bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature-Driven Developmental Modulation of Yield Response to Nitrogen in Wheat and Maize
Authors: Sadras Victor O. , Giordano Nicolas , Correndo Adrian , Cossani C. Mariano , Ferreyra Juan M. , Caviglia Octavio P. , Coulter Jeffrey A. , Ciampitti Ignacio A. , Lollato Romulo P.
Published: June 2022

Nitrogen management is central to the economic and environmental dimensions of agricultural sustainability. Yield response to nitrogen fertilisation results from multiple interacting factors. Theoretical frameworks are lagging for the interaction between nitrogen and air temperature, the focus of this study. We analyse the relation between yield response to nitrogen fertiliser and air temperature in the critical period of yield formation for spring wheat in Australia, winter wheat in the US, and maize in both the US and Argentina. Our framework assumes (i) yield response to nitrogen fertiliser is primarily related to grain number per m2, (ii) grain number is a function of three traits: the duration of the critical period, growth rate during the critical period, and reproductive allocation, and (iii) all three traits vary non-linearly with temperature. We show that “high” nitrogen supply may be positive, neutral, or negative for yield under “high” temperature, depending on the part of the response curve captured experimentally. The relationship between yield response to nitrogen and mean temperature in the critical period was strong in wheat and weak in maize. Negative associations for both spring wheat in Australia and winter wheat with low initial soil nitrogen (< 20 kg N ha-1) in the US highlight the dominant influence of a shorter critical period with higher temperature; with high initial soil nitrogen (> 120 kg N ha-1) that favoured grain number and compromised grain fill, the relation between yield response to nitrogen and temperature was positive for winter wheat. The framework is particularly insightful where data did not match predictions; a non-linear function integrating development, carbon assimilation and reproductive partitioning bounded the pooled data for maize in the US and Argentina, where water regime, previous crop, and soil nitrogen overrode the effect of temperature on yield response to nitrogen fertilisation.
Beth Levine’s Legacy: From the Discovery of BECN1 to Therapies. A Mentees’ Perspective
Authors: An Zhenyi , Chiang Wei-Chung , Fernández Álvaro F. , Franco Luis H. , He CongCong , Huang Shu-Yi , Lee Eunmyong , Liu Yang , Sebti Salwa , Shoji-Kawata Sanae , Sirasanagandla Shyam , Wang Richard C. , Wei Yongjie , Zhao Yuting , Vega-Rubin-de-Celis Silvia
Published: June 2022

With great sadness, the scientific community received the news of the loss of Beth Levine on 15 June 2020. Dr. Levine was a pioneer in the autophagy field and work in her lab led not only to a better understanding of the molecular mechanisms regulating the pathway, but also its implications in multiple physiological and pathological conditions, including its role in development, host defense, tumorigenesis, aging or metabolism. This review does not aim to provide a comprehensive view of autophagy, but rather an outline of some of the discoveries made by the group of Beth Levine, from the perspective of some of her own mentees, hoping to honor her legacy in science.
Synthesis and Evaluation of Coumarin-Chalcone Derivatives as α-Glucosidase Inhibitors
Authors: Hu Chun-Mei , Luo Yong-Xin , Wang Wen-Jing , Li Jian-Ping , Li Meng-Yue , Zhang Yu-Fei , Xiao Di , Lu Li , Xiong Zhuang , Feng Na , Li Chen
Published: June 2022

Coumarin and chalcone, two important kinds of natural product skeletons, both exhibit α-glucosidase inhibitory activity. In this work, coumarin-chalcone derivatives 3 (a∼v) were synthesized, and their α-glucosidase inhibitory activity was screened. The results showed that all synthetic derivatives (IC50: 24.09 ± 2.36 to 125.26 ± 1.18 μM) presented better α-glucosidase inhibitory activity than the parent compounds 3-acetylcoumarin (IC50: 1.5 × 105 μM) and the positive control acarbose (IC50: 259.90 ± 1.06 μM). Among them, compound 3t displayed the highest α-glucosidase inhibitory activity (IC50: 24.09 ± 2.36 μM), which was approximately 10 times stronger than that of acarbose. The kinetic assay of 3t (KI = 18.82 μM, KIS = 59.99 μM) revealed that these compounds inhibited α-glucosidase in a mixed-type manner. Molecular docking was used to simulate the interaction between α-glucosidase and compound 3t.
Immunological Characteristics of Patients Receiving Ultra-Short Treatment for Chronic Hepatitis C
Authors: Madsen Lone Wulff , Christensen Peer Brehm , Øvrehus Anne , Bryde Dorthe Marie Sjødahl , Holm Dorte Kinggaard , Lillevang Søren Thue , Nielsen Christian
Published: June 2022

Reducing the treatment duration for chronic hepatitis C could be an important tool in the effort to reach the elimination goals set by the World Health Organization. The current challenge is to predict the target group who will achieve sustained virological response at week 12 (SVR12) with shorter treatment duration. The aim of this exploratory study was to characterize immune subsets with focus on inhibitory receptors in patients who experienced SVR12 or virological relapse following four weeks treatment with glecaprevir/pibrentasvir with or without ribavirin. A total of 32 patients were included in this study of whom 21 achieved SVR12 and 11 had virological relapse. All available samples at baseline (n = 31) and end of treatment (EOT) (n = 30) were processed for flow cytometric analysis in order to measure the expression of PD-1, 2B4, BY55, CTLA-4, TIM-3 and LAG-3 on 12 distinct T cell subsets. At baseline, patients with SVR12 (n=21) had numerically lower frequencies of inhibitory receptors for 83% (60/72) of the investigated T-cell subtypes. The most significant difference observed between the two groups was a lower frequency of stem cell-like memory T-cells CD4+PD1+ in the SVR group (p = 0.007). Furthermore, we observed a significant positive correlation between baseline viral load and the expression of PD-1 on the total CD8+ T-cells and effector memory T-cells CD4+ and CD8+ for patients with virological relapse. This study suggests a measurable immunologic phenotype at baseline of patients achieving SVR12 after short treatment compared to patients with virological relapse.
Genetic Characterization of Chikungunya Virus Among Febrile Dengue Fever–Like Patients in Xishuangbanna, Southwestern Part of China
Authors: Zou Meng , Su Chunyan , Li Tingting , Zhang Jing , Li Daiying , Luan Ning , Ma Dehong , Liu Jiansheng , Sun Qiangming , Peng Xiaozhong , Liu Hongqi
Published: June 2022

Co-infection of chikungunya virus (CHIKV) has been recently reported during dengue fever epidemics. However, the infection of CHIKV is often neglected due to its misdiagnosis as dengue virus (DENV) infection. In the summer of 2019 when dengue fever was epidemic, we collected 697 serum samples from febrile dengue fever–like patients in Xishuangbanna, southwestern part of China. DENV RNA was detectable in 99.42% of these patients. Notably, 88 patients (12.62%) showed the presence of CHIKV RNA, among which 86 patients were co-infected with DENV and CHIKV. We sequenced and analyzed the full genome of CHIKV virus in four out of 88 samples (two CHIKV infected and two co-infected). The results suggested that the four strains were all Asian genotype and had the highest homology (99.4%) with the SZ1239 strain (accession number MG664851) isolated in 2012 and possibly introduced from Indonesia. Further comparison with the conserved sequences in the whole genome of 47 strains of CHIKV showed that there were 13 and 15 amino acid mutants in structural proteins and non-structural proteins, respectively. The previously reported adaptive mutations of E2-W64R, E2-I211T, E2-K233E, E1-A98T, and E1-K211E occurred in the four strains of this study. In conclusion, this study reports a co-infection of CHIKV during the DENV epidemic in the city Xishuangbanna, 2019. Molecular epidemiology revealed that CHIKV identified in this study was indigenous and belongs to Asian lineage with lineage-specific mutations and some reported adaptive mutations, which is distinct from the recently reported CHIKV (East/Central/South African) in Ruili, the city next to Xishuangbanna.
Democratizing Glacier Data – Maturity of Worldwide Datasets and Future Ambitions
Authors: Gärtner-Roer Isabelle , Nussbaumer Samuel U. , Raup Bruce , Paul Frank , Welty Ethan , Windnagel Ann K. , Fetterer Florence , Zemp Michael
Published: June 2022

The creation and curation of environmental data present numerous challenges and rewards. In this study, we reflect on the increasing amount of freely available glacier data (inventories and changes), as well as on related demands by data providers, data users, and data repositories in-between. The amount of glacier data has increased significantly over the last two decades as remote sensing techniques have improved and free data access is much more common. The portfolio of observed parameters has increased as well, which presents new challenges for international data centers, and fosters new expectations from users. We focus here on the service of the Global Terrestrial Network for Glaciers (GTN-G) as the central organization for standardized data on glacier distribution and change. Within GTN-G, different glacier datasets are consolidated under one umbrella, and the glaciological community supports this service by actively contributing their datasets and by providing strategic guidance via an Advisory Board. To assess each GTN-G dataset, we present a maturity matrix and summarize achievements, challenges, and ambitions. The challenges and ambitions in the democratization of glacier data are discussed in more detail, as they are key to providing an even better service for glacier data in the future. Most challenges can only be overcome in a financially secure setting for data services and with the help of international standardization as, for example, provided by the CoreTrustSeal. Therefore, dedicated financial support for and organizational long-term commitment to certified data repositories build the basis for the successful democratization of data. In the field of glacier data, this balancing act has so far been successfully achieved through joint collaboration between data repository institutions, data providers, and data users. However, we also note an unequal allotment of funds for data creation and projects using the data, and data curation. Considering the importance of glacier data to answering numerous key societal questions (from local and regional water availability to global sea-level rise), this imbalance needs to be adjusted. In order to guarantee the continuation and success of GTN-G in the future, regular evaluations are required and adaptation measures have to be implemented.
The Influence of Shared Intentions With Others in Physical and Cognitive Tasks That Require Collaborative Solving in Elementary School
Authors: Kano Takahiro , Yokoyama Keiko , Yamamoto Yuji
Published: June 2022

Developing the competence to share intentions with others is an important role of elementary schools for the children’s future well-being. We analyzed and clarified the relationship between physical and cognitive tasks that require collaborative solving to cultivate the skill of sharing intentions with others through human movement. As a physical task, we designed a tag game in which two defenders prevented three attackers from passing through to reach the goal line. We focused on the defenders’ movement in the game and analyzed the efficiency of each defender’s movement as an individual behavior and the interpersonal distance between these two defenders as a pair behavior. As a cognitive task, we examined pair activities when understanding concepts in math classes. We observed talking and listening behaviors during the pair activities and analyzed the responsive behavior as an individual behavior, which comprised responsive utterances and active listening from the listener’s gaze direction. Role change during pair activities in math lessons was analyzed as a pair behavior. We then analyzed the relationship between behaviors in both tasks. The hypotheses were as follows: (1) task constraints lead to an interaction between individual and pair behaviors in both tasks and (2) individual and pair behaviors in the two tasks have similar characteristics. The results from both tasks support the first hypothesis that the efficiencies of individual movement and interpersonal distance in the tag game and the frequencies of responsive behavior and role changes in the pair activities in math classes are positively correlated. The results also support the second hypothesis that the individual and pair behaviors in the two tasks are significantly correlated. These results suggest that the competence to share intention with others is fundamental regardless of the task nature: physical or cognitive. The findings suggest that the task constraints of joint action in physical education lead to an understanding of the task goals and to exploring the solution for winning. These experiences might be generalized to all cognitive tasks for cultivating the competence to share intentions with others.
A Procedural Method to Predictively Assess Power-Quality Trade-Offs of Circuit-Level Adaptivity in IoT Systems
Authors: De Roose Jaro , Andraud Martin , Verhelst Marian
Published: June 2022

The constant miniaturization of IoT sensor nodes requires a continuous reduction in battery sizes, leading to more stringent needs in terms of low-power operation. Over the past decades, an extremely large variety of techniques have been introduced to enable such reductions in power consumption. Many involve some form of offline reconfigurability (OfC), i.e., the ability to configure the node before deployment, or online adaptivity (OnA), i.e., the ability to also reconfigure the node during run time. Yet, the inherent design trade-offs usually lead to ad hoc OnA and OfC, which prevent assessing the varying benefits and costs each approach implies before investing in implementation on a specific node. To solve this issue, in this work, we propose a generic predictive assessment methodology that enables us to evaluate OfC and OnA globally, prior to any design. Practically, the methodology is based on optimization mathematics, to quickly and efficiently evaluate the potential benefits and costs from OnA relative to OfC. This generic methodology can, thus, determine which type of solution will consume the least amount of power, given a specific application scenario, before implementation. We applied the methodology to three adaptive IoT system studies, to demonstrate the ability of the introduced methodology, bring insights into the adaptivity mechanics, and quickly optimize the OfC–OnA adaptivity, even under scenarios with many adaptivity variables.
Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond
Authors: Ong Shee Chee , Belgi Alessia , Merriman Allanah L. , Delaine Carlie A. , van Lierop Bianca , Andrikopoulos Sofianos , Robinson Andrea J. , Forbes Briony E.
Published: June 2022

The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6–A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
Thinning or Opening: A Randomized Sibling-Embryo Pilot Trial on the Efficacy of Two Laser-Assisted Hatching Modes During the Extended Culture of Highly Fragmented Cleavage Embryos
Authors: Zhang Ling , Zhou Yi-er , Wu Yue-jin , Wu Li-mei , Li Shi-shi , Zhang Lin , Jin Zhen , Shu Chong-yi , Xu Wei-hai , Shu Jing
Published: June 2022

A randomized sibling-embryo pilot trial investigated whether two ways of laser-assisted hatching result in different blastulation and clinical outcomes after extended in vitro culture process of highly fragmented day-3 cleavage embryos. From 92 couples, a total of 315 highly fragmented day-3 embryos (the fragmentation >25%) were recruited and randomized into laser-assisted zona thinning (LAT, n=157) and opening (LAO, n=158) groups, and then underwent a blastocyst culture in vitro. The main endpoint measurements including blastocyst formation and grading as well as the clinical pregnancy after blastocyst transfer were obtained during the treatment procedure of in vitro fertilization and embryo transfer, and then analyzed with generalized estimating equation (GEE) and/or time-to blastocyst analysis models. A total of 166 day-3 embryos developed into blastocyst stage (52.70%), of which 97 were viable blastocysts (30.79%), and 42 top-quality ones (13.33%). LAT did not have any inferior or superior to LAO in the endpoints of either total, viable, top-quality or hatched blastocyst formation, with the ORs (95%CI) from GEE model as 0.89 (0.55-1.45), 0.71 (0.42-1.21), 1.12 (0.56-2.25) and 0.68 (0.42-1.12) respectively for LAT treatment. And the time-to-blastocyst analysis showed a similar result. Additionally, no difference in clinical outcomes after blastocyst transfer was found between the two groups. The author concluded that when applying the LAHs during the extended culture of highly fragmented embryos, both LAT and LAO can generate a promising clinical outcome, and the LAT operation be equivalent to the LAO. Future well-designed, multiple-center, larger-sample investigations are required to ascertain above conclusion.
The Disconnect Between Development and Intended Use of Clinical Prediction Models for Covid-19: A Systematic Review and Real-World Data Illustration
Authors: Prosepe Ilaria , Groenwold Rolf H. H. , Knevel Rachel , Pajouheshnia Romin , van Geloven Nan
Published: June 2022

Background

The SARS-CoV-2 pandemic has boosted the appearance of clinical predictions models in medical literature. Many of these models aim to provide guidance for decision making on treatment initiation. Special consideration on how to account for post-baseline treatments is needed when developing such models. We examined how post-baseline treatment was handled in published Covid-19 clinical prediction models and we illustrated how much estimated risks may differ according to how treatment is handled.

Methods

Firstly, we reviewed 33 Covid-19 prognostic models published in literature in the period up to 5 May 2020. We extracted: (1) the reported intended use of the model; (2) how treatment was incorporated during model development and (3) whether the chosen analysis strategy was in agreement with the intended use. Secondly, we used nationwide Dutch data on hospitalized patients who tested positive for SARS-CoV-2 in 2020 to illustrate how estimated mortality risks will differ when using four different analysis strategies to model ICU treatment.

Results

Of the 33 papers, 21 (64%) had misalignment between intended use and analysis strategy, 7 (21%) were unclear about the estimated risk and only 5 (15%) had clear alignment between intended use and analysis strategy. We showed with real data how different approaches to post-baseline treatment yield different estimated mortality risks, ranging between 33 and 46% for a 75 year-old patient with two medical conditions.

Conclusions

Misalignment between intended use and analysis strategy is common in reported Covid-19 clinical prediction models. This can lead to considerable under or overestimation of intended risks.
Checkpoint Inhibitors Modulate Plasticity of Innate Lymphoid Cells in Peripheral Blood of Patients With Hepatocellular Carcinoma
Authors: Heinrich Bernd , Ruf Benjamin , Subramanyam Varun , Myojin Yuta , Lai Chunwei W. , Craig Amanda J. , Fu Jianyang , Xie Changqing , Kroemer Alexander , Greten Tim F. , Korangy Firouzeh
Published: June 2022

Innate lymphoid cells (ILC) are a heterogeneous and plastic population of cells of the innate immune system. Their role in cancer and specifically in hepatocellular carcinoma is unraveling. The presence of ILCs in peripheral blood of HCC patients has not been explored yet. Their role and function in response to checkpoint inhibitor therapy have also not been explored. Here, we characterized ILCs in PBMC of HCC patients at baseline and after treatment with immune checkpoint inhibitors (ICI) by flow cytometry and single-cell sequencing. Characterization of ILC subsets in PBMCs of HCC patients showed a significant increase in ILC1 and a decrease in ILC3 frequencies. Single-cell RNA-sequencing identified a subgroup of NK-like ILCs which expressed cytotoxicity markers as well as NKp80/KLRF1. This KLRF1high NK-like population showed low abundance in patients with HCC and was enhanced after combined anti-CTLA-4 and anti-PD-1immunotherapy. Trajectory analysis placed this population in between ILC1 and ILC3 cells. The transcriptomic signature of KLRF1high NK-like ILCs was associated with better progression-free survival in large HCC cohorts. This study shows a previously unknown effect of ICI on the composition and plasticity of ILCS in peripheral blood. Thus, ILCs from PBMC can be used to study changes in the innate immune system under immunotherapy.
Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses
Authors: Lacorcia Matthew , Kugyelka Réka , Spechtenhauser Lorenz , Prodjinotho Ulrich Fabien , Hamway Youssef , Spangenberg Thomas , da Costa Clarissa Prazeres
Published: June 2022

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.
Revealing the Key MSCs Niches and Pathogenic Genes in Influencing CEP Homeostasis: A Conjoint Analysis of Single-Cell and WGCNA
Authors: Li Weihang , Zhang Shilei , Zhao Yingjing , Wang Dong , Shi Quan , Ding Ziyi , Wang Yongchun , Gao Bo , Yan Ming
Published: June 2022

Degenerative disc disease (DDD), a major contributor to discogenic pain, which is mainly resulted from the dysfunction of nucleus pulposus (NP), annulus fibrosis (AF) and cartilage endplate (CEP) cells. Genetic and cellular components alterations in CEP may influence disc homeostasis, while few single-cell RNA sequencing (scRNA-seq) report in CEP makes it a challenge to evaluate cellular heterogeneity in CEP. Here, this study conducted a first conjoint analysis of weighted gene co-expression network analysis (WGCNA) and scRNA-seq in CEP, systematically analyzed the interested module, immune infiltration situation, and cell niches in CEP. WGCNA and protein-protein interaction (PPI) network determined a group of gene signatures responsible for degenerative CEP, including BRD4, RAF1, ANGPT1, CHD7 and NOP56; differentially immune analysis elucidated that CD4+ T cells, NK cells and dendritic cells were highly activated in degenerative CEP; then single-cell resolution transcriptomic landscape further identified several mesenchymal stem cells and other cellular components focused on human CEP, which illuminated niche atlas of different cell subpopulations: 8 populations were identified by distinct molecular signatures. Among which, NP progenitor/mesenchymal stem cells (NPMSC), also served as multipotent stem cells in CEP, exhibited regenerative and therapeutic potentials in promoting bone repair and maintaining bone homeostasis through SPP1, NRP1-related cascade reactions; regulatory and effector mesenchymal chondrocytes could be further classified into 2 different subtypes, and each subtype behaved potential opposite effects in maintaining cartilage homeostasis; next, the potential functional differences of each mesenchymal stem cell populations and the possible interactions with different cell types analysis revealed that JAG1, SPP1, MIF and PDGF etc. generated by different cells could regulate the CEP homeostasis by bone formation or angiogenesis, which could be served as novel therapeutic targets for degenerative CEP. In brief, this study mainly revealed the mesenchymal stem cells populations complexity and phenotypic characteristics in CEP. In brief, this study filled the gap in the knowledge of CEP components, further enhanced researchers’ understanding of CEP and their cell niches constitution.
Clinical Parameters in Osteoporosis Patients Supplemented With PMA-Zeolite at the End of 5-Year Double-Blinded Clinical Trial
Authors: Kraljević Pavelić Sandra , Krpan Dalibor , Žuvić Marta , Eisenwagen Sandra , Pavelić Krešimir
Published: June 2022

Osteoporosis is among the most common pathologies. Associated complications in osteoporotic patients, in particular hip fractures and vertebral fractures, cause disabilities and significant quality of life deterioration. Standard treatment of osteoporosis, based on pharmacotherapy does still not yield adequate results, and the problem of osteoporosis remains incompletely solved. Additionally, adverse drug events and fractures after long-termed pharmacotherapy pose additional challenges within designing a proper therapy regimen. Improved clinical approach and new synergistic treatment modalities are consequently still needed. The rationale of the presented study was accordingly, to expand our preclinical animal study on human patients with osteoporosis, based on positive effects on bones observed in animals with osteopenia treated with PMA-zeolite. We specifically monitored effects of PMA-zeolite on the bone quality parameters, fracture risk and quality of life in a cohort of initially recruited 100 osteoporosis patients during a follow-up period of 5 years within a randomized, placebo-controlled and double blinded clinical study (TOP study). Obtained results provide evidence on the PMA-zeolite positive effects on the bone strength of osteoporotic patients as the risk of fractures was significantly decreased in PMA-zeolite-treated patients with respect to time before entering the study (p = 0.002). Statistical evidence point also to positive bone changes in the 5-years TOP study course as evidenced through osteocalcin and beta-cross laps values showing a prevalence of the bone-formation process (p < 0.05). BMD values were not significantly affected after the 5-years follow-up in PMA-zeolite-treated patients in comparison with the Placebo group. Results support the initial expectations based on our previously published preclinical studies on clinoptilolite product PMA-zeolite in animals that could be a new therapeutic option in osteoporosis patients.
Lipid Profiles From Fresh Biofilms Along a Temperature Gradient on a Hydrothermal Stream at El Tatio (Chilean Andes), as a Proxy for the Interpretation of Past and Present Biomarkers Beyond Earth
Authors: Megevand Valentine , Carrizo Daniel , Lezcano María Ángeles , Moreno-Paz Mercedes , Cabrol Nathalie A. , Parro Víctor , Sánchez-García Laura
Published: June 2022

Hydrothermal systems and their deposits are primary targets in the search for fossil evidence of life beyond Earth. However, to learn how to decode fossil biomarker records in ancient hydrothermal deposits, we must first be able to interpret unambiguously modern biosignatures, their distribution patterns, and their association with physicochemical factors. Here, we investigated the molecular and isotopic profile of microbial biomarkers along a thermal gradient (from 29 to 72°C) in a hot spring (labeled Cacao) from El Tatio, a geyser field in the Chilean Andes with abundant opaline silica deposits resembling the nodular and digitate structures discovered on Mars. As a molecular forensic approach, we focused on the analysis of lipid compounds bearing recognized resistance to degradation and the potential to reconstruct the paleobiology of an environment on a broader temporal scale than other, more labile, biomolecules. By exploiting the lipid biomarkers’ potential to diagnose biological sources and carbon fixation pathways, we reconstructed the microbial community structure and its ecology along the Cacao hydrothermal transect. The taxonomic adscription of the lipid biomarkers was qualitatively corroborated with DNA sequencing analysis. The forensic capacity of the lipid biomarkers to identify biosources in fresh biofilms was validated down to the genus level for Roseiflexus, Chloroflexus, and Fischerella. We identified lipid biomarkers and DNA of several new cyanobacterial species in El Tatio and reported the first detection of Fischerella biomarkers at a temperature as high as 72°C. This, together with ecological peculiarities and the proportion of clades being characterized as unclassified, illustrates the ecological singularity of El Tatio and strengthens its astrobiological relevance. The Cacao hydrothermal ecosystem was defined by a succession of microbial communities and metabolic traits associated with a high- (72°C) to low-(29°C) temperature gradient that resembled the inferred metabolic sequence events from the 16S rRNA gene universal phylogenetic tree from thermophilic to anoxygenic photosynthetic species and oxygenic phototrophs. The locally calibrated DNA-validated lipidic profile in the Cacao biofilms provided a modern (molecular and isotopic) end member to facilitate the recognition of past biosources and metabolisms from altered biomarkers records in ancient silica deposits at El Tatio analogous to Martian opaline silica structures.
Antioxidant Mechanism of Lactiplantibacillus plantarum KM1 Under H2O2 Stress by Proteomics Analysis
Authors: Tian Yuan , Wang Yu , Zhang Nan , Xiao Minmin , Zhang Jing , Xing Xinyue , Zhang Yue , Fan Yuling , Li Xia , Nan Bo , Wang Yuhua , Liu Jingsheng
Published: June 2022

Lactiplantibacillus plantarum KM1 was screened from natural fermented products, which had probiotic properties and antioxidant function. The survival rate of L. plantarum KM1 was 78.26% at 5 mM H2O2. In this study, the antioxidant mechanism of L. plantarum KM1 was deeply analyzed by using the proteomics method. The results demonstrated that a total of 112 differentially expressed proteins (DEPs) were screened, of which, 31 DEPs were upregulated and 81 were downregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEPs participated in various metabolic pathways such as pyruvate metabolism, carbon metabolism, trichloroacetic acid cycle, amino acid metabolism, and microbial metabolism in diverse environments. These metabolic pathways were related to oxidative stress caused by H2O2 in L. plantarum KM1. Therefore, the antioxidant mechanism of L. plantarum KM1 under H2O2 stress provided a theoretical basis for its use as a potential natural antioxidant.
Designing of an Efficient Whole-Cell Biocatalyst System for Converting L-Lysine Into Cis-3-Hydroxypipecolic Acid
Authors: Hu Shewei , Li Yangyang , Zhang Alei , Li Hui , Chen Kequan , Ouyang Pingkai
Published: June 2022

Cis-3-hydroxypipecolic acid (cis-3-HyPip), a key structural component of tetrapeptide antibiotic GE81112, which has attracted substantial attention for its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. In this study, a combined strategy to increase the productivity of cis-3-HyPip was investigated. First, combinatorial optimization of the ribosomal binding site (RBS) sequence was performed to tune the gene expression translation rates of the pathway enzymes. Next, in order to reduce the addition of the co-substrate α-ketoglutarate (2-OG), the major engineering strategy was to reconstitute the tricarboxylic acid (TCA) cycle of Escherichia coli to force the metabolic flux to go through GetF catalyzed reaction for 2-OG to succinate conversion, a series of engineered strains were constructed by the deletion of the relevant genes. In addition, the metabolic flux (gltA and icd) was improved and glucose concentrations were optimized to enhance the supply and catalytic efficiency of continuous 2-OG supply powered by glucose. Finally, under optimal conditions, the cis-3-HyPip titer of the best strain catalysis reached 33 mM, which was remarkably higher than previously reported.
Neural Dysconnectivity in the Hippocampus Correlates With White Matter Lesions and Cognitive Measures in Patients With Coronary Artery Disease
Authors: Niu Jianhua , Zhang Jingchen , Yan Jueyue , Xu Zhipeng , Fang Xing , You Jingyu , Liu Zhihai , Wu Weifang , Li Tong
Published: June 2022

Purpose

Recent neuroimaging reports have shown the microstructural changes in coronary artery disease (CAD) and its correlation with cognitive dysfunction while little is known about the functional characteristics of CAD. We hypothesize that functional characteristics may give clues to underlying pathology in CAD and its link with cognitive dysfunction. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the neural connectivity changes in CAD patients compared with healthy controls and their correlation with cognitive measures.

Methods

Thirty CAD patients and 36 healthy controls were included in our study. All participants underwent functional magnetic resonance imaging (fMRI) of the brain. We performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity with other voxels. DC was measured by the fMRI graph method and comparisons between the two groups were done. All participants underwent neuropsychological assessment (Montreal Cognitive Assessment, MoCA and Mini-Mental State Examination, MMSE).

Results

Our data analysis included 30 CAD patients (59.90 ± 7.53 years) and 36 HCs (61.61 ± 6.19 years). CAD patients showed a greater prevalence of white matter lesions using the Fazekas score than healthy controls (P < 0.001). Importantly, CAD patients showed significantly lower (P < 0.001) MoCA and MMSE scores compared with healthy controls. CAD patients showed significantly decreased DC value (P < 0.001) in the right hippocampus (hippocampus_R), right lingual gyrus (lingual_R), and significantly increased DC value (P < 0.001) in the left middle frontal gyrus (Frontal_Mid_L) when compared with healthy controls respectively. DC value in the hippocampus_R significantly correlated (P < 0.00) with MMSE and MoCA scores in CAD patients. Fazekas scores in CAD patients showed a significant correlation (P < 0.001) with the DC value in the hippocampus_R.

Conclusion

These findings suggest that reduced cerebral neural connectivity in CAD may contribute to their cognitive impairment and white matter microstructural damage.
Duplex Ultrasonography for the Evaluation of Extracranial Vertebral Artery: A Prospective Comparison With Digital Subtraction Angiography
Authors: Zhang Jie , Xing Yingqi , Cui Li
Published: June 2022

Background and Objective

Patients with symptomatic vertebral artery stenosis are at high risk of stroke recurrence, especially ≥70% stenosis. Revascularization may be considered for extracranial vertebral artery stenosis in patients with recurrent ischemic events despite optimal medical management. Currently, there is a lack of consensus on the ultrasonic evaluation of extracranial vertebral artery stenosis in clinical practice. This study aimed to validate the efficiency of duplex ultrasonography and assess the optimal sonographic thresholds for predicting extracranial vertebral artery stenosis.

Methods

This is a prospective study of all patients with symptomatic posterior circulation stroke/transient ischemic attack who were scheduled to undergo digital subtraction angiography from April 2020 to October 2021. A total of 544 vertebral arteries with a normal lumen or extracranial stenosis confirmed with digital subtraction angiography were included in the study. The peak systolic velocity at the V1 segment (PSVv1) and the V2 segment (PSVv2) were measured and the PSVv1/PSVv2 and PSVv2/PSVv1 ratios were calculated. The cutoff values were determined using receiver operating characteristic analysis.

Results

The areas under the receiver operating characteristic curve of all the velocity parameters to predict extracranial vertebral artery stenosis were >0.80. The cutoff values for predicting ≥50% and ≥70% V1 segment stenosis were PSVv1 ≥146 cm/s (sensitivity 76.2%, specificity 86.3%) and PSVv1/PSVv2 ratio ≥2.2 (sensitivity 84.3%, specificity 77.6%), and PSVv1 ≥184 cm/s (sensitivity 80.8%, specificity 87.1%) and PSVv1/PSVv2 ratio ≥3.5 (sensitivity 79.5%, specificity 90.5%), respectively. The cutoff values for predicting ≥50% and ≥70% V2 segment stenosis were PSVv2 ≥80 cm/s (sensitivity 75.0%, specificity 91.0%) and PSVv2/PSVv1 ratio ≥1.2 (sensitivity 75.0%, specificity 94.8%), and PSVv2 ≥111 cm/s (sensitivity 81.0%, specificity 95.0%) and PSVv2/PSVv1 ratio ≥1.7 (sensitivity 81.0%, specificity 96.6%), respectively.

Conclusion

Symptomatic patients with the ultrasonic parameters of PSVv1 ≥146 cm/s and PSVv1/PSVv2 ratio ≥2.2 at V1 segment or PSVv2 ≥80 cm/s and PSVv2/PSVv1 ratio ≥1.2 at V2 segment need to be considered for further verification by digital subtraction angiography to seek revascularization. If the parameters increase to PSVv1 ≥184 cm/s and PSVv1/PSVv2 ratio ≥3.5 at the V1 segment or PSVv2 ≥111 cm/s and PSVv2/PSVv1 ratio ≥1.7 at the V2 segment, these patients have an increased risk of recurrent stroke and are more likely to need revascularization. The results can be used as a reference for the assessment and long-term management of patients with extracranial VA stenosis.
Different Types of Mastoid Process Vibrations Affect Dynamic Margin of Stability Differently
Authors: Lu Jiani , Xie Haoyu , Chien Jung Hung
Published: June 2022

The vestibular system is critical for human locomotion. Any deteriorated vestibular system leads to gait instability. In the past decades, these alternations in gait patterns have been majorly measured by the spatial-temporal gait parameters and respective variabilities. However, measuring gait characteristics cannot capture the full aspect of motor controls. Thus, to further understand the effects of deteriorated vestibular system on gait performance, additional measurement needs to be taken into consideration. This study proposed using the margin of stability (MOS) to identify the patterns of dynamic control under different types of mastoid vibrations in walking. This study hypothesized that (1) using the MOS method could facilitate the understanding of another aspect of motor control induced by different types of mastoid vibrations, and (2) applying the mastoid vibrations could induce the asymmetric MOS. Twenty healthy young adults were recruited. Two electromechanical vibrotactile transducers were placed on the bilateral mastoid process to apply different types of vestibular vibrations (bilateral, unilateral, and no vibration). A motion capture system with eight cameras was used to measure the MOSap (margin of stability in the anterior-posterior direction), MOSml (margin of stability in the medial-lateral direction), and respective variabilities. The results were in line with the hypotheses that both bilateral and unilateral mastoid vibrations significantly increased MOSap (p = 0.036, p < 0.001), MOSml (p = 0.012, p < 0.001), and respective variabilities p = 0.001, p < 0.001; p = 0.001, p < 0.01 when compared to the no vibration condition. Also, significantly larger MOSml (p = 0.001), MOSml variability (p < 0.023), MOSap (p < 0.001), and MOSap variability (p = 0.002) were observed under the unilateral vibration condition than that observed under the bilateral vibration condition. The above-mentioned result found that different types of mastoid vibrations affected the MOS differently, suggesting different patterns of control mechanisms under different sensory-conflicted situations. Besides, a significant difference between the dominant and non-dominant legs was observed in MOSml. Moreover, applying the unilateral mastoid vibrations induced a greater symmetric index of MOSml, suggesting that more active control in balance was needed in the medial-lateral than in the anterior-posterior direction.
Behavioral and Molecular Consequences of Chronic Sleep Restriction During Development in Fragile X Mice
Authors: Saré R. Michelle , Song Alex , Levine Merlin , Lemons Abigail , Loutaev Inna , Sheeler Carrie , Hildreth Christine , Mfon Angel , Smith Carolyn Beebe
Published: June 2022

Sleep is critical for brain development and synaptic plasticity. In male wild-type mice, chronic sleep restriction during development results in long-lasting impairments in behavior including hypoactivity, decreased sociability, and increased repetitive behavior. Disordered sleep is characteristic of many neurodevelopmental disorders. Moreover, the severity of behavioral symptoms is correlated with the degree of disordered sleep. We hypothesized that chronic developmental sleep restriction in a mouse model of fragile X syndrome (FXS) would exacerbate behavioral phenotypes. To test our hypothesis, we sleep-restricted Fmr1 knockout (KO) mice for 3 h per day from P5 to P52 and subjected mice to behavioral tests beginning on P42. Contrary to our expectations, sleep restriction improved the hyperactivity and lack of preference for social novelty phenotypes in Fmr1 KO mice but had no measurable effect on repetitive activity. Sleep restriction also resulted in changes in regional distribution of myelin basic protein, suggesting effects on myelination. These findings have implications for the role of disrupted sleep in the severity of symptoms in FXS.
Enhanced Visual Cortex Activation in People With Narcolepsy Type 1 During Active Sleep Resistance: An fMRI-EEG Study
Authors: Gool Jari K. , Fronczek Rolf , Bosma Peter , van der Meer Johan N. , van der Werf Ysbrand D. , Lammers Gert Jan
Published: June 2022

The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual’s ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting.
Identifying Modulated Functional Connectivity in Corresponding Cerebral Networks in Facial Nerve Lesions Patients With Facial Asymmetry
Authors: Ma Hao , Zhou Yu-lu , Wang Wen-jin , Chen Gang , Li Qing , Lu Ye-chen , Wang Wei
Published: June 2022

Facial asymmetry is the major complaint of patients with unilateral facial nerve lesions. Frustratingly, although patients experience the same etiology, the extent of oral commissure asymmetry is highly heterogeneous. Emerging evidence indicates that cerebral plasticity has a large impact on clinical severity by promoting or impeding the progressive adaption of brain function. However, the precise link between cerebral plasticity and oral asymmetry has not yet been identified. In the present study, we performed functional magnetic resonance imaging on patients with unilateral facial nerve transections to acquire in vivo neural activity. We then identified the regions of interest corresponding to oral movement control using a smiling motor paradigm. Next, we established three local networks: the ipsilesional (left) intrahemispheric, contralesional (right) intrahemispheric, and interhemispheric networks. The functional connectivity of each pair of nodes within each network was then calculated. After thresholding for sparsity, we analyzed the mean intensity of each network connection between patients and controls by averaging the functional connectivity. For the objective assessment of facial deflection, oral asymmetry was calculated using FACEgram software. There was decreased connectivity in the contralesional network but increased connectivity in the ipsilesional and interhemispheric networks in patients with facial nerve lesions. In addition, connectivity in the ipsilesional network was significantly correlated with the extent of oral asymmetry. Our results suggest that motor deafferentation of unilateral facial nerve leads to the upregulated ipsilesional hemispheric connections, and results in positive interhemispheric inhibition effects to the contralesional hemisphere. Our findings provide preliminary information about the possible cortical etiology of facial asymmetry, and deliver valuable clues regarding spatial information, which will likely be useful for the development of therapeutic interventions.