bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Principal’s Coaching and Supervision toward Teacher’s Performance
Authors: Atiah Nurma , Fitria Happy , Destiniar Destiniar
Published: January 2021

This study determined the effect of the pattern of guidance and supervision of school’s principals on teacher’s performance in SD Negeri 1 Gardu Harapan, Lais, Musi Banyuasin both persially and jointly. The instrument used was a questionnaire. Data analysis techniques use statistics. The results of this study obtained that the pattern of guidance and supervision of the Principal significantly influence the performance of teachers of SD Negeri 1 Gardu Harapan. This research contributes that if you want to improve teacher performance, you have to improve the pattern of coaching and supervision.
Long-Term Pioglitazone Treatment Augments Insulin Sensitivity and PKC-ε and PKC-θ Activation in Skeletal Muscles in Sucrose Fed Rats
Authors: Marková I , Zídek V , Musilová A , Šimáková M , Mlejnek P , Kazdová L , Pravenec M
Published: January 2021

It has been suggested that thiazolidinediones (TZDs) ameliorate
insulin resistance in muscle tissue by suppressing muscle lipid
storage and the activity of novel protein kinase C (nPKC)
isoforms. To test this hypothesis, we analyzed long-term
metabolic effects of pioglitazone and the activation of nPKC-ε and
-θ isoforms in an animal model of the metabolic syndrome, the
spontaneously hypertensive rat (a congenic SHR strain with wild
type Cd36 gene) fed a diet with 60 % sucrose from the age of 4
to 8 months. Compared to untreated controls, pioglitazone
treatment was associated with significantly increased basal
(809±36 vs 527±47 nmol glucose/g/2h, P<0.005) and insulinstimulated glycogenesis (1321±62 vs 749±60 nmol glucose/g/2h,
P<0.0001) in isolated gastrocnemius muscles despite increased
concentrations of muscle triglycerides (3.83±0.33 vs 2.25±0.12
μmol/g, P<0.005). Pioglitazone-treated rats exhibited
significantly increased membrane/total (cytosolic plus membrane)
ratio of both PKC-ε and PKC-θ isoforms compared to untreated
controls. These results suggest that amelioration of insulin
resistance after long-term pioglitazone treatment is associated
with increased activation of PKC-ε and -θ isoforms in spite of
increased lipid concentration in skeletal muscles.
Perinatal Hypoxic-Ischemic Damage: Review of the Current Treatment Possibilities
Authors: FRAJEWICKI A , LAŠTŮVKA Z , BORBÉLYOVÁ V , KHAN S , JANDOVÁ K , JANIŠOVÁ K , OTÁHAL J , MYSLIVEČEK J , RILJAK V
Published: January 2021

Neonatal hypoxic-ischemic encephalopathy is a disorder with heterogeneous manifestation due to asphyxia during perinatal period. It affects approximately 3-12 children per 1000 live births and cause death of 1 million neonates worldwide per year. Besides, motor disabilities, seizures, impaired muscle tone and epilepsy are few of the consequences of hypoxic-ischemic encephalopathy. Despite an extensive research effort regarding various treatment strategies, therapeutic hypothermia with intensive care unit supportive treatment remains the only approved method for neonates who have suffered from moderate to severe hypoxic-ischemic encephalopathy. However, these protocols are only partially effective given that many infants still suffer from severe brain damage. Thus, further research to systematically test promising neuroprotective treatments in combination with hypothermia is essential. In this review, we discussed the pathophysiology of hypoxic-ischemic encephalopathy and delved into different promising treatment modalities, such as melatonin and erythropoietin. However, preclinical studies and clinical trials are still needed to further elucidate the mechanisms of action of these modalities.
Neonatal Hypoxic-Ischemic Brain Injury Leads to Sex-Specific Deficits in Rearing and Climbing in Adult Mice
Authors: LAŠTŮVKA Z , BORBÉLYOVÁ V , JANIŠOVÁ K , OTÁHAL J , MYSLIVEČEK J , RILJAK V
Published: January 2021

The study examined the morphological and long-term behavioral impacts of neonatal hypoxic-ischemic brain injury in a mouse model. We investigated the modification of different behavioral domains, such as spontaneous climbing, which represents fine motor skills. We also focused on sex-dependent differences during hypoxic-ischemic encephalopathy. The Rice-Vannucci model of hypoxia-ischemia was used, adjusted and adapted to 7-day-old C57BL/6NTac mice. The effects of induced hypoxia and ischemia were also studied separately. At postnatal day 60, mice underwent behavioral testing using the LABORAS apparatus. The perfusion for histological evaluation was performed one day after the behavioral analyses. In groups with separately induced hypoxia or ischemia, the observed alterations in behavior were not accompanied by morphological changes in the cortex or hippocampal formation. Female mice naturally climbed significantly more and hypoxic females reared less than hypoxic males (p<0.05). Male mice postnatally exposed to hypoxia-ischemia exhibited significantly lower vertical activity and higher horizontal activity (p<0.05). Mild hypoxic damage may not be morphologically detectable but may induce substantial behavioral changes in adult mice. There were significant differences between horizontal and vertical activity in reaction to hypoxia-ischemia. Our study indicates that the importance of behavioral testing is irreplaceable and may be reflected in neonatal medicine.
COVID-19, ARDS, ACOVCS, MIS-C, KD, PMIS, TSS, MIS-A: Connecting the Alphabet?
Authors: William Chambers Patrick
Published: January 2021

Covid-19 has presented the world with a multitude of different clinical faces. To date their linkage eludes. This article attempts to establish linkage using recent research results regarding blood groups, clinical findings, cytokines, epidemiology, and the CD147 receptor, the orphan sister of ACE2. The role of the immune system controlled by the RAS and vitamin D is explored and recommendations ventured.
Spin transport and spin dynamics in antiferromagnets
Authors:   , Hoogeboom Geert
Published: January 2021

Ferromagnets (FMs) have been a key ingredient in information technology because it is easy to manipulate and read out the magnetization. Antiferromagnets (AFMs) have magnetic moments with alternating direction resulting in negligible magnetization. This gives them high processing and device downscaling features, but this also makes it challenging to manipulate and interact with the AFM order. This thesis studies this interaction with antiferromagnets. NiO AFM order has been read out by electrically injecting spin current via the spin Hall effect in thin heavy metal films. In DyFeO3, both Dy and Fe magnetic moments, their excitation and interaction have been probed. A magnetic field lifts the degeneracy of magnetic excitations with opposite magnon spin, allowing a spin current to be detected nonlocally. The AFM order and the generation of spin current can easily be controlled by an adjacent FM. Thereby, we show that AFMs have the potential to play an active role in spintronics.
ANALISIS KUALITAS AIR SUNGAI KIKIM DI KECAMATAN KIKIM TIMUR KABUPATEN LAHAT
Authors: Walid Ahmad , Turahmah Fadila , Ismarliana Pisi
Published: January 2021

This study aims to determine the physical properties of Kikim River water in Kikim Timur Subdistrict, Lahat Regency and find out the right way to solve water problems as an effort to treat water from physical parameters that exceed the quality standards according to the Regulation of the Minister of Health of the Republic of Indonesia Number 492 / MENKES / PER / IV / 2018 concerning requirements for drinking water quality. The parameters tested in this study included temperature, total suspended solid (TSS) and degree of acidity (pH). Sampling was carried out at three points, namely Point 01 in Gunung Kembang Village or Kikim Hulu River, Point 02 in Bungamas Village or Kikim Tengah River, and Point 03 in Lubuk Tampang Village or Kikim Hilir River. The results of the test analysis of the Kikim Timur River water samples carried out at the Environmental Service Unit of the Environmental Service Laboratory (DLH) of Lahat Regency at points 01, 02 and 03 indicate that the parameters tested, namely temperature, (TSS) and pH values still meet the standards according to Regulation of the Minister of Health of the Republic of Indonesia Number 492 / MENKES / PER / IV / 2018.
Influence of the Mechanical Environment on the Regeneration of Osteochondral Defects
Authors: Davis Sarah , Roldo Marta , Blunn Gordon , Tozzi Gianluca , Roncada Tosca
Published: January 2021

Articular cartilage is a highly specialised connective tissue of diarthrodial joints which provides a smooth, lubricated surface for joint articulation and plays a crucial role in the transmission of loads. In vivo cartilage is subjected to mechanical stimuli that are essential for cartilage development and the maintenance of a chondrocytic phenotype. Cartilage damage caused by traumatic injuries, ageing, or degradative diseases leads to impaired loading resistance and progressive degeneration of both the articular cartilage and the underlying subchondral bone. Since the tissue has limited self-repairing capacity due its avascular nature, restoration of its mechanical properties is still a major challenge. Tissue engineering techniques have the potential to heal osteochondral defects using a combination of stem cells, growth factors, and biomaterials that could produce a biomechanically functional tissue, representative of native hyaline cartilage. However, current clinical approaches fail to repair full-thickness defects that include the underlying subchondral bone. Moreover, when tested in vivo, current tissue-engineered grafts show limited capacity to regenerate the damaged tissue due to poor integration with host cartilage and the failure to retain structural integrity after insertion, resulting in reduced mechanical function. The aim of this review is to examine the optimal characteristics of osteochondral scaffolds. Additionally, an overview on the latest biomaterials potentially able to replicate the natural mechanical environment of articular cartilage and their role in maintaining mechanical cues to drive chondrogenesis will be detailed, as well as the overall mechanical performance of grafts engineered using different technologies.
Evaluation of Annona muricata Acetogenins as Potential Anti-SARS-CoV-2 Agents Through Computational Approaches
Authors: Prasad Shashanka K. , Pradeep Sushma , Shimavallu Chandan , Kollur Shiva Prasad , Syed Asad , Marraiki Najat , Egbuna Chukwuebuka , Gaman Mihnea-Alexandru , Kosakowska Olga , Cho William C. , Patrick-Iwuanyanwu Kingsley Chukwuemeka , Ortega Castro Joaquín , Frau Juan , Flores-Holguín Norma , Glossman-Mitnik Daniel
Published: January 2021

Annona muricata, a tropical plant which has been extensively used in ethnomedicine to treat a wide range of diseases, from malaria to cancer. Interestingly, this plant has been reported to demonstrate significant antiviral properties against the human immunodeficiency virus, herpes simplex virus, human papilloma virus, hepatitis C virus and dengue virus. Additionally, the bioactive compounds responsible for antiviral efficacy have also shown to be selectively cytotoxic while inhibiting tumorigenic cell growth without affecting the normal cell growth. Annonaceous Acetogenins are a class of bioactive compounds exclusive to the Annonaceae family at which the plant A. muricata belongs. In the current study, we have created a library of Acetogenins unique to the plant, comprising of Annomuricin A, Annomuricin B, Annomuricin C, Muricatocin C, Muricatacin, cis-Annonacin, Annonacin-10-one, cis-Goniothalamicin, Arianacin and Javoricin, for in silico and theoretical evaluations against the SARS-CoV-2 spike protein in an attempt toward promotion of plant based drug development for the current pandemic of coronavirus disease 2019 (COVID-19). We found that all the Acetogenins showing in silico spike protein significantly docking with good binding affinities. Moreover, we envision A. muricata Acetogenins can be further studied by in vitro and in vivo models to identify potential anti-SARS-CoV-2 agents.
The Immunomodulatory Potential of Copper and Silver Based Self-Assembled Metal Organic Biohybrids Nanomaterials in Cancer Theranostics
Authors: Prajapati Neela , Karan Anik , Khezerlou Elnaz , DeCoster Mark A.
Published: January 2021

Copper high aspect ratio structures (CuHARS) and silver cystine nanoparticles (AgCysNPs) are two unique micro/nano particles under study here that show extensive anti-cancer effects on a glioma tumor cell line. These micro/nano particles have shown potent toxicity in the presence of inflammatory stimulus (combination of tumor necrosis factor, [TNF] and lipo-polysaccharide, LPS). CuHARS with a concentration of 20 μg/ml uniquely increased the catalytic generation of nitric oxide (NO), an important contributor in the immune system. This NO was generated in a cell culture tumor microenvironment (TME) in the presence of 25 µM S-nitrosothiol (cysteine-NO) and the inflammatory stimulus. CuHARS increased the NO production by 68.75% when compared to untreated glioma cells with CysNO and inflammatory stimulus. The production of NO was significantly higher under similar circumstances in the case of normal primary structural cells like brain microvascular endothelial cells (BMVECs). The production of NO by BMVECs went up by 181.25% compared to glioma cells. This significant increase in the NO concentration could have added up to tumorigenesis but the anti-cancer effect of CuHARS was prominent enough to lower down the viability of glioma cells by approximately 20% and increased the metabolism of structural cells, BMVECs by approximately 200%. The immunomodulatory effect of NO in the TME under these circumstances in the presence of the novel micro/nano material, CuHARS has risen up compared to the effect of inflammatory stimulus alone. The potency and specific nature of these materials toward tumor cells may make them suitable candidates for cancer treatment. Successive treatment of CuHARS to glioma cells also proved to be an effective approach considering the decrease in the total count of cells by 11.84 fold in case of three successive treatments compared to a single dose which only decreased the cell count by 2.45 fold showing the dose-dependent increasing toxicity toward glioma cells. AgCysNPs are another potent nanomaterial which also proved its significant toxic nature toward tumor cell lines as demonstrated here, but their immunomodulatory response is still unclear and needs to be explored further.
Case Report: A Rare Case of Right-Sided Papillary Fibroelastoma in a 1-Year-Old With Congenital Heart Disease
Authors: Ahmad Ali , El-Am Edward A. , Kurmann Reto D. , Hagler Donald J. , Bois Melanie C. , Maleszewski Joseph J. , Klarich Kyle W.
Published: January 2021

Introduction: Cardiac papillary fibroelastomas (PFEs) are the most common primary benign cardiac tumors, although they are somewhat unusual in children and typically seen on the left-sided cardiac valves.

Case summary: A 10-week-old patient was found to have a partial atrioventricular canal defect, with associated tricuspid and mitral regurgitation. He was medically managed until 1 year of age, when surgical correction was done. During the procedure, a PFE was found incidentally on the TV.

Conclusion: This is one of the youngest patients to be reported with PFE, thus adding to the literature of these unusual cases in children.
Development of Deep-Sea Anoxia in Panthalassa During the Lopingian (Late Permian): Insights From Redox-Sensitive Elements and Multivariate Analysis
Authors: Onoue Tetsuji , Soda Katsuhito , Isozaki Yukio
Published: January 2021

The end-Permian mass extinction (EPME) was the most severe mass extinction event of the Phanerozoic, and was associated with the development of global oceanic anoxia. The intensification of ocean anoxia preceded the EPME, but the degree of intensity and timing of oceanic redox changes in the mid-Panthalassa Ocean remain debated. Here we present the results of geochemical and multivariate statistical analyses of a late Guadalupian to Lopingian (middle–late Permian) bedded chert succession from the Iwaidani section, Japan, which preserves pelagic deep-sea facies from the ocean floor to the lower flank of a mid-Panthalassan seamount. The entire section yields a low manganese-enrichment factor (MnEF <1), suggesting that suboxic conditions has appeared in the depositional environment already in the late Guadalupian. Enrichment factors of other redox-sensitive trace-elements (e.g., vanadium and uranium) and principle component analysis (PCA) of major element data show the development of suboxic to weakly anoxic conditions across the Guadalupian/Lopingian boundary. Subsequently, anoxic conditions, as inferred from enrichments in U, Mo, Ni, Cu, Zn, and Tl, were developed during the middle Lopingian. Extremely high concentrations of U and Mo (enrichment factors of ∼6 and ∼5,500, respectively) indicate that H2S-rich euxinic conditions developed during the latest Lopingian and around the time of the EPME. The cause of the shift toward more reducing conditions in the early–middle Lopingian is unknown, but PCA results suggest that the euxinic conditions occurred in association with intensified continental weathering in response to a temperature rise during the ca. 200 kyr before the EPME.
Functional Pituitary Networks in Vertebrates
Authors: Santiago-Andres Yorgui , Golan Matan , Fiordelisio Tatiana
Published: January 2021

The pituitary is a master endocrine gland that developed early in vertebrate evolution and therefore exists in all modern vertebrate classes. The last decade has transformed our view of this key organ. Traditionally, the pituitary has been viewed as a randomly organized collection of cells that respond to hypothalamic stimuli by secreting their content. However, recent studies have established that pituitary cells are organized in tightly wired large-scale networks that communicate with each other in both homo and heterotypic manners, allowing the gland to quickly adapt to changing physiological demands. These networks functionally decode and integrate the hypothalamic and systemic stimuli and serve to optimize the pituitary output into the generation of physiologically meaningful hormone pulses. The development of 3D imaging methods and transgenic models have allowed us to expand the research of functional pituitary networks into several vertebrate classes. Here we review the establishment of pituitary cell networks throughout vertebrate evolution and highlight the main perspectives and future directions needed to decipher the way by which pituitary networks serve to generate hormone pulses in vertebrates.
Vegetation Restoration Alleviated the Soil Surface Organic Carbon Redistribution in the Hillslope Scale on the Loess Plateau, China
Authors: Liang Yipeng , Li Xiang , Zha Tonggang , Zhang Xiaoxia
Published: January 2021

The redistribution of soil organic carbon (SOC) in response to soil erosion along the loess slope, China, plays an important role in understanding the mechanisms that underlie SOC’s spatial distribution and turnover. Consequently, SOC redistribution is key to understanding the global carbon cycle. Vegetation restoration has been identified as an effective method to alleviate soil erosion on the Loess Plateau; however, little research has addressed vegetation restoration’s effect on the SOC redistribution processes, particularly SOC’s spatial distribution and stability. This study quantified the SOC stock and pool distribution on slopes along geomorphic gradients in naturally regenerating forests (NF) and an artificial black locust plantation (BP) and used a corn field as a control (CK). The following results were obtained: 1) vegetation restoration, particularly NF, slowed the migration of SOC and reduced the heterogeneity of its distribution effectively. The topsoil SOC ratios of the sedimentary area to the stable area were 109%, 143%, and 210% for NF, BP, and CK, respectively; 2) during migration, vegetation restoration decreased the loss of labile organic carbon by alleviating the loss of dissolved organic carbon (DOC) and easily oxidized organic carbon (EOC). The DOC/SOC in the BP and NF increased significantly and was 13.14 and 17.57 times higher, respectively, than that in the CK (p < 0.05), while the EOC/SOC in the BP and NF was slightly higher than that in the CK. A relevant schematic diagram of SOC cycle patterns and redistribution along the loess slope was drawn under vegetation restoration. The results suggest that vegetation restoration in the loess slope, NF in particular, is an effective means to alleviate the redistribution and spatial heterogeneity of SOC and reduce soil erosion.
In Pursuit of Ecological Forestry: Historical Barriers and Ecosystem Implications
Authors: Gresh James M. , Courter Jason R.
Published: January 2021

The global need for ecological forestry is more important today than ever. But despite a century of technical advancements from forestry leaders—especially in North America and Europe—the world's forest ecosystem is declining at a time when carbon levels are rising, and biodiversity is at risk. Unfortunately, even the world's innovation leaders are struggling to change industry practices in their home countries. Undeterred by the lack of progress, new efforts are being attempted with Europe taking a markedly different path than the U.S. In the U.S., the pursuit of ecological forestry has embraced natural disturbance frameworks and stresses customized goals for local environments and social demands. In Europe, a broad application of low-intensity harvest protocols and canopy protection is being promoted for many forest types. The U.S. approach shows strong ecological promise at local and regional scales, but its broad adoption within the industry as a whole is limited and inconsistent. For the European approach, the broadly elevated priority of continuous canopy draws scientific critics, but their forestry industry is adopting and applying the concept. Although lower-intensity harvests are common to both regions, evidence suggests that Europe may be using low-intensity methods too broadly, while the U.S. is using them too little. The objective of this perspective is to describe the historical development of ecological forestry in Europe and the United States, and to propose research adjustments to help America pursue broader ecological forestry application. By understanding the historical precedents that influence forestry perceptions and the differences in contemporary approaches among forestry leaders, forestry scientists may be better equipped to design research and promote practices that can influence industry behavior for better ecosystem implications.
Prioritization and Evaluation of Flooding Tolerance Genes in Soybean [Glycine max (L.) Merr.]
Authors: Lai Mu-Chien , Lai Zheng-Yuan , Jhan Li-Hsin , Lai Ya-Syuan , Kao Chung-Feng
Published: January 2021

Soybean [Glycine max (L.) Merr.] is one of the most important legume crops abundant in edible protein and oil in the world. In recent years there has been increasingly more drastic weather caused by climate change, with flooding, drought, and unevenly distributed rainfall gradually increasing in terms of the frequency and intensity worldwide. Severe flooding has caused extensive losses to soybean production and there is an urgent need to breed strong soybean seeds with high flooding tolerance. The present study demonstrates bioinformatics big data mining and integration, meta-analysis, gene mapping, gene prioritization, and systems biology for identifying prioritized genes of flooding tolerance in soybean. A total of 83 flooding tolerance genes (FTgenes), according to the appropriate cut-off point, were prioritized from 36,705 test genes collected from multidimensional genomic features linking to soybean flooding tolerance. Several validation results using independent samples from SoyNet, genome-wide association study, SoyBase, GO database, and transcriptome databases all exhibited excellent agreement, suggesting these 83 FTgenes were significantly superior to others. These results provide valuable information and contribution to research on the varieties selection of soybean.
Lysophosphatidic Acid Is an Inflammatory Lipid Exploited by Cancers for Immune Evasion via Mechanisms Similar and Distinct From CTLA-4 and PD-1
Authors: Mathew Divij , Torres Raul M.
Published: January 2021

Immunological tolerance has evolved to curtail immune responses against self-antigens and prevent autoimmunity. One mechanism that contributes to immunological tolerance is the expression of inhibitory receptors by lymphocytes that signal to dampen immune responses during the course of an infection and to prevent immune-mediated collateral damage to the host. The understanding that tumors exploit these physiological mechanisms to avoid elimination has led to remarkable, but limited, success in the treatment of cancer through the use of biologics that interfere with the ability of cancers to suppress immune function. This therapy, based on the understanding of how T lymphocytes are normally activated and suppressed, has led to the development of therapeutic blocking antibodies, referred to as immune checkpoint blockade, which either directly or indirectly promote the activation of CD8 T cells to eradicate cancer. Here, we highlight the distinct signaling mechanisms, timing and location of inhibition used by the CTLA-4 and PD-1 inhibitory receptors compared to a novel inhibitory signaling axis comprised of the bioactive lipid, lysophosphatidic acid (LPA), signaling via the LPA5 receptor expressed by CD8 T cells. Importantly, abundant evidence indicates that an LPA-LPA5 signaling axis is also exploited by diverse cancers to suppress T cell activation and function. Clearly, a thorough molecular and biochemical understanding of how diverse T cell inhibitory receptors signal to suppress T cell antigen receptor signaling and function will be important to inform the choice of which complimentary checkpoint blockade modalities might be used for a given cancer.
The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease
Authors: Gbotosho Oluwabukola T. , Kapetanaki Maria G. , Kato Gregory J.
Published: January 2021

Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.
Impact of a Rapid Decline in Malaria Transmission on Antimalarial IgG Subclasses and Avidity
Authors: Ssewanyana Isaac , Rek John , Rodriguez Isabel , Wu Lindsey , Arinaitwe Emmanuel , Nankabirwa Joaniter I. , Beeson James G. , Mayanja-Kizza Harriet , Rosenthal Philip J. , Dorsey Grant , Kamya Moses R. , Drakeley Chris , Greenhouse Bryan , Tetteh Kevin K. A.
Published: January 2021

Understanding how immunity to malaria is affected by declining transmission is important to aid vaccine design and understand disease resurgence. Both IgG subclasses and avidity of antigen-specific responses are important components of an effective immune response. Using a multiplex bead array assay, we measured the total IgG, IgG subclasses, and avidity profiles of responses to 18 P. falciparum blood stage antigens in samples from 160 Ugandans collected at two time points during high malaria transmission and two time points following a dramatic reduction in transmission. Results demonstrated that, for the antigens tested, (i) the rate of decay of total IgG following infection declined with age and was driven consistently by the decrease in IgG3 and occasionally the decrease in IgG1; (ii) the proportion of IgG3 relative to IgG1 in the absence of infection increased with age; (iii) the increase in avidity index (the strength of association between the antibody and antigen) following infection was largely due to a rapid loss of non-avid compared to avid total IgG; and (iv) both avid and non-avid total IgG in the absence of infection increased with age. Further studies are required to understand the functional differences between IgG1 and IgG3 in order to determine their contribution to the longevity of protective immunity to malaria. Measuring changes in antibody avidity may be a better approach of detecting affinity maturation compared to avidity index due to the differential expansion and contraction of high and low avidity total IgG.
Interleukin-1 as Innate Mediator of T Cell Immunity
Authors: Van Den Eeckhout Bram , Tavernier Jan , Gerlo Sarah
Published: January 2021

The three-signal paradigm tries to capture how the innate immune system instructs adaptive immune responses in three well-defined actions: (1) presentation of antigenic peptides in the context of MHC molecules, which allows for a specific T cell response; (2) T cell co-stimulation, which breaks T cell tolerance; and (3) secretion of polarizing cytokines in the priming environment, thereby specializing T cell immunity. The three-signal model provides an empirical framework for innate instruction of adaptive immunity, but mainly discusses STAT-dependent cytokines in T cell activation and differentiation, while the multi-faceted roles of type I IFNs and IL-1 cytokine superfamily members are often neglected. IL-1α and IL-1β are pro-inflammatory cytokines, produced following damage to the host (release of DAMPs) or upon innate recognition of PAMPs. IL-1 activity on both DCs and T cells can further shape the adaptive immune response with variable outcomes. IL-1 signaling in DCs promotes their ability to induce T cell activation, but also direct action of IL-1 on both CD4+and CD8+T cells, either alone or in synergy with prototypical polarizing cytokines, influences T cell differentiation under different conditions. The activities of IL-1 form a direct bridge between innate and adaptive immunity and could therefore be clinically translatable in the context of prophylactic and therapeutic strategies to empower the formation of T cell immunity. Understanding the modalities of IL-1 activity during T cell activation thus could hold major implications for rational development of the next generation of vaccine adjuvants.
Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain TRM Formation and Function
Authors: Netherby-Winslow Colleen S. , Ayers Katelyn N. , Lukacher Aron E.
Published: January 2021

Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRMare predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRMare transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRMdiffer phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRMare governed by a contextual milieu that balances TRMactivation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRMphenotype and function, and discuss the contribution of TRMto promoting protective immune responsesin situwhile maintaining tissue homeostasis.
Surviving Heatwaves: Thermal Experience Predicts Life and Death in a Southern Ocean Diatom
Authors: Samuels Toby , Rynearson Tatiana A. , Collins Sinéad
Published: January 2021

Extreme environmental fluctuations such as marine heatwaves (MHWs) can have devastating effects on ecosystem health and functioning through rapid population declines and destabilization of trophic interactions. However, recent studies have highlighted that population tolerance to MHWs is variable, with some populations even benefitting from MHWs. A number of factors can explain variation in responses between populations including their genetic variation, previous thermal experience and the cumulative heatwave intensity (°C d) of the heatwave itself. We disentangle the contributions of these factors on population mortality and post-heatwave growth rates by experimentally simulating heatwaves (7.5 or 9.2°C, for up to 9 days) for three genotypes of the Southern Ocean diatom Actinocyclus actinochilus. The effects of simulated heatwaves on mortality and population growth rates varied with genotype, thermal experience and the cumulative intensity of the heatwave itself. Firstly, hotter and longer heatwaves increased mortality and decreased post-heatwave growth rates relative to milder, shorter heatwaves. Secondly, growth above the thermal optimum before heatwaves exacerbated heatwave-associated negative effects, leading to increased mortality during heatwaves and slower growth after heatwaves. Thirdly, hotter and longer heatwaves resulted in more pronounced changes to thermal optima (Topt) immediately following heatwaves. Finally, there is substantial intraspecific variation in post-heatwave growth rates. Our findings shed light on the potential of Southern Ocean diatoms to tolerate MHWs, which will increase both in frequency and in intensity under future climate change.
A Contribution to the Study of the Forming of Dry Unidirectional HiTape® Reinforcements for Primary Aircraft Structures
Authors: Bouquerel Laure , Moulin Nicolas , Drapier Sylvain
Published: January 2021

In the context of developing competitive liquid composites molding processes for primary aircraft structures, modeling the forming stage of automatically-placed initially flat stacks of dry reinforcements is of great interest. In the case of HiTape®, a dry unidirectional carbon fiber reinforcement designed to achieve performances comparable to state-of-the-art pre-impregnated materials, the presence of a thermoplastic veil on each side of the material for both processing and mechanical purposes should also be considered when modeling forming in hot conditions. As a dry unidirectional reinforcement, HiTape® is expected to exhibit a transversely isotropic behavior. Computation cost and strong characterization challenges led us to model its behavior at the forming process temperature (above the thermoplastic veil melting temperature) through a homogeneous equivalent continuous medium exhibiting four ‘classical’ deformation modes and a specific structural mode, namely out-of-plane bending. The response of both single plies and stacks of HiTape® to this latter structural mode was characterized at the forming process temperature using a modifiedPeirce flexometer. Results on single plies showed a non-linear softening moment-curvature behavior and a corresponding flexural stiffness much lower than what can be inferred from continuum mechanics. Moreover, testing stacks revealed that the veil acts as a thin load transfer layer between the plies undergoing relative in-plane displacement,i.e.inter-ply sliding. This inter-ply response was then characterized separately at the forming process temperature thanks to a specific method relying on apull-throughtest. Experiments performed at pressures and speeds representative of the forming stage revealed that a hydrodynamic lubricated friction regime predominates,i.e.a linearly increasing relationship between the friction coefficient and the modified Hersey number. From an industrial point of view, high forming pressures and low speeds are therefore recommended to promote inter-ply slip to limit the occurrence of defects such as wrinkles.
A Prospective Controlled Trial to Evaluate Safety and Efficacy of in vitro Expanded Recipient Regulatory T Cell Therapy and Tocilizumab Together With Donor Bone Marrow Infusion in HLA-Mismatched Living Donor Kidney Transplant Recipients (Trex001)
Authors: Oberbauer Rainer , Edinger Matthias , Berlakovich Gabriela , Kalhs Peter , Worel Nina , Heinze Georg , Wolzt Michael , Lion Thomas , Wekerle Thomas
Published: January 2021

Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient.

Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients.

Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients.

Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR <35 mL/min/1.73 m2], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation.

Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning.

Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.
Peripheral Anterior Chamber Depth and Angle Measurements Using Pentacam After Implantation of Toric and Non-toric Implantable Collamer Lenses
Authors: Zhao Jiao , Zhao Jing , Yang Wen , Miao Huamao , Niu Lingling , Shang Jianmin , Wang Xiaoying , Zhou Xingtao
Published: January 2021

Purpose: To evaluate the characteristics of peripheral anterior chamber measurements by Pentacam after posterior implantable collamer lenses (ICL) and toric ICL (TICL) with central hole (V4c) implantation.

Methods: Prospective, non-randomized consecutive case series. Forty-six patients undergoing ICL implantation in one eye (Group A) and identically sized TICL in the contralateral eye (Group B) in the Refractive Surgery Center of Eye and ENT Hospital of Fudan University were prospectively included. According to ICL/TICL size, these eyes were further divided into four subgroups. Peripheral anterior chamber depth (PACD) and angle (ACA) in nasal and temporal sides were measured using Pentacam pre-operatively and 12-month post-operatively.

Results: The safety indices were 1.34 ± 0.32 and 1.25 ± 0.16 and the efficacy indices were 1.20 ± 0.24 and 1.19 ± 0.19 for ICL and TICL groups, respectively. There was no significant difference in pre-operative PACD or ACA between the two groups. Post-operative PACD and ACA were significantly lower than pre-operative values. Variations of PACD and ACA of TICL group were significantly larger than those of ICL group. The change of ACA for 13.2 mm lenses was significantly larger than that of 12.6 mm lenses. Pre-operative CACD and vault were significantly associated with post-operative PACD, while pre-operative ACA and vault were significantly associated with post-operative ACA.

Conclusions: Variations of PACD and ACA were greater in eyes after TICL (V4c) implantation compared with identically sized ICL (V4c) implantation and with larger size than smaller size lens implantation. Pre-operative anterior chamber structure and vault affect post-operative PACD and ACA.
LncRNA NEAT1 Promotes High Glucose-Induced Mesangial Cell Hypertrophy by Targeting miR-222-3p/CDKN1B Axis
Authors: Liao Lin , Chen Jie , Zhang Chuanfu , Guo Yue , Liu Weiwei , Liu Wenrui , Duan Lianxiang , Liu Ziyang , Hu Jing , Lu Jianrao
Published: January 2021

Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p’s binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.
FOXO Regulates Neuromuscular Junction Homeostasis During Drosophila Aging
Authors: Birnbaum Allison , Sodders Maggie , Bouska Mark , Chang Kai , Kang Ping , McNeill Elizabeth , Bai Hua
Published: January 2021

The transcription factor foxo is a known regulator of lifespan extension and tissue homeostasis. It has been linked to the maintenance of neuronal processes across many species and has been shown to promote youthful characteristics by regulating cytoskeletal flexibility and synaptic plasticity at the neuromuscular junction (NMJ). However, the role of foxo in aging neuromuscular junction function has yet to be determined. We profiled adult Drosophila foxo- null mutant abdominal ventral longitudinal muscles and found that young mutants exhibited morphological profiles similar to those of aged wild-type flies, such as larger bouton areas and shorter terminal branches. We also observed changes to the axonal cytoskeleton and an accumulation of late endosomes in foxo null mutants and motor neuron-specific foxo knockdown flies, similar to those of aged wild-types. Motor neuron-specific overexpression of foxo can delay age-dependent changes to NMJ morphology, suggesting foxo is responsible for maintaining NMJ integrity during aging. Through genetic screening, we identify several downstream factors mediated through foxo-regulated NMJ homeostasis, including genes involved in the MAPK pathway. Interestingly, the phosphorylation of p38 was increased in the motor neuron-specific foxo knockdown flies, suggesting foxo acts as a suppressor of p38/MAPK activation. Our work reveals that foxo is a key regulator for NMJ homeostasis, and it may maintain NMJ integrity by repressing MAPK signaling.
Mitochondria: Novel Mechanisms and Therapeutic Targets for Secondary Brain Injury After Intracerebral Hemorrhage
Authors: Chen Weixiang , Guo Chao , Feng Hua , Chen Yujie
Published: January 2021

Intracerebral hemorrhage (ICH) is a destructive form of stroke that often results in death or disability. However, the survivors usually experience sequelae of neurological impairments and psychiatric disorders, which affect their daily functionality and working capacity. The recent MISTIE III and STICH II trials have confirmed that early surgical clearance of hematomas does not improve the prognosis of survivors of ICH, so it is vital to find the intervention target of secondary brain injury (SBI) after ICH. Mitochondrial dysfunction, which may be induced by oxidative stress, neuroinflammation, and autophagy, among others, is considered to be a novel pathological mechanism of ICH. Moreover, mitochondria play an important role in promoting neuronal survival and improving neurological function after a hemorrhagic stroke. This review summarizes the mitochondrial mechanism involved in cell death, reactive oxygen species (ROS) production, inflammatory activation, blood–brain barrier (BBB) disruption, and brain edema underlying ICH. We emphasize the potential of mitochondrial protection as a potential therapeutic target for SBI after stroke and provide valuable insight into clinical strategies.
Case Report: Posterior Reversible Leukoencephalopathy Syndrome (PRES) as a Biologically Predictable Neurological Association in Severe COVID-19. First Reported Case From Australia and Review of Internationally Published Cases
Authors: Wijeratne Tissa , Wijeratne Chanith , Karimi Leila , Sales Carmela , Crewther Sheila Gillard
Published: January 2021

Reports of different types of neurological manifestations of COVID-19 are rapidly increasing, including changes of posterior reversible leukoencephalopathy syndrome (PRES). Here we describe the first reported case of COVID-19 and PRES in Australia diagnosed on basis of MRI brain imaging and confirmed clinically by presence of confusion, delirium, headaches, also associated with hypertension and blood pressure variability and stable long-term kidney problems. He made full recovery as his blood pressure was controlled and clinical status was supported with appropriate supportive therapy. Although traditionally a rare condition, PRES is likely to be more common among patients with COVID-19 pathobiology there is Renin downregulation of ACE2 receptors, involvement of Renin-Angiotensin-Aldosterone system, endotheliitis, cytokine storm, and hyper-immune response. Thus we advocate clinical suspicion and early brain imaging with MRI brain among vulnerable patients with known co-morbidities, and diagnosed with COVID-19 given that hypertension and blood pressure variability are often exacerbated by acute SARS-CoV-2 immune reactions. Such acute hypertensive encephalopathy was able to be reversed with timely supportive therapy ensuring re-hydration and re-establishment of blood pressure control.