bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Efficiency, Stability, and Reputation in Fundraising and Generation of Resources in the Third Sector Institutions
Authors: da Silva Maciel Veronica , Da Costa FábioMoraes , Aroldo Freitas de Moura André
Published: May 2021

The purpose of this study is to verify if the efficiency, stability, and reputation are factors capable of impacting fundraising and resource generation of nonprofit institutions, bearers of the Federal Public Utility Title. Data was collected from the National Register of Public Utility Entities of the Ministry of Justice, a database developed by the Brazilian Ministry of Justice in which nonprofit organizations file their financial statements. The analysis comprised the available data, from 2010 to 2014. Results indicate that fundraising and generation of resources are significantly influenced by efficiency, stability, and reputation factors. The findings highlight the relevance of disclosing financial information in generating and attracting funds from these institutions.
KEBERHASILAN PEMBERDAYAAN EKONOMI MASYARAKAT DALAM EKSPOR KERAJINAN SANGKAR BURUNG
Authors: Dwi Angreni Dyah Kuntorini , Asmorowati Sulikah
Published: May 2021

Kerajinan sangkar burung adalah usaha ekonomi kreatif yang memanfaatkan potensi lokal juga mengasah kemampuan dan ketrampilan. Sangkar burung yang terbuat dari bahan kayu dengan tambah hiasan ukiran. Pengelolaan kerajinan sangkar burung mampu meningkatkan perekonomian warga Desa Gedog Wetan Kecamatan Turen, Kabupaten Malang. Mampu memproduksi kualitas super dengan pemasaran sudah luar Jawa bahkan mampu ekspor ke Meksiko. Pendekatan penelitian yang dilakukan peneliti adalah jenis penelitian kualitatif deskriptif. Tujuan penelitian adalah mendeskripsikan tentang pemberdayaan masyarakat dalam mengelola kerajinan sangkar burung dan dampak terhadap peningkatan perekonomian masyarakat Desa Gedog Wetan. Pemberdayaan ekonomi masyarakat desa dalam pembuatan sangkar burung sudah memiliki prospek ke depan yang bagus hingga mampu menjadi ciri khas desa dan mampu menyejahterakan perekonomian masyarakat desa. Penting untuk diteliti karena model yang telah diusulkan disetujui dan sudah diterapkan untuk anggaran pemerintah tahun depan sebagai percontohan proyek dengan dukungan berbagai pemangku kepentingan. Diharapkan model tersebut mampu mempercepat pembangunan ekonomi pedesaan, dan perluasan usaha kerajinan yang dikelola secara berkelanjutan.
RESEARCH OF METROLOGICAL CHARACTERISTICS OF THE STATE PRIMARY STANDARD OF UNIT OF SCALING FACTOR OF AC VOLTAGE TO 750/√3 kV
Authors:   State Enterprise ", Anokhin Yu. L. ,   All-Ukrainian State Research and Production Center for Standardization, Metrology, Certification and Consumer Protection", Velychko О. М. ,   State Enterprise "All-Ukrainian State Research and Production Center for Standardization, Metrology, Certification and Consumer Protection"
Published: May 2021

The article is devoted to the results of research of metrological characteristics of the newly created State primary standard of the unit of scaling factor of alternating current (AC) voltage up to 750/√3 kV. Until 2019, there was no metrological support for ultra-high voltage measurements in Ukraine. From 2016 to 2019, the State Enterprise "Ukrmetrteststandard" carried out research work on the development of the state primary standard unit of scaling factor of AC for ultra-high voltage. The created standard became the basis for metrological support of measurement of ultrahigh voltages of alternating current. The standard using for calibration of precision ultra-high voltage measuring transformers in the energy sector of the national economy. The created standard consists of a set of high-precision measuring instruments and is stored in a specially equipped laboratory. For reproduction and keeping of unit of scaling factor of AC voltage the method of comparison of currents with use of the bridge of AC and two measuring condensers is used. The article analyzes the conditions of keeping and using of the newly created standard, methods of measurement and reproduction of the unit of scaling factor of AC voltage. The results of the study of metrological characteristics of the standard are presented, which confirmed the characteristics regulated for the standard.
Mitigasi Cekaman Salinitas pada Fase Perkecambahan Kedelai melalui Invigorasi dengan Ekstrak Kulit Manggis dan Ekstrak Kunyit
Authors: Suryaman Maman , Hodiyah Ida , Nuraeni Yeni
Published: May 2021

Fase perkecambahan merupakan fase yang peka terhadap cekaman abiotik, termasuk cekaman salintas. Invigorasi dapat mengurangi efek negatif cekaman salinitas dan mempercepat proses perkecambahan. Penelitian ini bertujuan untuk mempelajari perlakuan invigorasi dalam memitigasi  cekaman salinitas pada fase perkecambahan. Penelitian dilaksanakan di rumah plastik Fakultas Pertanian Universitas Siliwangi. Penelitian ini menggunakan rancangan acak kelompok dengan pola faktorial yang diulang 3 kali. Faktor 1 = cekaman salinitas air laut, terdiri dari 3 level (0% = DHL = 0,6 mS cm-1; 10% = 7,69 mS cm-1;  dan  20% = 11,4 mS cm-1), Faktor 2 = invigorasi, terdiri dari 4 level (air  sebagai kontrol, ekstrak kulit manggis, ekstrak kunyit, dan campuran ekstrak kulit manggis dan ekstrak kunyit). Hasil  analisis menunjukkan bahwa tidak terjadi efek interaksi secara nyata antara cekaman salinitas dengan invigorasi terhadap semua parameter pengamatan, tetapi masing masing perlakuan secara  mandiri memberikan pengaruh yang signifikan. Cekaman salinitas menimbulkan efek negatif pada fase perkecambahan. Invigorasi dengan menggunakan ekstrak kulit manggis atau ekstrak kunyit dapat mempertahankan vigor kedelai pada kondisi cekaman salinitas, sehingga dapat digunakan untuk memitigasi cekaman salinitas pada fase perkecambahan.
Reactive Power of Asynchronous Electric Drives with Semiconductor Converters
Authors: Kovalova Yuliia , Kovalov Victor , Shcherbak Irina
Published: May 2021

The purpose of the article is to obtain a ratio for determining the reactive power of induction motors when powered by semiconductor converters. The task is to determine the dependence of reactive power on control parameters of the converters. The research method used is computer simulation of electric drive based on Fryze power theory for non-sinusoidal currents. The result is the obtained expression for the calculation of reactive power, which takes into account the rated idle current of the motor with sinusoidal power supply and the type of converter, due to introducing special coefficients. Numerical values of the latter, depending on the control parameter, are obtained on computer models with their subsequent approximation. The scientific novelty of the research is in the further development of Fryze power theory in the direction of decomposition of non-sinusoidal current components using computer models. The practical significance is the obtained expression for determining the reactive power of an asynchronous electric drive with a thyristor voltage converter, on the basis of which the capacity of compensating capacitors is calculated to increase its energy efficiency.
Subcutaneous, abdominal, and thoracic encapsulated fat necrosis in bowhead whales Balaena mysticetus from Alaska, USA
Authors: Stimmelmayr R , Rotstein DS , Sheffield G , George JC
Published: May 2021

We describe a case series of encapsulated fat necrosis with subcutaneous, abdominal, and thoracic locations in 7 subsistence-harvested bowhead whales Balaena mysticetus. Masses had a variably-dense fibrous capsule surrounding necrotic adipocytes and calcium salts (saponification). One animal also had prior concussive injury, pleural fibrosis, and hepatic lipoma; the other animals had no significant findings. The described condition is uncommon in bowhead whales, with 7/575 (1.2%) observed from 1996 to 2015. The exact mechanisms of development of encapsulated fat necrosis in bowhead whales remain to be determined. Encapsulated fat necrosis has been reported in other baleen whales, humans, and cows. It is usually an incidental finding during post-mortem examination that needs to be differentiated from neoplastic and inflammatory lesions, as the latter may have public health implications. Assessment of further cases in bowhead whales and other baleen whales is warranted to better understand their pathogenesis.
Searching on the edge: dynamic oceanographic features increase foraging opportunities in a small pelagic seabird
Authors: De Pascalis F , Pala D , Pisu D , Morinay J , Benvenuti A , Spano C , Ruiu A , Serra L , Rubolini D , Cecere JG
Published: May 2021

Ocean mesoscale and submesoscale features, such as eddies and filaments, play a key role in the foraging ecology of marine predators, by concentrating nutrients and acting as aggregative structures for pelagic organisms. Highly pelagic seabirds may exploit these features to find profitable food patches in a dynamic and complex 3-dimensional spatial environment. Using miniaturized GPS loggers, we investigated whether foraging habitat selection of the Mediterranean storm petrelHydrobates pelagicus melitensis, one of the smallest (ca. 28 g) seabirds worldwide, was affected by different static and dynamic oceanographic features during the breeding period. Individuals performed long foraging trips (up to 1113 km) in a relatively short time (1 to 2 d), covering large home ranges (up to 34370 km2), particularly during incubation. Different oceanographic features affected the at-sea distribution of storm petrels at different spatio-temporal scales. During incubation, individuals selected areas characterized by shallow waters and strong currents, conditions that may enhance vertical water mixing and increase food availability. During chick-rearing, they foraged closer to the colony, selecting shallow and productive areas, where increasing Lagrangian coherent structures and eddy kinetic energy enhanced foraging probability. These features could play an important role in storm petrels’ foraging habitat selection, especially during chick-rearing, given their need to find predictable food patches in a short timespan. Overall, our results suggest that marine circulation processes are key drivers of the at-sea distribution of this small pelagic surface predator.
Demographic responses to environmental change of the black-browed albatross, sentinel of the Patagonian Shelf Large Marine Ecosystem
Authors: Ventura F , Lukacs PM , Granadeiro JP , Matano R , Catry P
Published: May 2021

In long-lived marine top-predators with delayed sexual maturity such as seabirds, adult survival is predicted to drive population dynamics. Major knowledge gaps exist for the cryptic sub-adult stages of the population. Yet as the oceans undergo dramatic change, investigating the trends of top-predator populations and their responses to environmental variability is key for a process-based understanding of climate change. Using integrated population models based on a longitudinal data set spanning nearly 2 decades, we investigated the demographic rates and environmental drivers shaping the dynamics of a longevous marine top-predator population, the black-browed albatross Thalassarche melanophris in the Falklands. We quantified the dynamics of the whole population, including its cryptic sub-adult stages, and examined the effects of candidate environmental covariates on adult survival and productivity parameters. We found that high survival rates of both adults and juveniles are the main contributors to the growth of this albatross population, the only one that is increasing in the South Atlantic. The breeding parameters were affected by environmental fluctuations through bottom-up processes, with a negative effect of higher sea surface temperatures and a positive effect of wind intensity. The relatively constant adult survival was influenced by deeper ecosystem changes, captured by large-scale indices (Southern Annular Mode). Approximately half of the total population is composed of sub-adults, and the population dynamics are highly sensitive to changes in juvenile survival; addressing current knowledge gaps in these cryptic life-history stages is therefore a conservation goal of primary importance.
Self-control in old age: A grounded theory study
Authors: Caorong Laarni A.
Published: May 2021

Background: Self-control is associated with multiple positive outcomes. There are several studies on self-control, yet no literature describing the mechanism of self-control in old age.
Objective: This study aims to develop a substantive theory on the exercise of self-control in old age.
Methods: Grounded Theory methodology developed by Glaser & Strauss was utilized in the conduct of this study with ten (10) older adults as participants following the set of inclusion and exclusion criteria. Individual in-depth interviews of 30-45 minutes were observed to gather the needed verbatim narrative responses from each participant after careful consideration of the ethical procedures approved by the University research ethics board. Major themes with their respective sub-themes were generated after rigorous analysis of the participants’ responses following the steps provided by Glasser & Strauss in conducting grounded theory studies.
Results: This study resulted in the formulation of three propositions such as: (1) Older adults exercise self-control differently, (2) several personal motivations are involved in the exercise of self-control, and (3) the exercise of self-control leads to life satisfaction. From the propositions emerged the Theory of Self-control in Old age, which states that the process of self-control encompasses the human capability of exercising self-restraint to overrun different types of desires, passions, and temptations. The theory posits that older adults vary in their exercise of self-control depending upon their personal motivations. The theory also assumes that the exercise of self-control results in life satisfaction as displaying self-control is attributed to a host of positive life outcomes.
Conclusion: The present study has important implications in the field of gerontology and health care services since the older population is growing, and so does the demand for health care services. The need to understand the choices and decisions of older adult clients is fundamental in individualizing the health care services that may be designed and provided for them.
Funding: This research work was supported by Mindanao State University – Marawi under the APDP Scholarship.
Enhanced Anaerobic Biogas Production From Wheat Straw by Herbal-Extraction Process Residues Supplementation
Authors: Xi Yonglan , Liu Yang , Ye Xiaomei , Du Jing , Kong Xiangping , Guo Dong , Xiao Qingbo
Published: May 2021

Trace metals are essential constituents of cofactors and enzymes and that their addition to anaerobic digesters increases methane production. Many trace elements are contained in herbal-extraction process residues (HPR). The present study concerns the effect of six kinds of HPR [Danshen root (Dr), Astragalus membranaceus (Am), Isatis root (Ir), Angelica sinensis (As), and Pseudo-ginseng (Pg)] that were used as additives, respectively, in the anaerobic digestion of wheat straw on biogas and methane production. The ratios of HPR residues/wheat straw [based on total solids (TS), of wheat straw] were 3, 5, and 10%, respectively. The digesters were at 37 ± 1°C of water bath during 30 days of anaerobic digestion. The results showed that HPR had significant effects on the anaerobic co-digestion. The highest biogas productivity was achieved when treated with 10% Pseudo-ginseng residues (PGR), which yielded 337 ml/g TS of biogas and 178 ml/g TS of methane. Cumulative production of biogas and methane increased by 28 and 37% compared to the production achieved in the control. These results suggest that PGR is an effective HPR to enhance the production of methane.
Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis
Authors: Zhang Yingzhen , Yang Xiaoli , Li Zhongzhong , Bu Kailin , Li Tong , Ma Zhizhao , Wang Binbin , Ma Lina , Lu Honglin , Zhang Kun , Liu Luji , Zhao Yanying , Zhu Yipu , Qin Jin , Cui Junzhao , Liu Lin , Liu Shuxia , Fan Ping , Liu Xiaoyun
Published: May 2021

Objective: Multiple mechanisms including vascular endothelial cell damage have a critical role in the formation and development of atherosclerosis (AS), but the specific molecular mechanisms are not exactly clarified. This study aims to determine the possible roles of proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway in AS mouse model and H2O2-induced endothelial cell damage model and explore its possible mechanisms.

Approach and Results: The AS mouse model was established using apolipoprotein E-knockout (ApoE–/–) mice that were fed with a high-fat diet. It was very interesting to find that Pyk2/MCU expression was significantly increased in the artery wall of atherosclerotic mice and human umbilical vein endothelial cells (HUVECs) attacked by hydrogen peroxide (H2O2). In addition, down-regulation of Pyk2 by short hairpin RNA (shRNA) protected HUVECs from H2O2 insult. Furthermore, treatment with rosuvastatin on AS mouse model and H2O2-induced HUVEC injury model showed a protective effect against AS by inhibiting the Pyk2/MCU pathway, which maintained calcium balance, prevented the mitochondrial damage and reactive oxygen species production, and eventually inhibited cell apoptosis.

Conclusion: Our results provide important insight into the initiation of the Pyk2/MCU pathway involved in AS-related endothelial cell damage, which may be a new promising target for atherosclerosis intervention.
Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability
Authors: Rizzo Marilena , Stout Tom A. E. , Cristarella Santo , Quartuccio Marco , Kops Geert J. P. L. , De Ruijter-Villani Marta
Published: May 2021

Aneuploidy originating during meiosis in oocytes is the major cause of reduced fertility, implantation failure and miscarriage in women beyond their mid-thirties. Loss of chromosome cohesion, and defective microtubule dynamics and spindle assembly are, in turn, the major contributors to the error-prone nature of chromosome segregation in the oocytes of older women. However, the underlying molecular defects are not well understood. Altered function of MPS1 and AURKC have been shown to induce multipolar spindle phenotypes in murine oocytes and cancer cells, however, their role in reproductive aging associated oocyte aneuploidy is not known. Although age-related gamete and embryonic aneuploidy has been studied in female rodents, the horse may be a more appropriate animal model. Similar to women, aged mares suffer from reduced fertility and an increased incidence of oocyte aneuploidy. Moreover, mares show a long interval (decades) to reproductive senescence and, unlike rodents but similar to women, horse oocytes assemble the meiotic spindle in a slow and unstable manner, independent of microtubule organizing centers. In this study we found that oocytes from aged mares have lower expression of mRNA for Mps1, Spc25 and AurkC than oocytes from young mares while gene expression for other meiosis regulators did not differ. To assess the ability of horse oocytes to correctly form a bipolar spindle, in vitro matured MII oocytes were allowed to re-form their spindle after nocodazole-induced microtubule depolymerization. To investigate the importance of MPS1 and AURKC function in spindle (re)assembly, various concentrations of a MPS1 inhibitor (MPS1i, Compound 5) or an AURK inhibitor (AURKi, ZM447439) were included after nocodazole washout. MII oocytes from aged mares showed a higher incidence of spindle abnormalities after exposure to MPS1i. In contrast, Aurora kinase inhibition severely impaired microtubule organization and spindle formation in all oocytes, irrespective of mare age. In conclusion, gene expression for the kinases Mps1, Spc25, and AurkC is reduced in oocytes from aged mares. Moreover, spindle (re)assembly in aged mares’ oocytes is more unstable when Mps1 is inhibited. Overall, this suggests that compromised Mps1 activity predisposes to meiotic spindle instability in aged mare oocytes. This spindle instability could predispose to chromosome segregation errors.
Unraveling the Role of the Apical Papilla During Dental Root Maturation
Authors: Driesen Ronald B. , Gervois Pascal , Vangansewinkel Tim , Lambrichts Ivo
Published: May 2021

The apical papilla is a stem cell rich tissue located at the base of the developing dental root and is responsible for the progressive elongation and maturation of the root. The multipotent stem cells of the apical papilla (SCAP) are extensively studied in cell culture since they demonstrate a high capacity for osteogenic, adipogenic, and chondrogenic differentiation and are thus an attractive stem cell source for stem cell-based therapies. Currently, only few studies are dedicated to determining the role of the apical papilla in dental root development. In this review, we will focus on the architecture of the apical papilla and describe the specific SCAP signaling pathways involved in root maturation. Furthermore, we will explore the heterogeneity of the SCAP phenotype within the tissue and determine their micro-environmental interaction. Understanding the mechanism of postnatal dental root growth could further aid in developing novel strategies in dental root regeneration.
Using Advanced Cell Culture Techniques to Differentiate Pluripotent Stem Cells and Recreate Tissue Structures Representative of Teratoma Xenografts
Authors: Smith L. A. , Hidalgo Aguilar A. , Owens D. D. G. , Quelch R. H. , Knight E. , Przyborski S. A.
Published: May 2021

Various methods are currently used to investigate human tissue differentiation, including human embryo culture and studies utilising pluripotent stem cells (PSCs) such as in vitro embryoid body formation and in vivo teratoma assays. Each method has its own distinct advantages, yet many are limited due to being unable to achieve the complexity and maturity of tissue structures observed in the developed human. The teratoma xenograft assay allows maturation of more complex tissue derivatives, but this method has ethical issues surrounding animal usage and significant protocol variation. In this study, we have combined three-dimensional (3D) in vitro cell technologies including the common technique of embryoid body (EB) formation with a novel porous scaffold membrane, in order to prolong cell viability and extend the differentiation of PSC derived EBs. This approach enables the formation of more complex morphologically identifiable 3D tissue structures representative of all three primary germ layers. Preliminary in vitro work with the human embryonal carcinoma line TERA2.SP12 demonstrated improved EB viability and enhanced tissue structure formation, comparable to teratocarcinoma xenografts derived in vivo from the same cell line. This is thought to be due to reduced diffusion distances as the shape of the spherical EB transforms and flattens, allowing for improved nutritional/oxygen support to the developing structures over extended periods. Further work with EBs derived from murine embryonic stem cells demonstrated that the formation of a wide range of complex, recognisable tissue structures could be achieved within 2–3 weeks of culture. Rudimentary tissue structures from all three germ layers were present, including epidermal, cartilage and epithelial tissues, again, strongly resembling tissue structure of teratoma xenografts of the same cell line. Proof of concept work with EBs derived from the human embryonic stem cell line H9 also showed the ability to form complex tissue structures within this system. This novel yet simple model offers a controllable, reproducible method to achieve complex tissue formation in vitro. It has the potential to be used to study human developmental processes, as well as offering an animal free alternative method to the teratoma assay to assess the developmental potential of novel stem cell lines.
Self-Assembled H-Bonding Superstructures for Alkali Cation and Proton Transport
Authors: Licsandru Erol , Andrei Iuliana-Marilena , van der Lee Arie , Barboiu Mihail
Published: May 2021

Transmembrane protein channels are of significant importance for the design of biomimetic artificial ion channels. Regarding the transport principles, they may be constructed from amphiphilic compounds undergoing self-assembly that synergistically generate directional superstructures across bilayer membranes. Particularly interesting, these alignments may impose an artificial pore structure that may control the ionic conduction and translocate water and ions sharing one pathway across the cell membrane. Herein, we report that the imidazole and 3-amino-triazole amphiphiles self-assemble via multiple H-bonding to form stable artificial networks within lipid bilayers. The alignment of supramolecular assemblies influences the conduction of ions, envisioned to diffuse along the hydrophilic pathways. Compounds 1-8 present subtle variations on the ion transport activities, depending the structure of hydrophilic head and hydrophobic components. Fluorinated compounds 3, 4 and 7, 8 outperform the corresponding non-fluorinated counterparts 1, 2 and 5, 6. Under the same conditions, the R enantiomers present a higher activity vs. the S enantiomers. The present systems associating supramolecular self-assembly with ion-transport behaviors may represent very promising unexplored alternatives for ion-transport along with their transient superstructures within bilayer membranes, paralleling to that of biology.
A New Technique for Century-Scale Wind Component Indices
Authors: Smith Shawn R. , Richardson Renee , Stow Justin P. , Bourassa Mark A. , McMillan Homer
Published: May 2021

Advancing the understanding of how variations in the climate over the ocean influences the weather over the United States can be aided by developing marine climatic indices. Herein, wind component indices are developed using nearly 125 years of wind observations from ships. A new technique using probability density functions for the values of meridional and zonal wind components is developed to create indices for a user-selected region and accumulation interval (e.g., annual or seasonal) over a climatological period. The index is a measure of the shift in the likelihood of values above or below a threshold for a given season or year as compared to the long-term (e.g., 125 year) probability distribution. The new index method is demonstrated using ship-based wind observations for select regions of the Atlantic Ocean. Ship observations are extracted from release 3.0.0 of the International Comprehensive Ocean-Atmosphere Data Set. Prior to index creation, an assessment of wind data quality is completed, and suspect observations are removed. The method to create a probabilistic wind component index is described along with a metric of the uncertainty in the calculated index. Two wind component indices, for regions in the north Atlantic and eastern Gulf of Mexico, are presented to demonstrate the technique. Using the Gulf of Mexico index as a case study, we compare the wind component indices to precipitation measured over the Gulf coastal states and identify several relationships between multi-year changes in winds in the eastern Gulf of Mexico and precipitation on a seasonal basis. Exploring the spatiotemporal patterns of the onshore/offshore component wind indices derived from seasonal wind forecasts could provide a metric for future prediction of seasonal or annual precipitation to support the agricultural sector. The index method demonstrated can be applied to other spatiotemporal regions for different parameters and using other source datasets.
Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations
Authors: Chevalier Benjamin , Dupuis Hippolyte , Jannin Arnaud , Lemaitre Madleen , Do Cao Christine , Cardot-Bauters Catherine , Espiard Stéphanie , Vantyghem Marie Christine
Published: May 2021

Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.
Epidermal Growth Factor Modulates Palmitic Acid-Induced Inflammatory and Lipid Signaling Pathways in SZ95 Sebocytes
Authors: Törőcsik Dániel , Fazekas Fruzsina , Póliska Szilárd , Gregus Andrea , Janka Eszter Anna , Dull Katalin , Szegedi Andrea , Zouboulis Christos C. , Kovács Dóra
Published: May 2021

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.
Autologous Hematopoietic Stem Cell Transplantation for Behçet’s Disease: A Retrospective Survey of Patients Treated in Europe, on Behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation
Authors: Puyade Mathieu , Patel Amit , Lim Yeong Jer , Blank Norbert , Badoglio Manuela , Gualandi Francesca , Ma David D. , Maximova Natalia , Greco Raffaella , Alexander Tobias , Snowden John A.
Published: May 2021

Background

Behçet’s Disease (BD) is an autoimmune disease mostly presenting with recurrent oral and genital aphthosis, and uveitis. Patients are rarely refractory to immunosuppressive treatments. Autologous hematopoietic stem cell transplantation (aHSCT) is a standard of care in other autoimmune diseases. Some patients with BD have been treated with aHSCT based on compassionate use.

Objectives

Evaluate the outcome of aHSCT in adult patients with BD treated in member centers of the European Society for Blood and Marrow Transplantation (EBMT).

Methods

Adults who received aHSCT primarily for BD were identified retrospectively in the EBMT registry and/or in published literature. Data were extracted from either medical records of the patient or from publications.

Results

Eight out of 9 cases reported to the registry and extracted data of 2 further patients from literature were analyzed. Four were female, median age at onset of BD was 24y (range 9-50). Median age at aHSCT was 32y (27-51). Patients had received median 4 (2-11) previous lines of therapy (89% corticosteroids, 50% methotrexate, anti-TNFα therapy or cyclophosphamide). All patients had active disease before mobilization. Conditioning regimen was heterogeneous. Median follow-up was 48 months (range 6-240). No treatment-related mortality was reported. This procedure induced complete remission (CR) in 80%, partial remission in 10% and lack of response in 10% of the patients. Relapse rate was 30% (2 relapses in patients in CR and 1 relapse in the patient in PR) with panuveitis (n=1), aphthosis (n=2) and arthralgia (n=1). Six patients were in CR. No late complications were reported.

Conclusion

aHSCT has an acceptable safety profile and represents a feasible and relatively effective procedure in severe and conventional treatment-resistant cases of BD and has the potential to stabilize BD in patients with life-threatening involvements.
Anti-TNF-α agents Modulate SARS-CoV-2 Receptors and Increase the Risk of Infection Through Notch-1 Signaling
Authors: Keewan Esra’a , Beg Shazia , Naser Saleh A.
Published: May 2021

Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.
ILC-You in the Thymus: A Fresh Look at Innate Lymphoid Cell Development
Authors: Shin Samuel B. , McNagny Kelly M.
Published: May 2021

The discovery of innate lymphoid cells (ILCs) has revolutionized our understanding of innate immunity and immune cell interactions at epithelial barrier sites. Their presence and maintenance are critical for modulating immune homeostasis, responding to injury or infection, and repairing damaged tissues. To date, ILCs have been defined by a set of transcription factors, surface antigens and cytokines, and their functions resemble those of three major classes of helper T cell subsets, Th1, Th2 and Th17. Despite this, the lack of antigen-specific surface receptors and the notion that ILCs can develop in the absence of the thymic niche have clearly set them apart from the T-cell lineage and promulgated a dogma that ILCs develop directly from progenitors in the bone marrow. Interestingly however, emerging studies have challenged the BM-centric view of adult ILC development and suggest that ILCs could arise neonatally from developing T cell progenitors. In this review, we discuss ILC development in parallel to T-cell development and summarize key findings that support a T-cell-centric view of ILC ontogeny.
HIV Nef-mediated Ubiquitination of BCL2: Implications in Autophagy and Apoptosis
Authors: Castro-Gonzalez Sergio , Simpson Sydney , Shi Yuhang , Chen Yuexuan , Benjamin Jared , Serra-Moreno Ruth
Published: May 2021

Ubiquitination is a process that acts upon every step of the HIV replication cycle. The activity, subcellular localization, and stability of HIV dependency factors as well as negative modulators can be affected by ubiquitination. These modifications consequently have an impact on the progression and outcome of infection. Additionally, recent findings suggest new roles for ubiquitination in the interplay between HIV and the cellular environment, specifically in the interactions between HIV, autophagy and apoptosis. On one hand, autophagy is a defense mechanism against HIV that promotes the degradation of the viral protein Gag, likely through ubiquitination. Gag is an essential structural protein that drives virion assembly and release. Interestingly, the ubiquitination of Gag is vital for HIV replication. Hence, this post-translational modification in Gag represents a double-edged sword: necessary for virion biogenesis, but potentially detrimental under conditions of autophagy activation. On the other hand, HIV uses Nef to circumvent autophagy-mediated restriction by promoting the ubiquitination of the autophagy inhibitor BCL2 through Parkin/PRKN. Although the Nef-promoted ubiquitination of BCL2 occurs in both the endoplasmic reticulum (ER) and mitochondria, only ER-associated ubiquitinated BCL2 arrests the progression of autophagy. Importantly, both mitochondrial BCL2 and PRKN are tightly connected to mitochondrial function and apoptosis. Hence, by enhancing the PRKN-mediated ubiquitination of BCL2 at the mitochondria, HIV might promote apoptosis. Moreover, this effect of Nef might account for HIV-associated disorders. In this article, we outline our current knowledge and provide perspectives of how ubiquitination impacts the molecular interactions between HIV, autophagy and apoptosis.
Effects of Food Provisioning on the Daily Ration and Dive Site Use of Great Hammerhead Sharks, Sphyrna mokarran
Authors: Heim Vital , Dhellemmes Félicie , Smukall Matthew J. , Gruber Samuel H. , Guttridge Tristan L.
Published: May 2021

Wildlife provisioning is popular, economically valuable, and a rapidly growing part of marine tourism, with great potential to benefit conservation. However, it remains controversial due to limited understanding of its implications on the behavior and ecology of target species. In this study, we modeled how various abiotic and biotic factors influenced great hammerhead sharks’ (Sphyrna mokarran) use of a recreational dive site in Bimini, the Bahamas, where shark-feeding has been conducted since 2012. Further, we calculated bioenergetic models to estimate their daily ration and examined if individual sharks fulfilled their daily energetic requirements from food uptake during dives. Between December 2016 and May 2017, we collected data during 104 provisioning dives in collaboration with a local dive operator. Twenty-eight individual great hammerhead sharks were observed, 11 were philopatric (i.e., identified at the dive site in previous years), and 17 were new (i.e., identified at the dive site for the first time during this study) individuals. On average, four sharks were observed daily, occasionally up to nine individuals, with some individuals spending more than 2 h attending each dive, consuming up to 4.75 kg of provisioned food per dive and returning repeatedly throughout the study period. When we grouped sharks based on their previous experience of the dive site (i.e., philopatric vs. new sharks), we found significantly higher attendance indices, i.e., the number of attended dives divided by the total number dives, and longer presence times during dives in philopatric sharks and different responses toward the number of boats and conspecifics between the two groups. Overall, great hammerhead sharks increased their bait uptake during longer dives and when more boats were present at the dive site. Finally, nine of 12 provisioned great hammerhead sharks were regularly able to fuel their daily energetic requirements from provisioned food alone, with two sharks doing so on 77.8% of all dives. Our study provides insights into how large-bodied marine predators react toward wildlife tourism associated provisioning and allows further discussion about daily energy uptake during provisioning dives, its potential impacts on the ecological role of the target species and associated management measures.
PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research
Authors: Bao Weiqi , Xie Fang , Zuo Chuantao , Guan Yihui , Huang Yiyun Henry
Published: May 2021

Alzheimer's Disease (AD), the leading cause of senile dementia, is a progressive neurodegenerative disorder affecting millions of people worldwide and exerting tremendous socioeconomic burden on all societies. Although definitive diagnosis of AD is often made in the presence of clinical manifestations in late stages, it is now universally believed that AD is a continuum of disease commencing from the preclinical stage with typical neuropathological alterations appearing decades prior to its first symptom, to the prodromal stage with slight symptoms of amnesia (amnestic mild cognitive impairment, aMCI), and then to the terminal stage with extensive loss of basic cognitive functions, i.e., AD-dementia. Positron emission tomography (PET) radiotracers have been developed in a search to meet the increasing clinical need of early detection and treatment monitoring for AD, with reference to the pathophysiological targets in Alzheimer's brain. These include the pathological aggregations of misfolded proteins such as β-amyloid (Aβ) plagues and neurofibrillary tangles (NFTs), impaired neurotransmitter system, neuroinflammation, as well as deficient synaptic vesicles and glucose utilization. In this article we survey the various PET radiotracers available for AD imaging and discuss their clinical applications especially in terms of early detection and cognitive relevance.
Assessing Impulsivity in Humans and Rodents: Taking the Translational Road
Authors: Esteves Madalena , Moreira Pedro Silva , Sousa Nuno , Leite-Almeida Hugo
Published: May 2021

Impulsivity is a multidimensional construct encompassing domains of behavioral inhibition as well as of decision making. It is often adaptive and associated with fast responses, being in that sense physiological. However, abnormal manifestations of impulsive behavior can be observed in contexts of drug abuse and attention-deficit/hyperactivity disorder (ADHD), among others. A number of tools have therefore been devised to assess the different facets of impulsivity in both normal and pathological contexts. In this narrative review, we systematize behavioral and self-reported measures of impulsivity and critically discuss their constructs and limitations, establishing a parallel between assessments in humans and rodents. The first rely on paradigms that are typically designed to assess a specific dimension of impulsivity, within either impulsive action (inability to suppress a prepotent action) or impulsive choice, which implies a decision that weighs the costs and benefits of the options. On the other hand, self-reported measures are performed through questionnaires, allowing assessment of impulsivity dimensions that would be difficult to mimic in an experimental setting (e.g., positive/negative urgency and lack of premeditation) and which are therefore difficult (if not impossible) to measure in rodents.
Rod and Cone Connections With Bipolar Cells in the Rabbit Retina
Authors: Whitaker Christopher M. , Nobles Gina , Ishibashi Munenori , Massey Stephen C.
Published: May 2021

Rod and cone pathways are segregated in the first stage of the retina: cones synapse with both ON- and OFF-cone bipolar cells while rods contact only rod bipolar cells. However, there is an exception to this specific wiring in that rods also contact certain OFF cone bipolar cells, providing a tertiary rod pathway. Recently, it has been proposed that there is even more crossover between rod and cone pathways. Physiological recordings suggested that rod bipolar cells receive input from cones, and ON cone bipolar cells can receive input from rods, in addition to the established pathways. To image their rod and cone contacts, we have dye-filled individual rod bipolar cells in the rabbit retina. We report that approximately half the rod bipolar cells receive one or two cone contacts. Dye-filling AII amacrine cells, combined with subtractive labeling, revealed most of the ON cone bipolar cells to which they were coupled, including the occasional blue cone bipolar cell, identified by its contacts with blue cones. Imaging the AII-coupled ON cone bipolar dendrites in this way showed that they contact cones exclusively. We conclude that there is some limited cone input to rod bipolar cells, but we could find no evidence for rod contacts with ON cone bipolar cells. The tertiary rod OFF pathway operates via direct contacts between rods and OFF cone bipolar cells. In contrast, our results do not support the presence of a tertiary rod ON pathway in the rabbit retina.
Posterior Reversible Encephalopathy Syndrome Associated With Anlotinib: A Case Report and Literature Review
Authors: Nan Di , Yin Xiang , Ma Di , Jiang Xiaoyu , Wu Baihua , Feng Jiachun
Published: May 2021

Posterior reversible encephalopathy syndrome (PRES) is a relatively rare clinical disease, characterized by reversible subcortical vasogenic edema. Here, we present the first reported case of PRES induced by anlotinib, a multi-target tyrosine kinase inhibitor. A 56-year-old female patient with lung adenocarcinoma and bone metastasis experienced hypertension and mental confusion when she received anti-angiogenesis treatment. PRES was diagnosed after magnetic resonance of the patient's brain revealed hyperintensities bilaterally around the cerebellum, pons, fronto-parieto-occipital areas, and corona radiate. Diffusion-weighted imaging showed hyperintensities bilaterally in the parieto-occipital cortical regions. Subsequently, the patient was diagnosed with PRES, and remission was achieved with anti-hypertensive drugs. Six cases of rare adverse effects induced by anlotinib were reviewed in the literature. Since anlotinib has been widely applied as a novel third-line treatment in patients with non-small-cell lung cancer, the association between PRES and anlotinib would benefit neurologists and oncologists in future diagnoses and treatment.