bluuebunny/crossref_metadata_2025 huggingface dataset:
Season dynamics of microclimate parameters in the premises for keeping suckling sows farm with different ventilation systems
Authors: Mykhalko O. , Povod M.
Published: March 2021

The article investigated the dependence of the microclimate indicators in the premises for keeping suckling sows on the design features of the ventilation system. The annual dynamics of seasonal temperature fluctuations in both premises of the reproducer of the farm, as well as in the zone of piglets' vital activity, was recorded within the normal range. At the same time, when using the classical type of ventilation, the temperature indicators were significantly higher in summer compared to similar values in premises with a geothermal type of ventilation. At the same time, the amplitude of fluctuations in the annual dynamics of the piglet den temperature was higher in premises with an experimental type of ventilation relative to the traditional one and with a slight relative excess of the optimal value of the indicator by 0,1 ° C in the spring months. The temperature regime of the den of sows both in the study and in the control premises during the study period was characterized by uneven differences in off-season indicators: when using classical ventilation, the peak fell in the summer period, when using ventilation with underground air supply, in winter, however, without exceeding the optimal values. The air velocity in both rooms increased during the summer months. At the same time, with the traditional system for creating a microclimate, a stable reliable excess of this indicator relative to the values of the studied system was recorded, as well as its excess of the norm in summer. For the studied system with underground air supply, on the contrary, low values were noted and extremely low in the winter season. Both ventilation systems ensured optimal air humidity during the study period. The carbon dioxide content tended to increase in the autumn months in both premises, however, it exceeded the norm only when using traditional ventilation during this period – by 0,02% vol. Average values of ammonia content were kept in the optimal zone during all seasons with a slight increase in concentrations in autumn. However, the experimental microclimate system allowed a significantly higher NH3 content than in control premises system in the summer months at 1,99 mg/m3 or 150,09%. The hydrogen sulfide content was optimal for both premises during the year. But the premises where the investigated air preparation system "Exatop" was installed significantly higher in the concentration of H2 S, by 64,81% (p<0,001) in spring, by 61,14% (p<0,001) in summer and by 43,00% (p<0,001) in autumn, relative to premises with a traditional air preparation system. Despite the shown dependence of the microclimate indicators on the type of ventilation, it should be noted that it is important to continue further studies of the influence of these factors. Key words: sow, piglet, type of ventilation, multiple births, piglet nest weight, safety, season.
Avaliação da criminalidade no Estado do Pará
Authors: Regateiro Hugo Alexandre Santos , Ramos Edson Marcos Leal Soares , Souza Joyce Gama , Mello Cesar Maurício de Abreu
Published: March 2021

A violência e a criminalidade não são fenômenos presentes apenas nas grandes cidades e regiões metropolitanas, mas em todas as áreas que apresentam precarização nas condições sociais, necessitando, portanto, a compreensão das características e os impactos da criminalidade e violência nas cidades brasileiras. O objetivo do estudo é avaliar a criminalidade no Estado do Pará, Brasil, nos anos de 2017 a 2019. É um estudo quantitativo exploratório realizado nos 144 municípios do Estado do Pará, Brasil. Os dados dos crimes: (i) furto; (ii) roubo; (iii) roubo de veículo; (iv) homicídio; (v) latrocínio e (vi) lesão corporal seguida de morte, ocorridos no Pará, Brasil, foram extraídos dos Boletins de Ocorrência Policial. Os dados populacionais foram obtidos por meio do Instituto Brasileiro de Geografia e Estatística. Para mensurar a criminalidade violenta dos municípios do Pará, Brasil, utilizou-se o Índice de Criminalidade Média Bayesiana Duplamente Ponderada Padronizada para Municípios e para a apresentação espacial dos resultados, utilizaram-se os Sistemas de Informação Geográficas. Verificou-se que a maioria dos municípios apresentou índices baixos ou muito baixos de criminalidade no ano de 2019. Verificou-se, ainda, que os 5 primeiros colocados no ranking de 2018 e 2019 apresentaram índices muito alto de criminalidade. No entanto, em 2019, apenas um município apresentou índice muito alto. Foi possível avaliar a distribuição da criminalidade nos municípios do Pará, Brasil, alcançando, portanto, o objetivo do estudo. Espera-se que os resultados possam auxiliar os órgãos de segurança pública do estado na elaboração de ações efetivas nos municípios mais afetados pela criminalidade.
Avaliação de isolados de rizóbios tolerantes a acidez in vitro na simbiose com feijão Caupi (Vigna unguiculata L. Walp.) em Latossolo Amarelo
Authors: Hara Francisco Adilson dos Santos , Lopes Sophia Kathleen da Silva , Silva Theoderic Shay Botelho da , Vendruscolo Jhony , Mendes Angela  Maria da Silva , Inácio Ariele Cristine Ferreira , Souza Luiz Carlos Costa de
Published: March 2021

A baixa concentração de N nos solos agrícolas da Amazônia é um fator limitante para uma agricultura econômica e ecologicamente sustentável, logo, constata-se a grande importância da fixação biológica para   suprir a demanda deste macronutriente nos ecossistemas. O presente trabalho tem como objetivo, avaliar a capacidade infectiva de isolados de rizóbio e a eficiência na fixação do nitrogênio em um Latossolo Amarelo. O experimento foi instalado em delineamento inteiramente ao acaso, com esquema fatorial de 6 (4 Inoculantes e sem nitrogênio, 1 sem inoculantes e com nitrogênio, e 1 sem inoculante e sem nitrogênio) x 2 (calagem e sem calagem) em 4 repetições, perfazendo um total de 48 parcelas experimentais. A calagem aumentou a eficiência dos isolados e dos rizóbios nativos do solo em nodularem as plantas de caupi e estimularem o crescimento da biomassa. Os rizóbios nativos do solo apresentaram eficiência simbiótica semelhante aos isolados usados como inoculantes. O Isolado FCAN07B se equiparou à adubação nitrogenada em relação a proporcionar ganho de biomassa nas plantas de caupi. A dose de 20 kg ha-1 de nitrogênio foi deletéria para a nodulação do feijão caupi.
Climate change projections of maximum temperatures for southwest Iraq using statistical downscaling
Authors: Hassan WH
Published: March 2021

Global warming as an aspect of climate change has caused environmental problems, especially in dry regions. Identifying and assessing future climate change is therefore paramount to facilitate suitable environmental planning to adapt to, and reduce, its effects. Here, changes in the annual and seasonal maximum temperatures for 7 meteorological stations in southwestern Iraq were projected across mid-term (2040-2069) and long-term (2070-2099) time periods. Three different general circulation models (GCMs)—CanESM2, HadGEM2-ES, and MIROC5—were applied to 2 future emission representative concentration pathway scenarios—RCP4.5 and RCP8.5—using a statistical downscaling model (SDSM) applied to data collected over the period 1975-2005. The downscaling modeling process was effective at generating maximum temperatures over the selected time periods. The future simulation scenarios projected that temperatures will increase up to the end of the century, with the region potentially experiencing temperature increases of about 1.78-2.07°C during 2040-2069 and 2.2-2.63°C during 2070-2099 under RCP4.5. Projected warming for scenario RCP8.5 was 2.18-2.85°C and 2.93-3.7°C over the same time periods. These projected increases in temperature imply water scarcity and increases in desertification, which can be considered threats to the region.
The interaction of genetic and environmental factors in the etiology of hypertension
Authors: Kuneš J , Zicha J
Published: March 2021

Essential hypertension is a major risk factor for several
cardiovascular diseases. It is a complex trait resulting from the
interactions of multiple genetic and environmental factors.
Moreover, not only genetic but also epigenetic inheritance plays a
significant role. One can speculate that hypertension develops as
a consequence of “errors” in well-coordinated regulatory systems
of blood pressure. Errors in the cascade of molecular,
biochemical and genetic processes, which regulate blood
pressure, have finally enough potential to result in hypertension.
Numerous environmental factors surrounding the organism
during its development should influence the expression of genetic
information. However, despite the considerable research effort, it
is still difficult to identify all genes and/or other genetic
determinants leading to essential hypertension and other
cardiovascular diseases. This is mainly because these diseases
usually become a medical problem in adulthood, although their
roots might be traced back to earlier stages of ontogeny. The link
between distinct developmental periods (e.g. birth and
adulthood) should involve changes in gene expression involving
epigenetic phenomena. The purpose of the present paper is to
bring a piece of light on gene-environmental interactions
potentially implicated in the pathogenesis of hypertension.
Tissue-engineered heart valves
Authors: Filová E , Straka F , Miřejovský T , Mašín J , Bačáková L
Published: March 2021

Currently-used mechanical and biological heart valve prostheses
have several disadvantages. Mechanical prostheses, based on
carbon, metallic and polymeric components, require permanent
anticoagulation treatment, and their usage often leads to adverse
reactions, e.g. thromboembolic complications and endocarditis.
Xenogenous and allogenous biological prostheses are associated
with immune reaction, thrombosis and degeneration, and thus
they have a high rate of reoperation. Biological prostheses of
autologous origin, such as pulmonary autografts, often burden
the patient with a complicated surgery and the risk of
reoperation. Therefore, efforts are being made to prepare
bioartificial heart valves with an autologous biological component
by methods of tissue engineering. They should be biocompatible,
durable, endowed with appropriate mechanical properties and
able to grow with a child. For this purpose, scaffolds composed
of synthetic materials, such as poly(lactic acid),
poly(caprolactone), poly(4-hydroxybutyrate), hydrogels or natural
polymers, e.g. collagen, elastin, fibrin or hyaluronic acid, have
been seeded with autologous differentiated, progenitor or stem
cells. Promising results have been obtained with nanostructured
scaffolds, and also with cultivation in special dynamic bioreactors
prior to implantation of the bioartificial grafts into an animal
organism.
Detection of Secondary Metabolite of Mycena pelianthina Growth in Various Liquid Medium
Authors: Syarifah Nadya Denris Talitha , Ekowati Nuraeni , Mumpuni Aris , Iwan Saskiawan
Published: March 2021

Mushrooms which is mostly belong to the phylum Basidiomycota have been recognized as functional foods and a source for the nutraceuticals. Genus Mycena is one of mushrooms, which has been investigated for its secondary metabolites. Mycena pelianthina produces pelianthinarubins A, pelianthinarubins B, muscarin, and epimuscarin from alkaloid group. The purposes of this research were to determine the effects of composition of medium and incubation time on production of mycelial biomass of M. pelianthina in liquid medium and to know the group of secondary metabolite compounds produced. This research was done experimentally using a Factorial Completely Randomized Design consisted of 12 treatments and three replications. The first factor was medium type, which were Mushroom Complete Medium (MCM), Potato Dextrose Yeast Broth (PDYB), and Yeast Malt Extract Medium (YM). The second factor was the incubation time consisting of 15, 20, 25, and 30 days. The observed main parameters were the dry weight of mycelial biomass and the secondary metabolite groups. The dried weights of mycelia were analyzed using analysis of variance (ANOVA), continued with Duncan test at a 95% confidence level. The best growth of M. pelianthina mycelium was produced on PDYB medium at incubation time of 20 days with an average mycelial dry weight of 0.92 g/100 mL. M. pelianthina contained secondary metabolite compound groups of alkaloids, terpenoids, and flavonoids.
Redesain Metode Kerja Guna Reduksi Workload Fisik Dan Mental Pekerja Di Pt. Spu Palembang
Authors: Setiawan Heri , Kusmindari Christofora Desi
Published: March 2021

PT. SPU Palembang is an industrial company that produces Hospital Furniture and Rehabilitation products with the trademark SHIMA. This study aims to reduce the physical and mental workload received by workers in the Machine Shop Department. This research is focused on the production process .Measurement of physical workload uses the calculation of the worker's heart rate by calculating the percentage of Cardiovascular Load (CVL). Measurement of mental workload using the National Aeronautics and Space Administration Task Load Index (NASA-TLX) score calculation method. The results obtained based on the aspect of NASA-TLX before the proposal almost all workers receive a mental workload with a value of > 80 that is included in the category of heavy mental workloads except Milling-Drilling Workers (4) have a score < 80 in the category of moderate mental workload. After the proposal all workers have a score < 80 so that the mental workload received falls into the medium category. Based on the proposals applied to the Lathe Worker (1) and the Milling-Drilling Worker (4) namely the improvement of work methods in the process of turning, punching, and the proposed holding of a reminder as a tool to remember, the results obtained %CVL from both workers < 30%. Three other workers, although experiencing a decline, remained at > 30%. The category of mental workload received by workers from previously included in the category of heavy mental workload dropped to moderate
ANALISIA HIDROGRAF SATUAN DAN WIND ROSE PLOTS PADA DAERAH ALIRAN SUNGAI SEKANAK
Authors: Destania Henggar Risa , Syarifudin Achmad
Published: March 2021

Sekanak watershed is a basin in Palembang which is often affected by flood during the rainy season. The characteristics of the watershed by the impact of changes in land-use  by economic and settlement developments. Sekanak watershed has 3 retention ponds which have the function of accommodating temporary discharge during floods. The catchment capacity of the watershed soil type, storage conditions etc. Therefore we need an analysis of the transformation of rainfall data in the watershed into a flow at the watershed control point and an analysis of the transformation of runoff volume (effective rain) into a surface runoff hydrograph (unit hydrograph). Hydrographs measured at a watershed control point are the response or output from rain that falls on a watershed system. The size of the watershed depend on the watershed system. This is closely related in analyzing the availability of water that occurs in the watershed system.
Inspección y rehabilitación de puentes atirantados en la red de carreteras del Estado.
Authors: Criado Morán Emilio , Navareño Rojo Alvaro
Published: March 2021

En este artículo se describe la experiencia de los últimos años en la inspección y la ejecución de obras de rehabilitación de puentes atirantados pertenecientes a la Red de Carreteras del Estado, que gestiona directamente la Dirección General de Carreteras dependiente del Ministerio de Transportes Movilidad y Agenda Urbana. 

Durante los últimos años la Dirección General de Carreteras ha promovido la realización de numerosas inspecciones de puentes en su red de carreteras. Gracias a estas inspecciones se pudieron detectar deterioros significativos en cuatro de sus puentes atirantados más antiguos: el puente de Amposta, el puente de Fernando Reig en Alcoy, el puente del Centenario en Sevilla y el Puente Internacional sobre el río Guadiana, en Ayamonte. Esta detección precoz ha permitido realizar o proyectar en dichas estructuras las actuaciones de rehabilitación y sustitución de tirantes necesarias para garantizar la seguridad de los usuarios.   

Por lo tanto, es necesario destacar la importancia de realizar inspecciones especiales en los puentes atirantados construidos en España, ya que van alcanzando sus primeros 30-40 años de vida útil, para poder detectar la necesidad de reemplazar o sustituir algunos de sus elementos más vulnerables, como puede ser el sistema de atirantamiento.
Obras de sustitución de pretil del Viaducto de Ruitelán A-6 P.K. 424+000
Authors: Cerezo Macías José Alberto , Seguido Fernández-Tresguerres Elena , Del Pozo Vindel Florencio , Arrieta Torrealba José María , SAIZ GARCIA CARMEN
Published: March 2021

El Viaducto de Ruitelán se encuentra en la A-6, fue originalmente construido para el paso de la N-VI y posteriormente fue reconstruido parcialmente y su tablero ampliado, para alojar una de las dos calzadas de la Autovía. Se ha requerido una intervención por procedimiento de emergencia, en la margen derecha de su tablero, para realizar la sustitución del pretil, debido al deterioro que presentaba el mismo. Para ello se diseñó el nuevo pretil, de acuerdo con la actual normativa referente a los sistemas de contención, y las obras se realizaron aplicando distintas técnicas constructivas, con el objetivo de minimizar las afecciones a la estructura existente, así como también a los usuarios de esta vía.
Microbial Degradation of Naphthalene and Substituted Naphthalenes: Metabolic Diversity and Genomic Insight for Bioremediation
Authors: Mohapatra Balaram , Phale Prashant S.
Published: March 2021

Low molecular weight polycyclic aromatic hydrocarbons (PAHs) like naphthalene and substituted naphthalenes (methylnaphthalene, naphthoic acids, 1-naphthyl N-methylcarbamate, etc.) are used in various industries and exhibit genotoxic, mutagenic, and/or carcinogenic effects on living organisms. These synthetic organic compounds (SOCs) or xenobiotics are considered as priority pollutants that pose a critical environmental and public health concern worldwide. The extent of anthropogenic activities like emissions from coal gasification, petroleum refining, motor vehicle exhaust, and agricultural applications determine the concentration, fate, and transport of these ubiquitous and recalcitrant compounds. Besides physicochemical methods for cleanup/removal, a green and eco-friendly technology like bioremediation, using microbes with the ability to degrade SOCs completely or convert to non-toxic by-products, has been a safe, cost-effective, and promising alternative. Various bacterial species from soil flora belonging to Proteobacteria (Pseudomonas, Pseudoxanthomonas, Comamonas, Burkholderia, and Novosphingobium), Firmicutes (Bacillus and Paenibacillus), and Actinobacteria (Rhodococcus and Arthrobacter) displayed the ability to degrade various SOCs. Metabolic studies, genomic and metagenomics analyses have aided our understanding of the catabolic complexity and diversity present in these simple life forms which can be further applied for efficient biodegradation. The prolonged persistence of PAHs has led to the evolution of new degradative phenotypes through horizontal gene transfer using genetic elements like plasmids, transposons, phages, genomic islands, and integrative conjugative elements. Systems biology and genetic engineering of either specific isolates or mock community (consortia) might achieve complete, rapid, and efficient bioremediation of these PAHs through synergistic actions. In this review, we highlight various metabolic routes and diversity, genetic makeup and diversity, and cellular responses/adaptations by naphthalene and substituted naphthalene-degrading bacteria. This will provide insights into the ecological aspects of field application and strain optimization for efficient bioremediation.
Microfluidic Based Whole-Cell Biosensors for Simultaneously On-Site Monitoring of Multiple Environmental Contaminants
Authors: Cao Yiqi , Zhang Baiyu , Zhu Zhiwen , Xin Xiayin , Wu Hongjing , Chen Bing
Published: March 2021

Monitoring of environmental contaminants serves a vital role in proactive environmental management and pollution control. Research efforts have been centered on the development of robust whole-cell biosensors in recent years. However, data acquisition, multiple contaminants detection and biosafety issues limit the on-site application of such biosensors. Microfluidic system exhibits great potential to face these challenges via coupling biosensors. Here, we prospect a novel microfluidic based whole-cell biosensor (MWCB) for multiplexing monitoring of diverse contaminants, and design strategies to further increase the specificity, sensitivity and accuracy, reduce signal delay and expand shelf life of the proposed MWCB for on-site environmental applications. The development of MWCB demands multidisciplinary cooperation, and the sensing platforms are highly promising for real-world contaminants monitoring.
The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia
Authors: Ghafouri-Fard Soudeh , Abak Atefe , Mohaqiq Mahdi , Shoorei Hamed , Taheri Mohammad
Published: March 2021

The insulin-like growth factors (IGFs) are polypeptides with similar sequences with insulin. These factors regulate cell growth, development, maturation, and aging via different processes including the interplay with MAPK, Akt, and PI3K. IGF signaling participates in the pathogenesis of neoplasia, insulin resistance, diabetes mellitus, polycystic ovarian syndrome, cerebral ischemic injury, fatty liver disease, and several other conditions. Recent investigations have demonstrated the interplay between non-coding RNAs and IGF signaling. This interplay has fundamental roles in the development of the mentioned disorders. We designed the current study to search the available data about the role of IGF-associated non-coding RNAs in the evolution of neoplasia and other conditions. As novel therapeutic strategies have been designed for modification of IGF signaling, identification of the impact of non-coding RNAs in this pathway is necessary for the prediction of response to these modalities.
Insights Into Leukocyte Trafficking in Inflammatory Arthritis – Imaging the Joint
Authors: Manning Julia E. , Lewis Jonathan W. , Marsh Lucy-Jayne , McGettrick Helen M.
Published: March 2021

The inappropriate accumulation and activation of leukocytes is a shared pathological feature of immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Cellular accumulation is therefore an attractive target for therapeutic intervention. However, attempts to modulate leukocyte entry and exit from the joint have proven unsuccessful to date, indicating that gaps in our knowledge remain. Technological advancements are now allowing real-time tracking of leukocyte movement through arthritic joints orin vitrojoint constructs. Coupling this technology with improvements in analyzing the cellular composition, location and interactions of leukocytes with neighboring cells has increased our understanding of the temporal dynamics and molecular mechanisms underpinning pathological accumulation of leukocytes in arthritic joints. In this review, we explore our current understanding of the mechanisms leading to inappropriate leukocyte trafficking in inflammatory arthritis, and how these evolve with disease progression. Moreover, we highlight the advances in imaging of human and murine joints, along with multi-cellularex vivojoint constructs that have led to our current knowledge base.
Computational Design of gRNAs Targeting Genetic Variants Across HIV-1 Subtypes for CRISPR-Mediated Antiviral Therapy
Authors: Chung Cheng-Han , Allen Alexander G. , Atkins Andrew , Link Robert W. , Nonnemacher Michael R. , Dampier Will , Wigdahl Brian
Published: March 2021

Clustered regularly interspaced short palindromic repeats (CRISPR)-based HIV-1 genome editing has shown promising outcomes in in vitro and in vivo viral infection models. However, existing HIV-1 sequence variants have been shown to reduce CRISPR-mediated efficiency and induce viral escape. Two metrics, global patient coverage and global subtype coverage, were used to identify guide RNA (gRNA) sequences that account for this viral diversity from the perspectives of cross-patient and cross-subtype gRNA design, respectively. Computational evaluation using these parameters and over 3.6 million possible 20-bp sequences resulted in nine lead gRNAs, two of which were previously published. This analysis revealed the benefit and necessity of considering all sequence variants for gRNA design. Of the other seven identified novel gRNAs, two were of note as they targeted interesting functional regions. One was a gRNA predicted to induce structural disruption in the nucleocapsid binding site (Ψ), which holds the potential to stop HIV-1 replication during the viral genome packaging process. The other was a reverse transcriptase (RT)-targeting gRNA that was predicted to cleave the subdomain responsible for dNTP incorporation. CRISPR-mediated sequence edits were predicted to occur on critical residues where HIV-1 has been shown to develop resistance against antiretroviral therapy (ART), which may provide additional evolutionary pressure at the DNA level. Given these observations, consideration of broad-spectrum gRNAs and cross-subtype diversity for gRNA design is not only required for the development of generalizable CRISPR-based HIV-1 therapy, but also helps identify optimal target sites.
Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products
Authors: Nurkanto Arif , Jeelani Ghulam , Santos Herbert J. , Rahmawati Yulia , Mori Mihoko , Nakamura Yumi , Goto Kana , Saikawa Yoko , Annoura Takeshi , Tozawa Yuzuru , Sakura Takaya , Inaoka Daniel Ken , Shiomi Kazuro , Nozaki Tomoyoshi
Published: March 2021

Coenzyme A (CoA) is a well-known cofactor that plays an essential role in many metabolic reactions in all organisms. In Plasmodium falciparum, the most deadly among Plasmodium species that cause malaria, CoA and its biosynthetic pathway have been proven to be indispensable. The first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (PfPanK1 and 2) in this parasite. Here we produced, purified, and biochemically characterized recombinant PfPanK1 for the first time. PfPanK1 showed activity using pantetheine besides pantothenate, as the primary substrate, indicating that CoA biosynthesis in the blood stage of P. falciparum can bypass pantothenate. We further developed a robust and reliable screening system to identify inhibitors using recombinant PfPanK1 and identified four PfPanK inhibitors from natural compounds.
Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases
Authors: Massier Lucas , Blüher Matthias , Kovacs Peter , Chakaroun Rima M.
Published: March 2021

An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues via the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases.
Reduced Vitellogenesis and Female Fertility in Gper Knockout Zebrafish
Authors: Wu Xin-Jun , Williams Marcus Jermaul , Kew Kimberly Ann , Converse Aubrey , Thomas Peter , Zhu Yong
Published: March 2021

The role G-protein coupled estrogen receptor (GPER) plays in vertebrate reproduction remains controversial. To investigate GPER’s reproductive role, we generated a gper zebrafish mutant line (gper−/−) using TALENs. Gper mutant females exhibited reduced fertility with a 40.85% decrease in embryo production which was associated with a significant decrease in the number of Stage V (730–750 μm) ovulated oocytes. Correspondingly, the number of early vitellogenic follicles (Stage III, 400–450 µm) in gper−/− ovaries was greater than that in wildtypes (wt), suggesting that subsequent follicle development was retarded in the gper−/− fish. Moreover, plasma vitellogenin levels were decreased in gper−/− females, and epidermal growth factor receptor (Egfr) expression was lower in Stage III vitellogenic oocytes than in wt counterparts. However, hepatic nuclear estrogen receptor levels were not altered, and estrogen levels were elevated in ovarian follicles. These results suggest that Gper is involved in the control of ovarian follicle development via regulation of vitellogenesis and Egfr expression in zebrafish.
In Situ Spectroelectrochemical Investigation of Perovskite Quantum Dots for Tracking Their Transformation
Authors: Lee ChaeHyun , Kim Kyoungsoo , Shin YeJi , Han Donghoon , Yoon Seog Joon
Published: March 2021

All-inorganic lead-halide perovskite quantum dots (PQDs) (CsPbX3, where X is Cl, Br, or I) have been used successfully in optoelectronic applications, such as solar cells, light-emitting diodes, photocatalysts, and lasers. These PQDs work under electrochemical bias and/or illumination with charge separation/collection by interacting with the charge-transport medium. In this study, we discuss the spectroelectrochemical characteristics of PQDs to understand the oxidation and reduction processes that occur during photoinduced charge transport or charge injection under electrochemical conditions. We also found that the PQDs underwent irreversible transformation to the precursor state of plumbate complexes under electrochemical conditions. Furthermore,in situspectroelectrochemical analysis demonstrated that hole-mediated electrochemical oxidation of PQDs resulted in their irreversible transformation. Finally, the results presented herein contribute to our understanding of the charge-transfer-mediated process in PQDs and enhance their application potential in optoelectronic devices.
Serum Uric Acid Levels and Risk of Eight Site-Specific Cancers: A Mendelian Randomization Study
Authors: Jiang Minxiao , Ren Liangliang , Chen Songzan , Li Gonghui
Published: March 2021

The relationship between serum uric acid (UA) levels and cancer risk remains controversial. Here, a two-sample Mendelian randomization analysis was performed to identify a causal effect of serum UA levels on cancer risk. Twenty-six single nucleotide polymorphisms strongly associated with serum UA levels were screened as genetic variants from large-scale meta-analysis data of a genome-wide association study of 110,347 European individuals. Genetic associations with eight common site-specific cancers were subsequently explored. A total of six Mendelian randomization methods were used to estimate the potential effect of serum UA levels on cancer risk, including random effects inverse variance weighting, fix effects inverse variance weighting, MR-Egger, median weighting, mode weighting, and simple mode analysis. Our primary random effects inverse variance weighted analysis revealed that no significant associations with cancers was found (all p > 0.05). Sensitivity analyses and additional analyses also showed similar pooled results. In conclusion, no significant causality between serum UA levels and cancer risk was evidenced.
Potential Impact of DPYD Variation on Fluoropyrimidine Drug Response in sub-Saharan African Populations
Authors: da Rocha Jorge E. B. , Lombard Zané , Ramsay Michèle
Published: March 2021

Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase (DPYD) gene. There are clinical guidelines to improve safety outcomes of treatment, but these are primarily based on variants assessed in non-African populations. Whole genome sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess variation in DPYD in eight sub-Saharan African populations. Variant functional annotation was performed with a series of bioinformatics tools to assess potential likelihood of deleterious impact. There were 29 DPYD coding variants identified in the datasets assessed, of which 25 are rare, and some of which are known to be deleterious. One African-specific variant (rs115232898-C), is common in sub-Saharan Africans (1–4%) and known to reduce the function of the dihydropyrimidine dehydrogenase enzyme (DPD), having been linked to cases of severe toxicity. This variant, once validated in clinical trials, should be considered for inclusion in clinical guidelines for use in sub-Saharan African populations. The rs2297595-C variant is less well-characterized in terms of effect, but shows significant allele frequency differences between sub-Saharan African populations (0.5–11.5%; p = 1.5 × 10−4), and is more common in East African populations. This study highlights the relevance of African-data informed guidelines for fluorouracil drug safety in sub-Saharan Africans, and the need for region-specific data to ensure that Africans may benefit optimally from a precision medicine approach.
Stem Cell Factor Neutralization Protects From Severe Anaphylaxis in a Murine Model of Food Allergy
Authors: Ptaschinski Catherine , Rasky Andrew J. , Fonseca Wendy , Lukacs Nicholas W.
Published: March 2021

Food allergy is a growing public health problem with ~15 million people affected in the United States. In allergic food disease, IgE on mast cells bind to ingested antigens leading to the activation and degranulation of mast cells. Stem cell factor (SCF) is mast cell growth and activation factor that is required for peripheral tissue mast cells. We targeted a specific isoform of SCF, the larger 248 amino acid form, that drives peripheral tissue mast cell differentiation using a specific monoclonal antibody in a model of food allergy. Ovalbumin sensitized and intragastrically challenged mice were monitored for symptoms of anaphylaxis including respiratory distress, diarrhea, and a reduction in body temperature. During the second week of challenges, allergic mice were injected with an antibody to block SCF248 or given IgG control. Mice treated with α-SCF248 had a decreased incidence of diarrhea and no reduction in body temperature suggesting a reduction in anaphylaxis compared to IgG control treated animals. Re-stimulated mesenteric lymph nodes indicated that α-SCF248 treated mice had decreased OVA-specific Th2 cytokine production compared to IgG control treated allergic animals. The reduction of food induced anaphylaxis was accompanied by a significant reduction in gut leak. The mesenteric lymph node cells were analyzed by flow cytometry and showed a decrease in the number of type 2 innate lymphoid cells in mice injected with α-SCF248. Morphometric enumeration of esterase+ mast cells demonstrated a significant reduction throughout the small intestine. Using a more chronic model of persistent food-induced anaphylaxis, short term therapeutic treatment with α-SCF248 during established disease effectively blocked food induced anaphylaxis. Together, these data suggest that therapeutically blocking SCF248 in food allergic animals can reduce the severity of food allergy by reducing mast cell mediated disease activation.
Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock
Authors: König Rainer , Kolte Amol , Ahlers Olaf , Oswald Marcus , Krauss Veiko , Roell Daniela , Sommerfeld Oliver , Dimopoulos George , Tsangaris Iraklis , Antoniadou Eleni , Jaishankar Neeraja , Bogatsch Holger , Löffler Markus , Rödel Markus , Garcia-Moreno Marina , Tuchscherr Lorena , Sprung Charles L. , Singer Mervyn , Brunkhorst Frank , Oppert Michael , Gerlach Herwig , Claus Ralf A. , Coldewey Sina M. , Briegel Josef , Giamarellos-Bourboulis Evangelos J. , Keh Didier , Bauer Michael
Published: March 2021

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n= 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT,n= 118), and another, smaller clinical trial (Crossover study,n= 20). In addition,in vitroblood culture experiments andin vivoexperiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studiesin vitrorevealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, anin silicoanalysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.
PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis
Authors: Garcia de Moura Renan , Covre Luciana Polaco , Fantecelle Carlos Henrique , Gajardo Vitor Alejandro Torres , Cunha Carla Baroni , Stringari Lorenzzo Lyrio , Belew Ashton Trey , Daniel Camila Batista , Zeidler Sandra Ventorin Von , Tadokoro Carlos Eduardo , de Matos Guedes Herbert Leonel , Zanotti Raphael Lubiana , Mosser David , Falqueto Aloisio , Akbar Arne N. , Gomes Daniel Claudio Oliveira
Published: March 2021

Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.
Immunogenicity Risk Profile of Nanobodies
Authors: Ackaert Chloé , Smiejkowska Natalia , Xavier Catarina , Sterckx Yann G. J. , Denies Sofie , Stijlemans Benoit , Elkrim Yvon , Devoogdt Nick , Caveliers Vicky , Lahoutte Tony , Muyldermans Serge , Breckpot Karine , Keyaerts Marleen
Published: March 2021

Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required. In this study, we assessed the immunogenicity risk profile of two Nbs that are in phase II clinical trials: a first Nb against Human Epidermal growth factor Receptor 2 (HER2) for PET imaging of breast cancer and a second Nb with specificity to the Macrophage Mannose Receptor (MMR) for PET imaging of tumor-associated macrophages. For the anti-HER2 Nb, we show that only one out of 20 patients had a low amount of pre-existing anti-drug antibodies (ADAs), which only marginally increased 3 months after administering the Nb, and without negative effects of safety and pharmacokinetics. Further in vitro immunogenicity assessment assays showed that both non-humanized Nbs were taken up by human dendritic cells but exhibited no or only a marginal capacity to activate dendritic cells or to induce T cell proliferation. From our data, we conclude that monomeric Nbs present a low immunogenicity risk profile, which is encouraging for their future development toward potential clinical applications.

One Sentence Summary

Nanobodies, the recombinant single domain affinity reagents derived from heavy chain-only antibodies in camelids, are proven to possess a low immunogenicity risk profile, which will facilitate a growing number of Nanobodies to enter the clinic for therapeutic or in vivo diagnostic applications.
Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation
Authors: Dhatchinamoorthy Karthik , Colbert Jeff D. , Rock Kenneth L.
Published: March 2021

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.
The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic
Authors: Shah Priyanka , Canziani Gabriela A. , Carter Erik P. , Chaiken Irwin
Published: March 2021

As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.
Current Advance of Immune Evasion Mechanisms and Emerging Immunotherapies in Renal Cell Carcinoma
Authors: Jian Yuli , Yang Kangkang , Sun Xiaoxin , Zhao Jun , Huang Kai , Aldanakh Abdullah , Xu Zhongyang , Wu Haotian , Xu Qiwei , Zhang Lin , Xu Chunyan , Yang Deyong , Wang Shujing
Published: March 2021

Renal cell carcinoma is a highly heterogeneous cancer group, and the complex microenvironment of the tumor provides appropriate immune evasion opportunities. The molecular mechanism of immune escape in renal cell carcinoma is currently a hot issue, focusing primarily on the major complex of histocompatibility, immunosuppressive cells, their secreted immunosuppressive cytokines, and apoptosis molecule signal transduction. Immunotherapy is the best treatment option for patients with metastatic or advanced renal cell carcinoma and combination immunotherapy based on a variety of principles has shown promising prospects. Comprehensive and in-depth knowledge of the molecular mechanism of immune escape in renal cell carcinoma is of vital importance for the clinical implementation of effective therapies. The goal of this review is to address research into the mechanisms of immune escape in renal cell carcinoma and the use of the latest immunotherapy. In addition, we are all looking forward to the latest frontiers of experimental combination immunotherapy.