Matarazzo Mabel , Piciocchi Alfonso , Fazi Paola , Di Raimondo Francesco , Santoro Lidia , Fabbiano Francesco , Califano Catello , Martinelli Giovanni , Ronco Francesca , Ferrara Felicetto , Cascavilla Nicola , Bigazzi Catia , Tedeschi Alessandra , Sica Simona , Di Renzo Nicola , Melpignano Angela , Beltrami Germana , Vignetti Marco , Foa Robin
Published: February 2021

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39
Improving the safety of platelet transfusions by UV-C: Let’s go back to the bench
Authors: Prati Daniele
Published: February 2021

Not available.
School Management from the Perspective of Social Transformations at Work
Authors: Rosa Mauricio Bueno da , Eliane Griep Gomes Bitencourt  , Muhammad Ridwan
Published: February 2021

In this article we intend to address the context of the school routine that is governed by rules developed by the sectors responsible for school management. In the bureaucratization of school work we see the same meaning and dimensions as the bureaucratization of other sectors of production. As the training of the workforce was transferred to the school, this institution incorporated in its organization and functioning new elements and fundamental characteristics to achieve a good performance as a socializing agency for the worker. On the other hand, the figure of the autonomous teacher, of the humanist, encyclopedist type, has also disappeared. Whether in public education or in the private network, the vast majority of teachers are in the condition of salaried workers. In this way, the process of proletarianization of teaching workers is characterized, characterized by their working conditions. The division of school work, as it developed based on the same principles as the so-called management theories, reinforces the reproduction of capitalist logic in school pedagogical practice because new practices and relationships are crystallized in this practice.
Clinical implications of coronavirus disease 2019 in neonates
Authors: Kim Do-Hyun
Published: February 2021

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, a small number of coronavirus disease 2019 (COVID-19) cases in neonates have been reported worldwide. Neonates currently account for only a minor proportion of the pediatric population affected by COVID-19. Thus, data on the epidemiological and clinical features of COVID-19 in neonates are limited. Approximately 3% of neonates born to mothers with COVID-19 reportedly tested positive for SARS-CoV-2. Current limited data on neonates with COVID-19 suggest that neonatal COVID-19 shows a relatively benign course despite a high requirement for mechanical ventilation. However, neonates with pre-existing medical conditions and preterm infants appear to be at a higher risk of developing severe COVID-19. The greatest perinatal concern of the COVID-19 pandemic is the possibility of vertical transmission, especially transplacental transmission of SARS-CoV-2. Although direct evidence of the vertical transmission of SARS-CoV-2 is lacking, its possibility during late pregnancy cannot be ruled out. This review summarizes available case studies on COVID-19 in neonates and introduces what is currently known about neonatal COVID-19 with focus on its vertical transmission.
Workshop Pemanfaatan Market Place Dalam Menunjang Pemasaran Produk Pada Komunitas Mersi Fans Club Dimasa Pandemik Covid-19
Authors: Frieyadie Frieyadie , Nurajijah Nurajijah , Amsury Fachri , Sulistyowati Daning Nur , Fauziah Siti
Published: February 2021

PT Radio Swara Mersidiona atau yang lebih dikenal dengan nama Radio MeRsi yang dipercaya dalam dunia penyiaran, selalu memberikan kepuasan bagi pendengar. Sejak tahun 1971 radio mersi tetap konsisten dalam musik yang disugukan yaitu dangdut sehingga memiliki banyak penggemar setia sehingga terbentuklah komunitas yang bernama Mersi Fans Club (MFC). Permasalahan yang dihadapi oleh komunitas Mersi Fans Club (MFC) diantaranya para anggota Komunitas Mersi Fans Club l belum terlalu memahami bagaimana Pemanfaatan Market Place Dalam Menunjang Pemasaran Produk. Belum dapat mengimplementasikan pemasaran produk mereka pada Market Place. Juga dimasa pademik Covid-19 ini, kegiatan tatap muka juga menjadi kendala melanggar protokol kesehatan. Sebagai solusi kegiatan pengabdian masyarakat ini dengan mengadakan kegiatan Workshop secara daring dengan menggunakan fasilitas Zoom meeting. Hasil dari kegiatan ini, diharapkan dapat memahami dengan terus menurus dicoba dan mempraktekan yang sudah didapatkan, sekaligus dengan membuka komunkasi dengan WA Group.
Pengenalan Mudahnya Berkreasi Video Gaya Atraktif Pada Generasi Milenial
Authors: Maruloh Maruloh , Wigandi Dikdik Permana , Yulianto Agus
Published: February 2021

Survei We are Social menyebutkan 150 juta penduduk Indonesia aktif menggunakan media sosial (medsos). Dari beragam medsos, Youtube menjadi platform yang terbanyak diakses yaitu sekitar 88% dari pengguna medsos pada tahun 2019. Youtube menjadi medsos yang paling banyak diakses oleh generasi milenial. Dalam perkembangannya, munculah istilah konten kreator. Konten kreator merupakan orang yang berprofesi untuk membuat suatu konten, baik berupa tulisan, gambar, video, atau suara. Konten dengan menggunakan video merupakan salah satu yang paling popular saat ini. Banyak anak-anak dan remaja yang tertarik dengan aplikasi berkonten video. Kegiatan pengabdian masyarakat ini berlokasi di RPTRA Alur Dahlia dengan target peserta anak-anak dan remaja RPTRA Alur Dahlia, yang berlokasi di RT 2 RW 7, Kelurahan Tegal Alur Jakarta Barat. Permasalahan yang bisaa terjadi pada anak-anak dan remaja disana adalah intensya atau seringnya anak-anak dan remaja membuka Youtube atau aplikasi yang berkonten video. Entah itu untuk sekedar melihat atau mereka membuat konten video untuk diupload. Oleh karena itu perlu bimbingan dan pelatihan kepada mereka bagaimana membuat konten video yang tidak hanya menarik, tetapi juga mendidik dan bermanfaat untuk sesama. Dari permasalahan tersebut, kami melakukan kegiatan pengabdian masyarakat di RPTRA Alur Dahlia agar anak-anak disana bisa lebih terbuka wawasannya mengenai aturan pembuatan konten video dan mampu membuat video yang bermanfaat dan berguna untuk masyarakat.
Effect of Hemoglobin Levels Pregnant Women on the Predictive Value for Preeclampsia of ROT (Roll-Over Test)
Authors: Hidayatunnikmah Nina , Rihardini Tetty
Published: February 2021

Preeclampsia is a medical condition which accounts for the global incidence of maternal mortality of 76,000/year and infant mortality of 500,000/year. Early preventive action is a critical dimension to reduce the risk to the mother and the fetus. Roll Over Test (ROT) is one of the predictors of preeclampsia conducted in the 2nd trimester. High hemoglobin levels in pregnant women can lead to pregnancy hypertension, which can potentially lead to preeclampsia. This study aims to analyze the effect of hemoglobin levels on the predictive value for preeclampsia of ROT (Roll Over Test) among pregnant women. The benefits of this study are to get preventive method updates to decrease the incidence of preeclampsia in pregnant women as early as possible and to review the policy of giving Fe to all pregnant women from the 1st trimester to the 3rd trimester. The study was conducted for three months in the work area of Siwalankerto Community Health Center, Surabaya. Data on hemoglobin levels were obtained from the MCH booklet for pregnant women. ROT's preeclampsia's predictive value was obtained by checking supine values and left lateral blood pressure among 30 pregnant women. A statistical test was performed using a logistic regression test. Based on 30 samples of pregnant women, the results showed that 16 pregnant women had hemoglobin levels of >13gr/dl (53.3%), and 14 pregnant women (46.7%) had a positive predictive value of ROT. The effect test analysis results showed a positive relationship between hemoglobin levels and the predictive value for preeclampsia (p=0.04, B=1.299). Thus, pregnant women who experienced an increase in the hemoglobin levels of 1 g/dl had a potential of 1.299 times to have a positive ROT value.
‘It isn't my area.’ Coaches’ awareness of concussion protocols in Scottish youth football
Authors: McArdle David , DeMartini Anne , Kim Sungwon , Connaughton Daniel
Published: February 2021

This paper discusses an externally-funded project into Scottish coaches’ awareness of the sports concussion prevention initiative, If in Doubt, Sit Them Out. It explores the short-term risks of concussion to youth participants in particular before analysing the data from interviews with ten coaches of girls’ football. The coaches’ apparent lack of awareness of the policy are highlighted and the possibility that the different resources in girls’ and boys’ football, and between girls’ performance and girls’ recreational participation, might impact on injury recognition and treatment, are explored. The paper highlights the need for further research into those areas, and the need to immediately address the apparently low levels of awareness of If in Doubt. With that in mind, proposals for both immediate and longer-term reform for its dissemination are introduced.
ADMINISTRAÇÃO DO ESTOQUE DE EMPRESAS COM USO DE ESTATÍSTICA
Authors:   UEMG - Universidade do Estado de Minas Gerais - Unidade Frutal, SILVA Marcelo Júnio da , CARMO Wesley Pereira do ,   UEMG - Universidade do Estado de Minas Gerais - Unidade Frutal, FREITAS SILVA Josney ,   UEMG - Universidade do Estado de Minas Gerais - Unidade Frutal
Published: February 2021

The objective of the study is to demonstrate the way in which statistical devices are used in specific departments of companies, which are seen as a basic part of their strategic planning, a condition that has required managers to have a more powerful decision-making flow. The research methodology employed was that of the inductive method associated with the literature review. As partial results of the study, it is emphasized that the use of statistics as support for analysis, generally aims to achieve the most sensible choice among the list of tools used to control stocks. It justifies the conduct of the research, the current stage in which the relevance of the use of calculations and data has been discussed the most, seen as allies with theories in the field of statistics, which support operational research for successful decision making by managers
A ideologia do apartidarismo no ethos institucional do Congresso em Foco a partir de seu discurso autorreferencial
Authors: Oliveira de Medeiros Lucas , Dantas Lemos Daniel
Published: February 2021

O objetivo deste artigo é compreender como a ideologia do apartidarismo se manifesta no ethos institucional analisado a partir do discurso autorreferencial do website jornalístico brasileiro Congresso em Foco. Embasamo-nos na teoria sobre o ethos discursivo na Análise do Discurso para analisar o ethos discursivo institucional do website, aplicando-a como abordagem teórico-metodológica. Foram analisados enunciados publicados em gêneros de apresentação de si, quais sejam, a página “Quem somos”, a marca, o slogan, o mídia kit e um editorial derivado da página “Quem somos”. Foram identificadas doze unidades de sentido no ethos discursivo institucional do Congresso em Foco: apartidarismo; defesa da democracia, direitos humanos e diversidade; independência; jornalismo para mudar; credibilidade; empreendedorismo; pioneirismo; pluralismo de vozes; profissionalismo; relevância; “cão de guarda”; e jornalismo político. O apartidarismo é tão significativo no ethos institucional do website que se pode afirmar que é a própria ideologia operada no seu discurso. Todo o seu ethos institucional é significado para reforçá-lo.
El diseño de los diarios españoles en el crepúsculo de la prensa
Authors: Vizuete José Ignacio Armentia , Marín Murillo María Flora
Published: February 2021

En este artículo se analiza el diseño de la prensa española durante la última década. Las modificaciones que se han realizado en la morfología de los diarios no han sido tan espectaculares como las que ocurrieron en los años anteriores y posteriores a la llegada del nuevo siglo. La crisis a la que se enfrentan los periódicos impresos, con una imparable caída de ventas en los últimos lustros y con un descenso de la inversión publicitaria en dicho sector, ha podido influir en una mayor moderación a la hora de afrontar transformaciones de gran calado. De hecho, en la mayoría de las cabeceras son aún reconocibles las aportaciones formales de principio de siglo. La omnipresencia del color, el uso de tipografías diferenciadas y la apuesta por los formatos de doble velocidad de lectura son algunas de las características que permanecen en unas publicaciones que, en general, han reducido sus dimensiones.
Noción de verdad en los discursos mediáticos y digitales ante los desafíos para la comunicación en democracia
Authors: Piñuel Raigada Jose Luis
Published: February 2021

Con esta exposición quiero compartir aquellos conocimientos, experiencias y deseos que he adquirido tras una larga vida de profesor de Teoría y Metodología de la Investigación en Comunicación en la Universidad Complutense de Madrid. Conocimientos, ofrecidos por 40 años de docente y de investigador en Comunicación. Experiencias, vividas gracias al acercamiento y con frecuencia el ejercicio de periodista y editor. Deseos, finalmente, fomentados desde mi condición de ciudadano comprometido como militante de base en partidos de izquierda durante un periodo durante el cual España sale de una dictadura e instaura una sólida democracia. Y sobre conocimientos académicos, (1. El rol de la academia frente a las nociones de verdad), experiencias profesionales (2. El periodismo y la posverdad) y deseos ciudadanos (3. Nuevos sistemas de Comunicación en el Estado de Derecho) giran precisamente los ejes temáticos de este texto.
Sociedades dramatizadas: la ficción televisiva de calidad en España y México
Authors: Julian Smith Paul
Published: February 2021

Durante la última década, España y México han producido una extraordinaria abundancia de drama televisivo y se encuentran entre los líderes de sus respectivos continentes. Solo en 2014, México produjo más de cien mil horas de televisión que se exportaron a cien países. A diferencia del caso del cine, más frágil y vulnerable puesto que depende de los subsidios del gobierno y está dominado por Hollywood en las salas locales, la televisión en ambos países es una industria que goza de mucho éxito, conecta con el público nacional y lleva la producción de Estados Unidos al margen de la parrilla. Este trabajo tiene como objetivo explorar las similitudes significativas que existen entre estos dos territorios. Para ello, se recurre al estudio de los casos más relevantes de la ficción dramatizada en cada uno de los dos países.
Uso de Scopus y Web of Science para investigar y evaluar en comunicación social: análisis comparativo y caracterización
Authors: Codina Lluís , Morales-Vargas Alejandro , Rodríguez-Martínez Ruth , Pérez-Montoro Mario
Published: February 2021

El objetivo es caracterizar y comparar las opciones que ofrecen las principales bases de datos a los investigadores en comunicación social para buscar y evaluar información académica. Para ello, mediante una evaluación experta se examinaron las características funcionales de Scopus y Web of Science. Como resultado se presenta una revisión detallada de dimensiones como la cobertura, la recuperación de información y las herramientas de análisis de fuentes y autores presentes en cada una, además de métricas de impacto específicas. Entre las conclusiones se observan similitudes en las funciones disponibles, pero diferencias significativas en el número de revistas en ámbito de las ciencias sociales y las humanidades, lo que deja a Scopus en mejor posición en el caso de tener que optar.
Run-Time and Statistical Pedestrian Level Wind Map for Downtown Toronto
Authors: Chen Jiaxiang , Gianfelice Michael , Izukawa Nicole , Elshaer Ahmed , Aboshosha Haitham
Published: February 2021

Rapid population growth and urbanization have led to the development of high-density and high-rise structures around the world. Tall structures in proximity can negatively affect pedestrian comfort by directing strong winds to the ground near the structure. Pedestrian level wind (PLW) may affect local businesses/services, pedestrian comfort and in extreme cases jeopardizes pedestrian safety. The downtown portion of the City of Toronto (∼10 km2) was chosen as the study region due to the recent development of many high-rise structures. The region was split into 10 zones and Computational Fluid Dynamics (CFD) was utilized to study the wind effects of the local building geometry and arrangements. Wind velocities were extracted from Computational Fluid Dynamics and coupled with historical meteorological data from Billy Bishop Airport. The coupled velocities from CFD were found to be within 20 and 5% RMSE, respectively, of the recorded data at the wind station for 85% of the sampled data. Wind velocities were then extracted at various elevations and coupled with meteorological weather data to generate real-time, historical, and statistical visualization of local wind fields. This study enables the prediction of real-time, historical, and statistical wind speeds, bearings at various elevations. Visualization of the flow field provides important insights for pedestrians, architects, engineers, and city planners regarding local wind speeds and identify problematic areas.
TRPM8 Channel Promotes the Osteogenic Differentiation in Human Bone Marrow Mesenchymal Stem Cells
Authors: Henao Juan C. , Grismaldo Adriana , Barreto Alfonso , Rodríguez-Pardo Viviana M. , Mejía-Cruz Claudia Camila , Leal-Garcia Efrain , Pérez-Núñez Rafael , Rojas Patricio , Latorre Ramón , Carvacho Ingrid , Torres Yolima P.
Published: February 2021

Various families of ion channels have been characterized in mesenchymal stem cells (MSCs), including some members of transient receptor potential (TRP) channels family. TRP channels are involved in critical cellular processes as differentiation and cell proliferation. Here, we analyzed the expression of TRPM8 channel in human bone marrow MSCs (hBM-MSCs), and its relation with osteogenic differentiation. Patch-clamp recordings showed that hBM-MSCs expressed outwardly rectifying currents which were increased by exposure to 500 μM menthol and were partially inhibited by 10 μM of BCTC, a TRPM8 channels antagonist. Additionally, we have found the expression of TRPM8 by RT-PCR and western blot. We also explored the TRPM8 localization in hBM-MSCs by immunofluorescence using confocal microscopy. Remarkably, hBM-MSCs treatment with 100 μM of menthol or 10 μM of icilin, TRPM8 agonists, increases osteogenic differentiation. Conversely, 20 μM of BCTC, induced a decrease of osteogenic differentiation. These results suggest that TRPM8 channels are functionally active in hBM-MSCs and have a role in cell differentiation.
Metformin Attenuates Renal Fibrosis in a Mouse Model of Adenine-Induced Renal Injury Through Inhibiting TGF-β1 Signaling Pathways
Authors: Yi Hao , Huang Chunling , Shi Ying , Cao Qinghua , Chen Jason , Chen Xin-Ming , Pollock Carol A.
Published: February 2021

It is well-known that all progressive chronic kidney disease (CKD) is pathologically characterized by tubulointerstitial fibrosis process. Multiple studies have shown the critical role of inflammation and fibrosis in the development of CKD. Hence strategies that target inflammatory and fibrotic signaling pathways may provide promising opportunities to protect against renal fibrosis. Metformin has been used as the first-line glucose-lowering agent to treat patients with type 2 diabetes mellitus (T2DM) for over 50 years. Accumulating evidence suggests the potential for additional therapeutic applications of metformin, including mitigation of renal fibrosis. In this study, the anti-fibrotic effects of metformin independent of its glucose-lowering mechanism were examined in an adenine -induced mouse model of CKD. Expressions of inflammatory markers MCP-1, F4/80 and ICAM, fibrotic markers type IV collagen and fibronectin, and the cytokine TGF-β1 were increased in adenine-induced CKD when compared to control groups and significantly attenuated by metformin treatment. Moreover, treatment with metformin inhibited the phosphorylation of Smad3, ERK1/2, and P38 and was associated with activation of the AMP-activated protein kinase (AMPK) in the kidneys of adenine-treated mice. These results indicate that metformin attenuates adenine-induced renal fibrosis through inhibition of TGF-β1 signaling pathways and activation of AMPK, independent of its glucose-lowering action.
Chemically Modified SDF-1α mRNA Promotes Random Flap Survival by Activating the SDF-1α/CXCR4 Axis in Rats
Authors: Luo Zucheng , Bian Yujie , Zheng Gang , Wang Huijing , Yan Bingqian , Su Wenting , Dong Wei , Hu Zhichao , Ding Jian , Wang Anyuan , Li Shi , Fu Wei , Xue Jixin
Published: February 2021

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.
Endoplasmic Reticulum–Plasma Membrane Contact Sites: Regulators, Mechanisms, and Physiological Functions
Authors: Li Chenlu , Qian Tiantian , He Ruyue , Wan Chun , Liu Yinghui , Yu Haijia
Published: February 2021

The endoplasmic reticulum (ER) forms direct membrane contact sites with the plasma membrane (PM) in eukaryotic cells. These ER-PM contact sites play essential roles in lipid homeostasis, ion dynamics, and cell signaling, which are carried out by protein-protein or protein-lipid interactions. Distinct tethering factors dynamically control the architecture of ER-PM junctions in response to intracellular signals or external stimuli. The physiological roles of ER-PM contact sites are dependent on a variety of regulators that individually or cooperatively perform functions in diverse cellular processes. This review focuses on proteins functioning at ER-PM contact sites and highlights the recent progress in their mechanisms and physiological roles.
The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway
Authors: Cao Qiqi , Zhao Chun , Wang Congjing , Cai Lingbo , Xia Meng , Zhang Xiaolan , Han Jian , Xu Yangyang , Zhang Junqiang , Ling Xiufeng , Ma Xiang , Huo Ran
Published: February 2021

PAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations inPATL2those led to female infertility with oocyte maturation arrest; however, the mechanisms by which mutations affected meiotic maturation remained unclear. Here, we identified several novel and recurrent mutations ofPATL2in patients with similar phenotype, and chose the missense mutation c.649 T>A p.Tyr217Asn inPATL2(PATL2Y217N) as a typical to investigate the underlying mechanisms. We confirmed that this mutation disturbed oocyte maturation and observed morphological defects of large polar body, symmetrical division and abnormal spindle after microinjection of corresponding mutated mRNA. We further evaluated the effect of the PATL2Y217Nmutation in 293T cells, and found this mutation decreased the ubiquitination level and degradation of PATL2. Then, abnormally increased PATL2 bound mRNAs of Mos, an upstream activator of mitogen activated protein kinase (MAPK), to regulate its translational activity and subsequently impaired MAPK signaling pathway and oocyte meiosis. These results dissented from the previous view thatPATL2mutations reduced their expression and highlight the role of PATL2 in translational regulation of Mos and its association with MAPK signaling pathway during oocyte meiotic maturation.
CCDC154 Mutant Caused Abnormal Remodeling of the Otic Capsule and Hearing Loss in Mice
Authors: Xu Kai , Bai Xue , Chen Sen , Xie Le , Qiu Yue , Li He , Sun Yu
Published: February 2021

Osteopetrosis is a rare inherited bone disease characterized by dysfunction of osteoclasts, causing impaired bone resorption and remodeling, which ultimately leads to increased bone mass and density. Hearing loss is one of the most common complications of osteopetrosis. However, the etiology and pathogenesis of auditory damage still need to be explored. In this study, we found that a spontaneous mutation of coiled-coil domain-containing 154 (CCDC154) gene, a new osteopetrosis-related gene, induced congenital deafness in mice. Homozygous mutant mice showed moderate to severe hearing loss, while heterozygous or wild-type (WT) littermates displayed normal hearing. Pathological observation showed that abnormal bony remodeling of the otic capsule, characterized by increased vascularization and multiple cavitary lesions, was found in homozygous mutant mice. Normal structure of the organ of Corti and no substantial hair cell or spiral ganglion neuron loss was observed in homozygous mutant mice. Our results indicate that mutation of the osteopetrosis-related gene CCDC154 can induce syndromic hereditary deafness in mice. Bony remodeling disorders of the auditory ossicles and otic capsule are involved in the hearing loss caused by CDCC154 mutation.
Identifying Thyroid Carcinoma-Related Genes by Integrating GWAS and eQTL Data
Authors: Shen Fei , Gan Xiaoxiong , Zhong Ruiying , Feng Jianhua , Chen Zhen , Guo Mengli , Li Yayi , Wu Zhaofeng , Cai Wensong , Xu Bo
Published: February 2021

Thyroid carcinoma (TC) is the most common endocrine malignancy. The incidence rate of thyroid cancer has increased rapidly in recent years. The occurrence and development of thyroid cancers are highly related to the massive genetic and epigenetic changes. Therefore, it is essential to explore the mechanism of thyroid cancer pathogenesis. Genome-Wide Association Studies (GWAS) have been widely used in various diseases. Researchers have found multiple single nucleotide polymorphisms (SNPs) are significantly related to TC. However, the biological mechanism of these SNPs is still unknown. In this paper, we used one GWAS dataset and two eQTL datasets, and integrated GWAS with expression quantitative trait loci (eQTL) in both thyroid and blood to explore the mechanism of mutations and causal genes of thyroid cancer. Finally, we found rs1912998 regulates the expression of IGFALS (P = 1.70E-06) and HAGH (P = 5.08E-07) in thyroid, which is significantly related to thyroid cancer. In addition, KEGG shows that these genes participate in multiple thyroid cancer-related pathways.
HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells
Authors: Devadoss Dinesh , Singh Shashi P. , Acharya Arpan , Do Kieu Chinh , Periyasamy Palsamy , Manevski Marko , Mishra Neerad , Tellez Carmen S. , Ramakrishnan Sundaram , Belinsky Steven A. , Byrareddy Siddappa N. , Buch Shilpa , Chand Hitendra S. , Sopori Mohan
Published: February 2021

Background

The role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable.

Methods

Normal human bronchial epithelial cells (NHBEs) grown on air–liquid interface were infected with X4-tropic HIV-1LAV and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining.

Results and Discussion

NHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1LAV in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH.
The Use of Immersive Environments for the Early Detection and Treatment of Neuropsychiatric Disorders
Authors: Martin Robert F. K. , Leppink-Shands Patrick , Tlachac Matthew , DuBois Megan , Conelea Christine , Jacob Suma , Morellas Vassilios , Morris Theodore , Papanikolopoulos Nikolaos
Published: February 2021

Neuropsychiatric disorders are highly prevalent conditions with significant individual, societal, and economic impacts. A major challenge in the diagnosis and treatment of these conditions is the lack of sensitive, reliable, objective, quantitative tools to inform diagnosis, and measure symptom severity. Currently available assays rely on self-reports and clinician observations, leading to subjective analysis. As a step toward creating quantitative assays of neuropsychiatric symptoms, we propose an immersive environment to track behaviors relevant to neuropsychiatric symptomatology and to systematically study the effect of environmental contexts on certain behaviors. Moreover, the overarching theme leads to connected tele-psychiatry which can provide effective assessment.
Identification of a Metastasis-Associated Gene Signature of Clear Cell Renal Cell Carcinoma
Authors: Gao Suhua , Yan Lei , Zhang Hongtao , Fan Xiaoguang , Jiao Xiaojing , Shao Fengmin
Published: February 2021

Clear cell renal cell carcinoma (ccRCC) is one of the most frequent pathological subtypes of kidney cancer, accounting for ~70–75%, and the major cause of mortality is metastatic disease. The difference in gene expression profiles between primary ccRCC tumors and metastatic tumors has not been determined. Thus, we report integrated genomic and transcriptomic analysis for identifying differentially expressed genes (DEGs) between primary and metastatic ccRCC tumors to understand the molecular mechanisms underlying the development of metastases. The microarray datasets GSE105261 and GSE85258 were obtained from the Gene Expression Omnibus (GEO) database, and the R package limma was used for DEG analyses. In summary, the results described herein provide important molecular evidence that metastatic ccRCC tumors are different from primary tumors. Enrichment analysis indicated that the DEGs were mainly enriched in ECM–receptor interaction, platelet activation, protein digestion, absorption, focal adhesion, and the PI3K–Akt signaling pathway. Moreover, we found that DEGs associated with a higher level of tumor immune infiltrates and tumor mutation burden were more susceptible to poor prognosis of ccRCC. Specifically, our study indicates that seven core genes, namely the collagen family (COL1A2, COL1A1, COL6A3, and COL5A1), DCN, FBLN1, and POSTN, were significantly upregulated in metastatic tumors compared with those in primary tumors and, thus, potentially offer insight into novel therapeutic and early diagnostic biomarkers of ccRCC.
Agricultural Landscape Heterogeneity Matter: Responses of Neutral Genetic Diversity and Adaptive Traits in a Neotropical Savanna Tree
Authors: Amaral Tatiana Souza do , Santos Juliana Silveira dos , Rosa Fernanda Fraga , Pessôa Marcelo Bruno , Chaves Lázaro José , Ribeiro Milton Cezar , Collevatti Rosane Garcia
Published: February 2021

Plants are one of the most vulnerable groups to fragmentation and habitat loss, that may affect community richness, abundance, functional traits, and genetic diversity. Here, we address the effects of landscape features on adaptive quantitative traits and evolutionary potential, and on neutral genetic diversity in populations of the Neotropical savanna treeCaryocar brasiliense. We sampled adults and juveniles in 10 savanna remnants within five landscapes. To obtain neutral genetic variation, we genotyped all individuals from each site using nine microsatellite loci. For adaptive traits we measured seed size and mass and grown seeds in nursery in completely randomized experimental design. We obtained mean, additive genetic variance (Va) and coefficient of variation (CVa%), which measures evolvability, for 17 traits in seedlings. We found that landscapes with higher compositional heterogeneity (SHDI) had lower evolutionary potential (CVa%) in leaf length (LL) and lower aboveground dry mass (ADM) genetic differentiation (QST). We also found that landscapes with higher SHDI had higher genetic diversity (He) and allelic richness (AR) in adults, and lower genetic differentiation (FST). In juveniles, SHDI was also positively related toAR. These results are most likely due to longer dispersal distance of pollen in landscapes with lower density of flowering individuals. Agricultural landscapes with low quality mosaic may be more stressful for plant species, due to the lower habitat cover (%), higher cover of monocropping (%) and other land covers, and edge effects. However, in landscapes with higher SHDI with high quality mosaic, forest nearby savanna habitat and the other environments may facilitate the movement or provide additional habitat and resources for seed disperses and pollinators, increasing gene flow and genetic diversity. Finally, despite the very recent agriculture expansion in Central Brazil, we found no time lag in response to habitat loss, because both adults and juveniles were affected by landscape changes.
Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma
Authors: Su Miao , Qiao Kuang-Yuan , Xie Xiao-Li , Zhu Xin-Ying , Gao Fu-Lai , Li Chang-Juan , Zhao Dong-Qiang
Published: February 2021

Analysis of single-cell RNA sequencing (scRNA-seq) data of immune cells from the tumor microenvironment (TME) may identify tumor progression biomarkers. This study was designed to investigate the prognostic value of differentially expressed genes (DEGs) in intrahepatic cholangiocarcinoma (ICC) using scRNA-seq. We downloaded the scRNA-seq data of 33,991 cell samples, including 17,090 ICC cell samples and 16,901 ICC adjacent tissue cell samples regarded as normal cells. scRNA-seq data were processed and classified into 20 clusters. The immune cell clusters were extracted and processed again in the same way, and each type of immune cells was divided into several subclusters. In total, 337 marker genes of macrophages and 427 marker genes of B cells were identified by comparing ICC subclusters with normal subclusters. Finally, 659 DEGs were obtained by merging B cell and macrophage marker genes. ICC sample clinical information and gene expression data were downloaded. A nine-prognosis-related-gene (PRG) signature was established by analyzing the correlation between DEGs and overall survival in ICC. The robustness and validity of the signature were verified. Functional enrichment analysis revealed that the nine PRGs were mainly involved in tumor immune mechanisms. In conclusion, we established a PRG signature based on scRNA-seq data from immune cells of patients with ICC. This PRG signature not only reflects the TME immune status but also provides new biomarkers for ICC prognosis.
Complete CSN1S2 Characterization, Novel Allele Identification and Association With Milk Fatty Acid Composition in River Buffalo
Authors: Cosenza Gianfranco , Gallo Daniela , Auzino Barbara , Gaspa Giustino , Pauciullo Alfredo
Published: February 2021

The αs2-casein is one of the phosphoproteins secreted in all ruminants' milk, and it is the most hydrophilic of all caseins. However, this important gene (CSN1S2) has not been characterized in detail in buffaloes with only two alleles detected (reported as alleles A and B), and no association studies with milk traits have been carried out unlike what has been achieved for other species of ruminants. In this study, we sequenced the whole gene of two Mediterranean river buffalo homozygotes for the presence/absence of the nucleotide C (g.7539G>C) realized at the donor splice site of exon 7 and, therefore, responsible for the skipping of the same exon at mRNA level (allele B). A high genetic variability was found all over the two sequenced CSN1S2 alleles. In particular, 74 polymorphic sites were found in introns, six in the promoter, and three SNPs in the coding region (g.11072C>T, g.12803A>T, and g.14067A>G) with two of them responsible for amino acid replacements. Considering this genetic diversity, those found in the database and the SNP at the donor splice site of exon 7, it is possible to deduce at least eight different alleles (CSN1S2 A, B, B1, B2, C, D, E, and F) responsible for seven different possible translations of the buffalo αs2-casein. Haplotype data analysis suggests an evolutionary pathway of buffalo CSN1S2 gene consistent with our proposal that the published allele CSN1S2 A is the ancestral αs2-CN form, and the B2 probably arises from interallelic recombination (single crossing) between the alleles D and B (or B1). The allele CSN1S2 C is of new identification, while CSN1S2 B, B1, and B2 are deleted alleles because all are characterized by the mutation g.7539G>C. Two SNPs (g.7539G>C and g.14067A>G) were genotyped in 747 Italian buffaloes, and major alleles had a relative frequency of 0.83 and 0.51, respectively. An association study between these SNPs and milk traits including fatty acid composition was carried out. The SNP g.14067A>G showed a significant association (P < 0.05) on the content of palmitic acid in buffalo milk, thus suggesting its use in marker-assisted selection programs aiming for the improvement of buffalo milk fatty acid composition.
A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis
Authors: Jadeja Shahnawaz D. , Mayatra Jay M. , Vaishnav Jayvadan , Shukla Nirali , Begum Rasheedunnisa
Published: February 2021

Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics.
Apremilast in Refractory Behçet’s Syndrome: A Multicenter Observational Study
Authors: Vieira Matheus , Buffier Solène , Vautier Mathieu , Le Joncour Alexandre , Jamilloux Yvan , Gerfaud-Valentin Mathieu , Bouillet Laurence , Lazaro Estibaliz , Barete Stéphane , Misery Laurent , Gobert Delphine , Goulenok Tiphaine , Fain Olivier , Sacre Karim , Sève Pascal , Cacoub Patrice , Comarmond Cloé , Saadoun David
Published: February 2021

Objective

Mucocutaneous and joint disorders are the most common manifestations in Behçet’s syndrome (BS) and are frequently clustered in the so-called minor forms of BS. There remains a need for safe and effective treatment for joint lesions in BS. We report the long-term safety and effectiveness of apremilast in refractory joint and mucocutaneous manifestations of BS.

Methods

French nationwide multicenter study including 50 BS patients with either active joint and/or mucocutaneous manifestations resistant to colchicine and/or DMARDs. Patients received apremilast 30 mg twice a day. Primary effectiveness endpoint was the proportion of patients with complete response (CR) of articular symptoms at month 6 (M6), defined as resolution of inflammatory arthralgia and arthritis, with joint count equal to zero.

Results

At inclusion, the median tender and swollen joint count was of 4 [2-6] and 2 [1-2], respectively. The proportion of CR in joint disease at M6 was 65% (n = 15/23), and 17% (n = 4/23) were partial responders. CR of oral and genital ulcers, and pseudofolliculitis at M6 was 73% (n = 24/33), 94% (n = 16/17) and 71% (n = 10/14), respectively. The overall response at M6 was 74% for the entire cohort and 70% for the mucocutaneous-articular cluster (n = 27). The median Behçet’s syndrome activity score significantly decreased during study period [50 (40–60) vs. 20 (0–40); p <0.0001]. After a median follow-up of 11 [6-13] months, 27 (54%) patients were still on apremilast. Reasons for apremilast withdrawal included adverse events (n = 15, 30%) and treatment failure (n = 8, 16%). Thirty-three (66%) patients experienced adverse events, mostly diarrhea (n = 19, 38%), nausea (n = 17, 34%) and headache (n = 16, 32%).

Conclusion

Apremilast seems effective in BS-related articular disease refractory to colchicine and DMARDs. Discontinuation rates were significantly higher than that reported in clinical trials.
Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition
Authors: de Joode K. , Oostvogels A. A. M. , GeurtsvanKessel C. H. , de Vries R. D. , Mathijssen R. H. J. , Debets R. , van der Veldt A. A. M.
Published: February 2021

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.