bluuebunny/crossref_metadata_2025 huggingface dataset:
IMPORT SUBSTITUTION AS A FORM OF EFFECTIVE SOCIO-ECONOMIC POLICY OF THE STATE
Authors: Fokina-Mezentseva Katerina
Published: August 2021

The article is devoted to an urgent problem, the solution of which will improve the existing tools and approaches to import substitution in Ukraine. The article describes the process of import substitution as a kind of state policy. The main features of the process of import substitution and directions of implementation based on the criteria of economic, social and strategic expediency are given. The possibilities and limitations of the implementation of the import substitution policy as a method of stabilizing the economy are revealed. The necessity of applying the policy of protectionism, deregulation by the state to obtain a socio-economic effect has been substantiated. The study identifies the elements of the implementation of approaches to import substitution in Ukraine and proposes the directions of the organizational and economic mechanism for regulating import substitution.
Import substitution should be considered not only in the commodity sense, but also in its resource component, institutional aspect, the degree of influence on the rights of access to resources and markets, and the like. Taking these aspects into account makes it possible to systematically and comprehensively understand the scale of the import dependence of the domestic market and more effectively implement the import substitution policy.
Numerous studies of recent years indicate that the policy of import substitution is considered in the context of the problem of ensuring economic growth of the national economy, is constrained by the restriction of the balance of payments, and therefore, to support it, it is necessary either to increase exports or restrict imports. The import substitution policy must be implemented based on the criteria of economic, social and strategic expediency.
The result of the use of import substitution should be an increase in the competitiveness of domestic products by stimulating the modernization of production, increasing its efficiency and the development of new competitive types of products with a relatively high added value. This will allow the country to increase the level of gross domestic product production and compete on equal terms with developed industrial countries.
The Role of Social Capital on the Livelihood Strategy of the Pengkalen Batu Community, Payung Sub-district, South Bangka Regency
Authors: Isnawati Isnawati , Herdiyanti Herdiyanti , Rahman Bustami , Sulaiman Aimie , Hayati Laila , Dedoe Amir
Published: August 2021

This research is one of the studies that refer to the socio-economic conditions of the Bangka community, especially in Pengkalen Batu Hamlet, in carrying out livelihood strategies. This research aims to explain the livelihood strategies the people of Pengkalen Batu Hamlet implemented in carrying out their lives amid limited access away from the village, which makes the community have to survive. This is based on the variety of natural potentials owned by the community and can be utilized in carrying out life amidst the limitations possessed by the community. Conditions with limited access and far from rural and urban settlements encourage people to be more active and creative in managing nature wisely and wisely. The condition of assets the community owns varies from natural, physical, financial, social, and human capital. This research uses descriptive qualitative research methods and purposive sampling data collection techniques. Based on the results of the research, the Pengkalen Batu community carried out several livelihood strategies, including life engineering, job diversification strategies from the various natural potentials they had, then migration engineering strategies carried out by the local community. The three strategies carried out do not just appear. Still, a push for access to social capital makes people think and move creatively and innovatively in developing their natural potential.
O Cuidar de uma Pessoa com Câncer na Ótica de Familiares Cuidadores: Revisão de Literatura
Authors: Almeida de Oliveira Dionatan , De Mello Jonata , Vinicius de Souza Schenkel Yan , Mariza Hildebrandt Leila , De Andrade Andressa , Gindri Resta Fontana Dariele
Published: August 2021

Objetivo: identificar evidências científicas relativas às vivências de cuidadores familiares de pessoas que adoecem por câncer. Método: realizou-se uma revisão integrativa de literatura, baseada em seis etapa. A busca bibliográfica ocorreu em junho de 2020 por meio da Plataforma da Biblioteca Virtual de Saúde, pós a aplicação dos critérios de inclusão e exclusão foram selecionados 21 artigos para o estudo. Resultados: os artigos analisados indicaram a mulher como cuidadora principal da pessoa com câncer. Também foi identificado diversas vivências e sentimentos do familiar cuidador, englobando mudanças cotidianas, medo, angústia, ansiedade, incertezas, sobrecargas, receio da morte e sintomas depressivos, o que comprometeu a saúde mental, física e espiritual do cuidador, repercutindo na forma do cuidado ao familiar doente. Ainda, elementos de suporte foram evidenciados nos artigos analisados, como religiosidade, fé, crença em Deus, grupos de apoio e suporte de profissionais de saúde.Conclusão: as vivências e sentimentos dos familiares cuidadores de pessoas com câncer são semelhantes e requerem atenção dos profissionais de saúde.
MODULAR AND BRANCHED STRUCTURE OF INDIVIDUALIZED INTELLIGENT E-LEARNING MATERIALS FOR SCIENCE AND TECHNOLOGY SUBJECT COURSE
Authors: Dolenc Kosta , Pesek Igor , Aberšek Boris
Published: August 2021

E-learning and online education offers important opportunities for educators as well as for students. Traditional e-materials, as they are known today, do not allow the recognition of different parameters, such as: learning differences, prior knowledge, learning capabilities, learning environment, styles of learning, etc. Because e-materials are structured in such a way they cannot be successfully adapted for learners who consequently cannot control their own learning (Berge, 2002; Picciano, 2000; Saba, 2002). Such a result offers, among others, a highly anti-motivational effect. The preparation of modern e-materials therefore requires a thorough preparation in terms of content and design, which has to be (mostly) based on pedagogical and didactic theories. Modern e-materials, which can also be named educational e-materials, are usually accessible online (internet-based training (IBT), web-based training (WBT), online education, etc.), they enable and encourage self-learning, they are flexible, dynamic, interactive, use different types of media, individualized and adapted to the user’s needs. Mostly the latter characteristic will receive special attention in the following research.
Key words: individualized e-learning, intelligent system, metadata.
Factores de riesgo maternos asociados a parto prematuro en gestantes adolescentes atendidas en el Hospital Nacional Dos de Mayo año 2018 al 2019, Lima - Perú
Authors: Murguia-Ricalde Frankchesca N. , Indacochea-Cacéda Sonia , Roque Quezada Juan Carlos Ezequiel , De La Cruz-Vargas Jhony A.
Published: August 2021

INTRODUCCIÓN: La causa más frecuente de parto prematuro es idiopático, sin embargo se plantean diversos factores de riesgo que podrían desencadenarlo, que con un diagnóstico precoz y manejo oportuno podría disminuir la morbimortalidad neonatal y las secuelas posteriores. OBJETIVO: Determinar los factores de riesgo maternos que predisponen a parto prematuro en gestantes adolescentes atendidas en el Hospital Nacional Dos de Mayo, durante el periodo 2018 – 2019. MATERIALES Y MÉTODOS: Estudio analítico, observacional, retrospectivo, de tipo casos y controles. Se estudiaron 180 gestantes de 10 -19 años, divididas en 60 casos y 120 controles. Los resultados fueron ajustados mediante un modelo multivariado de regresión logística binaria. RESULTADOS: La edad materna promedio fue 17.49 años, el 71.7% de gestantes estuvieron en la etapa adolescencia tardía (17 – 19 años). Según el análisis multivariado, las variables: anemia (OR: 2,074; IC 95%= 1,075 - 4,001; p= 0,030), infección del tracto urinario (OR: 3,863; IC 95%= 1,508 - 9,896; p= 0,005) y preeclampsia (OR: 3,714; IC 95%=1,122 - 12,301; p= 0,032), se asociaron con un mayor riesgo de parto prematuro; mientras que no se encontró asociación estadísticamente significativa con la infección vaginal (OR: 2,111; IC 95%= 0,651 - 6,850; p= 0,205) y ruptura prematura de membranas (OR: 1,267; IC 95%= 0,609 - 2,633; p= 0,526). CONCLUSIONES: En nuestro estudio, Las variables asociadas a un mayor riesgo de parto prematuro en gestantes adolescentes fueron la anemia, infección del tracto urinario y preeclampsia.
Asociación entre morbilidad materna extrema y sepsis en neonatos atendidos en el Instituto Nacional Materno Perinatal, Lima 2016 – 2019
Authors: De La Cruz Davila Jean Pierre Eduardo , Munares García Oscar Fausto
Published: August 2021

Introducción: Entre 2012 al 2018 la prevalencia de Morbilidad Materna Extrema (MME) en el Instituto Nacional Materno Perinatal (INMP) fue 14.1 por 1000 nacidos vivos aumentando con los años, pudiendo ocasionar repercusiones en el recién nacido (RN) como natimuertos, prematuridad, bajo peso al nacer, entre otros. Objetivo: Determinar la asociación entre la MME y sepsis neonatal e identificar características del RN de madres con y sin MME y sus morbilidades. Materiales y métodos: Estudio longitudinal retrospectivo, en madres expuestas a MME (n=378) y no expuestas (n=378), se realizó el seguimiento del desenlace en su RN en sepsis neonatal, de casos atendidos en el INMP entre el 2016 a 2019. Utilizamos el programa Stata considerando significativos con valores p<0,05. Resultados: El 33% de recién nacidos de hijos de madre con MME presentaron sepsis neonatal (p<0.001), mostrando RR= 7.44 (IC95% 4.63-11.93) y RA= 1.59 (IC95% 0.88-2.84). La prematuridad (p<0.001), cesárea (p<0.001), hipertensión previa al embarazo (p <0.001) y líquido amniótico meconial o fétido (p<0.001) se asociaron a sepsis neonatal. En hijos de madre con MME, el 50.8% (p<0.001) presentaron peso al nacer <2500 g, 23% (p<0.001) requirieron reanimación al nacer, 12.4% (p<0.001) presentaron hipoglicemia, 49.7% (p<0.001) tuvieron una estancia hospitalaria >7 días y 7.1% (p<0.001) fallecieron. Respecto a las causas de MME, se identificó que el 57.67% de madres de este grupo presentaron trastornos hipertensivos durante la gestación, de las cuales 33.94% de sus hijos presentaron sepsis neonatal.  Conclusiones: En el análisis de frecuencias y riesgo relativo crudo se logra establecer una asociación entre el hijo de madre con MME y la presentación de sepsis en el recién nacido.
Factores asociados al nivel de conocimiento y actitudes sobre signos y síntomas de alarma en gestantes atendidas por teleconsulta en el Instituto Nacional Materno Perinatal durante el año 2020
Authors: Torres-Castillo Dayanara , Roque Quezada Juan Carlos
Published: August 2021

Objetivo: determinar los factores asociados al nivel de conocimiento y actitudes sobre signos y síntomas de alarma en gestantes atendidas por teleconsulta en el Instituto Nacional Materno Perinatal durante el año 2020. Materiales y métodos: el estudio es de tipo cuantitativo, observacional, analítico, transversal y retrospectivo. Se cuenta con una población de 1 000 gestantes y se toma como muestra 214 gestantes atendidas por teleconsulta del Instituto Nacional Materno Perinatal. Se aplicó un instrumento de 28 preguntas de selección múltiple. Resultados: el 88,3% de las gestantes presenta un nivel de conocimiento alto y un 75,7% una actitud favorable. Los factores asociados a una actitud favorable fueron: estado civil (p=0,013), paciente añosa (p= 0,002), abortos previos (p < 0,001), paridad previa (p=0,001) y gestaciones previas (p<0,001). Para nivel de conocimiento, encontramos asociación: estado civil (p<0,001) y paciente añosa (p<0,001). Conclusión: Los factores asociados significativamente a una actitud favorable y a un alto nivel de conocimiento fueron: estado civil y paciente añosa.
Kurang Energi Kronis Berhubungan dengan Kejadian Anemia pada Ibu Hamil
Authors: Subriah Subriah , Safitri Inka Dewi , Umar Syaniah , Saadong Djuhadiah
Published: August 2021

KEK (Chronic Energy Deficiency) is a condition caused by an imbalance in nutritional intake, which lasts (chronic) while the anemia in pregnant women is closely related to the nutritional status of pregnant women because anemia is one sign that the mother suffers from malnutrition. This study aims to determine the relationship between chronic energy deficiency and anemia in pregnant women at the Public healthcanter Mangasa, Makassar City. The type of research used is an analytic survey with a cross-sectional design. The sampling technique was purposive sampling with 78 respondents.  The results of the statistical test with the chi-square test are known as the significance value of p (0.005) <α (0.05), meaning that the p value is smaller than the value of α at 95% confidence level with 1 degree of freedom, it can be concluded that the null hypothesis is rejected and this accepted hypothesis means that there is a chronic lack of energy relationship with the incidence of anemia in pregnant women at the Public healthcenter Mangasa, Makassar City. Therefore, health workers are expected to be able to carry out continuous strengthening of KIE (communication, information, and education) in pregnant women with KEK risk and anemia to pay more attention to their health status from all factors in readiness to face pregnancy with a cross-sectoral approach.
Tingkat Kecemasan Berhubungan dengan Kualitas Tidur Ibu Hamil Trimester III
Authors: Sabatina Bingan Eline Charla
Published: August 2021

Pregnancy is a biological and psychological condition which certainly requires adaptation for women who are experiencing it. In the United States there are 40 million people experiencing anxiety disorders before childbirth. Third trimester pregnant women often feel afraid and anxious about the child who will be born later, so that pregnant women experience sleep quality disturbances. The purpose of this study was to determine the relationship between anxiety level and sleep quality of third trimester pregnant women at Ketapang Health Center. This type of quantitative research with a cross sectional approach. The population was 130 respondents in the third trimester of pregnant women at the Ketapang Health Center. The number of samples was 45 respondents using purposive sampling technique. Sleep quality variables used the PSQI (Pittsburgh Sleep Quality Index) questionnaire and the anxiety level variables used the HARS (Hamilton Rating Scale For Anxiety) questionnaire with data analysis tests using the Spearman Rho correlation test with a 95% confidence level. The results of the bivariate analysis showed that respondents who experienced mild anxiety with good sleep quality were 3 people (60%) and respondents who experienced severe anxiety with poor sleep quality were 15 people (83.3%). The correlation test between Anxiety Level and Sleep Quality for Third Trimester Pregnant Women obtained p value = 0.000, so it can be concluded that there is a relationship between anxiety levels and sleep quality for third trimester pregnant women at the Ketapang Health Center. Future research is expected to use other factors that can affect the quality of sleep of pregnant women, especially in the third trimester of pregnancy.
Responsibility before the World: Cinema, Perspectivism and a Nonhuman Ethics of Individuation
Authors: Lapworth Andrew
Published: August 2021

The recent ‘nonhuman turn’ in the theoretical humanities and social sciences has highlighted the need to develop more ontological modes of theorising the ethical ‘responsibility’ of the human in its relational encounters with nonhuman bodies and materialities. However, there is a lingering sense in this literature that such an ethics remains centred on a transcendent subject that would pre-exist the encounters on which it is called to respond. In this essay, I explore how Gilles Deleuze's philosophy offers potential opening for a more ontogenetic thinking of a ‘nonhuman ethics’. Specifically, I focus on how his theory of ‘individuation’ – conceived as a creative event of emergence in response to immanent ontological problems – informs his rethinking of ethics beyond the subject, opening thought to nonhuman forces and relations. I argue that if cinema becomes a focus of Deleuze's ethical discussions in his later work it is because the images and signs it produces are expressive of these nonhuman forces and processes of individuation, generating modes of perception and duration without ontological mooring in the human subject. Through a discussion of Verena Paravel and Lucien Castaing-Taylor's experimental film –  Leviathan (2012)  – I explore how the cinematic encounter dramatises different ethical worlds in which a multiplicity of nonhuman ‘points of view’ coexist without being reduced to a hierarchical or orienting centre that would unify and identify them. To conclude, I suggest that it is through the lens of an ethics of individuation that we can grasp the different sense of ‘responsibility’ alive in Deleuze's philosophy, one oriented not to the terms of the already-existing but rather to the nonhuman potential of what might yet come into being.
‘Our “China Within”’: Minjian Sinopsy Today, a Segue
Authors: Lee Kyoo
Published: August 2021

In this article I have set out to draw an ethnographically inflected, composite scene of what I would loosely term ‘Sinopsy’ today, drawing on a series of explorative conversations on ‘psychoanalysis in China’ and the questionnaire-based interviews I undertook (between 2015 and 2020) with 18 psychoanalysts, psychotherapists, psychological counselors and engaged academics in or from mainland China, ranging from seasoned professionals to new-generation trainees. My ongoing, modest hope is to get to see a bigger and ‘democalligraphically’ evolving picture of a kind of praxis-oriented community-serving minjian psychoanalysis on the ground. As I turn to this understudied, cartographically complex, porously open-ended zone of Sinopsychoanalysis in the making, a silhouette seems to be emerging on the horizon, itself a question in motion: What is (in) it for people in China, and across and beyond its great walls? Focusing on its transitional specificity, its active indeterminacy and eclectic adaptivity exemplified by Sino-Lacanian analysts’ practices among others, I also try to contextualize its deeper and broader psychocultural dimensions, especially given the turbulent (post)modernity of China, where its ongoing epochal traumas are inextricably private and public, familial, national and diasporic.
Access to Information Law in Brazil: What the Implementation Data Reveal
Authors: Capuano Ethel
Published: August 2021

This article shows the results of a research to evaluate the implementation process of the Access to Information Law in the Brazilian Federal Government using empirical data on the level of user satisfaction published since 2013 until 2020. The main goal of the research is to contribute to a revival of this complex issue for democracy in a sense of reality, using a twofold methodological axis: (i) analysis of an empirical and significant data sample collected from the system with statistics techniques, and (ii) logic assessment of the resulting statistics parameters based in the Expectancy-Disconfirmation Theory. The empirical data revealed, in one hand, that federal agencies and state-owned companies have evolved to improve the access to information but, in another hand, also revealed that in some areas of government there is still need of a broad communication to the citizens about the scope of the law.
Cholinergic Synapse Pathway Gene Polymorphisms Associated With Late-Phase Responses in Allergic Rhinitis
Authors: Samra Simranjit K. , Rajasekaran Ashwini , Sandford Andrew J. , Ellis Anne K. , Tebbutt Scott J.
Published: August 2021

Allergic rhinitis (AR) is characterized by an early-phase response (EPR), and in a subgroup of individuals, a late-phase response (LPR). We sought to investigate polymorphisms in cholinergic synapse pathway genes, previously associated with late-asthmatic responses, in the LPR. Twenty healthy participants and 74 participants with AR underwent allergen exposure using the Environmental Exposure Unit. Allergic participants were sub-phenotyped using self-reported nasal congestion scores; congestion is the predominant symptom experienced during the LPR. Acute congestion (AC, n = 36) participants developed only an EPR, while persistent congestion (PC, n = 38) participants developed both allergic responses. We interrogated blood samples collected before allergen exposure with genotyping and gene expression assays. Twenty-five SNPs located in ADCY3, AKT3, CACNA1S, CHRM3, CHRNB2, GNG4, and KCNQ4 had significantly different allele frequencies (P < 0.10) between PC and AC participants. PC participants had increased minor allele content (P = 0.009) in the 25 SNPs compared to AC participants. Two SNPs in AKT3 were associated with gene expression differences (FDR < 0.01) in PC participants. This study identified an association between the LPR and polymorphisms in the cholinergic synapse pathway genes, and developed a novel method to sub-phenotype AR using self-reported nasal congestion scores.
RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis
Authors: Wang Peipei , Feng Mengdie , Han Guoqiang , Yin Rong , Li Yashu , Yao Shuxin , Lu Pengbo , Wang Yuhua , Zhang Haojian
Published: August 2021

N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.
Biased Coupling to β-Arrestin of Two Common Variants of the CB2 Cannabinoid Receptor
Authors: Turu Gábor , Soltész-Katona Eszter , Tóth András Dávid , Juhász Cintia , Cserző Miklós , Misák Ádám , Balla András , Caron Marc G. , Hunyady László
Published: August 2021

β-arrestins are partners of the G protein-coupled receptors (GPCRs), regulating their intracellular trafficking and signaling. Development of biased GPCR agonists, selectively targeting either G protein or β-arrestin pathways, are in the focus of interest due to their therapeutic potential in different pathological conditions. The CB2 cannabinoid receptor (CB2R) is a GPCR involved in various functions in the periphery and the central nervous system. Two common occurring variants of CB2R, harboring Q63R or L133I missense mutations, have been implicated in the development of a diverse set of disorders. To evaluate the effect of these mutations, we characterized the binding profile of these mutant CB2 receptors to G proteins and β-arrestin2. Although their ability to inhibit cAMP signaling was similar, the Q63R mutant had increased, whereas the L133I mutant receptor had decreased β-arrestin2 binding. In line with these observations, the variants also had altered intracellular trafficking. Our results show that two common variants of the CB2 receptor have biased signaling properties, which may contribute to the pathogenesis of the associated disorders and may offer CB2R as a target for further development of biased receptor activation strategies.
The Immunomodulatory Effect of Triptolide on Mesenchymal Stromal Cells
Authors: He Haiping , Takahashi Atsuko , Mukai Takeo , Hori Akiko , Narita Miwako , Tojo Arinobu , Yang Tonghua , Nagamura-Inoue Tokiko
Published: August 2021

Mesenchymal stromal cells (MSCs) are known to have immunosuppressive ability and have been used in clinical treatment of acute graft-versus-host disease, one of severe complications of the hematopoietic stem cell transplantation. However, MSCs are activated to suppress the immune system only after encountering an inflammatory stimulation. Thus, it will be ideal if MSCs are primed to be activated and ready to suppress the immune reaction before being administered. Triptolide (TPL) is a diterpene triepoxide purified from a Chinese herb-Tripterygium wilfordii Hook.f. It has been shown to possess anti-inflammatory and immunosuppressive properties in vitro. In this study, we aimed to use TPL to prime umbilical cord-derived MSCs (TPL-primed UC-MSCs) to enter a stronger immunosuppressive status. UC-MSCs were primed with TPL, which was washed out thoroughly, and the TPL-primed UC-MSCs were resuspended in fresh medium. Although TPL inhibited the proliferation of UC-MSCs, 0.01 μM TPL for 24 h was tolerable. The surface markers of TPL-primed UC-MSCs were identical to those of non-primed UC-MSCs. TPL-primed UC-MSCs exhibited stronger anti-proliferative effect for activated CD4+ and CD8+ T cells in the allogeneic mixed lymphocyte reaction assay than the non-primed UC-MSCs. TPL-primed UC-MSCs promoted the expression of IDO-1 in the presence of IFN-γ, but TPL alone was not sufficient. Furthermore, TPL-primed UC-MSCs showed increased expression of PD-L1. Conclusively, upregulation of IDO-1 in the presence of IFN-γ and induction of PD-L1 enhances the immunosuppressive potency of TPL-primed UC-MSCs on the proliferation of activated T cells. Thus, TPL- primed MSCs may provide a novel immunosuppressive cell therapy.
Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models
Authors: Warwas Karsten M. , Meyer Marten , Gonçalves Márcia , Moldenhauer Gerhard , Bulbuc Nadja , Knabe Susanne , Luckner-Minden Claudia , Ziegelmeier Claudia , Heussel Claus Peter , Zörnig Inka , Jäger Dirk , Momburg Frank
Published: August 2021

Although T cell-recruiting CD3-binding bispecific antibodies (BiMAb) have been proven to be clinically effective for hematologic malignancies, the success of BiMAb targeting solid tumor-associated antigens (TAA) in carcinomas so far remains poor. We reasoned that provision of co-stimulatory BiMAb in combination with αTAA–αCD3 BiMAb would boost T cell activation and proliferative capacity, and thereby facilitate the targeting of weakly or heterogeneously expressed tumor antigens. Various αTAA–αCD3 and αTAA–αCD28 BiMAb in a tetravalent IgG1-Fc based format have been analyzed, targeting multiple breast cancer antigens including HER2, EGFR, CEA, and EpCAM. Moreover, bifunctional fusion proteins of αTAA–tumor necrosis factor ligand (TNFL) superfamily members including 4-1BBL, OX40L, CD70 and TL1A have been tested. The functional activity of BiMAb was assessed using co-cultures of tumor cell lines and purified T cells in monolayer and tumor spheroid models. Only in the presence of tumor cells, αTAA–αCD3 BiMAb activated T cells and induced cytotoxicity in vitro, indicating a strict dependence on cross-linking. Combination treatment of αTAA–αCD3 BiMAb and co-stimulatory αTAA–αCD28 or αTAA–TNFL fusion proteins drastically enhanced T cell activation in terms of proliferation, activation marker expression, cytokine secretion and tumor cytotoxicity. Furthermore, BiMAb providing co-stimulation were shown to reduce the minimally required dose to achieve T cell activation by at least tenfold. Immuno-suppressive effects of TGF-β and IL-10 on T cell activation and memory cell formation could be overcome by co-stimulation. BiMAb-mediated co-stimulation was further augmented by immune checkpoint-inhibiting antibodies. Effective co-stimulation could be achieved by targeting a second breast cancer antigen, or by targeting fibroblast activation protein (FAP) expressed on another target cell. In tumor spheroids derived from pleural effusions of breast cancer patients, co-stimulatory BiMAb were essential for the activation tumor-infiltrating lymphocytes and cytotoxic anti-tumor responses against breast cancer cells. Taken together we showed that co-stimulation significantly potentiated the tumoricidal activity of T cell-activating BiMAb while preserving the dependence on TAA recognition. This approach could provide for a more localized activation of the immune system with higher efficacy and reduced peripheral toxicities.
Advance Optical Properties and Emerging Applications of 2D Materials
Authors: Kumbhakar Partha , Chowde Gowda Chinmayee , Tiwary Chandra Sekhar
Published: August 2021

In the last several decades, significant efforts have been devoted to two-dimensional (2D) materials on account of their optical properties that have numerous applications in the optoelectronic world in the range of light-emitting diodes, optical sensors, solar energy conversion, photo-electrochemical cells, photovoltaic solar cells, and even the biomedical sector. First, we provide an outline of linear optical properties of 2D materials such as graphene, TMDs, h-BN, MXenes, perovskite oxide, and metal-organic framework. Then, we discuss the optoelectronic properties of the 2D materials. Along with these, we also highlight the important efforts in developing 2D optical materials with intensive emission properties at a broad wavelength from ultraviolet to near-infrared. The origin of this tunable emission has been discussed decoratively. Thickness and layer-dependent optical properties have been highlighted and are explained through surface defects, strain, vacancy, doping, and dangling bonds emerging due to structural change in the material. The linear and nonlinear optical properties in 2D MXene and perovskite oxides are also impressive due to their potential applications in next-generation devices with excellent optical sensitivity. Finally, technological innovations, challenges, and possible tuning of defects and imperfections in the 2D lattice are discussed.
Advances in the Relationships Between Cow’s Milk Protein Allergy and Gut Microbiota in Infants
Authors: Yang Yudie , Li Xiaoqi , Yang Ying , Shoaie Saeed , Zhang Cheng , Ji Boyang , Wei Yongjun
Published: August 2021

Cow’s milk protein allergy (CMPA) is an immune response to cow’s milk proteins, which is one of the most common food allergies in infants and young children. It is estimated that 2–3% of infants and young children have CMPA. The diet, gut microbiota, and their interactions are believed to be involved in the alterations of mucosal immune tolerance, which might lead to the development of CMPA and other food allergies. In this review, the potential molecular mechanisms of CMPA, including omics technologies used for analyzing microbiota, impacts of early microbial exposures on CMPA development, and microbiota–host interactions, are summarized. The probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and other modulation strategies for gut microbiota and the potential application of microbiota-based design of diets for the CMPA treatment are also discussed. This review not only summarizes the current studies about the interactions of CMPA with gut microbiota but also gives insights into the possible CMPA treatment strategies by modulating gut microbiota, which might help in improving the life quality of CMPA patients in the future.
The Role of graRS in Regulating Virulence and Antimicrobial Resistance in Methicillin-Resistant Staphylococcus aureus
Authors: Chen Le , Wang Zihui , Xu Tao , Ge Hongfei , Zhou Fangyue , Zhu Xiaoyi , Li Xianhui , Qu Di , Zheng Chunquan , Wu Yang , Zhao Keqing
Published: August 2021

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of both community- and hospital-associated infections. The antibiotic resistance and virulence characteristics of MRSA are largely regulated by two-component signal transduction systems (TCS) including the graRS TCS. To make a relatively comprehensive insight into graRS TCS in MRSA, the bioinformatics analysis of dataset GSE26016 (a S. aureus HG001 WT strain vs. the ΔgraRS mutant) from Gene Expression Omnibus (GEO) database was performed, and a total of 563 differentially expressed genes (DEGs) were identified. GO analysis revealed that the DEGs were mainly enriched in the “de novo” IMP biosynthetic process, lysine biosynthetic process via diaminopimelate, and pathogenesis; and they were mainly enriched in purine metabolism, lysine biosynthesis, and monobactam biosynthesis in KEGG analysis. WGCNA suggested that the turquoise module was related to the blue module, and the genes in these two modules were associated with S. aureus virulence and infection. To investigate the role of graRS in bacterial virulence, a graRS knockout mutant (ΔgraRS) was constructed using MRSA USA500 2,395 strain as a parent strain. Compared to the wild-type strain, the USA500ΔgraRS showed reduced staphyloxanthin production, retarded coagulation, weaker hemolysis on blood agar plates, and a decreased biofilm formation. These altered phenotypes were restored by the complementation of a plasmid-expressed graRS. Meanwhile, an expression of the virulence-associated genes (coa, hla, hlb, agrA, and mgrA) was downregulated in the ΔgraRS mutant. Consistently, the A549 epithelial cells invasion of the ΔgraRS mutant was 4-fold lower than that of the USA500 wild-type strain. Moreover, on the Galleria mellonella infection model, the survival rate at day 5 post infection in the USA500ΔgraRS group (55%) was obviously higher than that in the USA500 group (20%), indicating graRS knockout leads to a decreased virulence in vivo. In addition, the deletion of the graRS in the MRSA USA500 strain resulted in its increased susceptibilities to ampicillin, oxacillin, vancomycin, and gentamicin. Our work suggests that the graRS TCS plays an important role in regulating S. aureus virulence in vitro and in vivo and modulate bacterial resistance to various antibiotics.
miR-10a-5p Inhibits the Differentiation of Goat Intramuscular Preadipocytes by Targeting KLF8 in Goats
Authors: Xu Qing , Wang Yong , Li Xin , Du Yu , Li Yanyan , Zhu Jiangjiang , Lin Yaqiu
Published: August 2021

Intramuscular fat contributes to the improvement of meat quality of goats. MicroRNAs (miRNAs) have been reported to regulate adipocyte differentiation and maturation. The aim of our study was to clarify whether miR-10a-5p regulates goat intramuscular preadipocyte (GIPC) differentiation and its direct downstream signaling pathway. GIPCs were isolated from longissimus dorsi, whose miR-10a-5p level was measured at different time point of differentiation induction. Adipogenic differentiation of the GIPCs was evaluated by Oil Red O and BODIPY staining, and the expression changes of adipogenic genes like ACC, ATGL, CEBPβ, PPARγ, etc. Related mechanisms were verified by qPCR, a bioinformatic analysis, a dual-luciferase reporter assay, overexpression, and siRNA transfection. Oil Red O and BODIPY staining both with adipogenic gene detection showed that miR-10a-5p suppressed the accumulation of lipid droplets in GIPCs and inhibited its differentiation. The dual-luciferase reporter assay experiment revealed that miR-10a-5p regulates GIPC differentiation by directly binding to KLF8 3’UTR to regulate its expression. Thus, the results indicated that miR-10a-5p inhibits GIPC differentiation by targeting KLF8 and supply a new target for fat deposition and meat quality improvement.
Neuroimaging Anomalies in Community-Dwelling Asymptomatic Adults With Very Early-Stage White Matter Hyperintensity
Authors: Guan Shuai , Kong Xiangyu , Duan Shifei , Ren Qingguo , Huang Zhaodi , Li Ye , Wang Wei , Gong Gaolang , Meng Xiangshui , Ma Xiangxing
Published: August 2021

White matter hyperintensity (WMH) is common in healthy adults in their 60s and can be seen as early as in their 30s and 40s. Alterations in the brain structural and functional profiles in adults with WMH have been repeatedly studied but with a focus on late-stage WMH. To date, structural and functional MRI profiles during the very early stage of WMH remain largely unexplored. To address this, we investigated multimodal MRI (structural, diffusion, and resting-state functional MRI) profiles of community-dwelling asymptomatic adults with very early-stage WMH relative to age-, sex-, and education-matched non-WMH controls. The comparative results showed significant age-related and age-independent changes in structural MRI-based morphometric measures and resting-state fMRI-based measures in a set of specific gray matter (GM) regions but no global white matter changes. The observed structural and functional anomalies in specific GM regions in community-dwelling asymptomatic adults with very early-stage WMH provide novel data regarding very early-stage WMH and enhance understanding of the pathogenesis of WMH.
Virtual Support in Dementia: A Possible Viable Strategy for Caregivers
Authors: Ferretti Ceres , Nitrini Ricardo , Brucki Sonia M. D.
Published: August 2021

Background: In the last 10 months, due to the Covid-19 pandemic, several studies have shown that health education and virtual support strategies for caregivers of patients with dementia, in the management of home care, can be viable. Low and middle income countries, in particular, have sought to use these means to reduce the daily burden of caregivers, through virtual meetings of education and support.

Objectives: To present the feasibility of a pilot study on the use of a support action contemplated by the Caad Project–indirect costs of dementia–from HC-FMUSP.

Methods: Observational study in which 93 caregivers were invited to participate in virtual meetings on a frequency of three times/week, lasting 1 h each.

Results: Of the 93 invited family members, and after 3 months, 42 answered eight questions about the effectiveness of the action. High percentages of positive responses regarding program satisfaction ranged from 86 to 100%.

Conclusion: This study showed results of a very simple intervention that suggests that it is possible to offer caregivers of patients with dementia a program that can be used in primary care, in order to understand the difficulty of caregivers in their daily care of patients with dementia, with daily management guidelines on a case-by-case basis, in addition to promoting the implementation of an education strategy about the importance of knowing, and recognizing anatomophysiological changes in the aging process and its implications for the rupture of the imaginary line that involves senescence and senility. This allows the caregiver to feel able to protect his patient and himself by preventing the emergence of common diseases in this age group. Further studies are needed to explore this type of non-pharmacological support.
Clinica: An Open-Source Software Platform for Reproducible Clinical Neuroscience Studies
Authors: Routier Alexandre , Burgos Ninon , Díaz Mauricio , Bacci Michael , Bottani Simona , El-Rifai Omar , Fontanella Sabrina , Gori Pietro , Guillon Jérémy , Guyot Alexis , Hassanaly Ravi , Jacquemont Thomas , Lu Pascal , Marcoux Arnaud , Moreau Tristan , Samper-González Jorge , Teichmann Marc , Thibeau-Sutre Elina , Vaillant Ghislain , Wen Junhao , Wild Adam , Habert Marie-Odile , Durrleman Stanley , Colliot Olivier
Published: August 2021

We present Clinica (www.clinica.run), an open-source software platform designed to make clinical neuroscience studies easier and more reproducible. Clinica aims for researchers to (i) spend less time on data management and processing, (ii) perform reproducible evaluations of their methods, and (iii) easily share data and results within their institution and with external collaborators. The core of Clinica is a set of automatic pipelines for processing and analysis of multimodal neuroimaging data (currently, T1-weighted MRI, diffusion MRI, and PET data), as well as tools for statistics, machine learning, and deep learning. It relies on the brain imaging data structure (BIDS) for the organization of raw neuroimaging datasets and on established tools written by the community to build its pipelines. It also provides converters of public neuroimaging datasets to BIDS (currently ADNI, AIBL, OASIS, and NIFD). Processed data include image-valued scalar fields (e.g., tissue probability maps), meshes, surface-based scalar fields (e.g., cortical thickness maps), or scalar outputs (e.g., regional averages). These data follow the ClinicA Processed Structure (CAPS) format which shares the same philosophy as BIDS. Consistent organization of raw and processed neuroimaging files facilitates the execution of single pipelines and of sequences of pipelines, as well as the integration of processed data into statistics or machine learning frameworks. The target audience of Clinica is neuroscientists or clinicians conducting clinical neuroscience studies involving multimodal imaging, and researchers developing advanced machine learning algorithms applied to neuroimaging data.
Basal Synaptic Transmission and Long-Term Plasticity at CA3-CA1 Synapses Are Unaffected in Young Adult PINK1-Deficient Rats
Authors: Memon Adeel A. , Bagley Micah E. , Creed Rose B. , Amara Amy W. , Goldberg Matthew S. , McMahon Lori L.
Published: August 2021

Loss of function mutations in PARK6, the gene that encodes the protein PTEN-induced kinase 1 (PINK1), cause autosomal recessive familial Parkinson’s disease (PD). While PD is clinically diagnosed by its motor symptoms, recent studies point to the impact of non-motor symptoms, including cognitive dysfunction in the early pre-motor stages of the disease (Aarsland et al., 2004; Chaudhuri and Schapira, 2009). As the hippocampus is a key structure for learning and memory, this study aimed to determine whether synaptic transmission is affected at CA3-CA1 excitatory synapses in PINK1 knockout rats at an age when we recently reported a gain of function at excitatory synapses onto spiny projection neurons in the dorsal striatum (Creed et al., 2020) and when motor symptoms are beginning to appear (Dave et al., 2014). Using extracellular dendritic field excitatory postsynaptic potential recordings at CA3-CA1 synapses in dorsal hippocampus 4-to 5- month old PINK1 KO rats and wild-type littermate controls, we observed no detectable differences in the strength of basal synaptic transmission, paired-pulse facilitation, or long-term potentiation. Our results suggest that loss of PINK1 protein does not cause a general dysfunction of excitatory transmission throughout the brain at this young adult age when excitatory transmission is abnormal in the striatum.
The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling
Authors: Porciúncula Lisiane O. , Goto-Silva Livia , Ledur Pitia F. , Rehen Stevens K.
Published: August 2021

Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.
Clinicopathological Characteristics and Prognosis of Signet Ring Gastric Cancer: A Population-Based Study
Authors: Wei Qing , Gao Yiding , Qi Changsong , Yuan Xing , Li Jingjing , Xu Qi , Luo Cong , Chen Lei , Zhuo Wei , Xu Zhiyuan , Ying Jieer
Published: August 2021

Background

To better define the clinicopathologic characteristics of signet ring cell (SRC) gastric cancer and build a prognostic model for it.

Methods

SRC patient information from 2010 to 2015 were identified using Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and log-rank test were used to estimate Overall survival (OS) and to determine associations with histologic subtypes. In COX proportional hazards regression model–based univariate and multivariate analyses, significant variables for construction of a nomogram were screened out. The nomogram was validated by means of the concordance index (CI), calibration plots, and receiver operating characteristics (ROCs) curves.

Results

A total of 11,363 gastric cancer patients were enrolled. On dividing the patients into SRC, well-to-moderately differentiated (WMD) adenocarcinoma, and poorly differentiated (PD) adenocarcinoma, differences among these subgroups emerged. SRC patients were more likely to occur in female and young patients than other histologic subtypes. Larger tumors, stage T4, and node stage N3 were more likely to be found in the SRC group. The survival for SRC patients was better than non-SRC patients in stage I. Univariate and multivariate analyses identified age, tumor site, larger tumor size, advanced T classification, advanced N classification, advanced TNM stage, and surgery of primary site as independent prognostic indicators. Then an OS nomogram was formulated.

Conclusions

SRC had distinct clinicopathological characteristics. The nomogram provided an accurate tool to evaluate the prognosis of SRC.
Angelica Polysaccharide Antagonizes 5-FU-Induced Oxidative Stress Injury to Reduce Apoptosis in the Liver Through Nrf2 Pathway
Authors: Zeng Di , Wang Yaping , Chen Yi , Li Danyang , Li Guoli , Xiao Hanxianzhi , Hou Jiyin , Wang Ziling , Hu Ling , Wang Lu , Li Jing
Published: August 2021

Oxidative stress induced by chemotherapeutic agents causes hepatotoxicity. 5-Fluorouracil (5-FU) has been found to have a variety of side effects, but its toxic effect on the liver and the mechanism are still unclear. Angelica polysaccharide (ASP), the main active ingredient of Dang Gui, has antioxidative stress effects. In this study, we investigated the antagonistic effects of ASP on 5-FU-induced injury in the mouse liver and human normal liver cell line MIHA and the possible mechanism. Our results show that ASP inhibited 5-FU-induced the decrease in Bcl-2 protein and the increase in Bax protein. ASP alleviated 5-FU-induced the increase in alanine aminotransferase (ALT), triglyceride (TG), and aspartate aminotransferase (AST) content; hepatic steatosis; and liver fibrosis. ASP restored 5-FU-induced swelling of mitochondria and the endoplasmic reticulum. 5-FU promoted the expression of Keap1 and increased the binding to NF-E2-related factor 2 (Nrf2) to reduce the nuclear translocation of Nrf2, thereby weakening the transcriptional activity of Nrf2 to inhibit the expression of HO-1; reducing the activity of GSH, SOD, and CAT to increase ROS content; and aggravating DNA damage (indicated by the increase in 8-OHdG). However, ASP reversed these reactions. In conclusion, ASP attenuated the 5-FU-induced Nrf2 pathway barrier to reduce oxidative stress injury and thereby inhibit the disorder of lipid anabolism and apoptosis. The study provides a new protectant for reducing the hepatic toxicity caused by 5-FU and a novel target for treating the liver injury.