bluuebunny/crossref_metadata_2025 huggingface dataset:
Diketopyrrolopyrrole Based Organic Semiconductor Materials for Field-Effect Transistors
Authors: Zou Xiangyu , Cui Shuaiwei , Li Junqiang , Wei Xueling , Zheng Meng
Published: April 2021

Over the past several decades, organic conjugated materials as semiconductors in organic field effect transistors (OFETs) have attracted more and more attention from the scientific community due to their intriguing properties of mechanical flexibility and solution processability. However, the device fabrication technique, design, and synthesis of novel organic semiconductor materials with high charge carrier mobility is crucial for the development of high-performance OFETs. In the past few years, more and more novel materials were designed and tested in the OFETs. Among which, diketopyrrolopyrrole (DPP) and its derivatives, as the electron acceptors to build donor-acceptor (D-A) typed materials, are the perspective. In this article, recently reported molecules regarding the DPP and its derivatives for OFETs application are reviewed. In addition, the relationship between the chemical structures and the performance of the device are discussed. Furthermore, an outlook of DPP-based materials in OFETs with a future design concept and the development trend are provided.
Identification and Characterization of an O-Succinyl-L-Homoserine Sulfhydrylase From Thioalkalivibrio sulfidiphilus
Authors: Zhu Wen-Yuan , Niu Kun , Liu Peng , Fan Yu-Hang , Liu Zhi-Qiang , Zheng Yu-Guo
Published: April 2021

L-methionine is an important natural amino acid with broad application prospects. A novel gene encoding the enzyme with the ability to catalyze O-succinyl-L-homoserine (OSH) to L-methionine was screened and characterized. The recombinant O-succinyl-L-homoserine sulfhydrylase from Thioalkalivibrio sulfidiphilus (tsOSHS) exhibited maximum activity at 35°C and pH 6.5. OSHS displayed an excellent thermostability with a half-life of 21.72 h at 30°C. Furthermore, the activity of OSHS increased 115% after Fe2+ added. L-methionine was obtained with a total yield reaching 42.63 g/L under the concentration of O-succinyl-L-homoserine 400 mM (87.6 g/L). These results indicated that OSHS is a potential candidate for applying in the large-scale bioproduction of L-methionine.
Characterization of Three Pleiotropic Drug Resistance Transporter Genes and Their Participation in the Azole Resistance of Mucor circinelloides
Authors: Nagy Gábor , Kiss Sándor , Varghese Rakesh , Bauer Kitti , Szebenyi Csilla , Kocsubé Sándor , Homa Mónika , Bodai László , Zsindely Nóra , Nagy Gábor , Vágvölgyi Csaba , Papp Tamás
Published: April 2021

Mucormycosis is a life-threatening opportunistic infection caused by certain members of the fungal order Mucorales. This infection is associated with high mortality rate, which can reach nearly 100% depending on the underlying condition of the patient. Treatment of mucormycosis is challenging because these fungi are intrinsically resistant to most of the routinely used antifungal agents, such as most of the azoles. One possible mechanism of azole resistance is the drug efflux catalyzed by members of the ATP binding cassette (ABC) transporter superfamily. The pleiotropic drug resistance (PDR) transporter subfamily of ABC transporters is the most closely associated to drug resistance. The genome of Mucor circinelloides encodes eight putative PDR-type transporters. In this study, transcription of the eight pdr genes has been analyzed after azole treatment. Only the pdr1 showed increased transcript level in response to all tested azoles. Deletion of this gene caused increased susceptibility to posaconazole, ravuconazole and isavuconazole and altered growth ability of the mutant. In the pdr1 deletion mutant, transcript level of pdr2 and pdr6 significantly increased. Deletion of pdr2 and pdr6 was also done to create single and double knock out mutants for the three genes. After deletion of pdr2 and pdr6, growth ability of the mutant strains decreased, while deletion of pdr2 resulted in increased sensitivity against posaconazole, ravuconazole and isavuconazole. Our result suggests that the regulation of the eight pdr genes is interconnected and pdr1 and pdr2 participates in the resistance of the fungus to posaconazole, ravuconazole and isavuconazole.
Transcriptome Signatures Predict Phenotypic Variations of Candida auris
Authors: Jenull Sabrina , Tscherner Michael , Kashko Nataliya , Shivarathri Raju , Stoiber Anton , Chauhan Manju , Petryshyn Andriy , Chauhan Neeraj , Kuchler Karl
Published: April 2021

Health care facilities are facing serious threats by the recently emerging human fungal pathogenCandida aurisowing to its pronounced antifungal multidrug resistance and poor diagnostic tools. DistinctC. aurisclades evolved seemingly simultaneously at independent geographical locations and display both genetic and phenotypic diversity. Although comparative genomics and phenotypic profiling studies are increasing, we still lack mechanistic knowledge about theC. aurisspecies diversification and clinical heterogeneity. Since gene expression variability impacts phenotypic plasticity, we aimed to characterize transcriptomic signatures ofC. aurispatient isolates with distinct antifungal susceptibility profiles in this study. First, we employed an antifungal susceptibility screening of clinicalC. aurisisolates to identify divergent intra-clade responses to antifungal treatments. Interestingly, comparative transcriptional profiling reveals large gene expression differences between clade I isolates and one clade II strain, irrespective of their antifungal susceptibilities. However, comparisons at the clade levels demonstrate that minor changes in gene expression suffice to drive divergent drug responses. Finally, we functionally validate transcriptional signatures reflecting phenotypic divergence of clinical isolates. Thus, our results suggest that large-scale transcriptional profiling allows for predicting phenotypic diversities of patient isolates, which may help choosing suitable antifungal therapies of multidrug-resistantC. auris.
Brain-Computer Interfaces, Open-Source, and Democratizing the Future of Augmented Consciousness
Authors: Bernal Guillermo , Montgomery Sean M. , Maes Pattie
Published: April 2021

Accessibility, adaptability, and transparency of Brain-Computer Interface (BCI) tools and the data they collect will likely impact how we collectively navigate a new digital age. This discussion reviews some of the diverse and transdisciplinary applications of BCI technology and draws speculative inferences about the ways in which BCI tools, combined with machine learning (ML) algorithms may shape the future. BCIs come with substantial ethical and risk considerations, and it is argued that open source principles may help us navigate complex dilemmas by encouraging experimentation and making developments public as we build safeguards into this new paradigm. Bringing open-source principles of adaptability and transparency to BCI tools can help democratize the technology, permitting more voices to contribute to the conversation of what a BCI-driven future should look like. Open-source BCI tools and access to raw data, in contrast to black-box algorithms and limited access to summary data, are critical facets enabling artists, DIYers, researchers and other domain experts to participate in the conversation about how to study and augment human consciousness. Looking forward to a future in which augmented and virtual reality become integral parts of daily life, BCIs will likely play an increasingly important role in creating closed-loop feedback for generative content. Brain-computer interfaces are uniquely situated to provide artificial intelligence (AI) algorithms the necessary data for determining the decoding and timing of content delivery. The extent to which these algorithms are open-source may be critical to examine them for integrity, implicit bias, and conflicts of interest.
The Genetic Pathways Underlying Immunotherapy in Dilated Cardiomyopathy
Authors: Kadhi Ayat , Mohammed Fathima , Nemer Georges
Published: April 2021

Heart failure (HF) is a global public health threat affecting 26 million individuals worldwide with an estimated prevalence increase of 46% by 2030. One of the main causes of HF and sudden death in children and adult is Dilated Cardiomyopathy (DCM). DCM is characterized by dilation and systolic dysfunction of one or both ventricles. It has an underlying genetic basis or can develop subsequent to various etiologies that cause myocardium inflammation (secondary causes). The morbidity and mortality rates of DCM remains high despite recent advancement to manage the disease. New insights have been dedicated to better understand the pathogenesis of DCM in respect to genetic and inflammatory basis by linking the two entities together. This cognizance in the field of cardiology might have an innovative approach to manage DCM through targeted treatment directed to the causative etiology. The following review summarizes the genetical and inflammatory causes underlying DCM and the pathways of the novel precision-medicine-based immunomodulatory strategies to salvage and prevent the associated heart failure linked to the disease.
Late Quaternary Dust, Loess and Desert Dynamics in Upwind Areas of the Chinese Loess Plateau
Authors: Qiang Mingrui , Stevens Thomas , Li Guoqiang , Hu Ling , Wang Xiaowei , Lang Wenzhe , Chen Jie
Published: April 2021

As a key global climate and dust archive, the nature of Chinese loess generation, transport and deposition remains debated. The lack of consensus on dust dynamics from sources to leeward regions fundamentally limits interpretation of the preserved past climate and dust record. Here, we investigate chronostratigraphic variability of aeolian deposits in upwind regions of the modern Chinese Loess Plateau (CLP) and attempt to understand dust dynamics that potentially affects loess deposition downwind. The strata consist of alternating layers of typical loess, well-sorted sand, and sandy loess, with obvious unconformities occurring at the transitions from loess to sand. We suggest that pre-existing typical loess in regions to the northwest of the modern CLP was eroded by wind, providing a significant source of homogeneous dust for the dust deposits downwind. The sand deposits interbedded with typical loess at the study sites suggests that proximal deserts have greatly expanded and contracted repeatedly prior to the Holocene. However, the spatial extents of the deserts, as inferred from the sections here, have not markedly diminished after the major expansion during the Last Glacial Maximum. Such a pattern of proximal desert dynamics plays an important role in regulating dust emission and transport, strongly affecting dust sequences on the CLP. Our results suggest a complex scenario of dust dynamics in upwind regions of the CLP at least over the Late Quaternary; the involved processes have to be considered when using conventional proxies from Chinese loess deposits to recover the history of climate and dust changes.
Small Fibre Neuropathy Is Associated With Impaired Vascular Endothelial Function in Patients With Type 2 Diabetes
Authors: Ando Akihiko , Miyamoto Michiaki , Saito Naoko , Kotani Kazuhiko , Kamiya Hideki , Ishibashi Shun , Tavakoli Mitra
Published: April 2021

Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.
Immune Checkpoint Inhibitors: New Weapons Against Medullary Thyroid Cancer?
Authors: Di Molfetta Sergio , Dotto Andrea , Fanciulli Giuseppe , Florio Tullio , Feola Tiziana , Colao Annamaria , Faggiano Antongiulio
Published: April 2021

Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body’s natural antitumor defenses. The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma. After an extensive search, we found 7 useful data sources (one single-case report, one short article with very preliminary data, five ongoing registered clinical trials). Despite the lack of published evidence regarding the use of immune check point inhibitors, it must be considered that all the ongoing registered clinical trials saw first light in the last three years, thus indicating a growing interest of researchers in this field. Results coming from these trials, and hopefully, in the next future, from additional trials, will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma.
Charge Carrier Dynamics in Sn-Doped Two-Dimensional Lead Halide Perovskites Studied by Terahertz Spectroscopy
Authors: Qin Zhengyuan , Zhang Chunfeng , Chen Lan , Wang Xiaoyong , Xiao Min
Published: April 2021

Sn doping is established as an effective approach to promote the light emission properties in in two-dimensional lead-halide perovskites. However, the effect on the charge carrier dynamics is largely unexplored. In this work, we conduct terahertz spectroscopy to study the effects of Sn doping on the charge dynamics in the two-dimensional perovskites PEA2SnxPb1–xI4 (PEA = phenethylammonium) with different doping levels. The spectral dispersion analysis suggests that the early-stage dynamics with lifetime of ∼ 2 ps is contributed by both the transport of hot charge carriers and the polarizability of hot excitons. The long-lived component of first-order charge carrier recombination is dramatically improved when Sn doping increases, which is ascribed to the equilibrium between charge carriers and excitons with smaller bind energies in the higher-level Sn-doped samples. The finding in this work suggests Sn doping is an effective approach to optimize the charge carrier transport in 2D perovskite for potential optoelectronic applications.
Science-Narrative Explorations of “Drought Thresholds” in the Maritime Eden Catchment, Scotland: Implications for Local Drought Risk Management
Authors: McEwen Lindsey , Bryan Kimberly , Black Andrew , Blake James , Afzal Muhammad
Published: April 2021

Drought in the United Kingdom is a “hidden” pervasive risk, defined and perceived in different ways by diverse stakeholders and sectors. Scientists and water managers distinguish meteorological, agricultural, hydrological, and socio-economic drought. Historically triggers in drought risk management have been demarcated solely in specialist hydrological science terms using indices and critical thresholds. This paper explores “drought thresholds” as a bridging concept for interdisciplinary science-narrative enquiry. The Eden catchment, Scotland acts as an exemplar, in a maritime country perceived as wet. The research forms part of creative experimentation in science-narrative methods played out in seven United Kingdom case-study catchments on hydro-meteorological gradients in the Drought Risk and You (DRY) project, with the agricultural Eden the most northerly. DRY explored how science and stories might be brought together to support better decision-making in United Kingdom drought risk management. This involved comparing specialist catchment-scale modelling of drought risk with evidence gathered from local narratives of drought perceptions/experiences. We develop the concept of thresholds to include perceptual triggers of drought awareness and impact within and between various sectors in the catchment (agriculture, business, health and wellbeing, public/communities, and natural and built environments). This process involved developing a framework for science-narrative drought “threshold thinking” that utilizes consideration of severity and scale, spatial and temporal aspects, framing in terms of enhancing or reducing factors internal and external to the catchment and new graphical methods. The paper discusses how this extended sense of thresholds might contribute to research and practice, involving different ways of linking drought severity and perception. This has potential to improve assessment of sectoral vulnerabilities, development of adaptive strategies of different stakeholders, and more tailored drought communication and messaging. Our findings indicate that drought risk presents many complexities within the catchment, given its cross-sectoral nature, rich sources of available water, variable prior drought experience among stakeholders, and different quantitative and perceptual impact thresholds across and within sectors. Fuzziness in identification of drought thresholds was multi-faceted for varied reasons. Results suggest that a management paradigm that integrates both traditional and non-traditional “fuzzy” threshold concepts across sectors should be integrated into current and future policy frameworks for drought risk management.
Effect of Land Use Change on Gully Erosion Density in the Black Soil Region of Northeast China From 1965 to 2015: A Case Study of the Kedong County
Authors: Li Maojuan , Li Tianqi , Zhu Lianqi , Meadows Michael E. , Zhu Wenbo , Zhang Shuwen
Published: April 2021

Kedong County is typical of the black soil region of northeast China in being highly susceptible to accelerated soil erosion by gullying. Using data sourced from Corona satellite imagery for 1965, SPOT5 for 2005 and GF-1 for 2015, the spatial distribution of gullies in the research area was mapped. Land use data for 1965, 2005, and 2015 were obtained from the topographic map of 1954, and from Landsat images for 2005 and 2015. Over the last 50 years, the extent of gully erosion in the study area has increased markedly, most notably on cultivated land, while gully density rose from 2,756.16 m2/km2 to 14,294.19 m2/km2. Cultivating land on slopes, especially on slopes greater than ∼4°, may rapidly aggravate gully erosion. The greatest increases in gully density occurred in situations when cultivated land and other/degraded land were transformed, which gully erosion density increased by 49,526.69 m2/km2. Other/degraded land is the most vulnerable land in the study area, with the highest gully erosion density. In these cases, gully density initially increases and, although the “Grain for Green” project has been implemented, gully erosion density has not always declined in the recent past.
Symmetric and Asymmetric Impact of Poverty, Income Inequality, and Population on Carbon Emission in Pakistan: New Evidence From ARDL and NARDL Co-Integration
Authors: Khan Salim , Yahong Wang
Published: April 2021

Several researchers have studied the relationship between poverty and environmental degradation, as these concerns are remained at top priority in achieving Sustainable Development Goals (SDGs). However, the symmetric and asymmetric impact of poverty and income inequality along with population and economic growth on carbon emissions (CO2e) has not been studied in the case of Pakistan. For this purpose, the short and long-run impact of poverty, income inequality, population, and GDP per capita on CO2e investigated by applying the Autoregressive Distributive Lag (ARDL) along with Non-linear Autoregressive Distributive Lag (NARDL) co-integration approach in the context of Pakistan for period 1971–2015. The symmetric results of the current study show poverty and population density along with GDP per capita increase carbon emissions in both the short and long-run, while income inequality has no impact on carbon emissions in the short-run. While in the long-run the symmetric results show that income inequality weakens environmental degradation in terms of carbon emissions. The analysis of NARDL also supports the results obtained from ARDL and suggests a positive effect of poverty, population, and economic growth on carbon emission in Pakistan. The empirical findings of the current study provide policy implications in light of the United Nation's SDGs for the development of Pakistan.
Proportion of Grassland at Landscape Scale Drives Natural Pest Control Services in Agricultural Landscapes
Authors: Perrot Thomas , Rusch Adrien , Coux Camille , Gaba Sabrina , Bretagnolle Vincent
Published: April 2021

Managing regulating ecosystem services delivered by biodiversity in farmland is a way to maintain crop yields while reducing the use of agrochemicals. Because semi-natural habitats provide shelter and food for pest enemies, a higher proportion of semi-natural habitats in the landscape or their proximity to crops may enhance pest control in arable fields. However, the ways in which the spatial arrangement of these habitats affects the delivery of this beneficial ecosystem service to crops remains poorly known. Here, we investigated the relative effects of the amount of grassland in the landscape versus the distance to the nearest grassland on the predation rates of weed seeds and aphids into 52 cereal fields. We found that both seed and aphid predation levels increased with the proportion of grassland in a 500 m radius buffer while the distance to the nearest grassland displayed no effect. We show that increasing from 0 to 50% the proportion of grasslands in a 500 m radius, respectively, increased seed and aphid predation by 38 and 20%. In addition to the strong effect of the proportion of grassland, we found that seed predation increased with the proportion of forest fragments while aphid predation increased with the proportion of organic farming in the landscape. Overall, our results reveal that natural pest control in cereal crops is not related to the distance to the nearest grassland, suggesting that natural enemies are not limited by their dispersal ability. Our study indicates that maintaining key semi-natural habitats, such as grasslands, is needed to ensure natural pest control and support food production in agricultural landscapes.
Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1
Authors: Zhang Shimeng , Li Lei , Xie Danli , Reddy Srija , Sleasman John W. , Ma Li , Zhong Xiao-Ping
Published: April 2021

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.
Predicted Disease-Specific Immune Infiltration Patterns Decode the Potential Mechanisms of Long Non-Coding RNAs in Primary Sjogren’s Syndrome
Authors: Cheng Caiqi , Zhou Jun , Chen Ruiying , Shibata Yo , Tanaka Reina , Wang Jun , Zhang Jiaming
Published: April 2021

Primary Sjogren’s syndrome (pSS) is a chronic progressive autoimmune disease with clinical phenotypic “Sicca symptoms”. In some cases, the diagnosis of pSS is delayed by 6–7 years due to the inefficient differential diagnosis of pSS and non-SS “Sicca”. This study aimed to investigate the difference between these two diseases, and in particular, their immunopathogenesis. Based on their gene expression profiles, we systematically defined for the first time the predicted disease-specific immune infiltration pattern of patients with pSS differentiated from normal donors and patients with non-SS “Sicca”. We found that it was characterized by the aberrant abundance and interaction of tissue-infiltrated immune cells, such as a notable shift in the subpopulation of six immune cells and the perturbed abundance of nine subpopulations, such as CD4+ memory, CD8+ T-cells and gamma delta T-cells. In addition, we identified essential genes, particularly long non-coding RNAs (lncRNAs), as the potential mechanisms linked to this predicted pattern reprogramming. Fourteen lncRNAs were identified as the potential regulators associated with the pSS-specific immune infiltration pattern in a synergistic manner, among which the CTA-250D10.23 lncRNA was highly relevant to chemokine signaling pathways. In conclusion, aberrant predicted disease-specific immune infiltration patterns and relevant genes revealed the immunopathogenesis of pSS and provided some clues for the immunotherapy by targeting specific immune cells and genes.
The Impact of Acute and Chronic Exercise on Immunoglobulins and Cytokines in Elderly: Insights From a Critical Review of the Literature
Authors: Sellami Maha , Bragazzi Nicola Luigi , Aboghaba Baha , Elrayess Mohamed A.
Published: April 2021

The level of immunoglobulins and cytokines changes with an ageing immune system. This review summarizes findings from studies that have examined the impact of acute and chronic exercise on immunoglobulins and cytokines in the elderly. Our literature analysis revealed that acute endurance exercise resulted in increased secretory salivary immunoglobulin A (SIgA), while acute bouts of muscle strengthening exercise (i.e., isokinetic, eccentric, knee extensor exercise) increased plasma/muscle interleukin (IL)-6, IL-8 and tumor necrosis factor alpha (TNF-α) levels. Chronic exercise in the form of short-term endurance training (i.e., 12-16 weeks) and long-term combined endurance and resistance training (i.e., 6-12 months) induced increases in salivary SIgA concentration. We additionally identified that short-term endurance training at moderate intensities and the combination of endurance, strength, balance, and flexibility training increase plasma IL-10 and reduce plasma IL-6 and TNF-α in healthy elderly adults and male patients with chronic heart failure. Strength training for 6-12 weeks did not alter plasma IL-1β, IL-2, IL-6 and TNF-α concentration in healthy elderly adults and patients with chronic-degenerative diseases, while 12 weeks of resistance training decreased muscle TNF-α mRNA in frail elderly individuals. Short-term (i.e., 10-24 weeks) moderate- to high-intensity strength training reduced LPS–IL-6, LPS, IL-1β, LPS–TNF-α and circulating concentrations of TNF-α and increased IL-10 in healthy elderly women and older people with cognitive impairment, respectively. In conclusion, it appears that acute bouts of endurance exercise and short-term chronic exercise training exercise are appropriate methods to enhance mucosal immune function, reduce systemic markers of inflammation, and promote anti-inflammatory processes in elderly individuals.
Clinical Experience and Recent Advances in the Development of Listeria-Based Tumor Immunotherapies
Authors: Oladejo Mariam , Paterson Yvonne , Wood Laurence M.
Published: April 2021

The promise of tumor immunotherapy to significantly improve survival in patients who are refractory to long-standing therapies, such as chemotherapy and radiation, is now being realized. While immune checkpoint inhibitors that target PD-1 and CTLA-4 are leading the charge in clinical efficacy, there are a number of other promising tumor immunotherapies in advanced development such as Listeria-based vaccines. Due to its unique life cycle and ability to induce robust CTL responses, attenuated strains of Listeria monocytogenes (Lm) have been utilized as vaccine vectors targeting both infectious disease and cancer. In fact, preclinical studies in a multitude of cancer types have found Listeria-based vaccines to be highly effective at activating anti-tumor immunity and eradicating tumors. Several clinical trials have now recently reported their results, demonstrating promising efficacy against some cancers, and unique challenges. Development of the Lm-based immunotherapies continues with discovery of improved methods of attenuation, novel uses, and more effective combinatorial regimens. In this review, we provide a brief background of Listeria monocytogenes as a vaccine vector, discuss recent clinical experience with Listeria-based immunotherapies, and detail the advancements in development of improved Listeria-based vaccine platforms and in their utilization.
Optimized Intracellular Staining Reveals Heterogeneous Cytokine Production Ability of Murine and Human Hematopoietic Stem and Progenitor Cells
Authors: Luo Shufeng , Lin Huiling , Zhu Lan , Chen Hai-Tian , Yang Siqian , Li Jinheng , Liu Mingyu , Zheng Limin , Wu Chong
Published: April 2021

Under stress conditions, hematopoietic stem and progenitor cells (HSPCs) can translate danger signals into a plethora of cytokine signals. These cytokines, or more precisely their combination, instruct HSPCs to modify the magnitude and composition of hematopoietic output in response to the threat, but investigations into the heterogeneous cytokine expression and regulatory mechanisms are hampered by the technical difficulty of measuring cytokine levels in HSPCs at the single-cell level. Here, we optimized a flow cytometry-based method for the simultaneous assessment of multiple intracellular cytokines in HSPCs. By selecting an optimal combination of cytokine restimulation reagents, protein transport inhibitors, and culture supplements, an optimized restimulation protocol for intracellular staining was developed. Using this method, we successfully examined expression levels of granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in murine and human HSPC subsets under steady-state or different stress conditions. Different cytokine expression patterns were observed, suggesting distinct regulatory modes of cytokine production dependent on the HSPC subset, cytokine, disease, organ, and species. Collectively, this technical advance may help to obtain a better understanding of the nature of HSPC heterogeneity on the basis of differential cytokine production.
Bispecific T-Cell Engaging Antibodies Against MUC16 Demonstrate Efficacy Against Ovarian Cancer in Monotherapy and in Combination With PD-1 and VEGF Inhibition
Authors: Yeku Oladapo O. , Rao Thapi Dharma , Laster Ian , Kononenko Artem , Purdon Terence J. , Wang Pei , Cui Ziyou , Liu Hong , Brentjens Renier J. , Spriggs David
Published: April 2021

Immunotherapy for ovarian cancer is an area of intense investigation since the majority of women with relapsed disease develop resistance to conventional cytotoxic therapy. The paucity of safe and validated target antigens has limited the development of clinically relevant antibody-based immunotherapeutics for this disease. Although MUC16 expression is almost universal in High Grade Serous Ovarian Cancers, engagement of the shed circulating MUC16 antigen (CA-125) presents a theoretical risk of systemic activation and toxicity. We designed and evaluated a series of bispecific tandem single-chain variable fragments specific to the retained portion of human MUC16 ectodomain (MUC16ecto) and human CD3. These MUC16ecto- BiTEDs retain binding in the presence of soluble MUC16 (CA-125) and show cytotoxicity against a panel of ovarian cancer cells in vitro. MUC16ecto- BiTEDs delay tumor progression in vivo and significantly prolong survival in a xenograft model of ovarian peritoneal carcinomatosis. This effect was significantly enhanced by antiangiogenic (anti-VEGF) therapy and immune checkpoint inhibition (anti-PD1). However, the combination of BiTEDs with anti-VEGF was superior to combination with anti-PD1, based on findings of decreased peritoneal tumor burden and ascites with the former. This study shows the feasibility and efficacy of MUC16ecto- specific BiTEDs and provides a basis for the combination with anti-VEGF therapy for ovarian cancer.
Are Feeding Modes Concealing Morphofunctional Diversity? The Case of the New World Parrotfishes
Authors: Pombo-Ayora Lucía , Tavera Jose
Published: April 2021

In functional ecology, morphology is expected to reflect function; however, occasional decoupling of these two can be found. In the case of feeding ecology, the diversity of the diet or diversity of the feeding modes within a clade is expected to be positively related to the diversity of the morphological traits involved in the feeding performance. Parrotfishes are separated into two main groups, the “reef” clade and the “seagrass” clade. Both groups have important differences in their evolutionary history. Still, more interestingly, they have important morphological and ecological differences. The generaScarusandSparisomaare the most specious genera of parrotfishes. They belong to each of those main groups, respectively. AllScarusspecies have the same feeding mode, while inSparisoma, there are three different feeding modes. We want to test if the morphological jaw diversity of these genera corresponds with the diversity in their feeding modes. Using a disparity analysis of feeding traits within a phylogenetical framework, we did not find a relationship between functional feeding morphology and feeding modes of the American parrotfishes of the generaScarusandSparisoma. Interestingly we found that some muscular traits are the source of the high disparity in the genusScarus. We explore some possible morpho-functional reasons for this phenomenon and reappraise the parrotfishes’ scraper feeding mode’s functional diversity. We also consider that there could be more ecological differentiation betweenScarusspecies that we are aware of. Using an ancestral reconstruction of feeding modes of 52 species of parrotfishes, we found that the scraping feeding mode exhibited by allScarusspecies is an evolutionary convergence with the scraping feeding modes performed by someSparisomaspecies. Different selective pressures or ecological conditions may have shaped the differences in the feeding ecology and the feeding morphology of these two genera. Probably, key novel structures and muscular properties found in theScarusspecies’ jaw played an essential role in this genus’s morpho-functional diversification. Finally, we propose that feeding modes may not fully capture the complexity of feeding ecology in parrotfishes.
Viral-Mediated Microbe Mortality Modulated by Ocean Acidification and Eutrophication: Consequences for the Carbon Fluxes Through the Microbial Food Web
Authors: Malits Andrea , Boras Julia A. , Balagué Vanessa , Calvo Eva , Gasol Josep M. , Marrasé Cèlia , Pelejero Carles , Pinhassi Jarone , Sala Maria Montserrat , Vaqué Dolors
Published: April 2021

Anthropogenic carbon emissions are causing changes in seawater carbonate chemistry including a decline in the pH of the oceans. While its aftermath for calcifying microbes has been widely studied, the effect of ocean acidification (OA) on marine viruses and their microbial hosts is controversial, and even more in combination with another anthropogenic stressor, i.e., human-induced nutrient loads. In this study, two mesocosm acidification experiments with Mediterranean waters from different seasons revealed distinct effects of OA on viruses and viral-mediated prokaryotic mortality depending on the trophic state and the successional stage of the plankton community. In the winter bloom situation, low fluorescence viruses, the most abundant virus-like particle (VLP) subpopulation comprising mostly bacteriophages, were negatively affected by lowered pH with nutrient addition, while the bacterial host abundance was stimulated. High fluorescence viruses, containing cyanophages, were stimulated by OA regardless of the nutrient conditions, while cyanobacteria of the genus Synechococcus were negatively affected by OA. Moreover, the abundance of very high fluorescence viruses infecting small haptophytes tended to be lower under acidification while their putative hosts' abundance was enhanced, suggesting a direct and negative effect of OA on viral–host interactions. In the oligotrophic summer situation, we found a stimulating effect of OA on total viral abundance and the viral populations, suggesting a cascading effect of the elevated pCO2 stimulating autotrophic and heterotrophic production. In winter, viral lysis accounted for 30 ± 16% of the loss of bacterial standing stock per day (VMMBSS) under increased pCO2 compared to 53 ± 35% in the control treatments, without effects of nutrient additions while in summer, OA had no significant effects on VMMBSS (35 ± 20% and 38 ± 5% per day in the OA and control treatments, respectively). We found that phage production and resulting organic carbon release rates significantly reduced under OA in the nutrient replete winter situation, but it was also observed that high nutrient loads lowered the negative effect of OA on viral lysis, suggesting an antagonistic interplay between these two major global ocean stressors in the Anthropocene. In summer, however, viral-mediated carbon release rates were lower and not affected by lowered pH. Eutrophication consistently stimulated viral production regardless of the season or initial conditions. Given the relevant role of viruses for marine carbon cycling and the biological carbon pump, these two anthropogenic stressors may modulate carbon fluxes through their effect on viruses at the base of the pelagic food web in a future global change scenario.
The msaABCR Operon Regulates Persister Formation by Modulating Energy Metabolism in Staphylococcus aureus
Authors: Pandey Shanti , Sahukhal Gyan S. , Elasri Mohamed O.
Published: April 2021

Staphylococcus aureus is a major human pathogen that causes chronic, systemic infections, and the recalcitrance of these infections is mainly due to the presence of persister cells, which are a bacterial subpopulation that exhibits extreme, yet transient, antibiotic tolerance accompanied by a transient halt in growth. However, upon cessation of antibiotic treatment, a resumption in growth of persister cells causes recurrence of infections and treatment failure. Previously, we reported the involvement of msaABCR in several important staphylococcal phenotypes, including the formation of persister cells. Additionally, observations of the regulation of several metabolic genes by the msaABCR operon in transcriptomics and proteomics analyses have suggested its role in the metabolic activities of S. aureus. Given the importance of metabolism in persister formation as our starting point, in this study we demonstrated how the msaABCR operon regulates energy metabolism and subsequent antibiotic tolerance. We showed that deletion of the msaABCR operon results in increased tricarboxylic acid (TCA) cycle activity, accompanied by increased cellular ATP content and higher NADH content in S. aureus cells. We also showed that msaABCR (through MsaB) represses the ccpE and ndh2 genes, thereby regulating TCA cycle activity and the generation of membrane potential, respectively. Together, the observations from this study led to the conclusion that msaABCR operon deletion induces a metabolically hyperactive state, leading to decreased persister formation in S. aureus.
Nomogram to Predict Cognitive Dysfunction After a Minor Ischemic Stroke in Hospitalized-Population
Authors: Gong Li , Wang Haichao , Zhu Xiaofeng , Dong Qiong , Yu Qiuyue , Mao Bingjie , Meng Longyan , Zhao Yanxin , Liu Xueyuan
Published: April 2021

An easily scoring system to predict the risk of cognitive impairment after minor ischemic stroke has not been available. We aimed to develop and externally validate a nomogram for predicting the probability of post-stroke cognitive impairment (PSCI) among hospitalized population with minor stroke. Moreover, the association of Trimethylamine N-oxide (TMAO) with PSCI is also investigated. We prospectively conducted a developed cohort on collected data in stroke center from June 2017 to February 2018, as well as an external validation cohort between June 2018 and February 2019. The main outcome is cognitive impairment defined as <22 Montreal Cognition Assessment (MoCA) score points 6 – 12 months following a minor stroke onset. Based on multivariate logistic models, the nomogram model was generated. Plasma TMAO levels were assessed at admission using liquid chromatography tandem mass spectrometry. A total of 228 participants completed the follow-up data for generating the nomogram. After multivariate logistic regression, seven variables remained independent predictors of PSCI to compose the nomogram included age, female, Fazekas score, educational level, number of intracranial atherosclerotic stenosis (ICAS), HbA1c, and cortical infarction. The area under the receiver-operating characteristic (AUC-ROC) curve of model was 0.829, C index was good (0.810), and the AUC-ROC of the model applied in validation cohort was 0.812. Plasma TMAO levels were higher in patients with cognitive impairment than in them without cognitive dysfunction (median 4.56 vs. 3.22 μmol/L; p ≤ 0.001). In conclusion, this scoring system is the first nomogram developed and validated in a stroke center cohort for individualized prediction of cognitive impairment after minor stroke. Higher plasma TMAO level at admission suggests a potential marker of PSCI.
Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review
Authors: Zhang Xi-Le , Zhang Xiao-Guang , Huang Yan-Ran , Zheng Yan-Yan , Ying Peng-Jie , Zhang Xiao-Jie , Lu Xiao , Wang Yi-Jing , Zheng Guo-Qing
Published: April 2021

Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, −3.37; 95% confidence interval, −3.83 to −2.90) and infarct volume (effect size, −11.37; 95% confidence interval, −12.89 to −9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.
The Oral-Gut-Brain AXIS: The Influence of Microbes in Alzheimer’s Disease
Authors: Narengaowa  , Kong Wei , Lan Fei , Awan Umer Farooq , Qing Hong , Ni Junjun
Published: April 2021

Alzheimer’s disease (AD) is one of the most frequently diagnosed neurodegenerative disorders worldwide and poses a major challenge for both affected individuals and their caregivers. AD is a progressive neurological disorder associated with high rates of brain atrophy. Despite its durable influence on human health, understanding AD has been complicated by its enigmatic and multifactorial nature. Neurofibrillary tangles and the deposition of amyloid-beta (Aβ) protein are typical pathological features and fundamental causes of cognitive impairment in AD patients. Dysbiosis of oral and gut microbiota has been reported to induce and accelerate the formation of Aβ plaques and neurofibrillary tangles. For instance, some oral microbes can spread to the brain through cranial nerves or cellular infections, which has been suggested to increase the risk of developing AD. Importantly, the interaction between intestinal microbiota and brain cells has been recognized as influencing the development of AD as well as other neurodegenerative diseases. In particular, the metabolites produced by certain intestinal microorganisms can affect the activity of microglia and further mediate neuroinflammation, which is a leading cause of neuronal necrosis and AD pathogenesis. Which pathogens and associated pathways are involved in the development and progression of AD remains to be elucidated; however, it is well-known that gut microbiota and their metabolites can affect the brain by both direct and indirect means. Understanding the specific mechanisms involved in the interaction between these pathogens and the nervous system is vital for the early intervention in AD. In this review, we aim to comprehensively discuss the possible mechanistic pathways underlying the oral-brain, the gut-brain and the oral-gut-brain associations.