bluuebunny/crossref_metadata_2025 huggingface dataset:
CITED2 inhibits STAT1‐IRF1 signaling and atherogenesis
Authors: Zafar Atif , Pong Ng Hang , Diamond‐Zaluski Rachel , Kim Gun‐Dong , Ricky Chan Ernest , Dunwoodie Sally L. , Smith Jonathan D. , Mahabeleshwar Ganapati H.
Published: August 2021

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage‐mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell‐intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300‐interacting transactivator with glutamic acid/aspartic acid‐rich carboxyl‐terminal domain 2 (CITED2) as one such cell‐intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid‐CITED2‐deficient mice on the Apoe−/− background have larger atherosclerotic lesions on both control and high‐fat/high‐cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro‐inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ‐induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA‐mediated knockdown of IRF1 completely reversed elevated pro‐inflammatory target gene expression in CITED2‐deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1‐IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.
The role of soils in delivering Nature's Contributions to People
Authors: Smith Pete , Keesstra Saskia D. , Silver Whendee L. , Adhya Tapan K.
Published: August 2021

This theme issue provides an assessment of the contribution of soils to Nature's Contributions to People (NCP). The papers in this issue show that soils can contribute positively to the delivery of all NCP. These contributions can be maximized through careful soil management to provide healthy soils, but poorly managed, degraded or polluted soils may contribute negatively to the delivery of NCP. Soils are also shown to contribute positively to the UN Sustainable Development Goals. Papers in the theme issue emphasize the need for careful soil management. Priorities for soil management must include: (i) for healthy soils in natural ecosystems,
protect
them from conversion and degradation, (ii) for managed soils,
manage
in a way to protect and enhance soil biodiversity, health, productivity and sustainability and to prevent degradation, and (iii) for degraded soils,
restore
to full soil health. Our knowledge of what constitutes sustainable soil management is mature enough to implement best management practices, in order to maintain and improve soil health. The papers in this issue show the vast potential of soils to contribute to NCP. This is not only desirable, but essential to sustain a healthy planet and if we are to deliver sustainable development in the decades to come.

This article is part of the theme issue ‘The role of soils in delivering Nature’s Contributions to People’.
The role of soils in habitat creation, maintenance and restoration
Authors: De Deyn Gerlinde B. , Kooistra Lammert
Published: August 2021

Soils are the fundament of terrestrial ecosystems. Across the globe we find different soil types with different properties resulting from the interacting soil forming factors: parent material, climate, topography, organisms and time. Here we present the role of soils in habitat formation and maintenance in natural systems, and reflect on how humans have modified soils from local to global scale. Soils host a tremendous diversity of life forms, most of them microscopic in size. We do not yet know all the functionalities of this diversity at the level of individual taxa or through their interactions. However, we do know that the interactions and feedbacks between soil life, plants and soil chemistry and physics are essential for soil and habitat formation, maintenance and restoration. Moreover, the couplings between soils and major cycles of carbon, nutrients and water are essential for supporting the production of food, feed and fibre, drinking water and greenhouse gas balances. Soils take thousands of years to form, yet are lost very quickly through a multitude of stressors. The current status of our soils globally is worrisome, yet with concerted action we can bend the curve and create win–wins of soil and habitat conservation, regeneration and sustainable development.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
The role of soils in the regulation of air quality
Authors: Giltrap Donna , Cavanagh Jo , Stevenson Bryan , Ausseil Anne-Gäelle
Published: August 2021

Soils play a key role in meeting the UN Sustainable Development Goals (SDGs). In this study, we review the contribution of soils to the regulation of air quality, which is one of ‘Nature's Contributions to People’ identified by the Intergovernmental-Policy Platform on Biodiversity and Ecosystem Services (IPBES). This is particularly relevant for SDG3 (health and well-being) and 11 (sustainable cities and well-being) but also impacts other SDGs. Soils can act as both a source and a sink of air pollutants (and their precursors). In addition, soils support plant growth which plays a major role in regulating air quality. The scale of the soil impacts on air quality range from global (e.g. greenhouse gas fluxes, stratospheric ozone depletion) to local (e.g. odours, particulates, pathogen transport). Harmful emissions from soil can be increased or decreased by anthropogenic activity, while climate change is likely to modify future emissions patterns, both directly and in response to human mitigation and adaption actions. Although soils are not the only source of these pollutants, it is worthwhile managing them to reduce erosion and nutrient losses to maintain soil health so we may continue to benefit from the contributions to good quality of life they provide.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
The role of soils in regulation and provision of blue and green water
Authors: Keesstra Saskia , Sannigrahi Srikanta , López-Vicente Manuel , Pulido Manuel , Novara Agata , Visser Saskia , Kalantari Zahra
Published: August 2021

The United Nations Sustainable Development Goal 6 aims for clean water and sanitation for all by 2030, through eight subgoals dealing with four themes: (i) water quantity and availability, (ii) water quality, (iii) finding sustainable solutions and (iv) policy and governance. In this opinion paper, we assess how soils and associated land and water management can help achieve this goal, considering soils at two scales: local soil health and healthy landscapes. The merging of these two viewpoints shows the interlinked importance of the two scales. Soil health reflects the capacity of a soil to provide ecosystem services at a specific location, taking into account local climate and soil conditions. Soil is also an important component of a healthy and sustainable landscape, and they are connected by the water that flows through the soil and the transported sediments. Soils are linked to water in two ways: through plant-available water in the soil (green water) and through water in surface bodies or available as groundwater (blue water). In addition, water connects the soil scale and the landscape scale by flowing through both. Nature-based solutions at both soil health and landscape-scale can help achieve sustainable future development but need to be embedded in good governance, social acceptance and economic viability.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
The role of soils in the disposition, sequestration and decontamination of environmental contaminants
Authors: Sarkar Binoy , Mukhopadhyay Raj , Ramanayaka Sammani , Bolan Nanthi , Ok Yong Sik
Published: August 2021

Soil serves as both a ‘source’ and ‘sink’ for contaminants. As a source, contaminants are derived from both ‘geogenic’ and ‘anthropogenic’ origins. Typically, while some of the inorganic contaminants including potentially toxic elements are derived from geogenic origin (e.g. arsenic and selenium) through weathering of parent materials, the majority of organic (e.g. pesticides and microplastics) as well as inorganic (e.g. lead, cadmium) contaminants are derived from anthropogenic origin. As a sink, soil plays a critical role in the transformation of these contaminants and their subsequent transfer to environmental compartments, including groundwater (e.g. pesticides), surface water (phosphate and nitrate), ocean (e.g. microplastics) and atmosphere (e.g. nitrous oxide emission). A complex transformation process of contaminants in soil involving adsorption, precipitation, redox reactions and biodegradation control the mobility, bioavailability and environmental toxicity of these contaminants. Soil also plays a major role in the decontamination of contaminants, and the ‘cleaning’ action of soil is controlled primarily by the physico-chemical interactions of contaminants with various soil components, and the biochemical transformations facilitated by soil microorganisms. In this article, we examine the geogenic and anthropogenic sources of contaminants reaching the soil, and discuss the role of soil in the sequestration and decontamination of contaminants in relation to various physico-chemical and microbial transformation reactions of contaminants with various soil components. Finally, we propose future actions that would help to maintain the role of soils in protecting the environment from contaminants and delivering sustainable development goals.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
Role of soil in the regulation of human and plant pathogens: soils' contributions to people
Authors: Samaddar Sandipan , Karp Daniel S. , Schmidt Radomir , Devarajan Naresh , McGarvey Jeffery A. , Pires Alda F. A. , Scow Kate
Published: August 2021

Soil and soil biodiversity play critical roles in Nature's Contributions to People (NCP) # 10, defined as Nature's ability to regulate direct detrimental effects on humans, and on human-important plants and animals, through the control or regulation of particular organisms considered to be harmful. We provide an overview of pathogens in soil, focusing on human and crop pathogens, and discuss general strategies, and examples, of how soils' extraordinarily diverse microbial communities regulate soil-borne pathogens. We review the ecological principles underpinning the regulation of soil pathogens, as well as relationships between pathogen suppression and soil health. Mechanisms and specific examples are presented of how soil and soil biota are involved in regulating pathogens of humans and plants. We evaluate how specific agricultural management practices can either promote or interfere with soil's ability to regulate pathogens. Finally, we conclude with how integrating soil, plant, animal and human health through a ‘One Health’ framework could lead to more integrated, efficient and multifunctional strategies for regulating detrimental organisms and processes.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
The role of soils in provision of energy
Authors: Smith Jo , Farmer Jenny , Smith Pete , Nayak Dali
Published: August 2021

Soils have both direct and indirect impacts on available energy, but energy provision, in itself, has direct and indirect impacts on soils. Burning peats provides only approximately 0.02% of global energy supply yet emits approximately 0.7–0.8% of carbon losses from land-use change and forestry (LUCF). Bioenergy crops provide approximately 0.3% of energy supply and occupy approximately 0.2–0.6% of harvested area. Increased bioenergy demand is likely to encourage switching from forests and pastures to rotational energy cropping, resulting in soil carbon loss. However, with protective policies, incorporation of residues from energy provision could sequester approximately 0.4% of LUCF carbon losses. All organic wastes available in 2018 could provide approximately 10% of global energy supply, but at a cost to soils of approximately 5% of LUCF carbon losses; not using manures avoids soil degradation but reduces energy provision to approximately 9%. Wind farms, hydroelectric solar and geothermal schemes provide approximately 3.66% of energy supply and occupy less than approximately 0.3% of harvested area, but if sited on peatlands could result in carbon losses that exceed reductions in fossil fuel emissions. To ensure renewable energy provision does not damage our soils, comprehensive policies and management guidelines are needed that (i) avoid peats, (ii) avoid converting permanent land uses (such as perennial grassland or forestry) to energy cropping, and (iii) return residues remaining from energy conversion processes to the soil.

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
The role of soils in provision of genetic, medicinal and biochemical resources
Authors: Thiele-Bruhn Sören
Published: August 2021

Intact, ‘healthy’ soils provide indispensable ecosystem services that largely depend on the biotic activity. Soil health is connected with human health, yet, knowledge of the underlying soil functioning remains incomplete. This review highlights selected services, i.e. (i) soil as a genetic resource and hotspot of biodiversity, forming the basis for providing (ii) biochemical resources and (iii) medicinal services and goods. Soils harbour an unrivalled biodiversity of organisms, especially microorganisms. Some of the abilities of autochthonous microorganisms and their relevant enzymes serve (i) to improve natural soil functions and in particular plant growth, e.g. through beneficial plant growth-promoting, symbiotic and mycorrhizal microorganisms, (ii) to act as biopesticides, (iii) to facilitate biodegradation of pollutants for soil bioremediation and (iv) to yield enzymes or chemicals for industrial use. Soils also exert direct effects on human health. Contact with soil enriches the human microbiome, affords protection against allergies and promotes emotional well-being. Medicinally relevant are soil substrates such as loams, clays and various minerals with curative effects as well as pharmaceutically active organic chemicals like antibiotics that are formed by soil microorganisms. By contrast, irritating minerals, soil dust inhalation and misguided soil ingestion may adversely affect humans.

This article is part of the theme issue ‘The role of soils in delivering Nature’s Contributions to People.
The role of soil in regulation of climate
Authors: Lal Rattan , Monger Curtis , Nave Luke , Smith Pete
Published: August 2021

The soil carbon (C) stock, comprising soil organic C (SOC) and soil inorganic C (SIC) and being the largest reservoir of the terrestrial biosphere, is a critical part of the global C cycle. Soil has been a source of greenhouse gases (GHGs) since the dawn of settled agriculture about 10 millenia ago. Soils of agricultural ecosystems are depleted of their SOC stocks and the magnitude of depletion is greater in those prone to accelerated erosion by water and wind and other degradation processes. Adoption of judicious land use and science-based management practices can lead to re-carbonization of depleted soils and make them a sink for atmospheric C. Soils in humid climates have potential to increase storage of SOC and those in arid and semiarid climates have potential to store both SOC and SIC. Payments to land managers for sequestration of C in soil, based on credible measurement of changes in soil C stocks at farm or landscape levels, are also important for promoting adoption of recommended land use and management practices. In conjunction with a rapid and aggressive reduction in GHG emissions across all sectors of the economy, sequestration of C in soil (and vegetation) can be an important negative emissions method for limiting global warming to 1.5 or 2°C

This article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’.
Neutralizing antibody responses to SARS-CoV-2 variants in vaccinated Ontario long-term care home residents and workers
Authors: Abe Kento T. , Hu Queenie , Mozafarihashjin Mohammad , Samson Reuben , Manguiat Kathy , Robinson Alyssia , Rathod Bhavisha , Hardy W. Rod , Wang Jenny H. , Iskilova Mariam , Pasculescu Adrian , Fazel-Zarandi Mahya , Li Angel , Paterson Aimee , Chao Gary , Green Karen , Gilbert Lois , Barati Shiva , Haq Nazrana , Takaoka Alyson , Takaoka Julia Garnham , De Launay Keelia Quinn , Fahim Christine , Sheikh-Mohamed Salma , Arita Yuko , Durocher Yves , Marcusson Eric G. , Gommerman Jennifer L. , Ostrowski Mario , Colwill Karen , Straus Sharon E. , Wood Heidi , McGeer Allison J. , Gingras Anne-Claude
Published: August 2021

Prioritizing Ontario’s long-term care home (LTCH) residents for vaccination against severe acute respiratory syndrome coronavirus 2 has drastically reduced their disease burden; however, recent LTCH outbreaks of variants of concern (VOCs) have raised questions regarding their immune responses. In 198 residents, mRNA vaccine dose 1 elicited partial spike and receptor binding domain antibody responses, while the second elicited a response at least equivalent to convalescent individuals in most residents. Residents administered mRNA-1273 (Moderna) mounted stronger total and neutralizing antibody responses than those administered BNT162b2 (Pfizer-BioNTech). Two to four weeks after dose 2, residents (n= 119, median age 88) produced 4.8–6.3-fold fewer neutralizing antibodies than staff (n= 78; median age 47) against wild-type (with D614G) pseudotyped lentivirus, and residents administered BNT162b2 produced 3.89-fold fewer neutralizing antibodies than those who received mRNA-1273. These effects were exacerbated upon serum challenge with pseudotyped VOC spike, with up to 7.94-fold reductions in B.1.351 (Beta) neutralization. Cumulatively, weaker vaccine stimulation, age/comorbidities, and the VOC produced an ∼130-fold reduction in apparent neutralization titers in LTCH residents and 37.9% of BNT162b2-vaccinated residents had undetectable neutralizing antibodies to B.1.351. Continued immune response surveillance and additional vaccine doses may be required in this population with known vulnerabilities.
Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts
Authors: Ferretti Luca , Wymant Chris , Nurtay Anel , Zhao Lele , Hinch Robert , Bonsall David , Kendall Michelle , Masel Joanna , Bell John , Hopkins Susan , Kilpatrick A. Marm , Peto Tim , Abeler-Dörner Lucie , Fraser Christophe
Published: August 2021

Quarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.
Surveillance genome sequencing reveal multiple SARS-CoV-2 variants circulating in the central Texas, USA with a predominance of Delta variant and review of vaccine breakthrough cases
Authors: Mutnal Manohar B. , Johnson Shelby , Mohamed Nada , Abddelgader Rasha , Morales Linden , Volz Marcus , Walker Kimberly , Arroliga Alejandro C. , Rao Arundhati
Published: August 2021

As surges in the COVID-19 pandemic have continued worldwide, SARS-CoV-2 has mutated, spawning several new variants, and impacting, to various degrees, transmission, disease severity, diagnostics, therapeutics, and natural and vaccine-induced immunity. Baylor Scott & White Health has implemented, along with laboratory diagnosis, SARS-CoV-2 sequencing to identify variants in its geographical service area. We analyzed virus sequencing results of specimens collected across Central Texas and found dramatic changes in variant distribution in the first half of 2021. The alpha variant (B 1.1.7) became predominant at week 13 and continued dominance until week 25. A growth rate of 1.20 (R2 = 0.92) for the first 15 weeks was noted and this growth gradually declined to -0.55 (R2 = 0.99) for the final 13 weeks. Currently, B.1.1.7 is being displaced with B.1.617.2 at 0.58 growth rate (R2 = 0.97). We also investigated vaccine breakthrough cases within our healthcare system and present clinical data on 28 symptomatic patients.
Treatment with a polyherbal extract improves fat metabolism, attenuates hepatic stellate cell activation and fibrogenesis
Authors: Pavan KB , Baig Mirza Rizwan , Murthy Mallappa Onkar , Azeemuddin Mohammed , Hariprasad V.R , Rafiq Mohamed , Rao Raghavendra P
Published: August 2021

Non-alcoholic steatohepatitis (NASH) involves dysregulations indenovolipogenesis, fatty acid oxidation, and fibrogenesis. Targeting these pathways holds promise for the treatment of liver disorders. Here we test the extract of a polyherbal formulation (namely Liv.52), which is approved by the Government of India’s Drug Regulatory Authority - AYUSH. The current study evaluates the effect of Liv.52 ondenovolipogenesis, fatty acid oxidation, and fibrogenesis. Bothin vivoandin vitromodel systems were employed to evaluate the efficacy of this polyherbal formulation. Male Wistar rats were dosed with Liv.52 for 2 weeks (250mg/k.g) and expression levels of the genes involved inde novolipogenesis and fatty acid oxidation pathways were analysed by quantitative real time PCR. Liv.52 treatment resulted in increased hepatic fatty acid oxidation and decreasedde novolipogenesis in these rats. It also reduced hepatic stellate cell activation in CCL4treated Wistar rats as evidenced by histological evaluation. Forin vitroexperiments, HepG2 cells were cultured under lipotoxic conditions (using 200μM palmitic acid) and the conditioned media from these cells were used for inducing activation and fibrogenesis in human hepatic stellate cells (HHSteC). Treatment with lipotoxic conditioned media resulted in activation of hepatic stellate cells and fibrogenesis, as evidenced by increased expression of α-smooth muscle actin (α-SMA), and desmin (markers of stellate cell activation) and increased levels of collagen and lumican (markers of fibrogenesis). Treatment with Liv.52 reversed the up-regulation of α-SMA, collagen and lumican levels in HHSteC cells. These results indicate that Liv.52 exerts its hepatoprotective effect by improving fatty acid metabolism and fibrogenesis.
Cross-Individual Affective Detection Using EEG Signals with Audio-Visual Embedding
Authors: Liang Zhen , Zhang Xihao , Zhou Rushuang , Zhang Li , Li Linling , Huang Gan , Zhang Zhiguo
Published: August 2021

EEG signals have been successfully used in affective detection applications, which could directly capture brain dynamics and reflect emotional changes at a high temporal resolution. However, the generalized ability of the model across individuals has not been thoroughly developed yet. An involvement of other data modality, such as audio-visual information which are usually used for emotion eliciting, could be beneficial to estimate intrinsic emotions in video content and solve the individual differences problem. In this paper, we propose a novel deep affective detection model, named as EEG with audio-visual embedding (EEG-AVE), for cross-individual affective detection. Here, EEG signals are exploited to identify the individualized emotional patterns and contribute the individual preferences in affective detection; while audio-visual information is leveraged to estimate the intrinsic emotions involved in the video content and enhance the reliability of the affective detection performance. Specifically, EEG-AVE is composed of two parts. For EEG-based individual preferences prediction, a multi-scale domain adversarial neural network is developed to explore the shared dynamic, informative, and domain-invariant EEG features across individuals. For video-based intrinsic emotions estimation, a deep audio-visual feature based hypergraph clustering method is proposed to examine the latent relationship between semantic audio-visual features and emotions. Through an embedding model, both estimated individual preferences and intrinsic emotions are incorporated with shared weights and further are used together to contribute to affective detection across individuals. We conduct cross-individual affective detection experiments on two well-known emotional databases for model evaluation and comparison. The results show our proposed EEG-AVE model achieves a better performance under a leave-one-individual-out cross-validation individual-independent evaluation protocol. EEG-AVE is demonstrated as an effective model with good generalizability, which makes it a power tool for cross-individual emotion detection in real-life applications.
Establishment of a Prognostic Prediction and Drug Selection Model for Patients with Clear Cell Renal Cell Carcinoma by Multi-Omics Data Analysis
Authors: Jiang Aimin , Bao Yewei , Wang Anbang , Gan Xinxin , Wang Jie , Bao Yi , Wu Zhenjie , Liu Bing , Lu Juan , Wang Linhui
Published: August 2021

Rationale

Patients with clear cell renal cell cancer (ccRCC) may have completely different treatment choices and prognoses due to the wide range of heterogeneity of the disease. However, there is a lack of effective models for risk stratification, treatment decision making and prognostic prediction of renal cancer patients. The aim of the present study was to establish a model to stratify ccRCC patients in terms of prognostic prediction and drug selection based on multi-omics data analysis.

Methods

This study was based on the multi-omics data (including mRNA, lncRNA, miRNA, methylation and WES) of 258 ccRCC patients from TCGA database. Firstly, we screened the feature values that had impact on the prognosis and obtained two subtypes. Then, we used 10 algorithms to achieve multi-omics clustering, and conducted pseudo-timing analysis to further validate the robustness of our clustering method, based on which the two subtypes of ccRCC patients were further subtyped. Meanwhile, the immune infiltration was compared between the two subtypes, and drug sensitivity and potential drugs were analyzed. Furthermore, to analyze the heterogeneity of patients at the multi-omics level, biological functions between two subtypes were compared. Finally, Boruta and PCA methods were used for dimensionality reduction and cluster analysis to construct a renal cancer risk model based on mRNA expression.

Results

A prognosis predicting model of ccRCC was established by dividing patients into high- and low-risk groups. It was found that overall survival (OS) and progression-free interval (PFI) were significantly different between the two groups (p<0.01). The area under the OS time dependent ROC curve for 1, 3, 5 and 10 years in the training set was 0.75, 0.72, 0.71 and 0.68 respectively.

Conclusion

The model could precisely predict the prognosis of ccRCC patients and may have implications for drug selection for ccRCC patients.
Identification and Targeting Putative G-Quadruplex Sequences in Candida glabrata: A Route to Virulence and Pathogenesis Control?
Authors: Yadav Ankush
Published: August 2021

An increase in the number of Candida species that are resistant to antifungal medication and increases worldwide. Even individuals that are never exposed to antibiotics showing resistance to antifungal drugs. The increase in resistant candida species strains requires a search for novel targets for new antifungal agents. Preventing infection caused by candida species is a tremendous challenge in medicine. Although availability and use of antifungal drugs, disseminated candidiasis leads to a high mortality rate of about 40-60%, poor diagnosis, and improper disease management. Interest in G-quadruplexes as a therapeutic target has been increased in recent years, following the implication of this non-canonical G-quadruplex secondary structure in pathological diseases. However, G-quadruplex has been reported in many pathogens contributing to virulence and pathogenesis, including bacterial pathogens such as Staphylcoccus aureus and Enterococcus spp. Etc, viruses such as SARS-CoV2, HIV, HPV etc., and Fungi such as Candida species, Aspergillus fumigatus, etc. The present aim of the study is to identify and targeting G-Quadruplex forming sequences present in the Candida glabrata. PQSFinder (R Package) identified more than 5000 putative G-quadruplex forming sequences. Out of these, we have used PQS present in the SDH1 gene of Candida glabrata. It may be a key target to ameliorate the C.glabrata infection because it encodes a protein that plays a vital role in energy production in C.glabrata cells shown in the figure. The structure was built based on the already current structure that is telomeric G4 AGGG (TTAGGG)3 {PDB ID-4G0F} for identifying its stabilization by Gold carbine derivatives. Molecular docking and ADMET analysis show that Compound A has the highest binding affinity and has the best ADMET properties among the two compounds. The present study represents PQS in the SDH1 gene could be a novel antifungal target.
Printed Texts Tracking and Following for a Finger-Wearable Electro-Braille System Through Opto-electrotactile Feedback
Authors: Rahimi Mehdi , Shen Yantao , Liu Zhiming , Jiang Fang
Published: August 2021

This paper presents our recent development on a portable and refreshable text reading and sensory substitution system for the blind or visually impaired (BVI), called Finger-eye. The system mainly consists of an opto-text processing unit and a compact electro-tactile based display that can deliver text-related electrical signals to the fingertip skin through a wearable and Braille-dot patterned electrode array and thus delivers the electro-stimulation based Braille touch sensations to the fingertip. To achieve the goal of aiding BVI to read any text not written in Braille through this portable system, in this work, a Rapid Optical Character Recognition (R-OCR) method is firstly developed for real-time processing text information based on a Fisheye imaging device mounted at the finger-wearable electrotactile display. This allows real-time translation of printed text to electro-Braille along with natural movement of user’s fingertip as if reading any Braille display or book. More importantly, an electro-tactile neuro-stimulation feedback mechanism is proposed and incorporated with the R-OCR method, which facilitates a new opto-electrotactile feedback based text line tracking control approach that enables text line following by user fingertip during reading. Multiple experiments were designed and conducted to test the ability of blindfolded participants to read through and follow the text line based on the opto-electrotactile-feedback method. The experiments show that as the result of the opto-electrotactile-feedback, the users were able to maintain their fingertip within a 2mmdistance of the text while scanning a text line. This research is a significant step to aid the BVI users with a portable means to translate and follow to read any printed text to Braille, whether in the digital realm or physically, on any surface.
Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity
Authors: Derosiere Gerard , Thura David , Cisek Paul , Duque Julie
Published: August 2021

Humans and other animals are able to adjust their speed-accuracy tradeoff (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. Fifty subjects performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in two contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation on multiple motor representations, eliciting motor evoked potentials (MEP) in nine finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while subjects were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, though this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.
Classification and genetic targeting of cell types in the primary taste and premotor center of the Drosophila brain
Authors: Sterne Gabriella R. , Otsuna Hideo , Dickson Barry J. , Scott Kristin
Published: August 2021

Neural circuits carry out complex computations that allow animals to evaluate food, select mates, move toward attractive stimuli, and move away from threats. In insects, the subesophageal zone (SEZ) is a brain region that receives gustatory, pheromonal, and mechanosensory inputs and contributes to the control of diverse behaviors, including feeding, grooming, and locomotion. Despite its importance in sensorimotor transformations, the study of SEZ circuits has been hindered by limited knowledge of the underlying diversity of SEZ neurons. Here, we generate a collection of split-GAL4 lines that provides precise genetic targeting of 138 different SEZ cell types in D. melanogaster, comprising approximately one third of all SEZ neurons. We characterize the single cell anatomy of these neurons and find that they cluster by morphology into six supergroups that organize the SEZ into discrete anatomical domains. We find that the majority of local SEZ interneurons are not classically polarized, suggesting rich local processing, whereas SEZ projection neurons tend to be classically polarized, conveying information to a limited number of higher brain regions. This study provides insight into the anatomical organization of the SEZ and generates resources that will facilitate further study of SEZ neurons and their contributions to sensory processing and behavior.
Comparative untargeted metabolomic profiling of induced mitochondrial fusion in pancreatic cancer
Authors: Nguyen Nicholas D. , Yu Meifang , Reddy Vinit Y. , Acevedo-Diaz Ariana , Mesarick Enzo C. , Jaoude Joseph Abi , Yuan Min , Asara John M. , Taniguchi Cullen M.
Published: August 2021

Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems [1]. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
Top-down feedback enables flexible coding strategies in olfactory cortex
Authors: Chen Zhen , Padmanabhan Krishnan
Published: August 2021

In chemical sensation, multiple models have been proposed to explain how odors are represented by patterns of neuronal activity in the olfactory cortex. One hypothesis is that the identity of combinations of active neurons within specific sniff-related time windows are critical for encoding information about odors. Another model is that patterns of neural activity evolve across time and it is this temporal structure that is essential for encoding odor information. Interestingly, we found that top-down feedback to the olfactory bulb dictates what information is transmitted to the olfactory cortex by switching between these two strategies. Using a detailed model of the early olfactory system, we demonstrate that feedback control of inhibitory granule cells in the main olfactory bulb influences the balance between excitatory and inhibitory synaptic currents in mitral cells, thereby restructuring the firing patterns of piriform cortical cells across time. This resulted in performance gains in both the accuracy and reaction time of odor discrimination tasks. These findings lead us to propose a new framework for early olfactory computation, one in which top-down feedback to the bulb flexibly controls the temporal structure of neural activity in olfactory cortex, allowing the early olfactory system to dynamically switch between two distinct models of coding.

Highlights

Centrifugal feedback shapes the temporal structure of neuronal firing in piriform cortical cells

Feedback controls information to piriform cortex by restructuring the ratio of excitatory and inhibitory synaptic inputs in the bulb

Centrifugal feedback restructures how identity and timing of glomerular activity is represented in temporal patterns of activity in piriform cortex

Temporal information improves behavioral performance in accuracy and reaction time of odor discrimination
Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome
Authors: Le Steven Q. , Kan Shih-hsin , Roberts Marie S. , Dearborn Joshua T. , Wang Feng , Li Shan , Snella Elizabeth M. , Jens Jackie K. , Valentine Bethann N. , Nelvagal Hemanth R. , Sorensen Alexander , Chintalapati Keerthana , Ohlemiller Kevin , Vogler Carole , Cooper Jonathan D. , Chou Tsui-Fen , Ellinwood N. Matthew , Smith Jodi D. , Sands Mark S. , Dickson Patricia I.
Published: August 2021

Recombinant human alpha-N-acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. Because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated, we generated a fusion protein of NAGLU with IGF2 to permit its binding to the cation-independent mannose 6-phosphate receptor. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice, and demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied repeated intracerebroventricular rhNAGLU-IGF2 delivery in both murine and canine Sanfilippo B to determine potential effects on their behavioral phenotypes and survival. Treated mice showed improvement in disease markers such as heparan sulfate glycosaminoglycans, beta-hexosaminidase, microglial activation, and lysosomal-associated membrane protein-1. Sanfilippo B mice treated with rhNAGLU-IGF2 displayed partial normalization of their stretch attend postures, a defined fear pose in mice (p<0.001). We found an improved rotarod performance in Sanfilippo B mice treated with rhNAGLU-IGF2 compared to vehicle-treated Sanfilippo B mice (p=0.002). We also found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53w, median 48w) compared to vehicle-treated Sanfilippo B mice (mean 33w, median 37w; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized HS and beta-hexosaminidase activity in gray and white matter brain regions. Proteomic analysis of cerebral cortex showed restoration of protein expression levels in pathways relevant to cognitive, synaptic, and lysosomal functions. These data suggest that treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.
Exploration of novel αβ-protein folds throughde novodesign
Authors: Minami Shintaro , Kobayashi Naohiro , Sugiki Toshihiko , Nagashima Toshio , Fujiwara Toshimichi , Koga Rie , Chikenji George , Koga Nobuyasu
Published: August 2021

Most naturally occurring protein folds have likely been discovered1–3. The question is whether natural evolution has exhaustively sampled almost all possible protein folds4, or whether a large fraction of the possible folds remains unexplored5–7. To address this question, we introduce a set of rules for β-sheet topology to predict novel folds, and carry out the systematic de novo protein design for the novel folds predicted by the rules. The rules predicted eight novel αβ-folds with a four-stranded β-sheet, including a knot-forming one. We designed proteins for all the predicted αβ-folds and found that all the designs are monomeric with high thermal stability and fold into the structures close to the design models, demonstrating the ability of the set of rules to predict novel αβ-folds. The rules also predicted about twelve thousand novel αβ-folds with five- to eight-stranded β-sheets; the number is far exceeding the number of αβ-folds observed so far. This result suggests that the enormous number of αβ-folds are possible but have not emerged or become extinct due to evolutionary bias. The predicted novel folds should open up the possibility of designing functional proteins of our interests.
Temporally Auto-Correlated Predator Attacks Structure Ecological Communities
Authors: Schreiber Sebastian J.
Published: August 2021

For species primarily regulated by a common predator, the P* rule of Holt and Lawton [1993] predicts that the prey species that supports the highest mean predator density (P*) excludes the other prey species. This prediction is re-examined in the presence of temporal fluctuations in the vital rates of the interacting species including predator attack rates. When the fluctuations in predator attack rates are temporally uncorrelated, the P* rule still holds even when the other vital rates are temporally auto-correlated. However, when temporal auto-correlations in attack rates are positive but not too strong, the prey species can coexist due to the emergence of a positive covariance between predator density and prey vulnerability. This coexistence mechanism is similar to the storage effect for species regulated by a common resource. Negative or strongly positive auto-correlations in attack rates generate a negative covariance between predator density and prey vulnerability and a stochastic priority effect can emerge: with non-zero probability either prey species is excluded. These results highlight how temporally auto-correlated species’ interaction rates impact the structure and dynamics of ecological communities.
Production and characterization of virus-free, CRISPR-CAR T cells capable of inducing solid tumor regression
Authors: Mueller Katherine P. , Piscopo Nicole J. , Forsberg Matthew H. , Saraspe Louise A. , Das Amritava , Russell Brittany , Smerchansky Madeline , Shi Lei , Shankar Keerthana , Ali Adeela , Lazzarotto Cicera R. , Tsai Shengdar Q. , Capitini Christian M. , Saha Krishanu
Published: August 2021

Background

Chimeric antigen receptor (CAR) T cells traditionally harbor viral vector-based sequences that encode the CAR transgene in the genome. These T cell products have yet to show consistent anti-tumor activity in patients with solid tumors. Further, viral vector manufacturing is resource intensive, suffers from batch-to-batch variability, and includes several animal components, adding regulatory and supply chain pressures.

Methods

Anti-GD2 CAR T cells were generated using CRISPR/Cas9 within nine days using recombinant Cas9 protein and nucleic acids, without any viral vectors or animal components. The CAR was specifically targeted to the T Cell Receptor Alpha Constant gene (TRAC). T cell products were characterized at the level of the genome, transcriptome, proteome, and secretome using CHANGE-seq, scRNA-seq, spectral cytometry, and ELISA assays. Functionality was evaluated in vivo in an NSG xenograft neuroblastoma model.

Results

In comparison to traditional retroviral CAR T cells, virus-free CRISPR CAR (VFC-CAR) T cells exhibit TRAC-targeted genomic integration of the CAR transgene, elevation of transcriptional and protein characteristics associated with a memory phenotype, and low tonic signaling prior to infusion arising in part from the the knockout of the TCR. Upon exposure to the GD2 target antigen, anti-GD2 VFC-CAR T cells exhibited specific cytotoxicity against GD2+ cells in vitro and induced solid tumor regression in vivo, with robust homing, persistence, and low exhaustion against a human neuroblastoma xenograft model.

Conclusions

This proof-of-principle study leveraging virus-free genome editing technology could enable flexible manufacturing of clinically relevant, high-quality CAR T cells to treat cancers, including solid tumors.