bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunometabolism of Macrophages in Bacterial Infections
Authors: Galli Gaël , Saleh Maya
Published: January 2021

Macrophages are important effectors of tissue homeostasis, inflammation and host defense. They are equipped with an arsenal of pattern recognition receptors (PRRs) necessary to sense microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit rapid energetically costly innate immunity responses to protect the organism. The interaction between cellular metabolism and macrophage innate immunity is however not limited to answering the cell’s energy demands. Mounting evidence now indicate that in response to bacterial sensing, macrophages undergo metabolic adaptations that contribute to the induction of innate immunity signaling and/or macrophage polarization. In particular, intermediates of the glycolysis pathway, the Tricarboxylic Acid (TCA) cycle, mitochondrial respiration, amino acid and lipid metabolism directly interact with and modulate macrophage effectors at the epigenetic, transcriptional and post-translational levels. Interestingly, some intracellular bacterial pathogens usurp macrophage metabolic pathways to attenuate anti-bacterial defenses. In this review, we highlight recent evidence describing such host-bacterial immunometabolic interactions.
Comparative Proteomic Analysis of Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) Tropical and Temperate Lineages: Uncovering Differences During Ehrlichia canis Infection
Authors: Sanches Gustavo Seron , Villar Margarita , Couto Joana , Ferrolho Joana , Fernández de Mera Isabel G. , André Marcos Rogério , Barros-Battesti Darci Moraes , Machado Rosangela Zacarias , Bechara Gervásio Henrique , Mateos-Hernández Lourdes , de la Fuente José , Antunes Sandra , Domingos Ana
Published: January 2021

The tick vector Rhipicephalus sanguineus is established as a complex of closely related species with high veterinary-medical significance, in which the presence of different genetic, morphological, and biological traits has resulted in the recognition of different lineages within taxa. One of the most striking differences in the “temperate” and “tropical” lineages of R. sanguineus (s.l.) is the vector competence to Ehrlichia canis, suggesting that these ticks tolerate and react differently to pathogen infection. The present study addresses the SG and MG proteome of the R. sanguineus tropical and temperate lineages and compares their proteomic profile during E. canis infection. Batches of nymphs from the two lineages were allowed to feed on naïve and experimentally E. canis infected dogs and after molting, adults were dissected, and salivary glands and midgut tissues separated. Samples were screened for the presence of E. canis before proteomic analyses. The representation of the proteins identified in infected and non-infected tissues of each lineage was compared and gene ontology used for protein classification. Results highlight important differences in those proteomic profiles that added to previous reported genetic, biological, behavioral, and morphological differences, strengthening the hypothesis of the existence of two different species. Comparing infected and non-infected tissues, the results show that, while in midgut tissues the response to E. canis infection is similar in the salivary glands, the two lineages show a different pattern of protein representation. Focusing on the proteins found only in the infected condition, the data suggests that the cement cone produced during tick feeding may be implicated in pathogen infection. This study adds useful information to the debate on the controversial R. sanguineus systematic status, to the discussion related with the different vectorial competence occurring between the two lineages and identifies potential targets for efficient tick and tick-borne disease control.
Preparing for Transmission: Gene Regulation in Plasmodium Sporozoites
Authors: Briquet Sylvie , Marinach Carine , Silvie Olivier , Vaquero Catherine
Published: January 2021

Plasmodium sporozoites are transmitted to mammals by anopheline mosquitoes and first infect the liver, where they transform into replicative exoerythrocytic forms, which subsequently release thousands of merozoites that invade erythrocytes and initiate the malaria disease. In some species, sporozoites can transform into dormant hypnozoites in the liver, which cause malaria relapses upon reactivation. Transmission from the insect vector to a mammalian host is a critical step of the parasite life cycle, and requires tightly regulated gene expression. Sporozoites are formed inside oocysts in the mosquito midgut and become fully infectious after colonization of the insect salivary glands, where they remain quiescent until transmission. Parasite maturation into infectious sporozoites is associated with reprogramming of the sporozoite transcriptome and proteome, which depends on multiple layers of transcriptional and post-transcriptional regulatory mechanisms. An emerging scheme is that gene expression in Plasmodium sporozoites is controlled by alternating waves of transcription activity and translational repression, which shape the parasite RNA and protein repertoires for successful transition from the mosquito vector to the mammalian host.
The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner
Authors: Skurski Joseph , Dixit Garima , Blobel Carl P. , Issuree Priya D. , Maretzky Thorsten
Published: January 2021

A well-controlled innate immune response is characterized by a rapid yet self-limiting inflammatory response. Although much is known about the range of inflammatory stimuli capable of triggering an innate immune response, the mechanisms which govern the degree of inflammation induced by inflammatory insults and the mechanisms in place to reset or maintain homeostasis are poorly understood. Tumor necrosis factor (TNF) is a potent early response pro-inflammatory cytokine produced by immune cells following a broad range of insults spanning autoimmunity and metabolic diseases to pathogenic infections. Previous studies have shown that a disintegrin and metalloproteinase (ADAM) 17 controls the release of soluble TNF and epidermal growth factor receptor signaling. Utilizing a genetic model of ADAM17 deficiency through the deletion of its regulator, the inactive rhomboid 2 (iRhom2), we show that loss of ADAM17 activity in innate immune cells leads to decreased expression of various cytokines in response to low levels of pathogen-associated molecular pattern (PAMP) stimulation but not at high-dose stimulation. In addition, TNF receptor (TNFR) 1/2-deficient bone marrow-derived macrophages yielded significantly reduced TNF expression following low levels of PAMP stimulation, suggesting that signaling through the TNFRs in immune cells drives a feed-forward regulatory mechanism wherein low levels of TNF allow sustained enhancement of TNF expression in an iRhom2/ADAM17-dependent manner. Thus, we demonstrate that inflammatory expression of TNF and IL1β is differentially regulated following high or low doses of PAMP stimulation, invoking the activation of a previously unknown regulatory mechanism of inflammation.
What’s Trust Got to do With it? Lessons From Cross-Sectoral Research on Natural Resource Management in Australia and the U.S.
Authors: Toman Eric Lee , Curtis Allan Lindsay , Shindler Bruce
Published: January 2021

Natural resource management (NRM) is conducted within a complex context. This is particularly true at the interface of public and private interests where policy and management actions are often closely scrutinized by stakeholders. In these settings, natural resource managers often seek to achieve multiple objectives including ecosystem restoration, biodiversity conservation, commodity production, and the provision of recreation opportunities. While some objectives may be complementary, in many cases they involve tradeoffs that are contested by stakeholders. Substantial prior work has identified concepts related to trust as critical to the success of natural resource management particularly in cases of high complexity and uncertainty with high stakes for those involved. However, although regularly identified as a central variable of influence, trust appears to be conceptualized differently or entangled with related constructs across this prior research. Moreover, much of the research in NRM considers trust as an independent variable and considers the influence of trust on other variables of interest (e.g., acceptance of a particular management practices, willingness to adopt a best management practice). In this paper, we develop a conceptualization of trust drawing on different literature areas and consider how trust is related to constructs such as trustworthiness and confidence. We then consider trust in the context of natural resource management drawing on examples from the U.S. and Australia. We then consider implications of these findings for building trust in natural resource management.
Pituitary Remodeling Throughout Life: Are Resident Stem Cells Involved?
Authors: Laporte Emma , Vennekens Annelies , Vankelecom Hugo
Published: January 2021

The pituitary gland has the primordial ability to dynamically adapt its cell composition to changing hormonal needs of the organism throughout life. During the first weeks after birth, an impressive growth and maturation phase is occurring in the gland during which the distinct hormonal cell populations expand. During pubertal growth and development, growth hormone (GH) levels need to peak which requires an adaptive enterprise in the GH-producing somatotrope population. At aging, pituitary function wanes which is associated with organismal decay including the somatopause in which GH levels drop. In addition to these key time points of life, the pituitary’s endocrine cell landscape plastically adapts during specific (patho-)physiological conditions such as lactation (need for PRL) and stress (engagement of ACTH). Particular resilience is witnessed after physical injury in the (murine) gland, culminating in regeneration of destroyed cell populations. In many other tissues, adaptive and regenerative processes involve the local stem cells. Over the last 15 years, evidence has accumulated that the pituitary gland houses a resident stem cell compartment. Recent studies propose their involvement in at least some of the cell remodeling processes that occur in the postnatal pituitary but support is still fragmentary and not unequivocal. Many questions remain unsolved such as whether the stem cells are key players in the vivid neonatal growth phase and whether the decline in pituitary function at old age is associated with decreased stem cell fitness. Furthermore, the underlying molecular mechanisms of pituitary plasticity, in particular the stem cell-linked ones, are still largely unknown. Pituitary research heavily relies on transgenicin vivomouse models. While having proven their value, answers to pituitary stem cell-focused questions may more diligently come from a novel powerfulin vitroresearch model, termed organoids, which grow from pituitary stem cells and recapitulate stem cell phenotype and activation status. In this review, we describe pituitary plasticity conditions and summarize what is known on the involvement and phenotype of pituitary stem cells during these pituitary remodeling events.
Clinical Presentation and Treatment Outcomes of Children and Adolescents With Pheochromocytoma and Paraganglioma in a Single Center in Korea
Authors: Park Hyojung , Kim Min-Sun , Lee Jiwon , Kim Jung-Han , Jeong Byong Chang , Lee Sanghoon , Lee Suk-Koo , Cho Sung Yoon , Jin Dong-Kyu
Published: January 2021

Purpose

Pheochromocytoma (PCC) and paraganglioma (PGL) (PPGL) are rare neuroendocrine tumors, and data on managing these conditions in children and adolescents are lacking. The objective of this study was to demonstrate the clinical presentation and treatment outcomes in children and adolescents with PPGL in a single tertiary care center in Korea.

Methods

This retrospective study included 23 patients diagnosed with PCC (n = 14) and PGL (n = 9) before the age of 21 at Samsung Medical Center (from June 1994 to June 2019). We describe age, gender, family history, clinical characteristics, laboratory findings, pathologic findings, therapeutic approaches, and treatment outcomes.

Results

Of the 23 patients, 14 had PCC and nine had PGL. The median age at diagnosis was 16.8 years (range, 6.8–20.8 years). The common presenting symptoms were hypertension (n = 10), headache (n = 9), palpitation (n = 4), and sweating (n = 4). The plasma or 24-hour urine catecholamine and/or metabolite concentrations were markedly elevated in 22 patients with PPGL, but were normal in one patient with carotid body PGL. All tumors were visualized on computed tomography. Genetic tests were performed in 15 patients, and seven patients showed mutations in RET (n = 3), SDHB (n = 3), and VHL (n = 1). All patients underwent surgery, and complete excision was performed successfully. Three patients with metastasis underwent postoperative adjuvant therapy.

Conclusion

This study suggests that pediatric PPGL tends to be extra-adrenal and bilateral and shows a higher potential for genetic mutations. Considering the hereditary predisposition of pediatric PPGL, genetic screening tests are strongly recommended, and lifelong follow-up is needed to detect recurrence and metastasis. Further research with a larger sample size and routine genetic screening is needed to better understand the genetic conditions and long-term prognosis of PPGL.
Controlled Signaling—Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments
Authors: Rieger Leonie , O’Connor Rosemary
Published: January 2021

Ligand-induced activation of the IGF-1 receptor triggers plasma-membrane-derived signal transduction but also triggers receptor endocytosis, which was previously thought to limit signaling. However, it is becoming ever more clear that IGF-1R endocytosis and trafficking to specific subcellular locations can define specific signaling responses that are important for key biological processes in normal cells and cancer cells. In different cell types, specific cell adhesion receptors and associated proteins can regulate IGF-1R endocytosis and trafficking. Once internalized, the IGF-1R may be recycled, degraded or translocated to the intracellular membrane compartments of the Golgi apparatus or the nucleus. The IGF-1R is present in the Golgi apparatus of migratory cancer cells where its signaling contributes to aggressive cancer behaviors including cell migration. The IGF-1R is also found in the nucleus of certain cancer cells where it can regulate gene expression. Nuclear IGF-1R is associated with poor clinical outcomes. IGF-1R signaling has also been shown to support mitochondrial biogenesis and function, and IGF-1R inhibition causes mitochondrial dysfunction. How IGF-1R intracellular trafficking and compartmentalized signaling is controlled is still unknown. This is an important area for further study, particularly in cancer.
Tissue Hydrogen Peroxide Concentration Can Explain the Invasiveness of Aquatic Macrophytes: A Modeling Perspective
Authors: Asaeda Takashi , Rashid Md Harun , Schoelynck Jonas
Published: January 2021

In recent years, an invasive macrophyte, Egeria densa, has overwhelmingly colonized some midstream reaches of Japanese rivers. This study was designed to determine how E. densa has been able to colonize these areas and to assess the environmental conditions that limit or even prevent colonization. Invasive species (E. densa and Elodea nuttallii), and Japanese native species (Myriophyllum spicatum, Ceratophyllum demersum, and Potamogeton crispuss) were kept in experimental tanks and a flume with different environmental conditions. Tissue hydrogen peroxide (H2O2) concentrations were measured responding to either individual or multiple environmental factors of light intensity, water temperature, and water flow velocity. In addition, plants were sampled in rivers across Japan, and environmental conditions were measured. The H2O2 concentration increased in parallel to the increment of unpreferable levels of each abiotic factor, and the trend was independent of other factors. The total H2O2 concentration is provided by the sum of contribution of each factor. Under increased total H2O2 concentration, plants first started to decrease in chlorophyll concentration, then reduce their growth rate, and subsequently reduce their biomass. The H2O2 concentration threshold, beyond which degradation is initiated, was between 15 and 20 µmol/gFW regardless of the environmental factors. These results highlight the potential efficacy of total H2O2 concentration as a proxy for the overall environmental condition. In Japanese rivers, major environmental factors limiting macrophyte colonization were identified as water temperature, high solar radiation, and flow velocity. The relationship between the unpreferable levels of these factors and H2O2 concentration was empirically obtained for these species. Then a mathematical model was developed to predict the colonization area of these species with environmental conditions. The tissue H2O2 concentration decreases with increasing temperature for E. densa and increases for other species, including native species. Therefore, native species grow intensively in spring; however, they often deteriorate in summer. For E. densa, on the other hand, H2O2 concentration decreases with high water temperature in summer, allowing intensive growth. High solar radiation increases the H2O2 concentration, deteriorating the plant. Although the H2O2 concentration of E. densa increases with low water temperature in winter, it can survive in deep water with low H2O2 concentration due to diffused solar radiation. Currently, river rehabilitation has created a deep zone in the channel, which supports the growth and spreading of E. densa.
The Consequences of Glacier Retreat Are Uneven Between Plant Species
Authors: Losapio Gianalberto , Cerabolini Bruno E. L. , Maffioletti Chiara , Tampucci Duccio , Gobbi Mauro , Caccianiga Marco
Published: January 2021

Glaciers are retreating worldwide, exposing new terrain to colonization by plants. Recently-deglaciated terrains have been a subject of ecological studies for a long time, as they represent a unique natural model system for examining the effects of global warming associated with glacier retreat on biodiversity and the spatio-temporal dynamic of communities. However, we still have a limited understanding of how physical and biotic factors interactively influence species persistence and community dynamics after glacier retreat and glacier extinction. Using hierarchical joint species distribution models, we integrated data on plant species occurrence at fine spatial scale, spatio-temporal context, environmental conditions, leaf traits, and species-to-species associations in plant communities spanning 0 to c 5,000 years on average after glacier retreat. Our results show that plant diversity initially increases with glacier retreat, but ultimately decreases after glacier extinction. The 22% of plant species non-linearly respond to glacier retreat and will locally disappear with glacier extinction. At the local scale, soil carbon enrichment and reduction of physical (topographic) disturbance positively contribute to distribution patterns in 66% of the species, indicating a strong impact of community-level environmental conditions. Furthermore, positive and negative associations among species play a relevant role (up to 34% of variance) in driving the spatio-temporal dynamic of plant communities. Global warming prompts a shift from facilitation to competition: positive associations prevail among pioneer species, whereas negative associations are relatively more common among late species. This pattern suggests a role of facilitation for enhancing plant diversity in recently ice-free terrains and of competition for decreasing species persistence in late stages. Associated to that, species persisting the most show more “conservative” traits than species of concern. In summary, although plant diversity initially increases with glacier retreat, more than a fifth of plant species are substantially declining and will disappear with glacier extinction. Even for the “winners,” the “victory” is not to be taken for granted due to the negative impact of rising competition. Integrating survey data with hierarchical and network models can help to forecast biodiversity change and anticipate cascading effects of glacier retreat on mountain ecosystems. These effects include the reduction of ecosystem services and benefits to humans, including food production from the pioneer species Artemisia genipi.
Neutrophil Extracellular Traps Tied to Rheumatoid Arthritis: Points to Ponder
Authors: Song Wenpeng , Ye Jing , Pan Nanfang , Tan Chunyu , Herrmann Martin
Published: January 2021

In recent years, neutrophil extracellular traps at the forefront of neutrophil biology have proven to help capture and kill pathogens involved in the inflammatory process. There is growing evidence that persistent neutrophil extracellular traps drive the pathogenesis of autoimmune diseases. In this paper, we summarize the potential of neutrophil extracellular traps to drive the pathogenesis of rheumatoid arthritis and experimental animal models. We also describe the diagnosis and treatment of rheumatoid arthritis in association with neutrophil extracellular traps.
A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease
Authors: Bäuerlein Carina A. , Qureischi Musga , Mokhtari Zeinab , Tabares Paula , Brede Christian , Jordán Garrote Ana-Laura , Riedel Simone S. , Chopra Martin , Reu Simone , Mottok Anja , Arellano-Viera Estibaliz , Graf Carolin , Kurzwart Miriam , Schmiedgen Katharina , Einsele Hermann , Wölfl Matthias , Schlegel Paul-Gerhardt , Beilhack Andreas
Published: January 2021

Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8+ T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.
Case Report: Combination of Omalizumab and Dupilumab for Recalcitrant Bullous Pemphigoid
Authors: Seyed Jafari S. Morteza , Feldmeyer Laurence , Bossart Simon , Simon Dagmar , Schlapbach Christoph , Borradori Luca
Published: January 2021

Bullous pemphigoid (BP) is a blistering autoimmune skin disease. Omalizumab, a monoclonal antibody directed to IgE, showed a beneficial effect in treatment of recalcitrant BP in case series. More recently, dupilumab, an interleukin (IL)-4-receptor alpha antagonist, also showed promising preliminary results. We describe a patient with refractory BP who showed a complete response to a combination therapy with omalizumab and dupilumab.
STAT6 Pathway Is Critical for the Induction and Function of Regulatory T Cells Induced by Mucosal B Cells
Authors: Chu Kuan-Hua , Lin Szu-Yu , Chiang Bor-Luen
Published: January 2021

B cells could convert naïve T cells into regulatory T cells (so-called Treg-of-B cells) which have the ability to treat animal models of inflammatory diseases, including allergic asthma, collagen-induced arthritis and colitis; however, the mechanisms of Treg-of-B cell generation remain unclear. In this study, we investigated the role of STAT6 in the generation of Treg-of-B (P) cells, which Treg cells were generated by Peyer’s patch B cells (P stands for Peyer’s patch). CD4+CD25- T cells from wild type, STAT6 knockout and IL-4 knockout mice were cocultured with wild type Peyer’s patch B cells for Treg-of-B (P) cell generation. A murine asthmatic model was used to analyze thein vivoregulatory function of Treg-of-B (P) cells. The data demonstrated that STAT6 played a critical role in the generation of Treg-of-B (P) cells, which confirmed with STAT6-deficient T cells and the STAT6 inhibitor AS1517499. When STAT6 was lacking, Treg-of-B (P) cells exerted impaired suppressive ability with decreased LAG3 expression. Furthermore, Peyer’s patch B cells played an essential role in regulatory T cell generation. In the absence of Peyer’s patch B cells, T cells expressed decreased phosphorylated STAT6, which was followed by decreased LAG3 expression and impaired suppressive ability, suggesting that Peyer’s patch B cells provided the critical signal to activate STAT6 phosphorylation in T cells. Moreover, STAT6 deficient Treg-of-B (P) cells could not alleviate inflammation in an animal model of asthmain vivo. IL-4 was downstream of phosphorylated STAT6 and maintained Treg-of-B (P) cell survival with increased expression of Bcl-2 and BclXL. We reported a novel finding that the STAT6-LAG3 signaling axis is important for the induction and function of Treg-of-B (P) cells.
The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer’s Disease
Authors: de Wit Nienke M. , Mol Kevin , Rodríguez-Lorenzo Sabela , de Vries Helga E. , Kooij Gijs
Published: January 2021

Alzheimer’s disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients’ lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
Assessing Autophagy in Microglia: A Two-Step Model to Determine Autophagosome Formation, Degradation, and Net Turnover
Authors: Plaza-Zabala Ainhoa , Sierra-Torre Virginia , Sierra Amanda
Published: January 2021

Autophagy is a complex process that encompasses the enclosure of cytoplasmic debris or dysfunctional organelles in membranous vesicles, the autophagosomes, for their elimination in the lysosomes. Autophagy is increasingly recognized as a critical process in macrophages, including microglia, as it finely regulates innate immune functions such as inflammation. A gold-standard method to assess its induction is the analysis of the autophagic flux using as a surrogate the expression of the microtubule-associated light chain protein 3 conjugated to phosphatidylethanolamine (LC3-II) by Western blot, in the presence of lysosomal inhibitors. Therefore, the current definition of autophagy flux actually puts the focus on the degradation stage of autophagy. In contrast, the most important autophagy controlling genes that have been identified in the last few years in fact target early stages of autophagosome formation. From a biological standpoint is therefore conceivable that autophagosome formation and degradation are independently regulated and we argue that both stages need to be systematically analyzed. Here, we propose a simple two-step model to understand changes in autophagosome formation and degradation using data from conventional LC3-II Western blot, and test it using two models of autophagy modulation in cultured microglia: rapamycin and the ULK1/2 inhibitor, MRT68921. Our two-step model will help to unravel the effect of genetic, pharmacological, and environmental manipulations on both formation and degradation of autophagosomes, contributing to dissect out the role of autophagy in physiology and pathology in microglia as well as other cell types.
Char Products From Bamboo Waste Pyrolysis and Acid Activation
Authors: Parthasarathy Prakash , Mackey Hamish R. , Mariyam Sabah , Zuhara Shifa , Al-Ansari Tareq , McKay Gordon
Published: January 2021

Bamboo is found worldwide but is especially concentrated in tropical and subtropical areas with the major producing nations being China, Indonesia and Thailand with an annual production of 12 million tonnes. It has found uses in many applications such as: furniture, flooring, roofing, fencing, interior design and scaffolding in the construction industry. In this study, discarded waste bamboo furniture was used in the ground form as the raw material feedstock for the production of a series of biochars and activated carbons. The biochars were produced at different temperatures, namely, 723, 823, 923, 1,023, 1,123 and 1223 K, in a muffle furnace inerted with nitrogen and for different pyrolysis times. The product chars yields were 20–30% by weight of the raw material, surface areas were 100–350 m2/g. Other tests include elemental analysis, helium displacement density, pH, ICP-AES on a leachate sample. Four of the different temperature samples of biochar were used to adsorb the basic dye methylene blue and were shown to possess high adsorption capacities. Then, the same bamboo raw material powder was treated with acid and pyrolysed/activated in a nitrogen atmosphere at the same range of temperatures to produce activated carbons; these were characterized using similar test methods to the biochars. The yields are in the range 20–40% by weight of the raw material feedstock and the BET surface areas are in the range 200–600 m2/g. Three of the different temperature activated carbons were used to adsorb methylene blue and the results were compared with the biochar results. All the adsorption experimental isotherm results were analyzed using conventional isotherm equations. The benefits and cost implications of both biochar and activated carbon routes are discussed. The methylene blue adsorption capacities are extremely attractive in the range 0.42–1.12 mmol/g (150–300 mg/g char product) and extend to over 2.35 mmol/g (700 mg/g) for the bamboo derived activated carbons. The micropore and mesopore volumes have been determined under the various char and activated carbon experimental conditions and coupled with the surface areas; these results have been used to explain the trends in the methylene blue adsorption capacities.
Differences in Highly Pathogenic H5N6 Avian Influenza Viral Pathogenicity and Inflammatory Response in Chickens and Ducks
Authors: Wang Bo , Su Qianqian , Luo Jing , Li Meng , Wu Qiaoxing , Chang Han , Du Juan , Huang Chengmei , Ma Jiajun , Han Shuyi , Yuan Guohui , He Yapeng , Guo Minglei , Zhang Qingxun , He Hongxuan
Published: January 2021

Infection with H5N6 highly pathogenic avian influenza virus caused high mortality in chickens, while ducks often appear to be asymptomatic. But, some recent H5Nx subtype viruses could cause high mortality in ducks. The variation between different species and the mechanisms by which some H5Nx viruses cause death in ducks requires investigation to identify the key processes in influenza susceptibility and pathogenesis. Here, we characterized two representative H5N6 viruses, A/Pavo cristatus/Jiangxi/JA1/2016 (JA1) and A/Anas crecca/shanghai/SH1/2016 (SH1), and compared their pathogenicity and expression profiles of immune-related genes in chickens and ducks to identify the elements of the host immune-related response that were involved in disease lethality. Results suggested that H5N6 HPAIVs had higher pathogenic and inflammatory effect in chickens than in ducks. Importantly, the TNF-α, IL-6, IFN-γ and iNOS levels were significantly higher in the lung of SH1 infected chickens compared to those of ducks. And we found higher systemic levels of IL-6 induced by JA1 in chickens than in ducks. In addition, our experiments demonstrated that JA1 was associated with greater pathogenicity in ducks were accompanied by the excessive expression of iNOS in the brain. These results are helpful to understand the relationship between the pathogenicity of H5N6 AIVs and inflammatory responses to them in chickens and ducks.
Long Non-coding RNA BTG3-7:1 and JUND Co-regulate C21ORF91 to Promote Triple-Negative Breast Cancer Progress
Authors: Dan Zheng , Xiujing He , Ting Luo , Xiaorong Zhong , Hong Zheng , Jiqiao Yang , Yanchu Li , Jing Jing
Published: January 2021

Background

Triple-negative breast cancer (TNBC) is a type of highly invasive breast cancer with poor prognosis. Recently, massive data reveal that long non-coding RNAs (lncRNAs) play important roles in cancer progress. Recently, although the role of lncRNAs in breast cancer has been well documented, few focused on TNBC. In this study, we aimed to systematically identify functional lncRNAs and to explore its molecular mechanism on TNBC progress.

Methods

The recurrence of lncRNAs and their target genes were validated with TNBC biopsies and cell lines. Total one hundred and thirteen TNBC biopsies, including nineteen patient-matched samples, were collected. The profile of TNBC-related lncRNAs and their target genes were characterized by RNA sequencing (RNA-seq) and bioinformatic analysis. Tumor specific lncRNAs, which also showed biological function correlated with TNBC, were identified as potential candidates; and the target genes, which regulated by the identified lncRNAs, were predicted by the analysis of expression correlation and chromosome colocalization. Cross bioinformatic validation was performed with TNBC independent datasets from the cancer genome atlas (TCGA). The biological functions and molecular mechanism were investigated in TNBC model cell lines by cell colony forming assay, flow cytometry assay, western-blot, RNA Fluorescence in situ Hybridization assay (RNA FISH) and chromatin immunoprecipitation-qPCR (ChIP-qPCR).

Results

Abundant Lnc-BTG3-7:1, which targets gene C21ORF91, was specifically observed in TNBC biopsies and cell lines. Knockdown of Lnc-BTG3-7:1 or C21ORF91 strongly inhibited cell proliferation, promoted cell apoptosis and cell cycle G1-arrested. Meanwhile, investigation of molecular mechanism indicated that Lnc-BTG3-7:1, cooperated with transcription factor JUND, cis-regulated the transcription of C21ORF91 gene, and down-regulation of Lnc-BTG3-7:1/C21ORF91 suppressed GRB2-RAS-RAF-MEK-ERK and GRB2-PI3K-AKT-GSK3β-β-catenin pathways.

Conclusions

In this study, we identified a TNBC specific lncRNA Lnc-BTG3-7:1, which sustained tumor progress. Up-regulation of Lnc-BTG3-7:1 promoted the transcription of oncogene C21ORF91 and activated PI3K-AKT-GSK3β-β-catenin and MAPK pathways. Taken together, our results not only identified a biomarker for diagnosis but also provided a potential therapeutic target against TNBC.
Full Spectrum Flow Cytometry as a Powerful Technology for Cancer Immunotherapy Research
Authors: Bonilla Diana L. , Reinin Gil , Chua Edmond
Published: January 2021

The Nobel Prize-deserving concept of blocking inhibitory pathways in T cells, to unleash their anti-tumoral capacity, became one of the pillars of cancer treatment in the last decade and has resulted in durable clinical responses for multiple cancer types. Currently, two of the most important goals in cancer immunotherapy are to understand the mechanisms resulting in failure to checkpoint blockade and to identify predictive immunological biomarkers that correlate to treatment response, disease progression or adverse effects. The identification and validation of biomarkers for routine clinical use is not only critical to monitor disease or treatment progression, but also to personalize and develop new therapies. To achieve these goals, powerful research tools are needed. Flow cytometry stands as one of the most successful single-cell analytical tools used to characterize immune cell phenotypes to monitor solid tumors, hematological malignancies, minimal residual disease or metastatic progression. This technology has been fundamental in diagnosis, treatment and translational research in cancer clinical trials. Most recently, the need to evaluate simultaneously more features in each cell has pushed the field to implement more powerful adaptations beyond conventional flow cytometry, including Full Spectrum Flow Cytometry (FSFC). FSFC captures the full emission spectrum of fluorescent molecules using arrays of highly sensitive light detectors, and to date has enabled characterization of 40 parameters in a single sample. We will summarize the contributions of this technology to the advancement of research in immunotherapy studies and discuss best practices to obtain reliable, robust and reproducible FSFC results.
Intercellular Communication by Vascular Endothelial Cell-Derived Extracellular Vesicles and Their MicroRNAs in Respiratory Diseases
Authors: Fujimoto Shota , Fujita Yu , Kadota Tsukasa , Araya Jun , Kuwano Kazuyoshi
Published: January 2021

Respiratory diseases and their comorbidities, such as cardiovascular disease and muscle atrophy, have been increasing in the world. Extracellular vesicles (EVs), which include exosomes and microvesicles, are released from almost all cell types and play crucial roles in intercellular communication, both in the regulation of homeostasis and the pathogenesis of various diseases. Exosomes are of endosomal origin and range in size from 50 to 150 nm in diameter, while microvesicles are generated by the direct outward budding of the plasma membrane in size ranges of 100–2,000 nm in diameter. EVs can contain various proteins, metabolites, and nucleic acids, such as mRNA, non-coding RNA species, and DNA fragments. In addition, these nucleic acids in EVs can be functional in recipient cells through EV cargo. The endothelium is a distributed organ of considerable biological importance, and disrupted endothelial function is involved in the pathogenesis of respiratory diseases such as chronic obstructive pulmonary disease, pulmonary hypertension, and acute respiratory distress syndrome. Endothelial cell-derived EVs (EC-EVs) play crucial roles in both physiological and pathological conditions by traveling to distant sites through systemic circulation. This review summarizes the pathological roles of vascular microRNAs contained in EC-EVs in respiratory diseases, mainly focusing on chronic obstructive pulmonary disease, pulmonary hypertension, and acute respiratory distress syndrome. Furthermore, this review discusses the potential clinical usefulness of EC-EVs as therapeutic agents in respiratory diseases.
New Insights Into the Anatomy, Connectivity and Clinical Implications of the Middle Longitudinal Fasciculus
Authors: Latini Francesco , Trevisi Gianluca , Fahlström Markus , Jemstedt Malin , Alberius Munkhammar Åsa , Zetterling Maria , Hesselager Göran , Ryttlefors Mats
Published: January 2021

The middle longitudinal fascicle (MdLF) is a long, associative white matter tract connecting the superior temporal gyrus (STG) with the parietal and occipital lobe. Previous studies show different cortical terminations, and a possible segmentation pattern of the tract. In this study, we performed a post-mortem white matter dissection of 12 human hemispheres and an in vivo deterministic fiber tracking of 24 subjects acquired from the Human Connectome Project to establish whether a constant organization of fibers exists among the MdLF subcomponents and to acquire anatomical information on each subcomponent. Moreover, two clinical cases of brain tumors impinged on MdLF territories are reported to further discuss the anatomical results in light of previously published data on the functional involvement of this bundle. The main finding is that the MdLF is consistently organized into two layers: an antero-ventral segment (aMdLF) connecting the anterior STG (including temporal pole and planum polare) and the extrastriate lateral occipital cortex, and a posterior-dorsal segment (pMdLF) connecting the posterior STG, anterior transverse temporal gyrus and planum temporale with the superior parietal lobule and lateral occipital cortex. The anatomical connectivity pattern and quantitative differences between the MdLF subcomponents along with the clinical cases reported in this paper support the role of MdLF in high-order functions related to acoustic information. We suggest that pMdLF may contribute to the learning process associated with verbal-auditory stimuli, especially on left side, while aMdLF may play a role in processing/retrieving auditory information already consolidated within the temporal lobe.
Case Report: Brain Metastasis Confined to the Infarcted Area Following Stroke
Authors: Gwak Dong-Seok , Hwang Yang-Ha , Kim Yong-Won
Published: January 2021

Background: Ischemic stroke and cancer are frequent in the elderly and are the two common causes of death and disability. They are related to each other, and cancer may lead to ischemic stroke and vice versa. If patients with cancer exhibited recurrent acute neurological deficits after index stroke, a cancer-related stroke could be considered. However, a brain metastasis is another common cause of neurological complications and has a poor prognosis in patients with ischemic stroke and comorbid cancer. Here, we report a rare case of metastatic cancer that occurred after index stroke in a patient with renal cell carcinoma (RCC) and unusual imaging findings. Through the case, we discuss the pathophysiology and probable predisposing factors for metastatic disease in areas of infarction.

Case Presentation: A 48-year-old man presented with sudden onset of left facial palsy and hemiparesis. He had a history of hypertension and RCC with pulmonary metastases treated with radical nephrectomy and chemotherapy. Brain magnetic resonance imaging (MRI) revealed multiple scattered acute infarctions in the right insular, frontal, parietal, and left occipital cortices. There were no definite sources of embolism. Eight months after the index stroke, he presented with subacute onset of progressive left hemiparesis. He had no focal neurological deficits except left-sided weakness and left nasolabial fold blunting. MRI scan demonstrated partial diffusion restriction on the right frontotemporal cortices without decline of apparent diffusion coefficient values on the corresponding lesions and T1 hypointensities and T2 hyperintensities with perilesional vasogenic edema on the right insular, frontal, parietal, and left occipital cortices, indicative of brain metastases confined to the area of previous infarctions.

Conclusions: Cerebral infarctions can cause neovascularization and disruption of the blood–brain barrier. Moreover, the compartmentalized cavity formed by the ischemic injury may accept a large volume of metastatic tumor cells. Such an altered microenvironment of infarcted tissue would be suitable for the colonization and proliferation of metastatic seed. Further, brain metastases should be considered, in addition to recurrence, when new focal neurological deficits develop in patients with ischemic stroke and comorbid cancer.
Walking Speed Reliably Measures Clinically Significant Changes in Gait by Directional Deep Brain Stimulation
Authors: Hurt Christopher P. , Kuhman Daniel J. , Guthrie Barton L. , Lima Carla R. , Wade Melissa , Walker Harrison C.
Published: January 2021

Introduction: Although deep brain stimulation (DBS) often improves levodopa-responsive gait symptoms, robust therapies for gait dysfunction from Parkinson's disease (PD) remain a major unmet need. Walking speed could represent a simple, integrated tool to assess DBS efficacy but is often not examined systematically or quantitatively during DBS programming. Here we investigate the reliability and functional significance of changes in gait by directional DBS in the subthalamic nucleus.

Methods: Nineteen patients underwent unilateral subthalamic nucleus DBS surgery with an eight-contact directional lead (1-3-3-1 configuration) in the most severely affected hemisphere. They arrived off dopaminergic medications >12 h preoperatively and for device activation 1 month after surgery. We measured a comfortable walking speed using an instrumented walkway with DBS off and at each of 10 stimulation configurations (six directional contacts, two virtual rings, and two circular rings) at the midpoint of the therapeutic window. Repeated measures of ANOVA contrasted preoperative vs. maximum and minimum walking speeds across DBS configurations during device activation. Intraclass correlation coefficients examined walking speed reliability across the four trials within each DBS configuration. We also investigated whether changes in walking speed related to modification of step length vs. cadence with a one-sample t-test.

Results: Mean comfortable walking speed improved significantly with DBS on vs. both DBS off and minimum speeds with DBS on (p < 0.001, respectively). Pairwise comparisons showed no significant difference between DBS off and minimum comfortable walking speed with DBS on (p = 1.000). Intraclass correlations were ≥0.949 within each condition. Changes in comfortable walk speed were conferred primarily by changes in step length (p < 0.004).

Conclusion: Acute assessment of walking speed is a reliable, clinically meaningful measure of gait function during DBS activation. Directional and circular unilateral subthalamic DBS in appropriate configurations elicit acute and clinically significant improvements in gait dysfunction related to PD. Next-generation directional DBS technologies have significant potential to enhance gait by individually tailoring stimulation parameters to optimize efficacy.