bluuebunny/crossref_metadata_2025 huggingface dataset:
Transforming Growth Factor (TGF) β and Endometrial Vascular Maturation
Authors: Lu Qinsheng , Sun Dingqian , Shivhare Sourima Biswas , Hou Huomei , Bulmer Judith N. , Innes Barbara A. , Hapangama Dharani K. , Lash Gendie E.
Published: April 2021

Appropriate growth and development of the endometrium across the menstrual cycle is key for a woman’s quality of life and reproductive well-being. Recurrent pregnancy loss (RPL) and heavy menstrual bleeding (HMB) affect a significant proportion of the female population worldwide. These endometrial pathologies have a significant impact on a woman’s quality of life as well as placing a high economic burden on a country’s health service. An underlying cause for both conditions is unknown in approximately 50% of cases. Previous research has demonstrated that aberrant endometrial vascular maturation is associated with both RPL and HMB, where it is increased in RPL but reduced in HMB. TGFβ1 is one of the key growth factors that regulate vascular maturation, by inducing phenotypic switching of vascular smooth muscle cells (VSMCs) from a synthetic phenotype to a more contractile one. Our previous data demonstrated an increase in TGFβ1 in the endometrium of RPL, while others have shown a decrease in women with HMB. However, TGFβ1 bioavailability is tightly controlled, and we therefore sought to perform an extensive immunohistochemical analysis of different components in the pathway in the endometrium of normal controls, women with HMB or RPL. In addition, twoin vitromodels were used to examine the role of TGFβ1 in endometrial vascular maturation and endothelial cell (EC):VSMC association. Taken all together, the immunohistochemical data suggest a decrease in bioavailability, receptor binding capacity, and signaling in the endometrium of women with HMB compared with controls. In contrast, there is an increase in the bioavailability of active TGFβ1 in the endometrium of women with RPL compared with controls. Endometrial explants cultured in TGFβ1 had an increase in the number of vessels associated with contractile VSMC markers, although the total number of vessels did not increase. In addition, TGFβ1 increased EC:VSMC association in anin vitromodel. In conclusion, TGFβ1 is a key regulator of endometrial vascular maturation and could be considered as a therapeutic target for women suffering from HMB and/or RPL.
A Phosphotyrosine Switch in Estrogen Receptor β Is Required for Mouse Ovarian Function
Authors: Yuan Bin , Yang Jing , Dubeau Louis , Hu Yanfen , Li Rong
Published: April 2021

The two homologous estrogen receptors ERα and ERβ exert distinct effects on their cognate tissues. Previous work from our laboratory identified an ERβ-specific phosphotyrosine residue that regulates ERβ transcriptional activity and antitumor function in breast cancer cells. To determine the physiological role of the ERβ phosphotyrosine residue in normal tissue development and function, we investigated a mutant mouse model (Y55F) whereby this particular tyrosine residue in endogenous mouse ERβ is mutated to phenylalanine. While grossly indistinguishable from their wild-type littermates, mutant female mice displayed reduced fertility, decreased ovarian follicular cell proliferation, and lower progesterone levels. Moreover, mutant ERβ from female mice during superovulation is defective in activating promoters of its target genes in ovarian tissues. Thus, our findings provide compelling genetic and molecular evidence for a role of isotype-specific ERβ phosphorylation in mouse ovarian development and function.
Effect of Small Molecule on ex vivo Expansion of Cord Blood Hematopoietic Stem Cells: A Concise Review
Authors: Ghafouri-Fard Soudeh , Niazi Vahid , Taheri Mohammad , Basiri Abbas
Published: April 2021

Hematopoietic stem cells (HSCs) are a group of cells being produced during embryogenesis to preserve the blood system. They might also be differentiated to non-hematopoietic cells, including neural, cardiac and myogenic cells. Therefore, they have vast applications in the treatment of human disorders. Considering the restricted quantities of HSCs in the umbilical cord blood, inadequate mobilization of bone marrow stem cells, and absence of ethnic dissimilarity, ex vivo expansion of these HSCs is an applicable method for obtaining adequate amounts of HSCs. Several molecules such as NR-101, zVADfmk, zLLYfmk, Nicotinamide, Resveratrol, the Copper chelator TEPA, dmPGE2, Garcinol, and serotonin have been used in combination of cytokines to expand HSCs ex vivo. The most promising results have been obtained from cocktails that influence multipotency and self-renewal features from different pathways. In the current manuscript, we provide a concise summary of the effects of diverse small molecules on expansion of cord blood HSCs.
Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease
Authors: Zhou Lan-Ting , Zhang Juan , Tan Lu , Huang He-Zhou , Zhou Yang , Liu Zhi-Qiang , Lu Youming , Zhu Ling-Qiang , Yao Chengye , Liu Dan
Published: April 2021

Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.
An Assessment of the 2015–2017 Drought in Windhoek
Authors: van Rensburg Pierre , Tortajada Cecilia
Published: April 2021

Namibia is the most arid country in Sub-Saharan Africa. In Windhoek, the capital city, accelerated population growth and expanding economic activities, coupled with highly variable rainfall and multiyear droughts, have jeopardized water security and put enormous stress on socioeconomic development. This paper offers a review of the 2015–2017 drought and the responses that were implemented during it, with a focus on engagement with the public, industries, and public institutions to achieve water-saving targets. It also considers how the use of the Windhoek Drought Response Plan during the 2015–2017 drought furthered preparedness efforts for future droughts. The assessment ends with a discussion of government responses, challenges faced, and lessons learned—lessons that can hopefully pave the way for more effective responses to future drought situations in the country.
How Finnish and Portuguese Parents’ Implicit Beliefs About Learning Actualize at Home
Authors: Levinthal Cristiana , Kuusisto Elina , Tirri Kirsi
Published: April 2021

The purpose of this qualitative study was to explore parental engagement in the home learning environment, and parents’ implicit beliefs about learning underlying such engagement. Nineteen parents of school children between 7 and 12 years old were interviewed in two different cultural contexts, Finland (N= 10) and Portugal (N= 9). The interviews were subjected to inductive and deductive content analysis. Forms of parental engagement at home were similar in both countries, divided between two main categories:engagement with their child’s holistic developmentandengagement with the child’s schooling process. Parental narratives about engagement were, for the most part, embedded in a growth mindset (or an incremental meaning system). The most common actualizations of engagement included considering the child’s learning contexts and emotions; encouraging effort, persistence and practice; approaching difficulties as a natural part of learning and suggesting strategies for overcoming them. Parental practices of engagement were combined with the actualization of their implicit beliefs to create parental engagement–mindset profiles. Twelve parents were classified as having agrowth mindset to support the child’s holistic developmentprofile, and the other seven were distributed amongst the three remaining profiles. The study contributes to the growing interest on the association between parental engagement and their learning-related implicit beliefs, giving clear first-person illustrations of how both occur and interact in the home learning environment. Implications for practice are discussed.
Insights Into Students’ Experiences and Perceptions of Remote Learning Methods: From the COVID-19 Pandemic to Best Practice for the Future
Authors: Nguyen Trang , Netto Camila L. M. , Wilkins Jon F. , Bröker Pia , Vargas Elton E. , Sealfon Carolyn D. , Puthipiroj Pipob , Li Katherine S. , Bowler Jade E. , Hinson Hailey R. , Pujar Mithil , Stein Geneva M.
Published: April 2021

This spring, students across the globe transitioned from in-person classes to remote learning as a result of the COVID-19 pandemic. This unprecedented change to undergraduate education saw institutions adopting multiple online teaching modalities and instructional platforms. We sought to understand students’ experiences with and perspectives on those methods of remote instruction in order to inform pedagogical decisions during the current pandemic and in future development of online courses and virtual learning experiences. Our survey gathered quantitative and qualitative data regarding students’ experiences with synchronous and asynchronous methods of remote learning and specific pedagogical techniques associated with each. A total of 4,789 undergraduate participants representing institutions across 95 countries were recruited via Instagram. We find that most students prefer synchronous online classes, and students whose primary mode of remote instruction has been synchronous report being more engaged and motivated. Our qualitative data show that students miss the social aspects of learning on campus, and it is possible that synchronous learning helps to mitigate some feelings of isolation. Students whose synchronous classes include active-learning techniques (which are inherently more social) report significantly higher levels of engagement, motivation, enjoyment, and satisfaction with instruction. Respondents’ recommendations for changes emphasize increased engagement, interaction, and student participation. We conclude that active-learning methods, which are known to increase motivation, engagement, and learning in traditional classrooms, also have a positive impact in the remote-learning environment. Integrating these elements into online courses will improve the student experience.
Competing Processes Drive the Resistance of Soil Carbon to Alterations in Organic Inputs
Authors: Pierson Derek , Peter-Contesse Hayley , Bowden Richard D. , Nadelhoffer Knute , Kayhani Kamron , Evans Lucas , Lajtha Kate
Published: April 2021

Protecting existing soil carbon (C) and harnessing the C sequestration potential of soils require an improved understanding of the processes through which soil organic matter accumulates in natural systems. Currently, competing hypotheses exist regarding the dominant mechanisms for soil C stabilization. Many long-standing hypotheses revolve around an assumed positive relationship between the quantity of organic inputs and soil C accumulation, while more recent hypotheses have shifted attention toward the complex controls of microbial processing and organo-mineral complexation. Here, we present the observed findings of soil response to 20 years of detrital manipulations in the wet, temperate forest of the H.J. Andrews Experimental Station. Annual additions of low-quality (high C:N content) wood litter to the soil surface led to a greater positive effect on observed mean soil C concentration relative to additions of higher-quality (low C:N content) needle litter over the 20-year study period. However, high variability in measurements of soil C led to a statistically non-significant difference in C concentration between the two treatments and the control soil. The observed soil C responses to these two addition treatments demonstrates the long timescale and potential magnitude of soil C responses to management or disturbance led changes in forest litter input composition. Detrital input reduction treatments, including cutting off live root activity and the aboveground removal of surface litter, led to relatively small, non-significant effects on soil C concentrations over the 20-year study period. Far greater negative effects on mean soil C concentrations were observed for the combined removal of both aboveground litter and belowground root activity, which led to an observed, yet also non-significant, 20% decline in soil C stocks. The substantial proportion of remaining soil C following these dramatic, long-term reductions in above- and belowground detrital inputs suggests that losses of C in these forest soils are not readily achieved over a few decades of reductions in detrital input and may require far greater periods of time or further perturbations to the environment. Further, the observed soil C responses to detrital manipulations support recent hypotheses regarding soil C stabilization, which emphasize litter quality and mineral stabilization as relevant controls over forest soil C.
Vertical Distribution of Bacterial Community in Water Columns of Reservoirs With Different Trophic Conditions During Thermal Stratification
Authors: Yue Yihong , Cai Ling , Tang Yi , Zhang Yuanyuan , Yang Ming , Wang Fushun
Published: April 2021

Water eutrophication is a global ecological issue, and thermal stratification of water bodies can enable eutrophication. We examined bacterial communities in the stratified water columns and sediments in two different trophic reservoirs along the Wujiang River using quantitative real-time PCR and high-throughput sequencing. Bacterial 16S rRNA gene copies varied from 3.70 × 107to 5.27 × 108copies/L in the water column of Hongjiadu (HJD) Reservoir (60 m water depth) with slightly stratified variation; while in Wujiangdu (WJD) Reservoir (70 m water depth), bacterial abundance decreased markedly from the surface to the bottom(1.74 × 109to 2.38 × 107copies/L). The vertical distribution patterns of bacteria in both reservoirs resembled those of water Chlorophylla(Chla) concentrations. The abundance was negatively correlated with water depth (D), total nitrogen (TN), nitrate (NO3–-N), and positively correlated with water temperature (T) and dissolved oxygen (DO) level. In contrast, the alpha diversity of bacteria showed the opposite trend in the vertical water column.Proteobacteria,Actinobacteria, andBacteroideteswere the predominant phyla in the water column of both reservoirs. Compared to WJD Reservoir, HJD Reservoir displayed marked vertical spatial difference in bacterial community structure during thermal stratification. In particular,Pseudomonaswas frequently detected at the bottom of the HJD Reservoir. These results were consistent with predictive metagenomic profiling that revealed different vertical functional variation patterns of the bacterial communities in the two reservoirs. The bacterial community structure of HJD Reservoir was associated with water D, ammonium (NH4+-N), nitrite (NO2–-N), and total phosphorus (TP). The community structure of WJD Reservoir was related to water T, Chla, NO3–-N, and TN. The findings highlighted the important roles played by thermal stratification and nutrients in shaping the water bacterial community structure. Additionally, the absolute abundance of water nitrifiers (AOBgene copies) and denitrifiers (narG,nirS,norB, andnosZgene copies) displayed significant vertical differences in the water columns of both reservoirs. Gene copies involved in denitrification were significantly higher than those involved in nitrification. Water phosphorus and nitrogen contents were important variables influencing the absolute abundance of ammonia oxidizers and denitrifying bacteria, respectively. Our study revealed that the emergence of thermal stratification was responsible for the vertical stratification of bacteria in water and affected the bacterial community structure together with nutrients.
Identification of Seven-Gene Hypoxia Signature for Predicting Overall Survival of Hepatocellular Carcinoma
Authors: Bai Yuping , Qi Wenbo , Liu Le , Zhang Jing , Pang Lan , Gan Tiejun , Wang Pengfei , Wang Chen , Chen Hao
Published: April 2021

Background

Hepatocellular carcinoma (HCC) is ranked fifth among the most common cancer worldwide. Hypoxia can induce tumor growth, but the relationship with HCC prognosis remains unclear. Our study aims to construct a hypoxia-related multigene model to predict the prognosis of HCC.

Methods

RNA-seq expression data and related clinical information were download from TCGA database and ICGC database, respectively. Univariate/multivariate Cox regression analysis was used to construct prognostic models. KM curve analysis, and ROC curve were used to evaluate the prognostic models, which were further verified in the clinical traits and ICGC database. GSEA analyzed pathway enrichment in high-risk groups. Nomogram was constructed to predict the personalized treatment of patients. Finally, real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expressions of KDELR3 and SCARB1 in normal hepatocytes and 4 HCC cells. The expressions of SCARB1 in hepatocellular carcinoma tissue in 46 patients were detected by immunohistochemistry, and the correlation between its expressions and disease free survival of patient was calculated.

Results

Through a series of analyses, seven prognostic markers related to HCC survival were constructed. HCC patients were divided into the high and low risk group, and the results of KM curve showed that there was a significant difference between the two groups. Stratified analysis, found that there were significant differences in risk values of different ages, genders, stages and grades, which could be used as independent predictors. In addition, we assessed the risk value in the clinical traits analysis and found that it could accelerate the progression of cancer, while the results of GSEA enrichment analysis showed that the high-risk group patients were mainly distributed in the cell cycle and other pathways. Then, Nomogram was constructed to predict the overall survival of patients. Finally, RT-qPCR showed that KDELR3 and SCARB1 were highly expressed in HepG2 and L02, respectively. Results of IHC staining showed that SCARB1 was highly expressed in cancer tissues compared to adjacent normal liver tissues and its expression was related to hepatocellular carcinoma differentiation status. The Kaplan-Meier survival showed a poor percent survival in the SCARB1 high group compared to that in the SCARB1 low group.

Conclusion

This study provides a potential diagnostic indicator for HCC patients, and help clinicians to deepen the comprehension in HCC pathogenesis so as to make personalized medical decisions.
Molecular and Cellular Mechanisms of Lipid Droplet Breakdown in the Liver of Chinese Soft-Shelled Turtle (Pelodiscus sinensis)
Authors: Huang Yufei , Yang Sheng , Bai Xuebing , Shi Yonghong , Chen Qiusheng
Published: April 2021

The Chinese soft-shelled turtle (Pelodiscus sinensis) is among the most primitive amphibians and reptiles in nature. On account of its environmental suitability and unique hibernation habit, the peculiar physiological phenomenon in P. sinensis attracted the attention of researchers in the field of marine science. The present study aimed to investigate the molecular mechanisms underlying the periodic variation of lipid droplet (LD) in the liver of P. sinensis. Histological results indicated that accumulated LD in the liver of P. sinensis during non-hibernation was gradually consumed during hibernation. RNA-Seq results revealed that genes responsible for carbohydrate catabolism were down-regulated during hibernation, while genes involved in lipid oxidation were up-regulated. These results suggest that energy metabolism in the liver of P. sinensis changes during hibernation, i.e., the energy generation mode shifted from carbohydrate catabolism to lipid oxidation. Further analysis of RNA-Seq results indicated that both lipolysis and autophagy could promote the degradation of hepatic LD during hibernation. To further determine the relationship between lipolysis and autophagy in the process of LD breakdown, we applied the inhibitors of lipolysis and autophagy (diethylumbelliferyl phosphate and 3-Methyladenine) in cultured primary hepatocytes of P. sinensis. The results indicated that lipolysis is the main way for LD degradation in the hepatocyte of P. sinensis. These data provide clear evidence about the seasonal changes in hepatocytes, corresponding with the different energy generation mode in the liver of P. sinensis.
Selective Feeding by a Predatory Sea Star Across a Depth Gradient in Northern Patagonia, Chile
Authors: Garrido Ignacio , Pardo Luis Miguel , Johnson Ladd E. , Schories Dirk
Published: April 2021

Sea stars often function as keystone predators in food webs of intertidal and subtidal communities, especially in temperate and sub-polar regions. In South America the sea starCosmasterias luridais distributed along both the Atlantic and Pacific coasts of Patagonia and is one of the most conspicuous and abundant benthic predators in the shallow subtidal zone (<25 m). Its feeding strategy and prey selection are, however, still poorly known. This study describes the feeding behavior ofC. luridaat a site in the Seno del Reloncaví (Chile), assessing its abundance, size and prey selection in the field relative to observed prey abundance and size along a bathymetric gradient. We hypothesized thatC. luridais a generalist predator, feeding on suitable prey according to their availability. However, we found that this predator only consumed a limited number (7 of 48) of potential prey species, primarily the slipper limpetsCrepipatellaspp. and the musselsAulacomya aterandMytilus chilensis. Electivity analysis revealed a clear preference for one mussel (A. ater) but not the other (M. chilensis) as well as depth-dependent selectivity for the slipper limpets, which changed from avoidance to preference with increasing depth. Sea star densities varied with depth, peaking between depths of 5 and 10 m, but the size of sea stars and the size of their prey did not vary significantly along a depth gradient. No significant correlations were found with the most commonly selected prey. These results would indicate that while this predator may be a generalist–opportunist, its feeding behavior is context-dependent and its high selectivity for certain species suggests that this sea star plays a key role structuring subtidal benthic communities in Patagonia.
Temperature Fluctuation Attenuates the Effects of Warming in Estuarine Microbial Plankton Communities
Authors: Cabrerizo Marco J. , Marañón Emilio , Fernández-González Cristina , Alonso-Núñez Adrián , Larsson Henrik , Aranguren-Gassis María
Published: April 2021

Sea surface warming has the potential to alter the diversity, trophic organization and productivity of marine communities. However, it is unknown if temperature fluctuations that ecosystems naturally experience can alter the predicted impacts of warming. We address this uncertainty by exposing a natural marine plankton community to warming conditions (+3°C) under a constant vs. fluctuating (±3°C) temperature regime using an experimental mesocosm approach. We evaluated changes in stoichiometry, biomass, nutrient uptake, taxonomic composition, species richness and diversity, photosynthetic performance, and community metabolic balance. Overall, warming had a stronger impact than fluctuating temperature on all biological organization levels considered. As the ecological succession progressed toward post-bloom, the effects of warming on phytoplankton biomass, species richness, and net community productivity intensified, likely due to a stimulated microzooplankton grazing, and the community metabolic balance shifted toward a CO2 source. However, fluctuating temperatures reduced the negative effects of warming on photosynthetic performance and net community productivity by 40%. Our results demonstrate that temperature fluctuations may temper the negative effect of warming on marine net productivity. These findings highlight the need to consider short-term thermal fluctuations in experimental and modeling approaches because the use of constant warming conditions could lead to an overestimation of the real magnitude of climate change impacts on marine ecosystems.
Solution-Processed Epitaxial Growth of MAPbI3 Single-Crystal Films for Highly Stable Photodetectors
Authors: Xu Yubing , Wang Xin , Zhao Jingda , Pan Yuzhu , Li Yuwei , Elemike Elias Emeka , Li Qing , Zhang Xiaobing , Chen Jing , Zhao Zhiwei , Akram Javed , Bae Byung Seong , Bin Suhaidi , Lei Wei
Published: April 2021

Recent years, organic-inorganic hybrid perovskites (OIHPs) have been widely used in applications, such as solar cells, lasers, light-emission diodes, and photodetectors due to their outstanding optoelectronic properties. Nowadays photodetectors based on perovskite films (PFs) suffer from surface and interface traps, which result from low crystalline quality of perovskite films and lattice mismatch between perovskite films and substrates. Herein, we fabricate MAPbI3-(MA = CH3NH3) single-crystal films (SCFs) on MAPbBr3single crystal substrates in MAPbI3precursor solution during crystallization process via solution-processed epitaxy. Benefit from the good lattice matching, epitaxial MAPbI3SCFs with high crystallinity and smooth morphology are of comparable quality to MAPbI3PSCs and are of better quality than MAPbI3polycrystalline films. Here we report that epitaxial MAPbI3SCFs have a low trap density of 5.64×1011cm–3and a long carrier lifetime of 11.86 μs. In this work, photodetector based on epitaxial MAPbI3single-crystal film (SCF) exhibits an excellent stability of a long-term stable response after 120 days, a fast response time of 2.21 μs, a high responsivity of 1.2 A W–1and a high detectivity of 3.07 ×1012jones.
Coelimycin Synthesis Activatory Proteins Are Key Regulators of Specialized Metabolism and Precursor Flux in Streptomyces coelicolor A3(2)
Authors: Bednarz Bartosz , Millan-Oropeza Aaron , Kotowska Magdalena , Świat Michał , Quispe Haro Juan J. , Henry Céline , Pawlik Krzysztof
Published: April 2021

Many microbial specialized metabolites are industrially relevant agents but also serve as signaling molecules in intra-species and even inter-kingdom interactions. In the antibiotic-producingStreptomyces, members of the SARP (Streptomycesantibiotic regulatory proteins) family of regulators are often encoded within biosynthetic gene clusters and serve as their direct activators. Coelimycin is the earliest, colored specialized metabolite synthesized in the life cycle of the model organismStreptomyces coelicolorA3(2). Deletion of its two SARP activatorscpkOandcpkNabolished coelimycin synthesis and resulted in dramatic changes in the production of the later, stationary-phase antibiotics. The underlying mechanisms of these phenotypes were deregulation of precursor flux and quorum sensing, as shown by label-free, bottom-up shotgun proteomics. Detailed profiling of promoter activities demonstrated that CpkO is the upper-level cluster activator that induces CpkN, while CpkN activates type II thioesterase ScoT, necessary for coelimycin synthesis. What is more, we show thatcpkNis regulated by quorum sensing gamma-butyrolactone receptor ScbR.
Targets and Mechanisms of Geminivirus Silencing Suppressor Protein AC2
Authors: Veluthambi Karuppannan , Sunitha Sukumaran
Published: April 2021

Geminiviruses are plant DNA viruses that infect a wide range of plant species and cause significant losses to economically important food and fiber crops. The single-stranded geminiviral genome encodes a small number of proteins which act in an orchestrated manner to infect the host. The fewer proteins encoded by the virus are multifunctional, a mechanism uniquely evolved by the viruses to balance the genome-constraint. The host-mediated resistance against incoming virus includes post-transcriptional gene silencing, transcriptional gene silencing, and expression of defense responsive genes and other cellular regulatory genes. The pathogenicity property of a geminiviral protein is linked to its ability to suppress the host-mediated defense mechanism. This review discusses what is currently known about the targets and mechanism of the viral suppressor AC2/AL2/transcriptional activator protein (TrAP) and explore the biotechnological applications of AC2.
Structure-Based Virtual Screening to Identify Novel Potential Compound as an Alternative to Remdesivir to Overcome the RdRp Protein Mutations in SARS-CoV-2
Authors: Kumar D Thirumal , Shaikh Nishaat , Kumar S Udhaya , Doss C George Priya , Zayed Hatem
Published: April 2021

The number of confirmed COVID-19 cases is rapidly increasing with no direct treatment for the disease. Few repurposed drugs, such as Remdesivir, Chloroquine, Hydroxychloroquine, Lopinavir, and Ritonavir, are being tested against SARS-CoV-2. Remdesivir is the drug of choice for Ebola virus disease and has been authorized for emergency use. This drug acts against SARS-CoV-2 by inhibiting the RNA-dependent-RNA-polymerase (RdRp) of SARS-CoV-2. RdRp of viruses is prone to mutations that confer drug resistance. A recent study by Pachetti et al. in 2020 identified the P323L mutation in the RdRp protein of SARS-CoV-2. In this study, we aimed to determine the potency of lead compounds similar to Remdesivir, which can be used as an alternative when variants of SARS-CoV-2 develop resistance due to RdRp mutations. The initial screening yielded 704 compounds that were 90% similar to the control drug, Remdesivir. On further evaluation through drugability and antiviral inhibition percentage analyses, we shortlisted 32 and seven compounds, respectively. These seven compounds were further analyzed for their molecular interactions, which revealed that all seven compounds interacted with RdRp with higher affinity than Remdesivir under native conditions. However, three compounds failed to interact with the mutant protein with higher affinity than Remdesivir. Dynamic cross-correlation matrix (DCCM) and vector field collective motions analyses were performed to identify the precise movements of docked complexes' residues. Furthermore, the compound SCHEMBL20144212 showed a high affinity for native and mutant proteins and might provide an alternative against SARS-CoV-2 variants that might confer resistance to Remdesivir. Further validations by in vitro and in vivo studies are needed to confirm the efficacy of our lead compounds for their inhibition against SARS-CoV-2.
A Pilot Study on the Cutoff Value of Related Brain Metabolite in Chinese Elderly Patients With Mild Cognitive Impairment Using MRS
Authors: Zhao Lihua , Teng Jinlong , Mai Wei , Su Jiahui , Yu Bihan , Nong Xiucheng , Li Chong , Wei Yichen , Duan Gaoxiong , Deng Xiangming , Deng Demao , Chen Shangjie
Published: April 2021

Objective: This cross-sectional study aimed to distinguish patients with mild cognitive impairment (MCI) from patients with normal controls (NCs) by measuring the levels of N-acetyl aspartate (NAA), total creatinine (tCr), and choline (Cho) in their hippocampus (HIP) and their posterior cingulate gyrus (PCG) by using proton magnetic resonance spectroscopy (MRS) and to predict the cutoff value on the ratios of metabolites. We further aimed to provide a reference for the diagnosis of MCI in elderly patients in China.

Methods: About 69 patients who underwent a clinical diagnosis of the MCI group and 67 patients with NCs, the Mini-Mental Status Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and MRS of the bilateral HIP and bilateral PCG were considered. The ratio of NAA/tCr and Cho/tCr in the bilateral HIP and bilateral PCG was calculated. The relationship between the ratios of metabolites and the scores of MMSE and MoCA was analyzed, and the possible brain metabolite cutoff point for the diagnosis of MCI was evaluated.

Results: Compared with the NC group, the scores of MMSE and MoCA in the MCI group decreased significantly (p < 0.05); the ratio of NAA/tCr in the bilateral HIP and bilateral PCG and the ratio of Cho/tCr at the right HIP in the MCI group decreased significantly (p < 0.05); however, there was no significant difference in the ratio of Cho/tCr in the left HIP and bilateral PCG between the two groups (p > 0.05). The correlation coefficient between MMSE/MoCA and the ratio of NAA/tCr was 0.49–0.56 in the bilateral HIP (p < 0.01). The best cutoff value of NAA/creatine (Cr) in the left HIP and the right HIP was 1.195 and 1.19. Sensitivity, specificity, and the Youden index (YDI) in the left HIP and the right HIP were (0.725, 0.803, 0.528) and (0.754, 0.803, 0.557), respectively.

Conclusion: The level of metabolites in the HIP and the PCG of patients with MCI and of those with normal subjects has a certain correlation with the score of their MMSE and MoCA. When the value of NAA/tCr in the left HIP and right HIP is <1.19, it suggests that MCI may have occurred. According to this cutoff point, elderly patients with MCI in China could be screened.
Blockade of Motor Cortical Long-Term Potentiation Induction by Glutamatergic Dysfunction Causes Abnormal Neurobehavior in an Experimental Subarachnoid Hemorrhage Model
Authors: Fujiki Minoru , Kuga Kazuhiro , Ozaki Harushige , Kawasaki Yukari , Fudaba Hirotaka
Published: April 2021

Subarachnoid hemorrhage (SAH) is a life-threatening condition that can also lead to permanent paralysis. However, the mechanisms that underlying neurobehavioral deficits after SAH have not been fully elucidated. As theta burst stimulation (TBS) can induce long-term potentiation (LTP) in the motor cortex, we tested its potential as a functional evaluation tool after experimentally induced SAH. Motor cortical inter-neuronal excitability was evaluated in anesthetized rats after 200 Hz-quadripulse TBS (QTS5), 200 Hz-quadripulse stimulation (QPS5), and 400 Hz-octapulse stimulation (OPS2.5). Furthermore, correlation between motor cortical LTP and N-methyl-D-aspartate-receptor activation was evaluated using MK-801, a NMDA-receptor antagonist. We evaluated inhibition-facilitation configurations [interstimulus interval: 3 ms; short-latency intracortical inhibition (SICI) and 11 ms; intracortical facilitation (ICF)] with paired electrical stimulation protocols and the effect of TBS paradigm on continuous recording of motor-evoked potentials (MEPs) for quantitative parameters. SAH and MK-801 completely blocked ICF, while SICI was preserved. QTS5, QPS5, and OPS2.5 facilitated continuous MEPs, persisting for 180 min. Both SAH and MK-801 completely blocked MEP facilitations after QPS5 and OPS2.5, while MEP facilitations after QTS5 were preserved. Significant correlations were found among neurological scores and 3 ms-SICI rates, 11 ms-ICF rates, and MEP facilitation rates after 200 Hz-QTS5, 7 days after SAH (R2= 0.6236;r= −0.79,R2= 0.6053;r= −0.77 andR2= 0.9071;r= 0.95,p< 0.05, respectively). Although these findings need to be verified in humans, our study demonstrates that the neurophysiological parameters 3 ms-SICI, 11 ms-ICF, and 200 Hz-QTS5-MEPs may be useful surrogate quantitative biomarkers for assessing inter-neuronal function after SAH.
Case Report: Neurogenic Thoracic Outlet Syndrome Without Electrophysiologic Abnormality
Authors: Kim Sun Woong , Sung Duk Hyun
Published: April 2021

Neurogenic thoracic outlet syndrome (N-TOS) is a chronic compressive brachial plexopathy that involves the C8, T1 roots, and/or lower trunk. Medial antebrachial cutaneous (MABC) nerve conduction study (NCS) abnormality is reportedly one of the most sensitive findings among the features of N-TOS. The aim of the present study was to report clinical features, imaging findings, treatment, and prognoses of two N-TOS patients with no abnormalities in electrophysiological studies. Both patients presented with paresthesia of unilateral arm, and examination revealed no neurologic deficits. Electrophysiologic studies including MABC NCS were normal. Computed tomography (CT) angiography and brachial plexus magnetic resonance imaging (MRI) of the patients showed compression and displacement of the neurovascular bundle in the thoracic outlet by causative structures. Due to their sensory symptoms and CT angiography and brachial plexus MRI findings, after excluding other diseases, we diagnosed them with N-TOS. With the development of imaging techniques, more patients presenting with clinical features of lower trunk brachial plexopathy and anomalous structures compressing the neurovascular bundle on imaging studies can be diagnosed with N-TOS, even if electrophysiologic studies including MABC NCS do not show abnormalities.
The Need for Structured Strategies to Improve Stroke Care in a Rural Telestroke Network in Northern New South Wales, Australia: An Observational Study
Authors: Kashida Yumi Tomari , Garcia-Esperon Carlos , Lillicrap Thomas , Miteff Ferdinand , Garcia-Bermejo Pablo , Gangadharan Shyam , Chew Beng Lim Alvin , O'Brien William , Evans James , Alanati Khaled , Bivard Andrew , Parsons Mark , Majersik Jennifer Juhl , Spratt Neil James , Levi Christopher ,   The members of Northern NSW Telestroke investigators for this project
Published: April 2021

Introduction: A telestroke network in Northern New South Wales, Australia has been developed since 2017. We theorized that the telestroke network development would drive a progressive improvement in stroke care metrics over time.

Aim: This study aimed to describe changes in acute stroke workflow metrics over time to determine whether they improved with network experience.

Methods: We prospectively collected data of patients assessed by telestroke who received multimodal computed tomography (mCT) and were diagnosed with ischemic stroke or transient ischemic attack from January 2017 to July 2019. The period was divided into two phases (phase 1: January 2017 – October 2018 and phase 2: November 2018 – July 2019). We compared median door-to-call, door-to-image, and door-to-decision time between the two phases.

Results: We included 433 patients (243 in phase 1 and 190 in phase 2). Each spoke site treated 1.5–5.2 patients per month. There were Door-to-call time (median 39 in phase 1, 35 min in phase 2, p = 0.18), and door-to-decision time (median 81.5 vs. 83 min, p = 0.31) were not improved significantly. Similarly, in the reperfusion therapy subgroup, door-to-call time (median 29 vs. 24.5 min, p = 0.12) and door-to-decision time (median 70.5 vs. 67.5 min, p = 0.75) remained substantially unchanged. Regression analysis showed no association between time in the network and door-to-decision time (coefficient 1.5, p = 0.32).

Conclusion: In our telestroke network, acute stroke timing metrics did not improve over time. There is the need for targeted education and training focusing on both stroke reperfusion competencies and the technical aspects of telestroke in areas with limited workforce and high turnover.
White-Matter Repair as a Novel Therapeutic Target for Early Adversity
Authors: Islam Rafiad , Kaffman Arie
Published: April 2021

Early adversity (EA) impairs myelin development in a manner that persists later in life across diverse mammalian species including humans, non-human primates, and rodents. These observations, coupled with the highly conserved nature of myelin development suggest that animal models can provide important insights into the molecular mechanisms by which EA impairs myelin development later in life and the impact of these changes on network connectivity, cognition, and behavior. However, this area of translational research has received relatively little attention and no comprehensive review is currently available to address these issues. This is particularly important given some recent mechanistic studies in rodents and the availability of new agents to increase myelination. The goals of this review are to highlight the need for additional pre-clinical work in this area and to provide specific examples that demonstrate the potential of this work to generate novel therapeutic interventions that are highly needed.
Dietary Inflammatory Index Is Associated With Inflammation in Japanese Men
Authors: Kotemori Ayaka , Sawada Norie , Iwasaki Motoki , Yamaji Taiki , Shivappa Nitin , Hebert James R. , Ishihara Junko , Inoue Manami , Tsugane Shoichiro
Published: April 2021

Background: Dietary components are known to affect chronic low-grade inflammation status. The dietary inflammatory index (DII®) was developed to measure the potential impact of a diet on an individual's inflammatory status, and it has been validated mainly in Western countries.

Objective: This study aimed to examine the validity of the energy-adjusted DII (E-DIITM) using high-sensitivity C-reactive protein (hs-CRP) concentration in Japanese men and women.

Methods: In total, 6,474 volunteers from a cancer-screening program (3,825 men and 2,649 women) completed a food frequency questionnaire (FFQ) and their hs-CRP concentrations were evaluated. E-DII scores were calculated on the basis of 30 food parameters derived from the FFQ. Higher E-DII scores reflect a greater pro-inflammatory potential of the diet. The associations between E-DII quartiles and hs-CRP concentration were assessed using regression models adjusted for age, body mass index, smoking status, and amount of physical activity.

Results: Mean E-DII in men and women was + 0.62 ± 1.93 and −1.01 ± 2.25, respectively. The proportion of men and women who had hs-CRP concentration >3 mg/L was 4.7 and 3.1%, respectively. A significant positive association was observed between E-DII score and hs-CRP concentration in men; geometric mean of hs-CRP concentration in the lowest and highest E-DII quartiles was 0.56 mg/L and 0.67 mg/L (Ptrend < 0.01), respectively. The odds ratio (95% confidence interval) of having an elevated hs-CRP concentration (>3 mg/L) was 1.72 (1.10–2.67) in the highest E-DII quartile (Ptrend = 0.03) in men. However, no association was observed between E-DII score and hs-CRP concentration in women, except in those not taking prescription medications.

Conclusions: DII was associated with inflammation status in Japanese men, but the association was limited in Japanese women.
Silencing of miR-150-5p Ameliorates Diabetic Nephropathy by Targeting SIRT1/p53/AMPK Pathway
Authors: Dong Wenmin , Zhang Huiqian , Zhao Cheng , Luo Yun , Chen Ying
Published: April 2021

Diabetic nephropathy (DN) is a common complication of diabetes and an important cause of end-stage renal disease. Increasing evidence suggests that microRNAs (miRNAs) regulate the development of DN. In a preliminary study, high levels of miR-150-5p were detected in the serum and urine of patients with DN. Consequently, we investigated the effect and mechanism of action of miR-150-5p in DN in vitro and in vivo. Our results showed that inhibition of miR-150-5p reversed high glucose-induced podocyte injury and Streptozocin (STZ)-induced diabetic nephropathy in mice. Further analysis revealed that miR-150-5p targeted the 3′ untranslated region (UTR) of sirtuin 1 (SIRT1), consequently decreasing SIRT1 levels in podocytes. Importantly, we found that the silencing of miR-150-5p promoted the interaction between SIRT1 and p53, causing the suppression of p53 acetylation in podocytes and kidney tissue. This resulted in the stimulation of AMP-activated protein kinase (AMPK)-dependent autophagy. In conclusion, our study demonstrated that the silencing of miR-150-5p played a reno-protective role in DN mice through targeting SIRT1.
Evolution of the Subgroup 6 R2R3-MYB Genes and Their Contribution to Floral Color in the Perianth-Bearing Piperales
Authors: Muñoz-Gómez Sarita , Suárez-Baron Harold , Alzate Juan F. , González Favio , Pabón-Mora Natalia
Published: April 2021

Flavonoids, carotenoids, betalains, and chlorophylls are the plant pigments responsible for floral color. Anthocyanins, a class of flavonoids, are largely responsible for the red, purple, pink, and blue colors. R2R3-MYB genes belonging to subgroup 6 (SG6) are the upstream regulatory factors of the anthocyanin biosynthetic pathway. The canonical members of these genes in Arabidopsis include AtMYB75, AtMYB90, AtMYB113, and AtMYB114. The Aristolochiaceae is an angiosperm lineage with diverse floral groundplans and perianth colors. Saruma henryi exhibits a biseriate perianth with green sepals and yellow petals. All other genera have sepals only, with colors ranging from green (in Lactoris) to a plethora of yellow to red and purple mixtures. Here, we isolated and reconstructed the SG6 R2R3-MYB gene lineage evolution in angiosperms with sampling emphasis in Aristolochiaceae. We found numerous species-specific duplications of this gene lineage in core eudicots and local duplications in Aristolochiaceae for Saruma and Asarum. Expression of SG6 R2R3-MYB genes examined in different developmental stages and plant organs of four Aristolochiaceae species, largely overlaps with red and purple pigments, suggesting a role in anthocyanin and flavonoid synthesis and accumulation. A directed RNA-seq analysis corroborated our RT-PCR analyses, by showing that these structural enzymes activate during perianth development in Aristolochia fimbriata and that the regulatory genes are expressed in correlation with color phenotype. Finally, the reconstruction of the flavonoid and anthocyanin metabolic pathways using predicted peptides from transcriptomic data show that all pivotal enzymes are present in the analyzed species. We conclude that the regulatory genes as well as the biosynthetic pathway are largely conserved across angiosperms. In addition, the Aristolochiaceae emerges as a remarkable group to study the genetic regulatory network for floral color, as their members exhibit an outstanding floral diversity with elaborate color patterns and the genetic complement for SG6 R2R3-MYB genes is simpler than in core eudicot model species.